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{ "abstract": "This is a descriptive case series of 3 patients with uncontrolled intraocular pressure that developed reticular corneal changes after initiating netarsudil (0.02%). In all cases, upon observing reticular corneal edema, netarsudil (0.02%) was stopped followed by disappearance of corneal honeycombing. With the increasing use of this novel glaucoma medication, potentially more rare side effects will be observed. Reticular corneal edema or corneal honeycombing is an ocular examination finding that can rarely occur after initiating netarsudil (0.02%) regardless of prior corneal edema status. In our experience, the reticular changes resolve upon cessation of netarsudil.", "affiliations": "Touro College of Osteopathic Medicine, New York, NY.;Washington University in St. Louis School of Medicine, St. Louis, MO.;Glaucoma Associates of Texas, Dallas, TX.;Glaucoma Associates of Texas, Dallas, TX.;Glaucoma Associates of Texas, Dallas, TX.", "authors": "Moumneh|Khaled|K|;Sheybani|Arsham|A|;Fellman|Ronald L|RL|;Godfrey|David G|DG|;Grover|Davinder S|DS|", "chemical_list": "D000959:Antihypertensive Agents; D001565:Benzoates; D009883:Ophthalmic Solutions; D015091:beta-Alanine; C000603944:netarsudil", "country": "United States", "delete": false, "doi": "10.1097/IJG.0000000000001516", "fulltext": null, "fulltext_license": null, "issn_linking": "1057-0829", "issue": "29(7)", "journal": "Journal of glaucoma", "keywords": null, "medline_ta": "J Glaucoma", "mesh_terms": "D000368:Aged; D000959:Antihypertensive Agents; D001565:Benzoates; D015715:Corneal Edema; D005260:Female; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D009798:Ocular Hypertension; D009883:Ophthalmic Solutions; D014065:Tonometry, Ocular; D015091:beta-Alanine", "nlm_unique_id": "9300903", "other_id": null, "pages": "607-610", "pmc": null, "pmid": "32398584", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Reticular Corneal Edema or Corneal Honeycombing in Eyes Treated With Netarsudil: A Case Series.", "title_normalized": "reticular corneal edema or corneal honeycombing in eyes treated with netarsudil a case series" }

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"activesubstance": { "activesubstancename": "NETARSUDIL MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UVEITIC GLAUCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RHOPRESSA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BRINZOLAMIDE" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, TID OU", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRINZOLAMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BRIMONIDINE TARTRATE" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, TID OU", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRIMONIDINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOTEPREDNOL" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, TID OU", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOTEPREDNOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "NETARSUDIL MESYLATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRAOCULAR PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RHOPRESSA" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intraocular pressure increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Visual acuity reduced", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Corneal oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHEYBANI A.. RETICULAR CORNEAL EDEMA OR CORNEAL HONEYCOMBING IN EYES TREATED WITH NETARSUDIL: A CASE SERIES. JOURNAL OF GLAUCOMA. 2020", "literaturereference_normalized": "reticular corneal edema or corneal honeycombing in eyes treated with netarsudil a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200716", "receivedate": "20200716", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18032811, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-AERIE-US-2020-001520", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NETARSUDIL MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK GTT DROPS, QHS (LEFT EYE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRAOCULAR PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RHOPRESSA" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORZOLAMIDE + TIMOLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BRIMONIDINE TARTRATE" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRIMONIDINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PILOCARPINE" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRAOCULAR PRESSURE INCREASED", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PILOCARPINE." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Visual acuity reduced", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Corneal oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GROVER D.S, MOUMNEH K., SHEYBANI A. ET. AL.. RETICULAR CORNEAL EDEMA OR CORNEAL HONEYCOMBING IN EYES TREATED WITH NETARSUDIL: A CASE SERIES. JOURNAL OF GLAUCOMA. 2020", "literaturereference_normalized": "reticular corneal edema or corneal honeycombing in eyes treated with netarsudil a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200716", "receivedate": "20200716", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18032801, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-AERIE-US-2020-001521", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DORZOLAMIDE" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "OU, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORZOLAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAVOPROST" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "OU, QHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAVOPROST." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BRIMONIDINE TARTRATE" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "OU, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRIMONIDINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "NETARSUDIL MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "QHS (RIGHT EYE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRAOCULAR PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RHOPRESSA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "OD, QID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE ACETATE." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Corneal oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GROVER D.S? MOUMNEH K? SHEYBANI A? ET.AL. RETICULAR CORNEAL EDEMA OR CORNEAL HONEYCOMBING IN EYES TREATED WITH NETARSUDIL: A CASE SERIES. JOURNAL OF GLAUCOMA. 2020", "literaturereference_normalized": "reticular corneal edema or corneal honeycombing in eyes treated with netarsudil a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200716", "receivedate": "20200716", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18032823, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]

{ "abstract": "Takotsubo cardiomyopathy is an acute coronary syndrome that is believed to be brought on by stress. Symptoms, which are similar to an acute myocardial infarction, include chest pain, shortness of breath, arrhythmias, and cardiogenic shock, and the electrocardiogram often shows ST and T wave changes. Left ventricular wall hypokinesis along with a significantly reduced ejection fraction are seen on echocardiogram. The great majority of these symptoms all occur in the absence of occlusive disease. Many cases have been reported in which the development of takotsubo cardiomyopathy was associated with serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants. However, no cases of takotsubo cardiomyopathy have been reported involving selective serotonin reuptake inhibitors. This article presents the case of a 51-year-old woman receiving stable therapy with fluoxetine who developed takotsubo cardiomyopathy after an acute stress. We also discuss the clinical presentation of takotsubo cardiomyopathy, review possible causes, and discuss the treatment of depressive symptoms in patients who are at increased risk of developing this illness.", "affiliations": "CONRAD: Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL CATALANO M. and CATALANO G.: Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, and James A. Haley Veterans Hospital, Tampa, FL.", "authors": "Conrad|Suki K|SK|;Catalano|Maria C|MC|;Catalano|Glenn|G|", "chemical_list": "D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine", "country": "United States", "delete": false, "doi": "10.1097/PRA.0000000000000151", "fulltext": null, "fulltext_license": null, "issn_linking": "1527-4160", "issue": "22(3)", "journal": "Journal of psychiatric practice", "keywords": null, "medline_ta": "J Psychiatr Pract", "mesh_terms": "D003863:Depression; D005260:Female; D005473:Fluoxetine; D006801:Humans; D008875:Middle Aged; D017367:Serotonin Uptake Inhibitors; D054549:Takotsubo Cardiomyopathy", "nlm_unique_id": "100901141", "other_id": null, "pages": "234-8", "pmc": null, "pmid": "27123803", "pubdate": "2016-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The Use of Fluoxetine in a Patient With Takotsubo Cardiomyopathy.", "title_normalized": "the use of fluoxetine in a patient with takotsubo cardiomyopathy" }

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THE USE OF FLUOXETINE IN A PATIENT WITH TAKOTSUBO CARDIOMYOPATHY. 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{ "abstract": "Antipsychotic and antidepressant are often used in combination for the treatment of neuropsychiatric disorders. The concomitant use of antipsychotic and/or antidepressant with drugs that may interact can lead to rare, life-threatening conditions such as serotonin syndrome and neuroleptic malignant syndrome. We describe a patient who has a history of taking two offending drugs that interact with drugs given during the course of hospital treatment which leads to the development of serotonin syndrome overlapped with neuroleptic malignant syndrome. The physician should be aware that both NMS and SS can appear as overlapping syndrome especially when patients use a combination of both antidepressants and antipsychotics.", "affiliations": "Prince Sultan Military College of Health Sciences, King Fahad Military Medical Complex, Dhahran 31932, Saudi Arabia; King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia.;King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia.;Prince Sultan Military College of Health Sciences, King Fahad Military Medical Complex, Dhahran 31932, Saudi Arabia.;The New York School of Medical and Dental Assistants, Long Island City, NY, USA.", "authors": "Mazhar|Faizan|F|0000-0002-2818-1179;Akram|Shahzad|S|;Haider|Nafis|N|;Ahmed|Rafeeque|R|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/7128909", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/7128909Case ReportOverlapping of Serotonin Syndrome with Neuroleptic Malignant Syndrome due to Linezolid-Fluoxetine and Olanzapine-Metoclopramide Interactions: A Case Report of Two Serious Adverse Drug Effects Caused by Medication Reconciliation Failure on Hospital Admission http://orcid.org/0000-0002-2818-1179Mazhar Faizan \n1\n\n2\n\n*\nAkram Shahzad \n2\nHaider Nafis \n1\nAhmed Rafeeque \n3\n1Prince Sultan Military College of Health Sciences, King Fahad Military Medical Complex, Dhahran 31932, Saudi Arabia2King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia3The New York School of Medical and Dental Assistants, Long Island City, NY, USA*Faizan Mazhar: mfaizanbaig@hotmail.comAcademic Editor: Bruno Megarbane\n\n2016 28 6 2016 2016 712890923 4 2016 11 6 2016 12 6 2016 Copyright © 2016 Faizan Mazhar et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Antipsychotic and antidepressant are often used in combination for the treatment of neuropsychiatric disorders. The concomitant use of antipsychotic and/or antidepressant with drugs that may interact can lead to rare, life-threatening conditions such as serotonin syndrome and neuroleptic malignant syndrome. We describe a patient who has a history of taking two offending drugs that interact with drugs given during the course of hospital treatment which leads to the development of serotonin syndrome overlapped with neuroleptic malignant syndrome. The physician should be aware that both NMS and SS can appear as overlapping syndrome especially when patients use a combination of both antidepressants and antipsychotics.\n==== Body\n1. Introduction\nNeuroleptic (NL) or antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat neuropsychiatric disorders. The introduction of one or both of them when the patient is being treated with another potentially interacting drug sometimes triggers syndromes of varying severity as described in the literature [1–3].\n\nSerotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are life-threatening adverse reactions caused by serotonergic antidepressants and neuroleptics, respectively. Although NMS is historically associated with classic or “typical” antipsychotics, it is also a potential adverse effect of atypical antipsychotics [4]. The classic clinical features of NMS are hyperthermia, muscle rigidity, cardiovascular instability, elevated levels of creatinine phosphokinase (CPK), tachycardia, tachypnea, diaphoresis, leukocytosis, and altered state of consciousness. Drugs with serotonergic activity, including selective reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs, including linezolid), have a high potential to trigger SS. Clinical manifestations of SS are often mild and consist of confusion, myoclonus, hyperreflexia, and trembling [5]. However, certain forms can be life-threatening. Clinical manifestations of these life-threatening cases may include hyperthermia, muscle rigidity, autonomic dysfunction, shock, status epilepticus, and coma. Its presentation differs from NMS somewhat, which includes the following: (a) neuromuscular symptoms such as tremor and rigidity also occur in the NMS, but features such as chills, ataxia, myoclonus, hyperreflexia, and patellar clonus favor the diagnosis of serotonin syndrome; (b) gastrointestinal dysfunction involves presence of nausea, vomiting, and diarrhea which is a unique feature that is not typical of NMS [6]; (c) changes in mental status and autonomic dysfunction are similar, but the temperature increase is not as high as in the NMS; (d) leukocytosis and rise in serum creatine phosphokinase (CPK) and liver enzymes are inconsistent in NMS and minimally elevated in SS; (e) the course is usually benign and most patients recover between the first and the seventh day after the termination of the causative agent, whereas NMS recovery may take up to two weeks [7]. Distinctive, identical, and overlapping features of NMS, SS, and clinical manifestation sepsis are summarized in Table 1. Thus, SS and NMS have overlapping clinical features. There have been a few cases that reported an overlap between these two syndromes [8, 9].\n\nSimilarly to all drug toxicity reactions, SS and NMS are diagnoses of exclusion. Disorders to be ruled out include meningitis, malignant hyperthermia, tumor, viral encephalitis, seizure, acute lethal catatonia, hyperthyroidism, heatstroke, and anticholinergic drug intoxication. Given the similarity in presentation and symptoms of NMS and SS, the most effective approach to distinguish between these two syndromes is to obtain an accurate medication history. These can be avoided by appropriate medication reconciliation to ensure that the prescribed drugs do not interact with drugs that belong to these two groups.\n\nHere we described a rare case of a patient satisfying the criteria of both NMS and SS caused by the failure of medication reconciliation on hospital admission; later the patient was found to have a history of taking two offending agents that interact with drugs given during the course of hospital treatment.\n\n2. Case Presentation\nA 64-year-old 87 kg man with a past medical history of hypertension for 10 years, type 2 diabetes for 13 years, painful diabetic neuropathy, mild depression, and recent diabetic foot infection (DFI) related hospitalization initially presents to the emergency room with a 2-week history of left lower extremity edema, redness, and pain that limits his normal daily activities. He has a lesion close to his small toe that is macerated and foul-smelling. His physical examination was notable for temperature 38.2°C, blood pressure 145/90 mmHg, heart rate 92 beats/minute, respiratory rate 19 breaths/minute, and 1+ lower extremity edema. His initial laboratory values which were ordered in emergency room include sodium 139 mEq/L, potassium 4.3 mEq/L, BUN 19 mg/dL, SCr 0.9 mg/dL, glucose 180 mg/dL, A1C 8%, WBC 15 × 103 cells/mm3, hemoglobin 12 g/dL, hematocrit 36%, and platelet count 290,000 cells/mm3.\n\nAccording to a patient his home drugs include hydrochlorothiazide 25 mg/day, lisinopril 20 mg/day, glyburide 10 mg/day, metformin 1000 mg twice daily, olanzapine/fluoxetine, and aspirin 81 mg/day.\n\nHe was admitted to the hospital for the cleansing, irrigation, and surgical debridement of his ulcer. The surgical culture of ulcer specimen was positive for methicillin-resistant Staphylococcus aureus (MRSA) with following susceptibilities: Vancomycin (R), Clindamycin (S), linezolid (S), and Trimethoprim/sulfamethoxazole (S).\n\nOn the second day of admission he was started on IV linezolid 600 mg every 12 hrs and IV moxifloxacin 400 mg/day for the treatment of DFI. The first dose of antibiotics was uneventful. However, after the second dose of linezolid, he became severely nauseated for which he was given IV metoclopramide at 10 mg IV every 6 hrs.\n\nAfter 12 hrs patient was constantly nauseated and febrile (38.7°C). He was confused, diaphoretic, and dyspneic. ECG showed tachycardia at pulse 104 bpm without ST or T wave abnormalities; blood pressure was 127/87 mmHg. He started to desaturate gradually (oxygen saturation 84%) and was maintained on oxygen therapy via high flow nasal cannula.\n\nOn the third day of the hospital, he continued to desaturate and remained febrile and hypertensive at 160/90 mmHg; blood and urine cultures were ordered and returned negative. An X-ray of the chest was clear. Complete blood count showed leukocytosis.\n\nOn neurologic examination, he was rigid asymmetrically in upper and lower extremities and right lower limb showed hyperreflexia with clonus. On neurological examination nuchal rigidity was negative, and both eyes were responsive to light; all signs of meningism were negative. Due to the rigidity of extremities, a blood creatine phosphokinase (CPK) level was checked, and it was 1856 mcg/L. Magnetic resonance imaging of the brain was normal. There was no evidence of epileptiform activity on a 12-hour continuous electroencephalography.\n\nAfter ruling out all possible infections causes of aforesaid mentioned symptoms and giving the consideration on persistent muscle rigidity, high CPK levels, and causality of patient condition with the metoclopramide administration, a clinical diagnosis of the neuroleptic malignant syndrome was made and metoclopramide was stopped. The patient was treated with IV dantrolene 1 mg/Kg stat dose, carbidopa 25 mg/levodopa 100 mg PO, and baclofen 5 mg PO for rigidity. He was maintained on fluid and IV dimenhydrinate 100 mg q 4 hrs for nausea. Labetalol was used to normalize high blood pressure.\n\nTwelve hours after the dantrolene treatment CPK levels were rechecked; it was 780 mcg/L and physical examination showed improvement in rigidity. However, the patient has still exhibited a high fever with diaphoresis, high blood pressure with labetalol deescalation, consciousness disturbance, and myoclonus. The repeat blood complete count showed leukocytosis. Blood culture was negative. In arterial blood gas analysis, pCO2 was 27.2 mmHg and pO2 was 69.6 mmHg, sO2 81.3%. He was maintained on oxygen.\n\nBecause physicians suspected that, despite the execution of NMS treatment, her persistent increase in blood pressure, hyperthermia, and clonus may have been linked to serotonin syndrome. This information, together with his negative workup, prompts the medical team for medication reconciliation. Thorough medication reconciliation revealed that patient was recently started on olanzapine/fluoxetine by a general practitioner 4 days ago and the last dose was taken by the patient 1 day before arriving at ER.\n\nAt this point, after the consultation of a clinical pharmacist, it was decided to discontinue linezolid and maintain the patient on fluid, labetalol 20 mg IV, as needed for the control of blood pressure and cyproheptadine hydrochloride 12 mg PO stat, followed by 4 mg every 6 hours for 24 hours. Clonazepam was given to control myoclonus. After 24 hours all of the patient's symptoms abated except slight fever and mild clonus and hyperreflexia. The patient was discharged from the hospital on the 7th day with a prescription of PO cyproheptadine, PO paracetamol, and PO TMP/SMX with moxifloxacin for DFI treatment.\n\n3. Discussion\nThe case described here followed a complex course. The patient was admitted to the hospital for a care of diabetic foot infection, and he was started on IV antimicrobial therapy which consists of moxifloxacin with linezolid for MRSA. During his course of admission, he was found to have different clinical picture due to either an adverse effect of medication or interactions between different medications. Of note, a careful medication reconciliation in the later stage of hospitalization revealed that the patient was taking SYMBYAX® (3 mg/25 mg), a fixed-dose combination of olanzapine (3 mg), and fluoxetine (25 mg) prescribed by his primary care physician for mild depression. This was an off-label use as SYMBYAX is indicated for treatment-resistant major depression.\n\nFluoxetine is longest acting SSRIs, and its half-life is up to 7 days. Compared to other SSRIs fluoxetine has more potential to interact with other serotonergic drugs, like linezolid [10–12] in this case. Olanzapine is an atypical antipsychotic drug with low potential for extrapyramidal effects and NMS; however a number of cases of olanzapine-induced NMS have also been reported [13, 14].\n\nIn our patient after two doses of linezolid, he presented with severe nausea, hyperthermia, diaphoresis, dyspnea, tachycardia, asymmetric rigidity of limbs, and high blood pressure. Although not as prominent to make a definite diagnosis, these symptoms presented within the onset time of 24 hours after the administration of two serotonergic interacting drugs (fluoxetine owing to its long half-life and IV linezolid administration); this satisfies the Sternbach and Hunter criteria and is therefore consistent with SS at that point. However, given the failure of medication reconciliation and high frequency of gastrointestinal side effects of linezolid, he was treated with the antiemetic metoclopramide for severe nausea. Of note, metoclopramide has a dopamine D2 receptor blocking effect and is a known causative agent of NMS [15, 16].\n\nAfter four doses of metoclopramide, patients' muscle rigidity worsened as evident by physical examination and plasma CPK levels. Though CPK and temperature were not as elevated as expected to rise in these syndromes, overlap is possible and also reported [9]. Therefore, worsening of these signs is likely due to the interaction between olanzapine and metoclopramide which probably initiate or potentiate the signs of NMS, which started to overlap SS. Despite the discontinuation of metoclopramide and initiation of NMS treatment, patients' symptoms, specifically those of SS (blood pressure, hyperthermia, and clonus), did not remit. This in addition to medication history which enables us to diagnose SS and start its treatment protocol.\n\nIn clinical practice, the differential diagnosis between SS and NMS is difficult due to the overlap of symptoms and laboratory data, especially if it is triggered when NL and SSRI are used in combination. Some authors consider that it may be the same underlying process with different clinical manifestations [17, 18]. Nevertheless, the addition of an NL and/or SSRI with interacting drugs or vice versa can trigger severe syndromes, which are clinically very difficult to differentiate. Fortunately, and most importantly their initial treatment is common which consists of stopping the causative agent at an early stage and initiate supportive treatment.\n\n4. Conclusion\nThe review and case presented here is intended to highlight the following: (a) physician being aware that both NMS and SS can appear as overlapping syndrome and consider one of these and even both, overlapping specially when patients use combination of both antidepressants and antipsychotics; (b) being cautious when using these two classes of drugs with other interacting drugs, given our case, as both antipsychotic and antidepressants react with metoclopramide and linezolid, respectively; (c) importance of medication reconciliation on admission; and (d) actively participating in pharmacovigilance.\n\nCompeting Interests\nThe authors do not have any conflict of interests to declare.\n\nTable 1 Characteristics of neuroleptic malignant syndrome, serotonin syndrome, and sepsis.\n\n \t \tNeuroleptic malignant syndrome\tSerotonin syndrome\tSepsis\t\nPrecipitated by\tDopamine antagonists\tSerotonergic agents\t\nGeneral \n\n(i) Temperature > 38.3°C or < 36°C\n(ii) Heart rate > 90 beats/minute\n(iii) Respiratory rate > 20 beats/minute\n(iv) Altered mental status\n(v) Increased fluid balance (>20 mL/kg over 24 hr)\n(vi) Elevated blood glucose > 140 mg/dL (in absence of diabetes)\n\nInflammatory \n\n(i) WBC > 12 × 103 cells/mm3 or <4 × 103 cells/mm3 or >10% immature neutrophils\n(ii) Elevated plasma C-reactive protein\n(iii) Elevated plasma procalcitonin\n\nHemodynamic \n\n(i) Hypotension (SBP < 90 mmHg; MAP < 70 mmHg; or SBP decrease > 40 mmHg in adults or <2 SD below normal for age)\n\nTissue perfusion \n\n(i) Plasma lactate > 1 mmol/L\n(ii) Decrease capillary refill or mottling\t\nOnset\tVariable, 1–3 days\tVariable, <12 hours\t\nIdentical features\tVital signs\tHypertension\nTachycardia\nTachypnoea\nHyperthermia (>40°C)\tHypertension\nTachycardia\nTachypnoea\nHyperthermia (>40°C)\t\nMucosa\tHypersalivation\tHypersalivation\t\nOverlapping features\tSkin\tDiaphoresis\nPallor\tDiaphoresis\t\nMental status\tVariable, stupor, coma, alert\tVariable, agitation, coma\t\nMuscles\t“Lead-pipe” rigidity in all muscle groups\tIncreased tone, especially in lower extremities\t\nDistinct features\tReflexes\tHyporeflexia\tHyperreflexia\nClonus (unless masked by increased muscle tone)\t\nPupils\tNormal\tDilated\t\nBowel sounds\tNormal or decreased\tHyperactive\n==== Refs\n1 Carbone J. R. The neuroleptic malignant and serotonin syndromes Emergency Medicine Clinics of North America 2000 18 2 317 325 10.1016/s0733-8627(05)70127-9 2-s2.0-0034127738 10767887 \n2 Cassidy E. O'Kearne V. Neuroleptic malignant syndrome after venlafaxine The Lancet 2000 355 2164 2165 \n3 Tsai H.-C. Kuo P.-H. Yang P.-C. Fever, consciousness disturbance, and muscle rigidity in a 68-year-old man with depressive disorder Chest 2003 124 4 1598 1601 10.1378/chest.124.4.1598 2-s2.0-0142105856 14555596 \n4 Trollor J. N. Chen X. Sachdev P. S. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs CNS Drugs 2009 23 6 477 492 10.2165/00023210-200923060-00003 2-s2.0-66749158086 19480467 \n5 Dunkley E. J. C. Isbister G. K. Sibbritt D. Dawson A. H. Whyte I. M. The hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity Quarterly Journal of Medicine 2003 96 9 635 642 10.1093/qjmed/hcg109 2-s2.0-0042377403 \n6 Boyer E. W. Shannon M. The serotonin syndrome The New England Journal of Medicine 2005 352 11 1112 1120 10.1056/nejmra041867 2-s2.0-15044361698 15784664 \n7 Dosi R. Ambaliya A. Joshi H. Patell R. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary BMJ Case Reports 2014 2014 10.1136/bcr-2014-204154 2-s2.0-84903643135 \n8 Demirkiran M. Jankovic J. Dean J. M. Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome Clinical Neuropharmacology 1996 19 2 157 164 10.1097/00002826-199619020-00004 2-s2.0-0029921267 8777769 \n9 Nisijima K. Serotonin syndrome overlapping with neuroleptic malignant syndrome: a case report and approaches for differentially diagnosing the two syndromes Asian Journal of Psychiatry 2015 18 100 101 10.1016/j.ajp.2015.10.003 2-s2.0-84955294649 26506919 \n10 Kesavan S. Sobala G. M. Serotonin syndrome with fluoxetine plus tramadol Journal of the Royal Society of Medicine 1999 92 9 474 475 2-s2.0-0032834269 10645303 \n11 Morales N. Vermette H. Serotonin syndrome associated with linezolid treatment after discontinuation of fluoxetine Psychosomatics 2005 46 3 274 275 10.1176/appi.psy.46.3.274 2-s2.0-17844406388 15883150 \n12 Thomas C. R. Rosenberg M. Blythe V. Meyer W. J. III Serotonin syndrome and linezolid Journal of the American Academy of Child and Adolescent Psychiatry 2004 43 7 p. 790 10.1097/01.chi.0000128830.13997.aa 2-s2.0-3042607958 \n13 Ananth J. Parameswaran S. Gunatilake S. Burgoyne K. Sidhom T. Neuroleptic malignant syndrome and atypical antipsychotic drugs Journal of Clinical Psychiatry 2004 65 4 464 470 10.4088/JCP.v65n0403 2-s2.0-2442436578 15119907 \n14 Filice G. A. McDougall B. C. Ercan-Fang N. Billington C. J. Neuroleptic malignant syndrome associated with olanzapine Annals of Pharmacotherapy 1998 32 11 1158 1159 10.1345/aph.18151 2-s2.0-0031782854 9825080 \n15 Friedman L. S. Weinrauch L. A. D'Elia J. A. Metoclopramide-induced neuroleptic malignant syndrome Archives of Internal Medicine 1987 147 8 1495 1497 10.1001/archinte.1987.00370080133023 2-s2.0-0023388250 3632154 \n16 Sternbach H. The serotonin syndrome The American Journal of Psychiatry 1991 148 6 705 713 10.1176/ajp.148.6.705 2-s2.0-0025869797 2035713 \n17 Bhanushali M. J. Tuite P. J. The evaluation and management of patients with neuroleptic malignant syndrome Neurologic Clinics 2004 22 2 389 411 10.1016/j.ncl.2003.12.006 2-s2.0-1642298049 15062519 \n18 Kontaxakis V. P. Havaki-Kontaxaki B. J. Christodoulou N. G. Paplos K. G. Christodoulou G. N. Olanzapine-associated neuroleptic malignant syndrome: is there an overlap with the serotonin syndrome? Annals of General Psychiatry 2003 2, article 10 10.1186/1475-2832-2-10 2-s2.0-21244473266\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2016()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "7128909", "pmc": null, "pmid": "27433163", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "9825080;10767887;14613516;14555596;15119907;12925718;15213578;24957740;19480467;15062519;3632154;8777769;10645303;2035713;15784664;15883150;26506919;10902652", "title": "Overlapping of Serotonin Syndrome with Neuroleptic Malignant Syndrome due to Linezolid-Fluoxetine and Olanzapine-Metoclopramide Interactions: A Case Report of Two Serious Adverse Drug Effects Caused by Medication Reconciliation Failure on Hospital Admission.", "title_normalized": "overlapping of serotonin syndrome with neuroleptic malignant syndrome due to linezolid fluoxetine and olanzapine metoclopramide interactions a case report of two serious adverse drug effects caused by medication reconciliation failure on hospital admission" }

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"actiondrug": "5", "activesubstance": { "activesubstancename": "GLYBURIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIBENCLAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MAZHAR F, AKRAM S, HAIDER N, AHMED R. OVERLAPPING OF SEROTONIN SYNDROME WITH NEUROLEPTIC MALIGNANT SYNDROME DUE TO LINEZOLID-FLUOXETINE AND OLANZAPINE-METOCLOPRAMIDE INTERACTIONS: A CASE REPORT OF TWO SERIOUS ADVERSE DRUG EFFECTS CAUSED BY MEDICATION RECONCILIATION FAILURE ON HOSPITAL ADMISSION. CASE-REP-MED 2016.", "literaturereference_normalized": "overlapping of serotonin syndrome with neuroleptic malignant syndrome due to linezolid fluoxetine and olanzapine metoclopramide interactions a case report of two serious adverse drug effects caused by medication reconciliation failure on hospital admission", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20161005", "receivedate": "20161005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12818354, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "SA-NORTHSTAR HEALTHCARE HOLDINGS-SA-2016NSR001878", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INTRAVENOUS INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GLYBURIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLYBURIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "078374", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, EVERY 6 HRS", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE\\OLANZAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SYMBYAX" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INTRAVENOUS INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INTRAVENOUS INFUSION", "drugdosagetext": "400 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC FOOT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INTRAVENOUS INFUSION", "drugdosagetext": "600 MG, EVERY 12 HRS", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC FOOT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "87", "reaction": [ { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscle rigidity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperthermia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MAZHAR F, AKRAM S, HAIDER N, AHMED R. OVERLAPPING OF SEROTONIN SYNDROME WITH NEUROLEPTIC MALIGNANT SYNDROME DUE TO LINEZOLID-FLUOXETINE AND OLANZAPINE-METOCLOPRAMIDE INTERACTIONS: A CASE REPORT OF TWO SERIOUS ADVERSE DRUG EFFECTS CAUSED BY MEDICATION RECONCILIATION FAILURE ON HOSPITAL ADMISSION. CASE REP MED. 2016;DOI:10.1155/2016/7128909", "literaturereference_normalized": "overlapping of serotonin syndrome with neuroleptic malignant syndrome due to linezolid fluoxetine and olanzapine metoclopramide interactions a case report of two serious adverse drug effects caused by medication reconciliation failure on hospital admission", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20161122", "receivedate": "20161122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12965057, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "SA-IMPAX LABORATORIES, INC-2016-IPXL-02213", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, 2 /DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, EVERY 12HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC FOOT INFECTION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GLYBURIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLYBURIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE\\OLANZAPINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "(3/25) MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SYMBYAX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC FOOT INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "071250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, EVERY 6HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE HYDROCHLORIDE IR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "87", "reaction": [ { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MAZHAR F, AKRAM S, HAIDER N, AHMED R. OVERLAPPING OF SEROTONIN SYNDROME WITH NEUROLEPTIC MALIGNANT SYNDROME DUE TO LINEZOLID-FLUOXETINE AND OLANZAPINE-METOCLOPRAMIDE INTERACTIONS: A CASE REPORT OF TWO SERIOUS ADVERSE DRUG EFFECTS CAUSED BY MEDICATION RECONCILIATION FAILURE ON HOSPITAL ADMISSION. CASE REPORTS IN MEDICINE. 2016;1-4", "literaturereference_normalized": "overlapping of serotonin syndrome with neuroleptic malignant syndrome due to linezolid fluoxetine and olanzapine metoclopramide interactions a case report of two serious adverse drug effects caused by medication reconciliation failure on hospital admission", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20161202", "receivedate": "20161202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12995329, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "SA-CIPLA LTD.-2017SA18020", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAZHAR F, AKRAM S, HAIDER N AND AHMED R. OVERLAPPING OF SEROTONIN SYNDROME WITH NEUROLEPTIC MALIGNANT SYNDROME DUE TO LINEZOLID-FLUOXETINE AND OLANZAPINE-METOCLOPRAMIDE INTERACTIONS: A CASE REPORT OF TWO SERIOUS ADVERSE DRUG EFFECTS CAUSED BY MEDICATION RECONCILIATION FAILURE ON HOSPITAL ADMISSION. CASE REP MED.. 2016", "literaturereference_normalized": "overlapping of serotonin syndrome with neuroleptic malignant syndrome due to linezolid fluoxetine and olanzapine metoclopramide interactions a case report of two serious adverse drug effects caused by medication reconciliation failure on hospital admission", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20171012", "receivedate": "20171012", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14077050, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "Atovaquone-proguanil (AP) and artemether-lumefantrine (AL) are both treatments for uncomplicated Plasmodium falciparum malaria, but comparative clinical trials are lacking. We performed a retrospective analysis, comparing treatment failure and fever clearance time in non-immune travelers with uncomplicated P. falciparum malaria, treated with AP or AL. Sixty-nine patients were included during 2001-2013: 44 in the AP group and 25 in the AL group. Treatment failure was observed in 6 of 44 (13.6%) and 1 of 25 (4.0%) patients in the AP and AL groups, respectively. Six treatment failures were observed in travelers from West Africa. Fever clearance time was 44 ± 23 h in AL group versus 77 ± 28 h in AP group, (P < 0.001). Hospitalization time was significantly shorter in the AL group; 3.8 + 1.3 versus 5.1 + 2.8 days in the AP group (P = 0.04) In conclusion, travelers with uncomplicated P. falciparum malaria recover faster on AL than on AP. The AL should probably be the drug of choice for this population.", "affiliations": "The Center of Geographic Medicine and Tropical Diseases, Sheba Medical Center, Tel Hashomer, Israel; The Infectious Diseases Unit, Shaare-Zedek Medical Center, Jerusalem, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Center of Geographic Medicine and Tropical Diseases, Sheba Medical Center, Tel Hashomer, Israel; The Infectious Diseases Unit, Shaare-Zedek Medical Center, Jerusalem, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Center of Geographic Medicine and Tropical Diseases, Sheba Medical Center, Tel Hashomer, Israel; The Infectious Diseases Unit, Shaare-Zedek Medical Center, Jerusalem, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Center of Geographic Medicine and Tropical Diseases, Sheba Medical Center, Tel Hashomer, Israel; The Infectious Diseases Unit, Shaare-Zedek Medical Center, Jerusalem, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Center of Geographic Medicine and Tropical Diseases, Sheba Medical Center, Tel Hashomer, Israel; The Infectious Diseases Unit, Shaare-Zedek Medical Center, Jerusalem, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel elischwa@post.tau.ac.il.", "authors": "Grynberg|Shirly|S|;Lachish|Tamar|T|;Kopel|Eran|E|;Meltzer|Eyal|E|;Schwartz|Eli|E|", "chemical_list": "D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; C109496:atovaquone, proguanil drug combination; D002727:Proguanil; D053626:Atovaquone", "country": "United States", "delete": false, "doi": "10.4269/ajtmh.14-0249", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9637", "issue": "92(1)", "journal": "The American journal of tropical medicine and hygiene", "keywords": null, "medline_ta": "Am J Trop Med Hyg", "mesh_terms": "D000328:Adult; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D053626:Atovaquone; D004338:Drug Combinations; D004983:Ethanolamines; D005260:Female; D005449:Fluorenes; D006801:Humans; D016778:Malaria, Falciparum; D008297:Male; D008875:Middle Aged; D002727:Proguanil; D014195:Travel", "nlm_unique_id": "0370507", "other_id": null, "pages": "13-7", "pmc": null, "pmid": "25371188", "pubdate": "2015-01", "publication_types": "D016428:Journal Article", "references": "22720832;11421377;12057021;17176344;21062666;19946387;19021900;15486832;21028985;22632033;18256423;12884171;22551095;10418762;19305055;21489374;17109092;15478057", "title": "Artemether-lumefantrine compared to atovaquone-proguanil as a treatment for uncomplicated Plasmodium falciparum malaria in travelers.", "title_normalized": "artemether lumefantrine compared to atovaquone proguanil as a treatment for uncomplicated plasmodium falciparum malaria in travelers" }

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{ "abstract": "Electrophysiological and hemodynamic data can be integrated to accurately and precisely identify the generators of abnormal electrical activity in drug-resistant focal epilepsy. Arterial Spin Labeling (ASL), a magnetic resonance imaging (MRI) technique for quantitative noninvasive measurement of cerebral blood flow (CBF), can provide a direct measure of variations in cerebral perfusion associated with the epileptic focus. In this study, we aimed to confirm the ASL diagnostic value in the identification of the epileptogenic zone, as compared to electrical source imaging (ESI) results, and to apply a template-based approach to depict statistically significant CBF alterations. Standard video-electroencephalography (EEG), high-density EEG, and ASL were performed to identify clinical seizure semiology and noninvasively localize the epileptic focus in 12 drug-resistant focal epilepsy patients. The same ASL protocol was applied to a control group of 17 healthy volunteers from which a normal perfusion template was constructed using a mixed-effect approach. CBF maps of each patient were then statistically compared to the reference template to identify perfusion alterations. Significant hypo- and hyperperfused areas were identified in all cases, showing good agreement between ASL and ESI results. Interictal hypoperfusion was observed at the site of the seizure in 10/12 patients and early postictal hyperperfusion in 2/12. The epileptic focus was correctly identified within the surgical resection margins in the 5 patients who underwent lobectomy, all of which had good postsurgical outcomes. The combined use of ESI and ASL can aid in the noninvasive evaluation of drug-resistant epileptic patients.", "affiliations": "Clinical Neurophysiology and Functional Neuroimaging Unit, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.;Department of Computer Science, University of Verona, Verona, Italy.;Clinical Neurophysiology and Functional Neuroimaging Unit, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.;Neuroradiology Unit, Department of Diagnostic and Pathology, University Hospital Verona, Verona, Italy.;Clinical Neurophysiology and Functional Neuroimaging Unit, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.;Department of Neurophysiology, Foundation IRCCS San Camillo Hospital, Venice, Italy.;Epilepsy Surgery Center, Niguarda Hospital, Milan, Italy.;Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.;Neuroradiology Unit, Department of Diagnostic and Pathology, University Hospital Verona, Verona, Italy.;Clinical Neurology Unit, Department of Medical Science, Surgery and Health, University of Trieste, Trieste, Italy.", "authors": "Boscolo Galazzo|Ilaria|I|;Storti|Silvia Francesca|SF|;Del Felice|Alessandra|A|;Pizzini|Francesca Benedetta|FB|;Arcaro|Chiara|C|;Formaggio|Emanuela|E|;Mai|Roberto|R|;Chappell|Michael|M|;Beltramello|Alberto|A|;Manganotti|Paolo|P|", "chemical_list": "D013113:Spin Labels", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0123975", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2594605510.1371/journal.pone.0123975PONE-D-14-44811Research ArticlePatient-Specific Detection of Cerebral Blood Flow Alterations as Assessed by Arterial Spin Labeling in Drug-Resistant Epileptic Patients Patient-Specific CBF Alterations in EpilepsyBoscolo Galazzo Ilaria \n1\n*Storti Silvia Francesca \n2\nDel Felice Alessandra \n1\nPizzini Francesca Benedetta \n3\nArcaro Chiara \n1\nFormaggio Emanuela \n4\nMai Roberto \n5\nChappell Michael \n6\nBeltramello Alberto \n3\nManganotti Paolo \n7\n\n1 \nClinical Neurophysiology and Functional Neuroimaging Unit, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy\n\n2 \nDepartment of Computer Science, University of Verona, Verona, Italy\n\n3 \nNeuroradiology Unit, Department of Diagnostic and Pathology, University Hospital Verona, Verona, Italy\n\n4 \nDepartment of Neurophysiology, Foundation IRCCS San Camillo Hospital, Venice, Italy\n\n5 \nEpilepsy Surgery Center, Niguarda Hospital, Milan, Italy\n\n6 \nInstitute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom\n\n7 \nClinical Neurology Unit, Department of Medical Science, Surgery and Health, University of Trieste, Trieste, Italy\nHoshi Yoko Academic Editor\nMedical Photonics Research Center. Hamamatsu University School of Medicine, JAPAN\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: IBG PM. Performed the experiments: IBG ADF FBP CA RM. Analyzed the data: IBG SFS. Contributed reagents/materials/analysis tools: IBG SFS EF MAC AB. Wrote the paper: IBG SFS ADF FBP EF MAC PM.\n\n* E-mail: ilaria.boscologalazzo@univr.it6 5 2015 2015 10 5 e01239758 10 2014 24 2 2015 © 2015 Boscolo Galazzo et al2015Boscolo Galazzo et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Electrophysiological and hemodynamic data can be integrated to accurately and precisely identify the generators of abnormal electrical activity in drug-resistant focal epilepsy. Arterial Spin Labeling (ASL), a magnetic resonance imaging (MRI) technique for quantitative noninvasive measurement of cerebral blood flow (CBF), can provide a direct measure of variations in cerebral perfusion associated with the epileptic focus. In this study, we aimed to confirm the ASL diagnostic value in the identification of the epileptogenic zone, as compared to electrical source imaging (ESI) results, and to apply a template-based approach to depict statistically significant CBF alterations. Standard video-electroencephalography (EEG), high-density EEG, and ASL were performed to identify clinical seizure semiology and noninvasively localize the epileptic focus in 12 drug-resistant focal epilepsy patients. The same ASL protocol was applied to a control group of 17 healthy volunteers from which a normal perfusion template was constructed using a mixed-effect approach. CBF maps of each patient were then statistically compared to the reference template to identify perfusion alterations. Significant hypo- and hyperperfused areas were identified in all cases, showing good agreement between ASL and ESI results. Interictal hypoperfusion was observed at the site of the seizure in 10/12 patients and early postictal hyperperfusion in 2/12. The epileptic focus was correctly identified within the surgical resection margins in the 5 patients who underwent lobectomy, all of which had good postsurgical outcomes. The combined use of ESI and ASL can aid in the noninvasive evaluation of drug-resistant epileptic patients.\n\nThe authors received no specific funding for this work. Data AvailabilityDue to ethical restrictions and confidentiality of patient information, the data are available upon request from Dr. Ilaria Boscolo Galazzo (ilaria.boscologalazzo@univr.it) or Dr. Paolo Manganotti (paolo.manganotti@univr.it).Data Availability\nDue to ethical restrictions and confidentiality of patient information, the data are available upon request from Dr. Ilaria Boscolo Galazzo (ilaria.boscologalazzo@univr.it) or Dr. Paolo Manganotti (paolo.manganotti@univr.it).\n==== Body\nIntroduction\nMultimodal approaches combining several imaging methods may further our understanding of the mechanisms underlying the epileptic process and aid in more accurately localizing abnormal neuronal activity, especially in patients with drug-resistant epilepsy [1–2]. In such patients, the mainstay therapeutic option for reducing or suppressing seizures is surgical resection of the epileptogenic zone [3–5]. Therefore, precise preoperative localization of the epileptogenic zone is crucial to spare non-epileptogenic brain tissue as best as possible and minimize postoperative neurological deficits [6]. Although highly invasive and burdened by potential risks limiting its use in clinical settings [7], invasive electroencephalography (EEG) (e.g., stereo-EEG [sEEG]) remains the gold standard to localize the epileptogenic focus when noninvasive presurgical evaluation fails to yield clear-cut information [8–10].\n\nNoninvasive presurgical workup will usually include long-term EEG, video-EEG and neuropsychological testing, which do not always provide the localization accuracy and precision required for surgical planning. Morphological magnetic resonance imaging (MRI) scans are also routinely acquired in epileptic patients to identify structural brain lesions such as tumors, cortical dysplasia or hippocampal sclerosis, which can define the seizure onset zone and guide surgical resection [11]. In the absence of these findings, however, the MRI scans may be inconclusive for delineating the location of the focal abnormality and will therefore need to be integrated with complementary neuroimaging studies.\n\nImaging techniques such as positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) [12–15], dipole localization or electrical source imaging (ESI) [16–19], and EEG-functional MRI (fMRI) [20–23] can all offer additional localization information and improve the yield of routine imaging studies. However, functional neuroimaging techniques (as PET, SPECT, fMRI), though each providing data on metabolism, perfusion, and blood oxygenation, have poor temporal resolution. Conversely, EEG, and high-density EEG (hdEEG) in particular, provide a direct measurement of neuronal activity with high temporal resolution which allows investigation of epileptic activity on a millisecond scale, from the initiation of seizure activity through to the propagation phase [24]. When combined, they can be used to evaluate the same phenomenon from different perspectives, overcoming the limitations inherent to each modality and thus obtain a more complete picture of the dynamics of the epileptic focus [25–29].\n\nSince the 1980s, perfusion changes during epileptic processes have been investigated using SPECT in combination with technetium-99m hexamethyl-propylene amine oxime (Tc-99m HMPAO) or Tc-99m ethyl cysteinate dimer (Tc-99m ECD), especially during the ictal and postictal phases [30]. While ictal and postictal SPECT demonstrate high sensitivity in focus localization (97–100% and 75–77%, respectively), their sensitivity during the interictal phase is about 50% lower [31–32]. Moreover, the technique has several limitations, including relatively low spatial resolution, high cost, and difficult logistics that restrict its availability to a few specialized neuroimaging centers [30]. In addition, the localization accuracy of SPECT during the ictal/early postictal phases depends critically on injecting the tracer as early as possible after seizure onset. If the timing is not precise, ambiguous blood flow changes may result, leading to misinterpretation of the main generator of seizure activity.\n\nRecently, newer MRI methods to study local cerebral perfusion have been proposed, offering several substantial advantages over nuclear medicine techniques, including noninvasiveness, no radiation exposure, easier accessibility, and higher spatial resolution [33–34]. Among these innovative techniques, Arterial Spin Labeling (ASL) MRI has been applied to noninvasively study and quantify perfusion changes related to the epileptic focus. ASL provides a quantitative measurement of regional cerebral blood flow (CBF) without the need for contrast agents. Similar in principle to nuclear medicine techniques, ASL utilizes magnetically labeled arterial blood-water proximal to the tissue of interest as an endogenous diffusible tracer [35–36]. The approach is to collect a labeled and a control image, which are equal for the static tissue signal but have different weights on flowing spins. Their subtraction (control-label) removes the signal from tissue, giving only the signal contribution from the CBF. Since the signal difference is on the order 0.5–1.5% of the full signal, the signal-to-noise (SNR) ratio in this technique is intrinsically low, so that multiple volume repetitions are needed to ensure a sufficient signal level and quantify the different perfusion parameters [37]. The noninvasive nature of ASL makes it a potential alternative to further invasive examinations with [18F]FDG-PET or SPECT, which are still considered the most useful neuroimaging techniques in the assessment of epileptic patients. Moreover, because it does not require the injection of radioligands, thus obviating the need to wait for tracer uptake, ASL can be usefully applied to map brain changes during the interictal, as well as the ictal and early postictal phases. To date, ASL has seldom been employed in epilepsy [38–40], but promising results have been obtained in combination and comparison with other techniques [41–42]. In a previous work, we assessed the diagnostic value of ASL perfusion MRI in identifying the epileptogenic zone by comparing the results to those obtained with ESI and [18F]FDG-PET in a group of 6 patients with drug-resistant focal epilepsy [29]. In all cases, the concordance between the altered patterns of metabolism and perfusion during both the interictal and early postictal phases was good. Moreover, the functional changes overlapped fairly well with the electrical changes localized by ESI, further demonstrating the usefulness of ASL as a valid alternative to [18F]FDG-PET.\n\nThe complexity and high variability of epilepsy (e.g., focus localization and structural, hemodynamic and metabolic abnormalities) often preclude group analyses, so that the individual peculiarities of each patient need to be assessed separately. The simplest quantitative approach to patient-specific analysis is represented by a one-versus-many parametric test, where a single patient is compared to a group of age-matched controls [43–44]. In order to perform this type of analysis and automatically identify the areas of statistically altered perfusion, two general approaches are currently in use. One is the homoscedastic approach, also referred to as the random-effect model [45–47], which assumes homogeneous within-subject variance across subjects or negligible by comparison to between-subject variance. The other is the heteroscedastic approach, also referred to as the mixed-effect model [48–49], which takes the heterogeneous within-subject variances into account. In ASL data, the importance of this second approach was recognized by Viviani et al. in 2009 [50] and then extensively investigated by Maumet and colleagues in 2013 [51], using general linear model analyses based on these two approaches in patients with brain tumors.\n\nIn this study, we used source imaging and electrophysiological data as the reference for focus localization to further assess the feasibility of ASL in detecting perfusion changes related to the epileptic focus in patients affected by drug-resistant focal epilepsy and potential candidates for surgery. Furthermore, we aimed to quantitatively detect the brain perfusion abnormalities in each patient, defining a template-based approach combined with a heteroscedastic model for the automatic detection of statistically significant CBF changes. Finally, the findings from postsurgery MRI scans and the clinical outcomes in a subgroup of patients were used as “ground truth” to evaluate the localization accuracy of the ASL and ESI results.\n\nMaterials and Methods\nPatients and Subjects\nThe study population was 6 consecutive patients (hereafter, patients nos. 7–12) with drug-resistant focal epilepsy admitted for presurgical assessment according to the following criteria: (i) drug-resistant epilepsy [52]; (ii) non-localizing seizure semeiology; (iii) multifocal scalp EEG discharges; and (iv) non-conclusive standard neuroimaging findings. A series of neurophysiological examinations (video-EEG and hdEEG) were performed to define clinical seizure semiology. As part of the presurgical examination protocol, advanced neuroimaging techniques, including the ASL sequence, were also performed on a 3T MRI scanner. In a previous study on a group of 6 other epileptic patients (hereafter, patients nos. 1–6) [29], the same protocol, plus [18F]FDG-PET, had been applied: the results from these patients are here completed with the more recent postsurgical information (when available) and ASL analyses. All new patients were classified as having either right or left temporal lobe epilepsy on the basis of clinical and electrophysiological information. In this new group, only one patient was evaluated with invasive EEG (sEEG) prior to surgery (patient no. 7).\n\nA control group underwent MRI evaluation using the same sequences as the patient group. The control group was composed of 17 healthy subjects (10 women, mean age 34±10 years) with no history of neurological or psychiatric disorders.\n\nIn accordance with the Declaration of Helsinki, written informed consent to take part in the study was obtained from all control subjects and patients. The study protocol was approved by the Local Ethics Committee of the University Department and Hospital of Verona. The individuals in this manuscript have given written informed consent (as outlined in PLOS consent form) to publish these case details.\n\nPatient No. 7\nThis 46-year-old, right-handed woman reported, at the age of 20, experiencing several brief episodes characterized by abnormal hearing followed by loss of consciousness on one occasion, after which she was discharged from the hospital with a diagnosis of partial epilepsy. Since then, she has had no more auditory symptoms, later classified as auras, despite having 5–6 seizures per month that she describes as sudden moments during which she cannot speak but is aware of her environment. After an attack, however, she often finds herself on the floor, unaware that she has fallen. Witnesses recalled right-sided mouth deviation, right-hand fiddling, and dystonic posturing of the left hand, followed by generalised convulsions. Standard EEG showed runs of sharp waves and rarer slow waves over the right frontotemporal leads. The MRI scan revealed no morphological abnormalities. The sEEG, subsequent to other imaging exams (hdEEG and ASL), pointed to an epileptogenic zone located over the right temporal pole, mainly involving the superior (T1) and middle (T2) temporal gyri. The patient underwent surgical removal of these portions, and has been seizure-free ever since (7 months).\n\nPatient No. 8\nThis 62-year-old, right-handed woman suffered repeated episodes of febrile convulsions at the age of 23 months. She remained seizure-free until age 18 years, when she began experiencing brief, sudden episodes of loss of contact that went unnoticed at that time. At the age of 32, she presented a generalized seizure, and a diagnosis of epilepsy was made. Currently, she has 3–4 seizures per month characterized by oral automatism, right-hand fiddling, and left dystonic hand posturing. On repeated occasions, relatives reported brief episodes of incongruous activity, during which she is unresponsive. Standard EEG showed runs of fast, spiky activity over the frontotemporal right leads, sometimes with bilateral expression over the frontal areas. Repeated MRI scans were reportedly normal.\n\nPatient No. 9\nThis 68-year-old, right-handed woman began suffering, at the age of 20, brief, sudden episodes of flushing, sensation of something rising from the stomach to the head followed by intense asthenia. The episodes clustered during a few months every year, then disappeared at the age of 35. Around age 60, they started again, this time associated with pervasive fear: she was initially referred for psychiatric evaluation because of suspected panic attacks. Standard EEG revealed right frontotemporal spikes, and a diagnosis of epilepsy was made. Fluid attenuated inversion recovery (FLAIR) MRI images showed bilateral hippocampal hyperintensity that was more evident on the right side.\n\nPatient No. 10\nThis 48-year-old, right-handed man suffered febrile convulsion episodes at the age of 2 years. At the age of 18, after a secondary generalized seizure, a diagnosis of temporal epilepsy was made. With hindsight, he referred always having had brief episodes of altered sensation associated with something rising from the stomach; witnesses also reported oral automatism. Since then, he has continued to experience weekly seizures despite appropriate drug treatment. Standard EEG showed the presence of sub-continuous spiky activity over the frontotemporal left leads. The MRI scan revealed no morphological abnormalities. The patient has been seizure-free since surgical resection of the left temporal lobe (1 year ago).\n\nPatient No. 11\nThis 48-year-old, right-handed man reported having suffered during childhood brief and sudden episodes of nausea misinterpreted as gastric disturbances at that time. At the age of 30, during hospitalization for injuries sustained in a car accident, a diagnosis of focal epilepsy was made based on EEG data and history. A few partial seizures occurred over the following months, then remitted for 15 years while he was on carbamazepine. At the age of 45, seizures reoccurred weekly, characterized by a rising gastric sensation, tachycardia, and subsequent depersonalization. Witnessed episodes were described as the patient fiddling with his right hand, dystonic posturing of the left arm, oral automatism, and inability to speak. Standard EEG showed only rare anterior temporal spikes, with right predominance. FLAIR MRI images showed mild bilateral hippocampal hyperintensity.\n\nPatient No. 12\nThis 28-year-old, right-handed woman had a positive family history for generalized epilepsy (maternal aunt). At the age of 26, she began experiencing repeated déjà vu episodes and uncomfortable feelings sometimes associated with anxiety and tachycardia. She was unaware of subsequent vocalizations, left head version and bilateral hand fiddling, and referred suffering headaches after the symptoms resolved. Antiepileptic treatment was only partially effective. Standard EEG showed left frontotemporal spikes. MRI scans revealed altered signal areas in the right lateral frontobasal lobe, left anteroinferior frontal lobe, medio-posterior portion of the left hippocampus, and at the left frontoparietal junction.\n\nData acquisition: hdEEG recording\nHdEEG was performed using 256 channels (Electrical Geodesic, Inc., Eugene, OR). The net was adjusted so that Fpz, Cz, Oz, and the pre-auricular points were correctly placed according to the international 10/20 system. The net's geodesic tension structure is such that all electrodes could be evenly distributed over the scalp at approximately the same location in all patients. The data were recorded against a vertex electrode reference (Cz) at a sampling rate of 250 Hz. Patients were seated in a relaxed position; the total EEG recording time was around 40 min.\n\nData acquisition: anatomical and ASL recording\nThe experiment was performed using a 3T MRI scanner (Allegra, Siemens, Erlangen, Germany) with a standard transmit/receive head coil. For the ASL data, a pulsed PICORE sequence (proximal inversion with a control for off-resonance effects) with the Q2TIPS scheme (QUIPSS II with thin-slice TI1 periodic saturation) was used [53]. Interleaved control and label images (80 volumes) were acquired using a 2D gradient-echo echo-planar imaging (GRE-EPI) readout with the following scan parameters: TR/TE = 3500/16 ms; TI1/TIs/TI2 = 700/1400/1600 ms and 90° flip angle. Sixteen axial slices in ascending order were prescribed and positioned parallel to the anterior-posterior commissure line (3.5x3.5x5 mm3, with an inter-slice gap of 1 mm) in order to cover the presumed focus location. The labeling slice was 10 cm thick and was separated from the proximal slice of the acquisition volume by a 20-mm gap. A calibration scan with the same parameters as the ASL sequence but longer TR (10 s) was also acquired to estimate the equilibrium magnetization of arterial blood (M0b). The overall acquisition time for ASL was approximatively 6 mins, including the additional calibration scan. A high-resolution whole brain anatomical scan was acquired for each subject using a 3D T1-weighted magnetization prepared rapid acquisition gradient echo sequence ([MPRAGE], TR/TE = 2300/3.9 ms; FOV = 192 x 192; matrix = 256 x 256; 176 sagittal slices 1.0 mm in thickness). Other high-resolution anatomical images, including T2-weighted, FLAIR and inversion recovery with 2D readout, were also acquired in order to assess for the presence of structural alterations such as hippocampal sclerosis or malformations of cortical development.\n\nData analysis: electrical source imaging\nHdEEG data were analyzed using Cartool software (http://sites.google.com/site/cartoolcommunity/). The T1-weighted anatomical images were used to create a realistic model of the brain for source localization. In each patient, the hdEEG and MRI data and the solution space were restricted to the gray matter. The solution space for the distributed source model contained from 3,028 to 3,088 points uniformly distributed over the gray matter of the brain and mapped onto the spherical head model with anatomical constraints (SMAC) space [54]. The peak of the spike was used as a trigger for averaging in epochs of ±500 ms. Two time frames were chosen to characterize spike topography: the first, from the beginning of the spike to the time point at 50% of the rising phase, was defined as an epoch characterizing a possible source of the spike generator [24]; in the second, an epoch at the peak of the spike was defined as indicating propagation. A standardized source imaging procedure, ([LORETA] low resolution brain electromagnetic tomography) [55] constrained to the individual gray matter, was applied to the averaged spikes. From the ESI, the current density (CD) was quantified at each solution point [μA/mm3].\n\nData analysis: ASL quantification\nASL data were preprocessed and analyzed using FSL 5.0.1 (FMRIB, Oxford, UK) and Matlab 7.14 (MathWorks, Natick, MA) with a dedicated home-made code created for this study. Motion correction was applied separately to the Control and Label volumes using the MCFLIRT tool and taking the first volume as reference. In particular, a six-parameter 3D rigid-body registration with a normalized correlation cost function was used. The ASL calibration scan was used for estimating the coregistration parameters from ASL to the individual T1-weighted image by applying a 3D rigid-body registration with a normalized mutual-information cost function and 7 degrees of freedom.\n\nAfter these pre-processing steps, surround subtraction was applied to the Control and Label volumes to obtain a 4D matrix representing the perfusion-weighted maps. Unlike what is usually done in ASL studies, ΔM represents the whole set of perfusion-weighted maps (one volume per repetition) instead of a single perfusion-weighted map obtained by averaging across the repetitions. In this way, a 4D matrix for the CBF parameter can be estimated for each subject and the temporal information given by the different repetitions will allow measurement of the within-subject variance [51]. The standard kinetic model [56] was applied to the 4D ΔM matrix to estimate the blood flow maps in physiological units [ml/100g/min]. The CBF values were calculated as follows:\n CBF = ΔM2αMobTI1e-(TI2+n-1*slicetime)T1B \nwhere ΔM is the difference signal, TI\n1 and TI\n2 are the sequence time parameters described above, n is the slice number, slice\ntime is the time taken to acquire each single slice (~ 50ms), T\n1B is the longitudinal relaxation time of blood (1664 ms at 3T), and α is the inversion efficiency (0.95 for pulsed ASL) [57]. M\nob was calculated as the ratio between the mean tissue equilibrium magnetization value in a cerebrospinal fluid (CSF) region (from the calibration scan) and the brain-blood partition coefficient.\n\nFor each subject, the mean and variance values over all repetitions were calculated for the CBF parameter. These maps in ASL space were affine-registered to the individual high-resolution anatomical images by applying the previously estimated transformation matrix. Each T1-weighted image was then registered to the Montreal Neurological Institute (MNI) space with 1x1x1 mm3 resolution using a non-linear method (FNIRT tool in FSL). Finally, the joint ASL/T1-weighted and T1-weighted/MNI space transformation parameters were used to spatially normalize the CBF maps representing the mean and variance values.\n\nData analysis: patient-specific detection of perfusion changes\nFor each subject, the CBF images in MNI space were intensity normalized to compensate for mean inter-subject perfusion variations. Indeed, voxel-wise ASL detection studies, where the focus is on local variations across the brain, have shown that an intensity normalization step is advised to increase the sensitivity [58], also due to the large inter-subject variability in global CBF values [59]. The value used for the intensity normalization was equal to the mean CBF in gray matter, applying a threshold of 70% for detecting pure gray matter voxels, similarly to [51, 60]. The partial volume estimates for gray matter were derived from segmentation of the normalized anatomical image using the FAST tool in FSL. In addition, the non-physiological negative perfusion estimates present in the gray matter normalization mask were excluded from the mean CBF calculation in order to define a more reliable reference value [51, 60].\n\nFor comparing each patient to the control group, a two-step procedure was performed: construction of a normal perfusion template and then a one-versus-many statistical analysis. The heteroscedastic approach was used in the analysis (mixed-effect model) [46, 50–51].\n\nThe first step entailed CBF template construction from the control group images. The template was created using the FLAME 1 (FMRIB's local analysis of mixed effects-stage 1) tool available in FSL software [61–62], which uses Bayesian modeling and explicitly accounts for the within-subject variance. For each subject, normalized CBF images representing the mean CBF estimates and the CBF within-subject variance were supplied to the FLAME 1 tool. The data from the healthy subjects were pooled into one group, and the group maps (mean and variance) were estimated with this tool. In a heteroscedastic model, the group variance will reflect both the within-subject and the between-subject variability.\n\nIn the second step, comparison of the control group versus each single patient was carried out using an unpooled-variance unpaired two-sample t-test in order to consider both the group variance and the patient variance. The t-statistic, for testing whether the estimated patient versus control group means were different, was calculated as:\n t = μc^- μp^σc2^Nc+σp2^Np \nwhere μ and σ\n2 represent the estimated mean and variance for the patient (p) and the control group (c) respectively, and N represents the number of subjects (17 and 1 for N\nc and N\np, respectively). A negative tvalue indicates that, at the voxel of interest, the mean is higher in the patient than in the control group, thus identifying possibly hyperperfused areas (patient > controls). Conversely, a positive tvalue indicates possible areas of hypoperfusion (patient < controls).\n\nThe simplest approximation was adopted for defining the degrees of freedom (df), assigning df = n-p-1, where n is the total number of subjects and p the number of fixed (dummy) variables such as subject-specific covariates like age or behavioral data [49]. The same approach was also implemented in the statistic test in FLAME 1 of FSL [62]. A false discovery rate (FDR) correction (q < 0.05) for multiple comparisons was applied to the statistical results [63] to detect the areas of statistically significant alterations in perfusion.\n\nThe procedure for the automatic detection of patient-specific perfusion abnormalities was applied to the 6 new patients and to the 6 patients evaluated in the previous study in order to further confirm the results and the observations from the region of interest (ROI) analysis.\n\nData analysis: ESI and ASL comparison\nFor each patient, the mean CBF map from ASL and ESI results was overlaid on individual T1-weighted anatomical MRI images to combine all of them in the same anatomical space using FSL tools. As in the previous study [29], a series of ROIs was identified using the Harvard-Oxford Atlas to compare the ESI and ASL results in terms of CD and CBF inside the same areas, using the spatially normalized data. Quantification was restricted to the gray matter, including voxels whose probability to belong to the gray matter was at least 80%. All measures were compared to the contralateral side. The five ROIs with the highest differences in CD and CBF values are reported here. This was done to quantitatively compare the information provided by ASL and ESI and to evaluate the agreement with the results of the statistical analysis. Areas over the epileptic focus are expected to be characterised by high CD values and low CBF values in comparison to the correspondent contralateral ROI, if the patient is in interictal phase.\n\nSurgical validation\nIn patients undergoing surgical resection, freedom from seizure following the operation can be considered the ground truth and the most unambiguous proof of correct localization of the epileptogenic focus [18]. In order to assess the localization reliability of the ESI and ASL results, the presurgical information were overlaid on the postoperative MRI scan of each patient to determine whether or not the ESI and ASL maps were congruent and overlapped well with the resected tissue areas. Importantly, although the extension of a resected area tends to be overestimated and larger than the actual epileptogenic zone in most patients, seizure freedom following resection can be taken as proof of correct localization on a sublobar level [64]. Therefore, the preoperative anatomical MRI scan was coregistered with the postoperative scan, and the estimated coregistration parameters were inversely transformed in order to project the postoperative image over the original preoperative scan. To assess the ESI and ASL results, the rising phase of epileptiform activity and the statistical maps were used, respectively, and were overlapped on the coregistered postoperative anatomical image.\n\nResults\nAll 6 patients (patients nos. 7–12) in the new group completed the protocol. Clinical information and quantification results for each patient are presented in Tables 1 and 2 and Figs 1 and 2.\n\n10.1371/journal.pone.0123975.t001Table 1 Clinical profile: age, gender, MRI abnormalities, EEG activity, and location of noninvasive techniques (ESI and ASL) and invasive techniques (sEEG).\nPt\tSex\tAge\tYears since beginning\tSeizure frequency\tHx\tCurrent antiepileptic therapy\tStandard MRI\tEEG\tESI\tASL\tsEEG\t\n7\tF\t46\t26\t5–6/month\tnegative\tVPA, LEV, ZNS\tnegative\tsharp-waves over the frontotemporal right derivations\tlocalization in right anterior temporal areas\thypoperfusion in right temporal and frontotemporal regions\tright temporal pole focus\t\n8\tF\t62\t30\t3–4/month\tfebrile convulsion\tCBZ\tnegative\truns of fast, spiky activity over the frontotemporal right leads\tlocalization in right temporal and frontotemporal areas\thypoperfusion in right temporal and frontotemporal regions\tnone\t\n9\tF\t68\t48\t1/day\tnegative\tCBZ, LTG\tbilateral hippocampal hyperintensity\tright frontotemporal spikes\tlocalization in right temporal and frontotemporal regions\thypoperfusion in right temporal regions\tnone\t\n10\tM\t48\t30\t1/day\tfebrile convulsion\tCBZ, LEV\tnegative\tleft frontotemporal spikes\tlocalization in left anterior temporal areas\thypoperfusion in left temporal and frontotemporal regions\tnone\t\n11\tM\t48\t18\t1/week\tnegative\tVPA, ZNS, LTG\tmild bilateral hippocampal hyperintensity\trare anterior temporal spikes, with right predominance\tlocalization in right anterior temporal areas\thypoperfusion localized to right temporal regions\tnone\t\n12\tF\t28\t2\t2–3/month\tfamiliar\tCBZ, VPA\taltered areas in the right lateral frontobasal lobe, left anteroinferior frontal lobe, medioposterior portion of the left hippocampus, left frontoparietal junction\tleft frontotemporal spikes\tlocalization in left temporal and frontotemporal regions\thypoperfusion localized to left temporal regions\tnone\t\nVPA = valproate; LEV = levetiracetam; ZNS = zonisamide; CBZ = carbamazepine; LTG = lamotrigine.\n\n10.1371/journal.pone.0123975.t002Table 2 Quantification results from ESI and ASL in the six patients (patients nos. 7–12) with focal epilepsy.\nRegions of Interest\t\n\nSubject 7\n\t\nr-H\n\t\nl-H\n\t\nr- ITGa\n\t\nl- ITGa\n\t\nr-TP\n\t\nl-TP\n\t\nr-FOrC\n\t\nl-FOrC\n\t\nr-TFCa\n\t\nl-TFCa\n\t\n\nCD\n\t0.047\t0.009\t0.123\t0.010\t0.066\t0.013\t0.037\t0.015\t0.142\t0.012\t\n\nCBF\n\t27.45\t38.44\t28.73\t35.22\t26.47\t39.36\t20.66\t35.72\t29.81\t36.18\t\n\nSubject 8\n\t\nr-MTGa\n\t\nl-MTGa\n\t\nr- ITGp\n\t\nl- ITGp\n\t\nr-FoC\n\t\nl-FoC\n\t\nr-CoC\n\t\nl-CoC\n\t\nr-PP\n\t\nl-PP\n\t\n\nCD\n\t0.033\t0.018\t0.032\t0.019\t0.025\t0.009\t0.019\t0.008\t0.019\t0.006\t\n\nCBF\n\t31.97\t39.76\t32.12\t45.08\t32.03\t38.43\t33.08\t37.95\t36.27\t44.44\t\n\nSubject 9\n\t\nr-TP\n\t\nl-TP\n\t\nr-MTGa\n\t\nl-MTGa\n\t\nr-STGa\n\t\nl-STGa\n\t\nr-FP\n\t\nl-FP\n\t\nr-FOrC\n\t\nl-FOrC\n\t\n\nCD\n\t0.045\t0.023\t0.032\t0.020\t0.038\t0.017\t0.044\t0.022\t0.040\t0.016\t\n\nCBF\n\t38.03\t45.48\t38.42\t43.60\t31.12\t39.26\t35.52\t37.17\t37.90\t47.51\t\n\nSubject 10\n\t\nr-TP\n\t\nl-TP\n\t\nr-MTGp\n\t\nl-MTGp\n\t\nr-TFCa\n\t\nl-TFCa\n\t\nr-STGa\n\t\nl-STGa\n\t\nr-FOrC\n\t\nl-FOrC\n\t\n\nCD\n\t0.006\t0.012\t0.003\t0.010\t0.006\t0.012\t0.003\t0.010\t0.003\t0.010\t\n\nCBF\n\t32.50\t23.63\t35.60\t27.35\t36.50\t31.30\t49.10\t38.30\t46.25\t35.62\t\n\nSubject 11\n\t\nr-TP\n\t\nl-TP\n\t\nr-ITGa\n\t\nl-ITGa\n\t\nr-ITGp\n\t\nl-ITGp\n\t\nr-STGa\n\t\nl-STGa\n\t\nr-TFCa\n\t\nl-TFCa\n\t\n\nCD\n\t0.087\t0.047\t0.093\t0.034\t0.051\t0.035\t0.033\t0.039\t0.143\t0.047\t\n\nCBF\n\t40.23\t45.62\t22.88\t29.89\t32.81\t37.25\t47.20\t55.32\t20.45\t26.18\t\n\nSubject 12\n\t\nr-TP\n\t\nl-TP\n\t\nr-ITGa\n\t\nl-ITGa\n\t\nr-MTGp\n\t\nl-MTGp\n\t\nr-H\n\t\nl-H\n\t\nr-TFCa\n\t\nl-TFCa\n\t\n\nCD\n\t0.123\t0.227\t0.060\t0.196\t0.066\t0.236\t0.050\t0.094\t0.102\t0.224\t\n\nCBF\n\t37.20\t26.35\t40.32\t30.35\t45.87\t31.58\t49.10\t38.15\t32.05\t29.24\t\nESI indicates current density (CD) at 50% rising phase of the peak [μA/mm3], while ASL indicates cerebral blood flow (CBF) [ml/100g/min]. Only the values for the five most significant regions are reported. H = hippocampus; ITGa = inferior temporal gyrus, anterior division; TP = temporal pole; FOrC = frontal orbital cortex; TFCa = temporal fusiform cortex, anterior division; MTGa = middle temporal gyrus, anterior division; ITGp = inferior temporal gyrus, posterior part; FoC = frontal opercolum cortex; CoC = central opercolar cortex; PP = planum temporale; STGa = superior temporal gyrus, anterior division; FP = frontal pole; MTGp = middle temporal gyrus, posterior division.\n\n10.1371/journal.pone.0123975.g001Fig 1 Average spike voltage maps.\nSpike average (epochs of 1 s) of interictal activities visualized according to the projected location of the scalp electrodes in the six patients.\n\n10.1371/journal.pone.0123975.g002Fig 2 Imaging analysis results in the six patients (patients nos. 7–12) with focal epilepsy.\nESI and ASL images of the same anatomical space were acquired for each patient and two axial sections are shown (z coordinates in native space). (A) Spike average: 256-channel EEG traces with a duration of 1 s (spike average). The global field power is used for the onset (red line). (B) ESI results: EEG source imaging at 50% rising phase of the peak (up) and at the peak (down). The scale indicates the current density (CD) [μA/mm3]. (C) ASL results. The scale indicates the cerebral blood flow (CBF) values [ml/100g/min].\n\nOn hdEEG, focal source localization was detected in all patients. Source analysis reliably revealed the area of initial epileptic activity (at 50% rising phase of interictal epileptiform discharges [IEDs]) [24] and the presumed epileptogenic zone in all patients. All patients were evaluated during the interictal phase and all had temporal seizures, with abnormal activity localized mainly over the temporal area (or more anterior temporal areas) which spread to the frontotemporal area at the peak of activity in some cases.\n\nASL changes were observed in all patients, and these activities were concordant with the source results. Hypoperfusion patterns were identified during interictal activity in all 6 patients. Statistical analysis automatically identified the areas of significantly decreased perfusion in all patients as compared to the control group and further confirmed the results of the ROI analysis, even in those patients in which the hemispheric asymmetries were not marked and the CBF maps were difficult to interpret (patients nos. 9 and 12). Fig 3 illustrates the results from the statistical analysis of the 6 new patients, together with the localization of the ROIs in each patient. Fig 4 shows the same information for the group of 6 epileptic patients (patients nos. 1–6) described in our previous study. In this case, hypoperfused areas were identified during the interictal phase (4 out of 6 patients), while hyperperfusion was detected in the postictal period (2 out of 6 patients).\n\n10.1371/journal.pone.0123975.g003Fig 3 ASL imaging results in the new group of six patients (patients nos. 7–12) with focal epilepsy.\nA) Regions of interest (ROIs) for the quantification of current density (CD) and cerebral blood flow (CBF) values at the same anatomical level in each subject. ROIs are superimposed over axial T1-weighted slices in MNI space. B) Statistical analysis results from the template-based comparison. CBF maps (normalized values) for the same axial slices reported in part A) are shown here for the control group (template) and patients, together with the statistical map. In all patients, only areas with a statistically significant decrease in perfusion as compared to the healthy subjects were detected (blue scale, FDR corrected, q < 0.05).\n\n10.1371/journal.pone.0123975.g004Fig 4 ASL imaging results in the six focal epilepsy patients described in the previous study (patients nos. 1–6).\nA) Regions of interest for quantification of current density (CD) and cerebral blood flow (CBF) values at the same anatomical level in each subject. ROIs are superimposed over axial T1-weighted slices in MNI space. B) Statistical analysis results from the template-based comparison. CBF maps (normalized values) for the same axial slices reported in part A) are shown here for the control group (template) and patients, together with the statistical map. Areas with a statistically significant decrease in perfusion (hypoperfusion), as compared to the healthy subjects, were detected in four patients (blue scale, FDR corrected, q < 0.05). Conversely, areas with a statistically significant increase in perfusion (hyperperfusion), as compared to the healthy subjects, were detected in two patients (yellow scale, FDR corrected, q < 0.05).\n\nSeveral sections of the normal perfusion template employed in the statistical analysis comparison are reported in Fig 5 in order to provide additional information for better interpreting each individual case. This figure includes the mean perfusion estimates (A) and the between-subject variance (D), as estimated by the heteroscedastic model from the data of the control group. In addition, we reported for a representative subject the within-subject variance (B), which was estimated across the different repetitions, and the average within-subject variance across all the subjects of the control group (C), to provide a global measure of the expected within-subject variance. Interestingly, the vascular structures are characterized by high variance values, in agreement with previous findings [50–51].\n\n10.1371/journal.pone.0123975.g005Fig 5 Parameter estimates for the normal perfusion template, computed from the control group.\nA) Mean CBF estimates expressed in normalized units. B) Within-subject variance, estimated from the temporal information given by the multiple repetitions, for a representative subject. C) Average within-subject variance in the control group. D) Between-subject variance estimated from the heteroscedastic model. Axial slices of interest are displayed in radiological convention.\n\nSingle-subject results\nPatient No. 7\nThe hdEEG showed runs of spikes over the right anterior temporal derivations; this pattern was associated with rare asynchronous spikes over the contralateral frontotemporal areas. On 2D visualization, they localized on the right anterior zygomatic leads (Fig 1). The CBF maps showed a reduction in perfusion in the right temporal regions (temporal pole [TP], inferior temporal gyrus—anterior division [ITGa], and hippocampus [H]) and in some parts of the right frontal lobe, mainly the frontal operculum cortex (FOrC) (Table 2; Figs 2 and 3a). These results were in agreement with source imaging, which placed the rising phase of the activity in the right temporal regions (mainly TP, ITGa, and temporal fusiform cortex—anterior division [TFCa]). Propagation of activity also remained restricted to those regions (Table 2; Fig 2). The ASL results from the ROI analysis were further confirmed by the statistical analysis, which detected statistically significant areas of hypoperfusion over the r-TP, r-ITGa, and r-FOrC in comparison to the control group (FDR, q < 0.05). The alterations over the hippocampal structures did not reach statistical significance, however (Fig 3b).\n\nPatient No. 8\nThe hdEEG showed spiky activity over the right temporal leads; this pattern was rarely associated with spreading to the ipsilateral frontal leads. On 2D visualization, the activity localized over the right zygomatic area (Fig 1). The CBF maps showed hypoperfusion in the right temporal areas (inferior temporal gyrus—posterior division [ITGp], middle temporal gyrus—anterior division [MTGa], and the planum temporale [PP]) (Table 2, Figs 2 and 3a). This was in agreement with the source imaging data, which placed the rising phase of activity in the right temporal areas. A marked spread around the rising localization was visible at the peak of activity (Table 2; Fig 2). Statistical analysis of the CBF maps confirmed the qualitative and quantitative results of the ROI analysis, detecting areas with a statistically significant reduction in perfusion (FDR, q<0.05) in the r-ITGp, r-MTGa, and frontotemporal regions (r-PP and right central opercolar cortex [r-CoC]) (Fig 3b).\n\nPatient No. 9\nThe hdEEG yielded repeated spikes over the right anterior temporal derivations. The 2D visualization showed right anterior temporal (zygomatic leads) localization (Fig 1). The CBF maps showed mild hypoperfusion in the right temporal regions (TP, MTGa, and superior temporal gyrus—anterior division [STGa]) and FOrC (Table 2, Figs 2 and 3a). Despite the slight reduction in perfusion visible on the CBF maps and the minor differences with respect to the contralateral regions, areas of statistically significant hyoperfusion were detected by the statistical analysis (FDR, q < 0.05). These mainly involved the r-MTGa, r-STGa, and r-H, with spread to the right frontal areas (frontal pole [FP] and FOrC) (Fig 3b). These results were in agreement with source imaging, which placed the rising phase of activity in the right frontotemporal areas and indicated maximum activity principally in the r-FP, r-FOrC, r-MTGa, and r-STGa. Marked spread around the rising localization was visible at the peak of the spike average, partially involving the contralateral lobe (Table 2, Fig 3).\n\nPatient No. 10\nThe hdEEG revealed repeated spikes over the left temporal derivations. The 2D rendering localized abnormal activity over the left zygomatic leads (Fig 1). Source analysis indicated maximum activity in the left temporal regions, principally localized in the TP, middle temporal gyrus—posterior division (MTGp), STGa, and TFCa. Propagation of activity was well limited to the left temporal regions (Table 2, Fig 2). The CBF maps showed areas of decreased perfusion in comparison to the contralateral side in the same left temporal regions identified by the ESI analysis and a mild decrease in the more anterior areas (Table 2, Figs 2 and 3a). This was confirmed on statistical analysis, which depicted altered hypoperfused voxels in the left temporal regions, with spreading over the frontotemporal lobe (FDR, q < 0.05) (Fig 3b).\n\nPatient No. 11\nThe hdEEG showed rare spike waves over the right temporal derivations. The 2D rendering localized these abnormalities over the right zygomatic temporal leads (Fig 1). Source analysis indicated maximum activity in the right temporal regions, principally localised in TP, ITGa, ITGp, and STGa. Propagation of activity remained well restricted to the rising localization (Table 2, Fig 2). Decrease in CBF was visible in the right temporal regions as compared to the left ones (Table 2, Figs 2 and 3a), which reached statistically significance (FDR, q < 0.05) mainly over the right TP, ITGp, and STGa (Fig 3b).\n\nPatient No. 12\nThe hdEEG showed spike-wave activity and slowing over the left temporal derivations. The 2D rendering localized the epileptiform abnormalities over the left temporal leads (Fig 1). Source analysis indicated maximum activity over the left temporal regions, principally localised in the TP, ITGa, MTGp, and TFCa. Mild propagation of activity was present around the rising localization and more anteriorly (Table 2, Fig 2). The CBF maps showed a slight reduction in perfusion over the left temporal lobe (Table 2, Figs 2 and 3a), which was confirmed by statistical analysis (FDR, q<0.05) showing involvement of all left temporal areas (Fig 3b).\n\nStatistical analysis of the previously studied epileptic group\nStatistical analysis based on the normal perfusion template was also applied to the previously studied group of 6 epileptic patients in order to evaluate agreement with the ROI analysis and the obtained results (Fig 4). In the two patients evaluated in the postictal phase (patients nos. 1 and 5), the areas of hyperperfusion previously depicted by the ROI analysis were confirmed by the statistic, which showed areas of significantly increased perfusion. Significant voxels were mainly located perilesionally in patient no. 1 and mainly distributed over the left STG and more anteriorly in patient no. 5, both findings in agreement with the ROI analysis. In patient no. 2, areas of significantly reduced perfusion were detected over the left TP, ITGa, and H, confirming the visual and quantitative analysis with the ROI approach. Large areas of significant hypoperfusion were identified over the right temporal lobe in two patients (nos. 3 and 4). In particular, in the case of patient no. 4, the statistical analysis allowed better interpretation and identification of the altered areas on the CBF maps. Specifically, visual assessment revealed no areas of evident perfusion alteration and the ROI analysis showed only minor asymmetries between the hemispheres which were difficult to interpret, whereas statistical analysis confirmed the ROI results, clearly identifying the areas of hypoperfusion. Finally, significant areas of hypoperfusion were found mainly over the right frontal lobe in patient no. 6, particularly in the frontomesial area, confirming the visual interpretation of the CBF maps and the ROI analysis.\n\nSurgical Validation\nFive of the 12 patients (patients nos. 2, 4, 6, 7, and 10) underwent surgical resection and 1 patient (patient no. 3) underwent brain thermocoagulation on the basis of the presurgical reported data. Besides patient no. 3, two other patients (patients nos. 6 and 7) underwent exploratory sEEG prior to surgery.\n\nThe surgical outcome in patients nos. 2 and 5 was reported in [29]; at that time, patients nos. 3 and 4 were waiting to be operated on. Patient no. 3 underwent radiofrequency thermocoagulation during a sEEG investigation to sever the right T1, hippocampus, and operculum. The patient is currently seizure free (10 months). In patient no. 4, the postoperative follow-up showed no seizure occurrence (1 year). A resected area encompassed the right T1, amygdala and uncus, with diffuse gliosis at histopathology.\n\nTwo of the 6 new patients also underwent surgical resection. In patient no. 7, the sEEG study, following these noninvasive investigations, confirmed the presence of a right temporal pole focus (T1 and T2) which was surgically removed. The patient has had no more seizures (7 months). The surgical specimen revealed severe temporal neocortical gliosis over T1. Patient no. 10 underwent surgery (left temporal lobe) without further sEEG investigations; no seizure occurrence was reported during the postoperative follow-up (1 year). The histopathological diagnosis was hippocampal sclerosis associated with temporal neocortical gliosis. On the basis of our findings, 4 patients were deemed ineligible for surgery (patients nos. 1, 5, 8 and 9); at present writing, the remaining 2 patients are waiting to be operated on.\n\nThe presurgical information for ESI and ASL overlaid on the postoperative MRI scan of each of the 5 patients is reported in Figs 6 and 7. With regard to the ESI results, there was good agreement between the areas of high activity, as identified by this technique, and the resected brain tissues in the 4 patients with temporal lobe epilepsy, whereas there was a non-complete concordance for the frontal lobe epilepsy patient. Indeed, ESI placed part of the highest activity more inferiorly than the resected portion of the frontal lobe, which was more superior and mesial. Conversely, in this patient ASL provided more concordant results, with hypoperfused voxels located well over the right frontomesial portion and with limited spread to other areas. A good overlap was seen between the hypoperfused regions and the resected tissues in the patients with temporal lobe epilepsy.\n\n10.1371/journal.pone.0123975.g006Fig 6 Postoperative imaging in three patients from the previously described patient group (patients nos. 2, 4 and 6).\nThe presurgical ESI and ASL results are overlaid on the coregistered postoperative MRI scans of each patient. Two different sections are shown for each plane (sagittal, coronal and axial). The rising phase of activity and the statistical results from the one-versus-many analysis are presented for ESI and ASL, respectively.\n\n10.1371/journal.pone.0123975.g007Fig 7 Postoperative imaging in two patients of the new group (patients. nos. 7 and 10).\nThe presurgical ESI and ASL results are overlaid on the coregistered postoperative MRI scans for each patient. Two different sections are shown for each plane (sagittal, coronal and axial). The rising phase of activity and the statistical results from the one-versus-many analysis are presented for ESI and ASL, respectively.\n\nDiscussion\nThe present study reports the results of a comprehensive assessment of the feasibility of ASL in detecting perfusion changes in epilepsy. The patients’ series now includes 12 drug-resistant epileptic patients, with the addition of 6 new patients since the publication of our first report [29]. In all these patients, significant CBF changes were detected which well matched the electrophysiological information, providing further evidence that ASL can be a useful aid in identifying epileptic activity-related CBF changes. The combination of ASL perfusion MRI with an already established method as ESI estimated from the hdEEG data (256 channels) produced a clearer picture of the epileptogenic zone in terms of perfusion and current density. In this series, the ASL and ESI results were concordant and provided complementary information borne out by quantitative assessment of specific parameters (CBF and CD, respectively) in the same anatomical regions. Differently from previous papers which performed only partially quantitative analyses [38, 40–41], this is the first ASL study to quantitatively fully assess CBF via a more complete statistical approach to automatically identify perfusion alterations in individual epileptic patients, along with ROI quantification and comparison with the ESI results. In 5 of the 12 epileptic patients, the presurgical ASL and ESI results were further confirmed by the surgical excision information, with a good overlap between the preoperative information and the resected area.\n\nASL has seldom been employed in the evaluation of epileptic patients, even though a good accuracy in identifying the focus localization has been demonstrated by ASL in combination with other methods as EEG, PET, SPECT or gadolinium-based perfusion MRI in all of these few cases [38–39, 41–42]. Perfusion alterations in epileptic brains are a well-known phenomenon described in both human studies, mainly with SPECT techniques [30–31], and in experimental animal models [65–66], and their assessment could enormously benefit from the application of a non-invasive technique as ASL. In particular, these studies showed that the different CBF levels detected during interictal/ictal/postictal phases hint not only at variations in this parameter but also in the underlying damage to the blood-brain barrier by inflammatory processes in the epileptogenic focus.\n\nWhile the previous study [29] focused mainly on comparing the results from ASL and [18F]FDG-PET, in the present study we further investigated the applicability of ASL in epilepsy by means of an automatic approach to reliably identify areas of epileptiform activity. Previous studies in ASL and epilepsy reported only on qualitative assessment of the CBF maps [41] or calculated the asymmetry index values between the right and the left hemispheres within ROIs manually drawn in specific portions of the brain [38–39, 42]. Here, two complementary approaches are proposed for assessing CBF maps at the patient level. We first adopted a ROI-based approach, already employed in the previous study, in order to quantitatively evaluate possible asymmetries between the two hemispheres and to obtain a preliminary picture of the main areas involved in the epileptic process. This analysis in addition allowed us to quantitatively compare the ESI and ASL results over the same anatomical regions, thus overcoming the limitations inherent to the differences in original spatial resolution and acquisition time. Nevertheless, visual analysis of the CBF maps and/or evaluation of the right-left asymmetries were difficult to interpret in some cases due to slight variations in the hemispheres or global reduction in total perfusion. For these reasons, a complementary analysis was performed, starting from the CBF maps of a control group and then constructing a normal perfusion template that served as reference for evaluating at the voxel level the individual CBF maps of each patient. This allowed us to provide the statistical significance to the previous results and more easily interpret the parametric CBF maps. In all 12 patients, the agreement between the first results from the ROI analysis and the statistical analyses was good, providing a clearer localization of the altered regions and thus of the possible epileptic focus.\n\nThis automatic approach represents a more complete tool for the one-versus-many analysis, where both within-subject and between-subject variability were taken into account in the template creation and the subsequent t-test. Traditionally, the importance of within-subject variance information is underestimated when a single subject is compared to a control group and variance values are not considered in the statistics [44, 67]. In particular, Petr et al. [60] presented a template-based analysis for detecting individual activation patterns in functional ASL data, which they also applied in combination with a z-score in an epileptic patient in order to detect hypoperfused areas associated with dysplasia. However, variance information was not taken into account in the construction of the template, where only the mean CBF maps of each subject were considered (DARTEL algorithm), and no quantitative validations were performed. A recent study by Maumet et al. [51] demonstrated, using a mixed-effect generalized hierarchical linear model, that the within-subject variance cannot be considered negligible by comparison to between-subject variance nor constant across subjects in ASL data. They in particular reported that the patient-specific brain perfusion abnormalities in a series of brain tumor patients could be correctly detected using ASL if the heterogeneous within-subject variances are properly modeled. In our study, we applied a slightly different approach, separating the construction of the normal perfusion template from the statistical analysis. In both steps, the within-subject variance was modeled in agreement with previous studies [50–51]. In the first step, the variance derived for the normal perfusion template included both within-subject and between-subject variability. Moreover, since both the mean and variance matrices for each subject were supplied to FLAME 1, the algorithm weighted the subjects according to their individual variance, so that the overall variance was a better reflection of the population. This group variance was then used, along with the patient variance, in the subsequent unpooled two-sample t-test to obtain a precise localization of perfusion alterations. The template-based approach allowed us to detect areas with a statistically significant decrease in perfusion during the interictal phase (10 out of 12 patients) and a statistically significant perfusion increase in the early postictal phase in the remaining 2 patients. This two-step methodology is flexible and can be easily applied to all types of ASL data, the only requirement is the creation of the own specific CBF template, since this can vary depending on the type of sequence used for the acquisition, its main parameters and the age-range of patients.\n\nIn all cases, localization of statistically significant alterations was concordant with the ESI results from the hdEEG recordings. Indeed, also in this study source imaging was used as a reliable reference to evaluate the localizing ability of ASL. To our knowledge, no previous studies, except our pilot work [29], have attempted to combine ASL-derived CBF maps with source imaging from hdEEG. In detail, ESI describes the propagation of electrical activity from an area of primary activation to other cortical regions. The electrical propagation can be estimated by analyzing the time course of the voltage fields, although only the rising phase and the peak activity were reported here by convention [24]. When the voltage fields change in amplitude but not in shape or location, this suggests a discrete source with no or limited propagation. Differently, changes in shape or amplitude reflect electrical propagation, as seen in patient no. 9 [68]. Importantly, it has to be underlined that our work was not aimed at substituting one technique (ASL) to another (ESI), but to support results soundness by a bidirectional concordance in drug-resistant epileptic patients who are candidate for surgery. In addition, due to the different signal source generators (electrical signal vs CBF) no perfect overlap between ESI and ASL results can be expected, pinpointing a complementarity rather than the interchangeability of the two methods. In particular, ESI is a modeled reconstruction of the cortical area generating the spike signal in a specific instant or time window, while ASL like PET encompasses a broader time frame and provides an average measure of any event that has occurred during acquisition. A multimodal approach can thus allow to obtain more reliable and complementary information to guide the identification of the epileptogenic zone, and not redundant ones, while compensating for the imprecision inherent to each modality.\n\nWhereas the robustness of ESI localization in epilepsy has been widely studied during the years and has been supported by the combination of invasive EEG (stereo-EEG) and postoperative results [17,19,64,69], depicting ESI as a reliable tool to identify the seizure onset zone to be resected, ASL validation and application for this pathology is still matter of research. However, the few available literature show promising results and, despite the limited number of patients, our results could help to further confirm ASL usefulness in epilepsy, especially in critical cases where ESI can have low sensitivity. Indeed, previously published data report on a limited sensitivity of ESI in detecting sources located in deeper gray matter areas—typically mesial temporal spikes, but also sources embedded in intricate circumvolutions and far from the skull, as can be for orbito-mesio-frontal regions. It seems that the major reasons for the limited sensitivity of the EEG to these spikes are the rapid decay of electrical activities with distance and the convoluted anatomy of deep lobe structures that tends to create electric/magnetic fields in close proximity [17]. Therefore, especially in these cases where ESI shows lower sensitivity and in patients with complex epilepsy patterns, additional non-invasive and quantitative information can be derived from ASL for a more precise focus localization.\n\nThe present investigation allowed us to correctly identify the epileptogenic zone in 5 patients (patients nos. 2, 4, 6, 7, and 10), in which the results were confirmed by the surgical resection and seizure freedom (gold standard). In another patient (patient no. 3), the ASL and ESI results were also confirmed by seizure freedom following radiofrequency thermocoagulation during a sEEG investigation performed on the basis of our findings. Information gleaned from postsurgical MRI scans and seizure freedom are essential for determining the localization accuracy of ASL and ESI techniques. In the temporal lobe epilepsy patients, for example, there was a good overlap between the resected areas and the presurgical ESI and ASL results in all cases, demonstrating that both techniques concur in correct focus localization. In some cases, as in patient no. 7, the area of altered perfusion appeared to be much smaller on the ASL image than the actual extent of the lesion, though this apparent discordance might also be attributed to the restrictive FDR correction applied to the statistical results. In the frontal lobe epilepsy patient, a non-complete overlap was detected. Indeed, part of the ESI was located more inferiorly than the resected portion of the frontal lobe, which was more superior and mesial, and contrary to ASL images which provided more concordant results. As reported elsewhere [17, 69–70], such cases pose diagnostic dilemmas probably because of the geometrical and cytoarchitectonic characteristics of the generator. Variations in the seizure generator may explain why it is so difficult to accurately localize the focus in mesial frontal epilepsy and confirm why a multimodal approach to presurgical localization of the focus in different types of epilepsy is important.\n\nCollectively, our results suggest that, differently from source imaging, perfusion alterations generally involve a series of areas. This is in agreement with previous studies with [18F]FDG-PET which generally showed areas of hypometabolism in regions beyond the temporal and frontal lobe in patients with temporal and frontal lobe epilepsy, respectively [14, 71–72]. An intriguing hypothesis could be that areas of altered perfusion extending beyond the limits of the epileptogenic zone could reflect subtler neuronal alterations, and thus delineate the so-called irritative zone, which, as defined by Luders et al. [73], is the area of cortex that generates interictal spikes, as opposed to the epileptogenic zone defined as the “minimal area of cortex that must be resected to produce seizure freedom”. Moreover, ASL as well as PET images of regional perfusion and metabolism can be interpreted as evidence for a dysfunctional epileptic network. This concept emerged in the last decade [74], and from it stems the definition of “system epilepsy”, highlighting that it is not the isolated epileptic focus that generates the full blown seizure, but rather the additive result of subsequent activation of multiple cortical areas that determines seizure semeiology.\n\nIn conclusion, multiple imaging modalities in the same patient allow for a more accurate and precise identification of the epileptogenic zone, providing better surgical outcomes and reduced postoperative deficits. The use of completely noninvasive techniques such as ESI and ASL could reduce the need for more expensive and risky sEEG investigations in candidates for surgery or allow for better targeting of intracranial electrode implantations if deemed necessary. 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J Nucl Med . 1998 ; 39 : 285 –293 .\n9476937 \n32 \nKim S , Mountz JM . SPECT Imaging of Epilepsy: An Overview and Comparison with F-18 FDG PET . Int J Mol Imaging \n2011 ; 2011 : 813028 \n10.1155/2011/813028 \n21785722 \n33 \nCalamante F , Thomas DL , Pell GS , Wiersma J , Turner R . Measuring cerebral blood flow using magnetic resonance imaging techniques . J Cereb Blood Flow Metab \n1999 ; 19 : 701 –735 .\n10413026 \n34 \nAlsop DC , Connelly A , Duncan JS , Hufnagel A , Pierpaoli C , Rugg-Gunn FJ . Diffusion and Perfusion MRI in Epilepsy . Epilepsia \n2002 ; 43 : 69 –77 .\n35 \nDetre JA , Leigh JS , Williams DS , Koretsky AP . Perfusion Imaging . Magn Reson Med . 1992 ; 23 : 37 –45 .\n1734182 \n36 \nWilliams DS , Detre JA , Leigh JS , Koretsky AP . Magnetic resonance imaging of perfusion using spin inversion of arterial water . Proc Natl Acad Sci U S A . 1992 ; 89 : 212 –216 .\n1729691 \n37 \nPetersen ET , Zimine I , Ho YC , Golay X . Non-invasive measurement of perfusion: a critical review of arterial spin labelling techniques . British Journal of Radiology \n2006 ; 79 : 688 –701 .\n16861326 \n38 \nWolf RL , Alsop DC , Levy-Reis I , Meyer PT , Maldjian JA , Gonzalez-Atavales J , et al\nDetection of mesial temporal lobe hypoperfusion in patients with temporal lobe epilepsy by use of Arterial Spin Labeled perfusion MR imaging . AJNR Am J Neuroradiol . 2001 ; 22 : 1334 –1341 .\n11498422 \n39 \nLim YM , Cho YW , Shamim S , Solomon J , Birn R , Luh WM , et al\nUsefulness of pulsed arterial spin labeling MR imaging in mesial temporal lobe epilepsy . Epilepsy Res . 2008 ; 82 : 183 –189 . 10.1016/j.eplepsyres.2008.08.001 \n19041041 \n40 \nHamandi K , Laufs H , Nöth U , Carmichael DW , Duncan JS , Lemieux L . BOLD and perfusion changes during epileptic generalised spike wave activity . Neuroimage \n2008 ; 39 : 608 –618 .\n17920297 \n41 \nPendse N , Wissmeyer M , Altrichter S , Vargas M , Delavelle J , Viallon M , et al\nInterictal arterial spin-labeling MRI perfusion in intractable epilepsy . J Neuroradiol . 2010 ; 37 :60 –63 . 10.1016/j.neurad.2009.05.006 \n19674791 \n42 \nPizzini FB , Farace P , Manganotti P , Zoccatelli G , Bongiovanni LG , Golay X , et al\nCerebral perfusion alterations in epileptic patients during peri-ictal and post-ictal phase: PASL vs DSC-MRI . Magn Reson Imaging \n2013 ; 31 : 1001 –1005 . 10.1016/j.mri.2013.03.023 \n23623332 \n43 \nSignorini M , Paulesu E , Friston K , Perani D , Colleluori A , Lucignani G , et al\nRapid assessment of regional cerebral metabolic abnormalities in single subjects with quantitative and nonquantitative [18F]FDG PET: A clinical validation of statistical parametric mapping . Neuroimage \n1999 ; 9 : 63 –80 .\n9918728 \n44 \nMühlau M , Wohlschläger AM , Gaser C , Valet M , Weindl A , Nunnemann S , et al\nVoxel-based morphometry in individual patients: a pilot study in early Huntington disease . AJNR Am J Neuroradiol . 2009 ; 30 : 539 –543 . 10.3174/ajnr.A1390 \n19074546 \n45 \nMumford JA , Hernandez-Garcia L , Lee GR , Nichols TE . Estimation efficiency and statistical power in arterial spin labeling fMRI . Neuroimage \n2006 ; 33 : 103 –114 .\n16860577 \n46 \nMumford JA , Nichols T . Simple group fMRI modeling and inference . Neuroimage \n2009 ; 47 : 1469 –1475 . 10.1016/j.neuroimage.2009.05.034 \n19463958 \n47 \nLindquist MA , Spicer J , Asllani I , Wager TD . Estimating and testing variance components in a multi-level GLM . Neuroimage \n2012 ; 59 : 490 –501 . 10.1016/j.neuroimage.2011.07.077 \n21835242 \n48 \nFriston KJ , Stephan KE , Lund TE , Morcom A , Kiebel S . Mixed-effects and fMRI studies . Neuroimage \n2005 ; 24 : 244 –252 .\n15588616 \n49 \nChen G , Saad ZS , Nath AR , Beauchamp MS , Cox RW . FMRI group analysis combining effect estimates and their variances . Neuroimage \n2012 ; 60 : 747 –765 . 10.1016/j.neuroimage.2011.12.060 \n22245637 \n50 \nViviani R , Sim EJ , Lo H , Richter S , Haffer S , Osterfeld N , et al\nComponents of variance in brain perfusion and the design of studies of individual differences: the baseline study . Neuroimage \n2009 ; 46 : 12 –22 . 10.1016/j.neuroimage.2009.01.041 \n19457381 \n51 \nMaumet C , Maurel P , Ferré JC , Carsin B , Barillot C . Patient-specific detection of perfusion abnormalities combining within-subject and between-subject variances in Arterial Spin Labeling . Neuroimage \n2013 ; 81 : 121 –30 . 10.1016/j.neuroimage.2013.04.079 \n23668968 \n52 \nKwan P , Brodie MJ . Early identification of refractory epilepsy . N Engl J Med . 2000 ; 342 : 314 –319 .\n10660394 \n53 \nLuh WM , Wong EC , Bandettini PA , Hyde JS . QUIPSS II with thin-slice TI1 periodic saturation: a method for improving accuracy of quantitative perfusion imaging using pulsed arterial spin labeling . Magn Res Med . 1999 ; 41 : 1246 –1254 .\n10371458 \n54 \nSpinelli L , Andino SG , Lantz G , Seeck M , Michel CM . Electromagnetic inverse solutions in anatomically constrained spherical head models . Brain Topogr . 2000 ; 13 : 115 –125 .\n11154101 \n55 \nPascual-Marqui RD , Michel CM , Lehmann D . Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain . Int J Psychophysiol . 1994 ; 18 : 49 –65 .\n7876038 \n56 \nBuxton RB , Frank LR , Wong EC , Siewert B , Warach S , Edelman RR . A general kinetic model for quantitative perfusion imaging with arterial spin labeling . Magn Reson Med \n1998 ; 40 : 383 –396 .\n9727941 \n57 \nAlsop DC , Detre JA , Golay X , Günther M , Hendrikse J , Hernandez-Garcia L , et al\nRecommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia . Magn Reson Med . 2015 ; 73 : 102 –116 .24715426 \n58 \nAslan S , Lu H . On the sensitivity of ASL MRI in detecting regional differences in cerebral blood flow . Magn Reson Imaging \n2010 ; 28 : 928 –935 . 10.1016/j.mri.2010.03.037 \n20423754 \n59 \nColes JP , Fryer TD , Bradley PG , Nortje J , Smielewski P , Rice K , et al\nIntersubject variability and reproducibility of 15O PET studies . J Cereb Blood Flow Metab . 2006 ; 26 : 48 –57 .\n15988475 \n60 \nPetr J , Ferré JC , Raoult H , Bannier E , Gauvrit JY , Barillot C . Template-based approach for detecting motor task activation-related hyperperfusion in pulsed ASL data . Hum Brain Mapp . 2014 ; 35 : 1179 –1789 . 10.1002/hbm.22243 \n23408457 \n61 \nBeckmann CF , Jenkinson M , Smith SM . General multilevel linear modeling for group analysis in FMRI . Neuroimage \n2003 ; 20 : 1052 –1063 .\n14568475 \n62 \nWoolrich MW , Behrens TE , Beckmann CF , Jenkinson M , Smith SM . Multilevel linear modelling for FMRI group analysis using Bayesian inference . Neuroimage \n2004 ; 21 : 1732 –1747 .\n15050594 \n63 \nBenjamini Y , Hochberg Y . Controlling the False Discovery Rate: a Practical and Powerful Approach to Multiple Testing . J. R. Statistic Soc B . 1995 ; 57 : 289 –300 .\n64 \nBrodbeck V , Spinelli L , Lascano AM , Pollo C , Schaller K , Vargas MI , et al\nElectrical source imaging for presurgical focus localization in epilepsy patients with normal MRI . Epilepsia \n2010 ; 51 : 583 –591 . 10.1111/j.1528-1167.2010.02521.x \n20196796 \n65 \nFabene PF , Merigo F ,Galiè M ,Benati D ,Bernardi P ,Farace P , et al\nPilocarpine-induced status epilepticus in rats involves ischemic and excitotoxic mechanisms . PloS One \n2007 ; 2 :e1105 \n17971868 \n66 \nFabene PF , Navarro Mora G , Martinello M , Rossi B , Merigo F , Ottoboni L , et al\nA role for leukocyte-endothelial adhesion mechanisms in epilepsy . Nat Med . 2008 ; 14 : 1377 –1383 . 10.1038/nm.1878 \n19029985 \n67 Corouge I, Esquevin A, Lejeune F, Ferré JC, Bannier E, Merck C, et al. Arterial Spin Labeling at 3T in semantic dementia: perfusion abnormalities detection and comparison with FDG-PET. MICCAI 2012 Workshop on Novel Biomarkers for Alzheimer’s Disease and Related Disorders.\n68 \nEbersole JS . Defining epileptogenic foci: past, present, future . J. Clin. Neurophysiol . 1997 ; 14 : 470 –483 .\n9458053 \n69 \nGavaret M , Badier JM , Marquis P , McGonigal A , Bartolomei F , Regis J , et al\nElectric source imaging in frontal lobe epilepsy . J Clin Neurophysiol . 2006 ; 23 : 358 –370 .\n16885710 \n70 \nUnnwongs K , Wehner T , Foldvary-Schaefer N . Mesial frontal lobe epilepsy . J Clin Neurophysiol . 2012 ; 29 : 371 –378 . 10.1097/WNP.0b013e31826b3c60 \n23027093 \n71 \nRosenow F , Lüders H . Presurgical evaluation of epilepsy . Brain \n2001 ; 124 : 1683 –1700 .\n11522572 \n72 \nWillmann O , Wennberg R , May T , Woermann FG , Pohlmann-Eden B . The contribution of 18F-FDG PET in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy: A meta-analysis . Seizure \n2007 ; 16 : 509 –520 .\n17532231 \n73 \nLüders H , Najm L , Nair D , Widdess-Walsh P , Bingman W . The epileptogenic zone: general principles . Epileptic Disord . 2006 ; 8 : S1 –9 .\n17012067 \n74 \nAvanzini G , Manganotti P , Meletti S , Moshé SL , Panzica F , Wolf P , et al\nThe system epilepsies: a pathophysiological hypothesis . Epilepsia \n2012 ; 53 : 771 –778 . 10.1111/j.1528-1167.2012.03462.x \n22533642\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "10(5)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000328:Adult; D002560:Cerebrovascular Circulation; D000069279:Drug Resistant Epilepsy; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013113:Spin Labels; D014741:Video Recording", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0123975", "pmc": null, "pmid": "25946055", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "22172768;9458053;19457381;10319968;19463958;23668968;16180210;22592963;20423754;20708083;24223569;11154101;15509916;16270685;10413026;14701992;23408457;21835242;11498422;7876038;11133305;9918728;23168681;21326599;23623332;18547769;8800934;17920297;19948231;15282217;1729691;17012067;21785722;19074546;8458998;11522572;15758038;9476937;10660394;20196796;10371458;19674791;19236949;22245637;15988475;24715426;19029985;23792219;19041041;14568475;21109007;17532231;1734182;15588616;23027093;11484687;9727941;16861326;15351361;21975586;16860577;22533642;17971868;17586868;15050594;19408351;15281956;15024956;12697625;24715886;16885710", "title": "Patient-specific detection of cerebral blood flow alterations as assessed by arterial spin labeling in drug-resistant epileptic patients.", "title_normalized": "patient specific detection of cerebral blood flow alterations as assessed by arterial spin labeling in drug resistant epileptic patients" }

[ { "companynumb": "IT-CIPLA LTD.-2015IT04647", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Partial seizures", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ILARIA BOSCOLO GALAZZO, SILVIA FRANCESCA STORTI, ALESSANDRA DEL FELICE, FRANCESCA BENEDETTA PIZZINI, CHIARA ARCARO, EMANUELA FORMAGGIO ET AL. PATIENT-SPECIFIC DETECTION OF CEREBRAL BLOOD FLOW ALTERATIONS AS ASSESSED BY ARTERIAL SPIN LABELING IN DRUG-RESISTANT EPILEPTIC PATIENTS. PLOS ONE. 2015;1-24", "literaturereference_normalized": "patient specific detection of cerebral blood flow alterations as assessed by arterial spin labeling in drug resistant epileptic patients", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150610", "receivedate": "20150610", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11177386, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "IT-CIPLA LTD.-2015IT04648", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depersonalisation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ILARIA BOSCOLO GALAZZO, SILVIA FRANCESCA STORTI, ALESSANDRA DEL FELICE, FRANCESCA BENEDETTA PIZZINI, CHIARA ARCARO, EMANUELA FORMAGGIO ET AL. PATIENT-SPECIFIC DETECTION OF CEREBRAL BLOOD FLOW ALTERATIONS AS ASSESSED BY ARTERIAL SPIN LABELING IN DRUG-RESISTANT EPILEPTIC PATIENTS. PLOS ONE. 2015;1-24", "literaturereference_normalized": "patient specific detection of cerebral blood flow alterations as assessed by arterial spin labeling in drug resistant epileptic patients", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150610", "receivedate": "20150610", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11177385, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "We report a case of acute necrotizing eosinophilic myocarditis (ANEM) secondary to drug rash with eosinophilia and systemic symptoms (DRESS) related to administration of minocycline. Myocarditis is a rare complication of DRESS and can manifest as either a self-limited hypersensitivity myocarditis or as the frequently fatal ANEM. Due to the high morbidity and mortality caused by this disease, emergency physicians should be aware of the potential of ANEM in patients with history of DRESS and new-onset cardiac dysfunction. This case reviews the clinical presentation and management of ANEM and the potential role of extracorporeal membrane oxygenation use in the emergency department.", "affiliations": "University of Rochester Medical Center, Department of Emergency Medicine, Rochester, New York.;University of Rochester Medical Center, Department of Emergency Medicine, Rochester, New York.", "authors": "Loner|Carly A|CA|;Crane|Peter W|PW|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.5811/cpcem.2018.11.40569", "fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 10.5811/cpcem.2018.11.40569cpcem-03-47Case ReportUse of Emergency Department Extracorporeal Membrane Oxygenation for Treatment of Acute Necrotizing Myocarditis Loner Carly A. MDCrane Peter W. MD, MBAUniversity of Rochester Medical Center, Department of Emergency Medicine, Rochester, New YorkAddress for Correspondence: Carly A. Loner, MD, University of Rochester Medical Center, Department of Emergency Medicine, 601 Elmwood Ave, Rochester, NY 14642. Email: carly_loner@urmc.rochester.edu.2 2019 04 1 2019 3 1 47 50 15 8 2018 09 10 2018 07 11 2018 Copyright: © 2019 Loner et al.2019This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/We report a case of acute necrotizing eosinophilic myocarditis (ANEM) secondary to drug rash with eosinophilia and systemic symptoms (DRESS) related to administration of minocycline. Myocarditis is a rare complication of DRESS and can manifest as either a self-limited hypersensitivity myocarditis or as the frequently fatal ANEM. Due to the high morbidity and mortality caused by this disease, emergency physicians should be aware of the potential of ANEM in patients with history of DRESS and new-onset cardiac dysfunction. This case reviews the clinical presentation and management of ANEM and the potential role of extracorporeal membrane oxygenation use in the emergency department.\n==== Body\nINTRODUCTION\nDrug rash with eosinophilia and systemic symptoms (DRESS) is a rare, drug-induced hypersensitivity syndrome most commonly associated with use of aromatic anticonvulsants and sulfonamides, but it can also occur with use of tetracyclines.1 Treatment of DRESS involves discontinuation of the offending drug and initiation of steroid therapy. Complications of DRESS include end organ dysfunction due to eosinophilic infiltration, including hepatic, renal, and cardiac dysfunction.2 The incidence of DRESS is one in 1,000–10,000 exposures with mortality estimated to be 10–20%, mainly caused by myocarditis and hepatic failure.3,4 The presentation of DRESS-associated myocarditis is delayed, presenting weeks to months after discontinuation of the causal drug.5 Most episodes of eosinophilic myocarditis are self-limited and will resolve with supportive therapy. However, some patients may develop a more severe form of myocarditis that involves eosinophilia and eventual necrosis of cardiomyocytes: acute necrotizing eosinophilic myocarditis (ANEM).6 This form of myocarditis can present with onset of rapidly deteriorating systolic dysfunction and hemodynamic instability.5\n\nEmergency physicians should be aware of the potential of ANEM in patients previously diagnosed with DRESS. ANEM has a mortality rate of greater than 50% and a mean survival of three to four days.5 Precipitating factors include viral reactivation (human herpesvirus 6) and lack of detoxifying enzymes, permitting accumulation of toxic drug metabolites.7,8 Age may be a less important factor with ANEM occurring in patients ranging in age from 2–83 years old.9\n\nTimely recognition of the potential diagnosis of ANEM is critical to starting appropriate therapy in these critically ill patients. The most common presenting symptoms are cardiogenic shock, hypotension, and chest pain.10 Few case reports in the emergency medicine literature depict the presentation of ANEM within the emergency department (ED), and even fewer detail the potential role of mechanical assist devices such as extracorporeal membrane oxygenation (ECMO) which are becoming increasingly prevalent within the ED.3,5,11 We present a case of ANEM secondary to DRESS after minocycline use, which required ECMO support due to cardiovascular collapse.\n\nCASE REPORT\nA 21-year-old woman presented to the ED with complaint of chest pain and shortness of breath. Prior to arrival to the ED she had an episode of near syncope. Her previous medical history included development of diffuse erythematous rash following a course of minocycline prescribed for acne three months prior to ED presentation. The minocycline was discontinued, and she was treated with 30 milligrams (mg) daily oral prednisone with improvement of the rash. Initial vitals included blood pressure of 81/68 millimeters of mercury (mmHg), heart rate of 121 beats per minute (bpm), and respiratory rate of 18 breaths per minute. She was afebrile (36.7ºC oral temperature) and had pulse oximetry (SpO2) of 100% on room air. Physical exam was within normal limits. Electrocardiogram (ECG) showed right bundle branch block and normal ST-T segments, but no previous ECG was available.\n\nWhile in the ED the patient had an episode of syncope during peripheral venous catheter placement, and intravenous (IV) fluids were administered due to concern of vasovagal event. She was also administered 5 mg IV dexamethasone due to possibility of adrenal suppression from steroid use. Her systolic pressure improved. However, the patient complained of worsening chest pain and then became unresponsive with pulseless electrical activity arrest (PEA). Cardiopulmonary resuscitation (CPR) and Advanced Cardiac Life Support were initiated. She received two doses of 1 mg IV epinephrine with return of spontaneous circulation (ROSC) in normal sinus rhythm of 70 bpm and blood pressure of 72/48 mmHg. Due to persistent hypotension, norepinephrine infusion was administered with improvement of blood pressure to 88/56 mmHg. She was intubated for airway protection.\n\nDue to concern for massive pulmonary embolus, computed tomography chest angiography was performed but was unremarkable. Point-of-care echocardiogram demonstrated no right heart strain and grossly reduced heart function. Telemetry demonstrated QRS widening and increasing bradycardia to 41 bpm. The patient then developed a second PEA arrest with ROSC after CPR and one dose of 1 mg IV epinephrine. She remained hypotensive with blood pressure of 60/40 mmHg despite norepinephrine infusion. Initial troponin-T measured was 8.56 nanograms/milliliter (ng/mL) (reference range 0.0–0.02 ng/mL) and complete blood count with differential showed leukocytosis of 17.5 × 103 cells/mL (reference range 4.0–10.0 × 103 cells/mL) and eosinophilia of 1.6 × 103 cells/mL r (reference range 0.0–0.4 × 103 cells/mL). The cardiology service was consulted and a formal echocardiogram demonstrated a severely reduced ejection fraction of 15% (normal range 55–70%).\n\nThe dermatology service was also consulted at bedside in the ED; concern for ANEM in setting of DRESS given the rapidity of onset of her cardiac dysfunction was discussed. Also, the differential diagnoses included coronary vasculitis, viral myocarditis, infiltrative cardiomyopathy, and sepsis. (She was administered 4.5 g piperacillin/tazobactam and 20 milligrams/kilogram (mg/kg) vancomycin, and 500 mg azithromycin IV.)\n\nWhile in the ED the patient developed further hypotension with blood pressure of 61/40 mmHg despite multiple vasopressors (IV vasopressin and norepinephrine infusions) and had severe acidemia and hypoxemia despite high ventilator support. Ventilator settings were tidal volume of 360mL, positive end-expiratory pressure of 20 centimeters of water (cmH2O), and fraction of inspired oxygen of 100%, and respiratory rate of 28 breaths per minute. Arterial blood gas (ABG) revealed respiratory acidosis with pH of 7.06, carbon dioxide partial pressure (pCO2) of 78 mmHg (reference range 33–43 mmHg), low arterial oxygen (PaO2) of 61 mmHg (reference range 80–100 mmHg), and normal bicarbonate. Basal metabolic panel was within normal limits. Due to continued decline, she received cannulation for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) within the ED. ECMO cannulation occurred within three hours of initial cardiac arrest. Once placed on ECMO she had significant improvement in her acidosis and hypoxemia on repeat ABG (pH 7.39, pCO2 41 mmHg, PaO2 135 mmHg) and was rapidly weaned from her vasopressors.\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nAcute necrotizing eosinophilic myocarditis (ANEM) is a rare complication of drug rash with eosinophilia and systemic symptoms. Presenting symptoms are cardiogenic shock, hypotension, and chest pain.\n\nWhat makes this presentation of disease reportable?\n\nFew case reports depict the presentation of ANEM in the emergency department (ED). We review the potential role of mechanical assist devices such as extracorporeal membrane oxygenation (ECMO) to manage ANEM.\n\nWhat is the major learning point?\n\nECMO is a potential therapy for cardiogenic shock resulting from ANEM. Early use of ECMO can preserve cardiac function and improve survival in these critically ill patients.\n\nHow might this improve emergency medicine practice?\n\nThis case highlights the presentation and management of ANEM, an emergent cause of cardiovascular compromise, and the use of ECMO in the ED.\n\nThe patient was admitted to the cardiac intensive care unit (ICU) for further management. Due to concern of DRESS-induced myocarditis, dexamethasone with a dose of 1 mg/kg/day was administered intravenously. On hospital day (HD) eight, cardiac biopsy demonstrated diffuse active myocarditis with coagulative myocyte necrosis and mixed infiltrate including eosinophils consistent with DRESS myocarditis. She was decannulated from ECMO on HD 16. She was eventually discharged after 20 days in the ICU and 62 total days in the hospital with a life vest and continued cardiac follow-up. An echocardiogram performed three months later demonstrated improved ejection fraction of 34%.\n\nDISCUSSION\nThis patient had cardiovascular collapse soon after presentation to the ED due to ANEM from minocycline-induced DRESS. This was caused by eosinophilic infiltration of the myocardium and eosinophilic degranulation, which caused necrosis and apoptosis of cardiomyocytes.6 Histology confirmed the diagnosis of ANEM with diffuse eosinophilic myocarditis with lymphocytic infiltrate and liquefactive necrosis.5 Patients may present with chest pain and hemodynamic instability. Additional findings include ST-T segment elevation on ECG, elevated troponin, normal coronary arteries on angiogram, and rapidly deteriorating systolic function.5,11 Cardiac echocardiogram will typically show increased wall thickness, severe biventricular failure and pericardial effusion.5 DRESS-induced myocarditis, especially ANEM, is an emergent diagnosis that can cause refractory cardiovascular shock and may require mechanical cardiac support if less-invasive measures are unsuccessful.\n\nTreatments commonly used in the treatment of DRESS-induced myocarditis include high dose systemic steroids (from 1 mg/kg to 1 gram IV daily), IV immunoglobulin, and mycophenolate mofetil.5 These treatments will limit eosinophilic infiltration into myocyte tissue and prevent degranulation.6 Plasmapheresis and immune suppressive agents such as mycophenolate mofetil, rituximab, and azathioprine can be used in conjunction with systemic steroids.6 These methods of treatment may be more appropriate in the setting of non-necrotizing hypersensitivity myocarditis, which often presents as slow-onset heart failure with improved hemodynamic stability in comparison to ANEM.6 In these cases, fluid restriction, angiotensin-converting enzyme inhibitors, beta blockers and diuretics can be used to prevent further decompensation.6\n\nIn the setting of cardiovascular shock, ECMO is an alternative therapy that can bypass the lungs and heart to support gas exchange and circulatory perfusion.12 There are two classifications of ECMO with different indications for initiation. VA-ECMO is used in cases of treatment-refractory cardiac failure or combined heart and lung failure to maintain systemic perfusion.12 In VA-ECMO, the venously drained blood is oxygenated extracorporeally, bypasses pulmonary circulation, and is returned to the aorta. Indications for VA-ECMO include ventricular dysrhythmias, pulmonary embolism, right and left ventricular failure, sepsis, and cardiac arrest.12,13 In contrast, venovenous ECMO (VV-ECMO) is indicated in severe hypoxemic respiratory distress. Venously drained blood is oxygenated and decarboxylated extracorporeally and returned to the right atrium. Indications for VV-ECMO include acute respiratory distress syndrome and hypercapnic failure.12,13\n\nThe time of initiation to ECMO is dependent on the rapidity of onset of systolic dysfunction, and earlier initiation may be associated with improved outcomes. The CHEER trial (mechanical CPR, hypothermia, ECMO, and early reperfusion) promotes the early use of ECMO in the setting of refractory cardiac arrest and cardiovascular shock. In this study, selected patients presenting with out-of-hospital or in-hospital cardiac arrest were started on ECMO with CPR if they had refractory cardiac arrest for greater than 30 minutes.14 ROSC was achieved in 92% (25/26) of patients, and the difference in median time of collapse to initiation of ECMO between survivors and non-survivors was 40 minutes compared to 78 minutes.14 Another study showed that ECMO use in pediatric patients with hemodynamic compromise from dysrhythmias of acute fulminant myocarditis had shorter times to recovering sinus rhythm (median time: 1.7 days vs. 7.35 days).15 ECMO has an important role in the treatment of refractory cardiovascular shock in patients with fulminant myocarditis.14,16,17 Early use of ECMO can preserve cardiac function and improve survival and morbidity.14,15,17 A multicenter, retrospective chart review would be beneficial to better quantify the benefits of ECMO use in DRESS-induced myocarditis in comparison to other therapies.\n\nCONCLUSION\nEmergency physicians should be aware of the potential of ANEM in patients with new-onset cardiac dysfunction and history concerning for DRESS. ECMO is becoming increasingly prevalent, with studies showing reduced morbidity and mortality with earlier ECMO initiation. In some Level I trauma settings cannulation for ECMO may occur within the resuscitation bay of the ED. It is important for ED providers to be aware of the generalized types of ECMO and their indications. Timely recognition of the potential diagnosis of ANEM is critical to starting appropriate therapy. Early use of ECMO can preserve cardiac function and improve survival in these critically ill patients.\n\nSection Editor: Christopher Sampson, MD\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nDocumented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 Kanno K Sakai H Yamada Y Drug-induced hypersensitivity due to minocycline complicated by severe myocarditis J Dermatol 2014 41 2 160 2 24471460 \n2 Tas S Simonart T Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) Acta Clin Belg 1999 54 4 197 200 10544509 \n3 James J Sammour YM Virata AR Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome secondary to furosemide: case report and review of literature Am J Case Rep 2018 19 163 70 29440628 \n4 Lopez-Rocha E Blancas K Rodriguez-Mireles A Prevalence of DRESS syndrome Rev Alerg Mex 2014 61 1 14 23 24912998 \n5 Bourgeois GP Cafadi JA Groysman SV Fulminant myocarditis as a late sequela of DRESS: two cases J Am Acad Dermatol 2011 65 4 889 90 21920256 \n6 Thongsri L Chularojanamantri L Pichler WJ Cardiac involvement in DRESS syndrome Asian Pac J Allerg Immunol 2017 35 1 3 10 \n7 Descamps V Valance A Edlinger C Association of herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms Arch Deramtol 2001 137 3 301 4 \n8 Parrillo JE Heart Disease and the eosinophil New Engl J Med 1990 323 22 1560 1 2233938 \n9 Kawano S Kato J Kawano Y Clinical features and outcomes of eosinophilic myocarditis patients treated with prednisolone at a single institutional over a 27-year period Intern Med 2011 50 9 975 81 21532219 \n10 Tsyrulnik A Landman A Drug rash with eosinophilia and systemic symptoms: two emergency department cases West J Emerg Med 2011 12 4 559 62 22224160 \n11 Bourgeois GP Cafardi JA Groysman V A review of DRESS-associated myocarditis J Am Acad Dermatol 2012 66 6 229 36 21596455 \n12 Beck L Burg MC Heindel W Extracorporeal membrane oxygenation in adults-variants, complications during therapy, and role of radiological imaging Rofo 2017 189 2 119 27 28033607 \n13 Makdisi G Weng I Extra corporeal membrane oxygenation (ECMO) review of a lifesaving technology J Thorac Dis 2015 7 7 E166 176 26380745 \n14 Stub D Bernard S Pellegrino V Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial) Resuscitation 2015 86 88 94 25281189 \n15 Lin KM Li MH Hsieh KS Impact of extracorporeal membrane oxygenation on acute fulminant myocarditis-related hemodynamic compromise arrythmia in children Pediatr Neonatol 2016 57 6 480 7 27132549 \n16 Lo MH Huang LS Chang HC Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support J Clin Pharm Ther 2013 38 2 172 4 23173909 \n17 Jentzer JC Clements CM Wright RS Improving survival from cardiac arrest; a review of contemporary practice and challenges Ann Emerg Med 2016 68 6 678 9 27318408\n\n", "fulltext_license": "CC BY", "issn_linking": "2474-252X", "issue": "3(1)", "journal": "Clinical practice and cases in emergency medicine", "keywords": null, "medline_ta": "Clin Pract Cases Emerg Med", "mesh_terms": null, "nlm_unique_id": "101718968", "other_id": null, "pages": "47-50", "pmc": null, "pmid": "30775664", "pubdate": "2019-02", "publication_types": "D002363:Case Reports", "references": "10544509;11255328;21532219;21658796;21920256;22224160;2233938;23173909;24471460;24912998;25281189;26380745;27132549;27318408;27996289;28033607;29440628", "title": "Use of Emergency Department Extracorporeal Membrane Oxygenation for Treatment of Acute Necrotizing Myocarditis.", "title_normalized": "use of emergency department extracorporeal membrane oxygenation for treatment of acute necrotizing myocarditis" }

[ { "companynumb": "US-ALVOGEN-2019-ALVOGEN-098726", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "63067", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eosinophilic myocarditis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "LITERATURE REFERENCE: LONER CA, CRANE PW. USE OF EMERGENCY DEPARTMENT EXTRACORPOREAL MEMBRANE?OXYGENATION FOR TREATMENT OF ACUTE NECROTIZING MYOCARDITIS. CLIN PRACT CASES?EMERG MED. 2019 JAN 4?3(1):47-50.", "literaturereference_normalized": "use of emergency department extracorporeal membrane oxygenation for treatment of acute necrotizing myocarditis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190312", "receivedate": "20190312", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16062160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]

{ "abstract": "Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.", "affiliations": "Nephrology and Kidney Transplantation Department, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Clínic, University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Department of Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Medical Intensive Care Unit, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Medical Intensive Care Unit, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Nephrology and Kidney Transplantation Department, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Clínic, University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIPABS), University of Barcelona, Barcelona, Spain.;Nephrology and Kidney Transplantation Department, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Clínic, University of Barcelona, Barcelona, Spain.;Nephrology and Kidney Transplantation Department, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Clínic, University of Barcelona, Barcelona, Spain.;Nephrology and Kidney Transplantation Department, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Clínic, University of Barcelona, Barcelona, Spain.;Josep Carreras Leukaemia Research Institute, Hospital Clinic/University of Barcelona Campus, Barcelona, Spain.;Barcelona Endothelium Team, Barcelona, Spain.;Josep Carreras Leukaemia Research Institute, Hospital Clinic/University of Barcelona Campus, Barcelona, Spain.", "authors": "Blasco|Miquel|M|0000-0003-0789-7992;Martínez-Roca|Alexandra|A|;Rodríguez-Lobato|Luis G|LG|;Garcia-Herrera|Adriana|A|;Rosiñol|Laura|L|0000-0002-2534-9239;Castro|Pedro|P|;Fernández|Sara|S|;Quintana|Luis F|LF|;Cibeira|María T|MT|;Bladé|Joan|J|;Fernández de Larrea|Carlos|C|;Tovar|Natalia|N|;Jimenez|Raquel|R|0000-0003-1333-0343;Poch|Esteban|E|;Guillen|Elena|E|;Campistol|Josep M|JM|;Carreras|Enric|E|0000-0002-3134-9964;Diaz-Ricart|Maribel|M|0000-0003-1122-0052;Palomo|Marta|M|0000-0002-3261-6577", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D015938:Complement Membrane Attack Complex; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C524865:carfilzomib; D003165:Complement System Proteins; C481642:eculizumab", "country": "England", "delete": false, "doi": "10.1111/bjh.16796", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1048", "issue": "193(1)", "journal": "British journal of haematology", "keywords": "C5b-9 deposits; carfilzomib; drug-induced thrombotic microangiopathy; eculizumab; endothelial cells", "medline_ta": "Br J Haematol", "mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D011446:Prospective Studies; D061988:Proteasome Inhibitors; D057049:Thrombotic Microangiopathies; D025801:Ubiquitin", "nlm_unique_id": "0372544", "other_id": null, "pages": "181-187", "pmc": null, "pmid": "32469083", "pubdate": "2021-04", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.", "title_normalized": "complement as the enabler of carfilzomib induced thrombotic microangiopathy" }

[ { "companynumb": "ES-AMGEN-ESPSP2020087415", "fulfillexpeditecriteria": "2", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202714", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "56 MILLIGRAM/SQ. METER", "drugenddate": "201711", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201709", "drugstartdateformat": "610", "drugstructuredosagenumb": "56", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARFILZOMIB" } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201709" } }, "primarysource": { "literaturereference": "MARTINEZ?ROCA A.. COMPLEMENT AS THE ENABLER OF CARFILZOMIB?INDUCED THROMBOTIC MICROANGIOPATHY. BRITISH JOURNAL OF HAEMATOLOGY. 2020?1?7", "literaturereference_normalized": "complement as the enabler of carfilzomib induced thrombotic microangiopathy", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20200710", "receivedate": "20200609", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17877755, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "We present the case of a patient with a first single episode of a dual drug-induced aseptic mening (DIAM) due to amoxicillin and ibuprofen and a short review of updated literature. A 76-year-old man was admitted to our hospital with slowness and confusion following a dental and gingival inflammation treated with oral amoxicillin 500 mg bid and ibuprofen 600 mg tid for 1 week. His mental state and higher functions abruptly worsened after therapy increase leading to hospitalization. Both the drugs were stopped and the patient improved rapidly within 2-3 days and was released asymptomatic after a week. On the basis of this temporal relationship with a comprehensive negative neuroimaging and laboratory testing for viral, bacterial, and mycobacterial micro-organisms, a DIAM by amoxicillin and ibuprofen was diagnosed. We support the hypothesis that this dual therapy was causative because of the progressive onset of central nervous system symptoms starting at a low amoxicillin dose with a high ibuprofen intake and that this sort of chemical meningoencephalitis was mostly due to the pharmacokinetic of amoxicillin after its dose increase. To our knowledge, this is the first documented publication of a severe first episode of DIAM with predominant higher function involvement caused by these two drugs commonly used together, amoxicillin and ibuprofen.", "affiliations": "Department of Neurology, Mauriziano Hospital Umberto I, Torino, Italy.;Department of Emergency, Mauriziano Hospital Umberto I, Torino, Italy.;Department of Emergency, Mauriziano Hospital Umberto I, Torino, Italy.", "authors": "Coletti Moja|Mario|M|https://orcid.org/0000-0002-8452-683X;Riva|Giovanna|G|;Catalfamo|Edoardo|E|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2050313X211021179", "fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211021179\n10.1177_2050313X211021179\nCase Report\nDual drug-induced aseptic meningoencephalitis: More than a suggestion\nhttps://orcid.org/0000-0002-8452-683X\nColetti Moja Mario 1\nRiva Giovanna 2\nCatalfamo Edoardo 2\n1 Department of Neurology, Mauriziano Hospital Umberto I, Torino, Italy\n2 Department of Emergency, Mauriziano Hospital Umberto I, Torino, Italy\nMario Coletti Moja, Department of Neurology, Mauriziano Hospital Umberto I, 10128 Torino, Italy. Email: mcolettimoja@hotmail.com\n3 6 2021\n2021\n9 2050313X21102117911 1 2021\n6 5 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nWe present the case of a patient with a first single episode of a dual drug-induced aseptic mening (DIAM) due to amoxicillin and ibuprofen and a short review of updated literature. A 76-year-old man was admitted to our hospital with slowness and confusion following a dental and gingival inflammation treated with oral amoxicillin 500 mg bid and ibuprofen 600 mg tid for 1 week. His mental state and higher functions abruptly worsened after therapy increase leading to hospitalization. Both the drugs were stopped and the patient improved rapidly within 2–3 days and was released asymptomatic after a week. On the basis of this temporal relationship with a comprehensive negative neuroimaging and laboratory testing for viral, bacterial, and mycobacterial micro-organisms, a DIAM by amoxicillin and ibuprofen was diagnosed. We support the hypothesis that this dual therapy was causative because of the progressive onset of central nervous system symptoms starting at a low amoxicillin dose with a high ibuprofen intake and that this sort of chemical meningoencephalitis was mostly due to the pharmacokinetic of amoxicillin after its dose increase. To our knowledge, this is the first documented publication of a severe first episode of DIAM with predominant higher function involvement caused by these two drugs commonly used together, amoxicillin and ibuprofen.\n\nAmoxicillin\naseptic meningoencephalitis\ndental inflammation therapy\ndentistry\ndrug toxicity\nibuprofen\nneurology\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nDrug-induced aseptic meningitis (DIAM) is a rare cause of adverse reaction to drug therapy. It is a rare idiosyncratic event which may occur after local or systemic drug administration and in which any other causes of meningoencephalitis were ruled out. Moreover, DIAM is a relatively uncommon and probably underestimated diagnosis, and only about 200 cases have been reported in the literature so far. 1 Clinical picture of DIAM can mimic a viral subacute infection and includes meningeal (headache, neck stiffness, Kernig and Brudzinski signs) and brain damage symptoms (slowness, somnolence, seizures) with a marked predominance of the former ones as reported in the literature. Fever, if present, is usually mild and inflammatory indexes as C reactive protein (CRP) are low. Many kinds of drugs are involved in DIAM and their number is continuously increasing. The most commonly involved drugs are nonsteroidal anti-inflammatory drugs (NSAID) as ibuprofen 2 which is a non-selective inhibitor of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). Pharmacokinetic properties of ibuprofen, especially its short plasma half-life of elimination and the lack of development of pathologically related metabolites, are in support for the view that these pharmacokinetic and notably metabolic effects of ibuprofen favour its low toxic potential. Nevertheless, ibuprofen at high doses can exert its toxicity on various cellular processes that are affected by the inhibition of the COX pathway or can act as a hapten with tissue proteins and cause a local inflammatory process. Other frequently reported offending therapies include many antimicrobials, such as co-trimoxazole, trimethoprim-sulfamethoxazole, metronidazole and isoniazid and the antibiotic compounds ciprofloxacin and cephalexin among cephalosporins and amoxicillin among penicillines.3,4 Amoxicillin has been in use since the 1970s; it is the most widely used penicillin both alone and in combination with the beta lactamase inhibitor clavulanic acid, and it is a mid-spectrum, bacteriolytic, β-lactam antibiotic commonly used to treat dental and upper airways infections. 5 It is commonly chosen among β-lactam antibiotics of this class because it is absorbed very well, after oral administration. 5 Finally also allopurinol, ranitidine, carbamazepine, vaccines, monoclonal antibodies against the T3 receptor and, pan T-cell antibodies and even intravenous immunoglobulin and radiographic agents have sometimes been implicated in causing DIAM. 3\n\nCase report\n\nA 76-year-old man with a negative history of any allergies or auto immune pathology started amoxicillin 500 mg bid and ibuprofen at high dose 600 mg tid for an aching dental and gingival infection with no detectable local abscess with fever; after 5–7 days he started feeling dizzy and then was suffering from somnolence, amnesia, ideative and perceptive slowing and was admitted to the hospital emergency room (ER). Blood values were normal at admittance and did not change during the time spent in hospital (creatinine = 1.16 mg/dL, glomerular filtration rate = 71 mL/min, aspartate transaminase = 20 U/L, alanine transaminase = 20 U/L) except C-reactive protein = 6.7 mg/L, white blood cell = 12.07 × 10E3 c/μL with neutrophils 9.36 × 10E3 c/μL. Computed tomographic scan of the brain was normal. Based on an oral inflammation clinical picture, amoxicillin was increased to 1 g tid, clavulanic acid was added and the patient was released. The next day his clinical picture worsened abruptly leading to a severe higher brain functions impairment with apraxia, mental slowing and marked somnolence with profound asthenia and hyporexia. Absent were clear meningitis symptoms (headache, meningism, stiffness) while a subtle myalgia was later reported during hospitalization. The patient was then admitted to ER with blood values similar to the day before and his neurological picture was unremarkable, with no headache or meningism. Also fever, seizures, myoclonus, ataxia and psychosis were absent. Cerebrospinal fluid (CSF) showed mononuclear pleocytosis (96/mm3), a normal glucose level and elevated protein concentration (82 mg/dL). CSF routine cultures and a full viral screening with multiplex polymerase chain reaction (PCR) assay for conventional meningoencephalitis from primary CSF cultures (namely Streptococcus pneumoniae and agalactiae, Neisseria meningitidis, Listeria monocytogenes, Haemophilus influenzae, Escherichia coli, cytomegalovirus, enteroviruses, herpes simplex virus type 1, 2 and 6 and varicella-zoster virus, human parechovirus, Cryptococcus neoformans) was negative. No brucellosis or Lyme disease risk was reported. Electroencephalogram (EEG) showed a marked slowing of the basal rhythm with diffuse theta-delta bursts lasting 3–4 s, predominantly rostrally that gradually disappeared in the following days. A brain Gadolinium magnetic resonance imaging (MRI) was normal too. Patient was then treated symptomatically with ceftriaxone 1 g bid for the dental infection and both amoxicillin and ibuprofen were promptly stopped. His symptoms resolved within 72 h after drugs discontinuation with a normalization of CRP value (1.6 mg/L). Prior and during this episode, he did not take any other drug. In the following weeks, CSF cultures were negative and no causative microorganism was identified and patient was free from toothache. At a 9-month follow-up the patient is asymptomatic.\n\nDiscussion\n\nDiagnosis of DIAM in our patient was based on published criteria: a temporal relationship with drug intake, CSF pleocytosis, negative extensive microbiological tests, rapid complete resolution after drug discontinuation; 6 positive rechallenge was not present in our case because after the amoxicillin dosage increase clinical picture clearly worsened and led to the suspicion of a drug-related encephalitis. Any concomitant abnormalities in renal or liver function were excluded. Detailed anamnesis is always essential to have a DIAM diagnosis, because it is particularly related to any medication used immediately prior to the appearance of symptoms of central nervous system (CNS) impairment and it is crucial establishing a temporal relationship between the administration of the drug, the onset of clinical symptoms and the rapid resolution of the syndrome after drug withdrawal. 7 As described in the literature, no gender predominance is reported in DIAM, mean age of reported cases is 60 years (29–86) with a latency time ranging from 12 h to 4 days from drug intake and a shorter resolution time in younger subjects but usually seen in 3–4 days. All the patients had CSF pleocytosis, 50% of the cases lymphocytes and 50% mononuclear while the 100% had an elevated protein and normal glucose amount. Of course extensive CSF cultures and viral PCR are negative as necessary criteria for diagnosing DIAM. As for our patient, we believe that both amoxicillin and ibuprofen could have caused our patient’s DIAM through a synergic effect of the two drugs because the first CNS symptoms were present with a high ibuprofen and a medium amoxicillin dose even if the marked worsening after the dose increase of amoxicillin makes very probable that the former could be the precipitating factor and most effective drug. Noteworthy in our case is the fact that the predominant clinical deficits were mostly only cortical and they fluctuated in some days from aspecific slowness with somnolence to apathy and ideative apraxia after 10 days at a full amoxicillin dose while meningitis symptoms were always mild and fever absent. Recovery was fully complete after 3–5 days from release and patient blood values prompt long-lasting normalization with CRP value 1.6 mg/L make a false negative CSF culture/PCR very unlikely. Moreover, the patient was on ceftriaxone therapy only a few days after release with no further infection symptoms. Physiopathological mechanisms of DIAM are little known and are partially described. They may be different according to the causing agent and the situation of every single patient. Two types of mechanisms are commonly proposed for DIAM: a direct chemical irritation of the meninges or a delayed hypersensitivity response while an IgE-mediated mechanism has never been reported. 8 We instead suggest that since amoxicillin absorption rate appears to be saturable, this results in a non-linear increase and a later maximal time for higher doses. 9 Increasing the dose results in a larger percentage of free minimal inhibitory concentration (MIC) due to this delayed absorption, despite the non-proportional increase in maximal concentration. However, a higher dose increases the risk of adverse events, and a shorter interval between doses leads to a larger free MIC as well. The dose/frequency balance should be optimal to get the most antimicrobial efficacy and the lowest risk of adverse events. In fact, DIAM CSF pattern could be related to this pharmacodinamic model. Clinicians should be cautious about prescribing ibuprofen or oral amoxicillin regimens at high doses as well as switching from twice to three times a day and this fits with our patient’s clinical course. 10 The absence of evident meningitis symptoms could be due to a minimal or totally absent inflammation of the meninges, as suggested by CSF pattern, with a predominant higher functions imbalance directly related to drugs effect and promptly withdrawing after therapy discontinuance.\n\nConclusion\n\nDIAM is a rare condition and can be a difficult diagnosis, commonly underrated in polytherapies. A detailed anamnesis, particularly focused on drugs used immediately prior to the onset of CNS impairment, is essential for DIAM diagnosis, even when a number of drugs are prescribed. In all previous literature cases of amoxicillin-related DIAM, a documented positive rechallenge since the first episode of aseptic meningitis is reported, ranging from 2 to 7 episodes, because DIAM was not attributed to amoxicillin at first, as exhaustively reviewed in published papers. Conversely, in our patient the amoxicillin dose increase led to a rapid and marked clinical worsening making rechallenge unnecessary for the diagnosis. We believe that this could be a further strong issue in diagnosing DIAM even at the very first episode. We suggest that non-linear absorption pharmacokinetics of amoxicillin should be kept in mind to avoid serious consequences related to dose regimens and leading to harmful clinical breakpoints mostly when other potentially harmful drugs (ibuprofen and NSAID) which are known to cause DIAM are prescribed together. This could be kept in mind by physicians who often prescribe this kind of medications in their daily practice, dentists and otorhinolaryngologists above all, who daily deal with patients’ oral and dental pathologies and inflammatory diseases.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: I have obtained the necessary written patient informed consent to publish patient information.\n\nORCID iD: Mario Coletti Moja https://orcid.org/0000-0002-8452-683X\n==== Refs\nReferences\n\n1 Morís G Garcia-Monco JC. The challenge of drug-induced aseptic meningitis revisited. JAMA Intern Med 2014; 174 (9 ): 1511–1512.25003798\n2 Desgranges F Tebib N Lamy O , et al . Meningitis due to non-steroidal anti-inflammatory drugs: an often-overlooked complication of a widely used medication. BMJ Case Rep 2019; 12 : e231619.\n3 Cascella C Nausheen S Cunha B. A differential diagnosis of drug-induced aseptic meningitis. Infect Med 2008; 25 : 331–334.\n4 Shahien R Vieksler V Bowirrat A. Amoxicillin-induced aseptic meningoencephalitis. Int J Gen Med 2010; 3 : 157–161.20689687\n5 Huttner A Bielicki J Clements MN , et al . Oral amoxicillin and amoxicillin-clavulanic acid: properties, indications and usage. Clin Microbiol Infect 2020; 26 : 871–879.31811919\n6 Meier JE Smith KP Meningitis I-AA . Ibuprofen-associated aseptic meningitis. J Pharm Pract 2006; 19 : 113–123.\n7 Yelehe-Okouma M Czmil-Garon J Pape E , et al . Drug-Induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol 2018; 32 (3 ): 252–260.29364542\n8 Periard D Mayor C Aubert V , et al . Recurrent ibuprofen-induced aseptic meningitis: evidence against an antigen-specific immune response. Neurology 2006; 67 : 539–540.16894131\n9 de Velde F de Winter BC Koch BC , et al . Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints. J Antimicrob Chemother 2016; 71 (10 ): 2909–2917.27330071\n10 Turk VE Šimić I Makar-Aušperger K , et al . Amoxicillin-induced aseptic meningitis: case report and review of published cases. Int J Clin Pharmacol Ther 2016; 54 (9 ): 716–718.27443662\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2050-313X", "issue": "9()", "journal": "SAGE open medical case reports", "keywords": "Amoxicillin; aseptic meningoencephalitis; dental inflammation therapy; dentistry; drug toxicity; ibuprofen; neurology", "medline_ta": "SAGE Open Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101638686", "other_id": null, "pages": "2050313X211021179", "pmc": null, "pmid": "34158945", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "29364542;20689687;27330071;16894131;27443662;25003798;31704799;31811919", "title": "Dual drug-induced aseptic meningoencephalitis: More than a suggestion.", "title_normalized": "dual drug induced aseptic meningoencephalitis more than a suggestion" }

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DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. 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DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. SAGE OPEN MEDICAL CASE REPORTS. 2021?9. 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DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. 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DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. SAGE?OPEN?MED?CASE?REP 2021?9:NO PAGINATION.", "literaturereference_normalized": "dual drug induced aseptic meningoencephalitis more than a suggestion", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210630", "receivedate": "20210630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19475960, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "IT-DRREDDYS-SPO/ITL/21/0136752", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLAVULANIC ACID" }, "drugadditional": "3", "drugadministrationroute": 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E. DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. SAGE OPEN MEDICAL CASE REPORTS. 2021?9. DOI: 10.1177/2050313X211021179.", "literaturereference_normalized": "dual drug induced aseptic meningoencephalitis more than a suggestion", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210702", "receivedate": "20210625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19460391, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "IT-GLAXOSMITHKLINE-ITCH2021GSK040278", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMOXICILLIN" }, "drugadditional": "1", "drugadministrationroute": null, 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"drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXYCILLIN" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Amnesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Illusion", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental impairment", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pleocytosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Apraxia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MOJA MC, RIVA G, CATALFAMO E.. DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. SAGE OPEN MEDICAL CASE REPORTS. 2021?9", "literaturereference_normalized": "dual drug induced aseptic meningoencephalitis more than a suggestion", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210624", "receivedate": "20210624", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19465401, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-303318", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TOOTHACHE", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRUFEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GINGIVITIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GINGIVITIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AUGMENTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AUGMENTIN" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis aseptic", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "COLETTI MOJA M, RIVA G, CATALFAMO E. DUAL DRUG?INDUCED ASEPTIC MENINGOENCEPHALITIS: MORE THAN A SUGGESTION. SAGE OPEN MED CASE REP. 2021?9: 1?3:3 PAGES", "literaturereference_normalized": "dual drug induced aseptic meningoencephalitis more than a suggestion", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210726", "receivedate": "20210707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19500993, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Acute generalised exanthematous pustulosis (AGEP) is a rare, cutaneous reaction characterised by sudden onset of numerous, non-follicular, sterile pustules on oedematous erythematous skin, accompanied by fever and neutrophilia. AGEP is predominantly drug-induced. Skin lesions appear rapidly within 1-3 days of drug exposure and upon drug withdrawal, resolve rapidly within 15 days.\n\n\n\nTo determine the clinical characteristics, culprit drugs and outcome of patients with AGEP.\n\n\n\nA retrospective note review of all AGEP patients seen from 2001-2015.\n\n\n\nAmong 21 AGEP patients, 76% were Malays, 9.5% Chinese, 9.5% Indians, and 5% Iban. Sixteen were females and 5 were males. Median age of patients was 40 years (IQR: 26). The main culprit drug was amoxicillin (10 cases), followed by cloxacillin (three cases), phenytoin (two cases) and one case each of carbamazepine, sulphasalazine, allopurinol, cephalexin, ceftriaxone, celecoxib and herbal product. The median time from drug initiation to onset of AGEP was 3 days (IQR: 5.5). Fever was documented in 52.4 %, mucosal involvement 9.5%, purpura 4.7% and blisters 4.7%. Neutrophilia was observed in 63.6% of patients and eosinophilia in 28.5%. While most patients required admission (67%), all achieved complete recovery within 15 days without any sequela.\n\n\n\nAGEP predominantly affects Malay females in this study. The most common culprit drug was amoxicillin. Our patients exhibited the classic clinical manifestations of AGEP and confirmed the generally benign nature of this reaction upon drug withdrawal. Although the overall prognosis is good, prompt diagnosis of AGEP is important because drug withdrawal is the mainstay therapy.", "affiliations": "Monash University, Jeffrey Cheah School of Medicine and Health Sciences, Malaysia. choonse@yahoo.co.uk.;Monash University, Jeffrey Cheah School of Medicine and Health Sciences, Malaysia.;Monash University, Jeffrey Cheah School of Medicine and Health Sciences, Malaysia.;Monash University, Jeffrey Cheah School of Medicine and Health Sciences, Malaysia.;Monash University, Jeffrey Cheah School of Medicine and Health Sciences, Malaysia.;Hospital Sultanah Aminah, Department of Dermatology, Johor Bahru, Malaysia.", "authors": "Choon|S E|SE|;Der|Y S|YS|;Lai|N L J|NLJ|;Yu|S E E|SEE|;Yap|X L|XL|;Nalini|N M|NM|", "chemical_list": null, "country": "Malaysia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-5283", "issue": "73(4)", "journal": "The Medical journal of Malaysia", "keywords": null, "medline_ta": "Med J Malaysia", "mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000328:Adult; D005260:Female; D006760:Hospitalization; D006801:Humans; D008296:Malaysia; D008297:Male; D012189:Retrospective Studies; D012867:Skin", "nlm_unique_id": "0361547", "other_id": null, "pages": "220-225", "pmc": null, "pmid": "30121684", "pubdate": "2018-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Clinical characteristics, culprit drugs and outcome of patients with Acute Generalised Exanthematous Pustulosis seen in Hospital Sultanah Aminah, Johor Bahru.", "title_normalized": "clinical characteristics culprit drugs and outcome of patients with acute generalised exanthematous pustulosis seen in hospital sultanah aminah johor bahru" }

[ { "companynumb": "MY-ACCORD-071393", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "203154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute generalised exanthematous pustulosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHOON SE, DER YS, LAI NLJ, YU SEE, YAP XL, NALINI NM. CLINICAL CHARACTERISTICS, CULPRIT DRUGS AND OUTCOME OF PATIENTS WITH ACUTE GENERALISED EXANTHEMATOUS PUSTULOSIS SEEN IN HOSPITAL SULTANAH AMINAH, JOHOR BAHRU. MED J MALAYSIA. 2018 AUG", "literaturereference_normalized": "clinical characteristics culprit drugs and outcome of patients with acute generalised exanthematous pustulosis seen in hospital sultanah aminah johor bahru", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20180910", "receivedate": "20180910", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15365232, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "OBJECTIVE\nInfants exposed to antidepressants in utero are at risk of developing poor neonatal adaptation (PNA). This study identified risk factors for PNA.\n\n\nMETHODS\nIn this cohort study, data on mothers and infants admitted to the maternity ward of a general hospital between 2007 and 2012 were analysed. All infants were exposed to an antidepressant during the last trimester of foetal life. The main outcome measure was PNA, defined as at least one Finnegan scores of four or more during admission. Risk factors analysed for their possible association with PNA included type of feeding, type and dosage of antidepressant, prematurity and maternal smoking, anxiety and depression.\n\n\nRESULTS\nWe included 247 infants in the study and 157 (64%) developed PNA. Formula feeding was associated with an increased risk of PNA compared to breastfeeding or mixed feeding (OR 3.16 95% CI 1.40-7.13 p = 0.003). Selective serotonin reuptake inhibitors (SSRIs) were associated with an increased risk of PNA compared to serotonin and noradrenaline reuptake inhibitors (OR 2.52 95% CI 1.07-5.95 p = 0.04). Dosage did not influence the risk of PNA (OR 1.50 95% CI 0.89-2.52 p = 0.13).\n\n\nCONCLUSIONS\nFormula feeding and exposure to SSRIs were associated with development of PNA, but dosage was not.", "affiliations": "Department of Paediatrics, Sint Lucas Andreas Hospital, Amsterdam, The Netherlands.", "authors": "Kieviet|Noera|N|;Hoppenbrouwers|Chris|C|;Dolman|Koert M|KM|;Berkhof|Johannes|J|;Wennink|Hanneke|H|;Honig|Adriaan|A|", "chemical_list": "D000928:Antidepressive Agents", "country": "Norway", "delete": false, "doi": "10.1111/apa.12921", "fulltext": null, "fulltext_license": null, "issn_linking": "0803-5253", "issue": "104(4)", "journal": "Acta paediatrica (Oslo, Norway : 1992)", "keywords": "Antidepressants; Neonatal abstinence; Poor neonatal adaptation; Serotonin reuptake inhibitors", "medline_ta": "Acta Paediatr", "mesh_terms": "D000223:Adaptation, Psychological; D000928:Antidepressive Agents; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors", "nlm_unique_id": "9205968", "other_id": null, "pages": "384-91", "pmc": null, "pmid": "25559357", "pubdate": "2015-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Risk factors for poor neonatal adaptation after exposure to antidepressants in utero.", "title_normalized": "risk factors for poor neonatal adaptation after exposure to antidepressants in utero" }

[ { "companynumb": "NL-ALEMBIC PHARMACUETICALS LIMITED-2015SCAL000146", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "078932", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neonatal behavioural syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIEVIET N, HOPPENBROUWERS C, DOLMAN K.M, BERKHOF J, WENNINK H, HONIG A. RISK FACTORS FOR POOR NEONATAL ADAPTATION AFTER EXPOSURE TO ANTIDEPRESSANTS IN UTERO. ACTA PAEDIATRICA. 2015;104(4):384-391", "literaturereference_normalized": "risk factors for poor neonatal adaptation after exposure to antidepressants in utero", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160422", "receivedate": "20160422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12294854, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "NL-ALEMBIC PHARMACUETICALS LIMITED-2015SCAL000145", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "090223", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neonatal behavioural syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIEVIET N, HOPPENBROUWERS C, DOLMAN K.M, BERKHOF J, WENNINK H, HONIG A. RISK FACTORS FOR POOR NEONATAL ADAPTATION AFTER EXPOSURE TO ANTIDEPRESSANTS IN UTERO. ACTA PAEDIATRICA. 2015;104(4):384-391", "literaturereference_normalized": "risk factors for poor neonatal adaptation after exposure to antidepressants in utero", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160422", "receivedate": "20160422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12294693, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "OBJECTIVE\nThis is the first study in which bortezomib and dexamethasone were administered on an alternating basis as up-front therapy in multiple myeloma (MM). We investigated the efficacy and kinetics of response to each drug and safety.\n\n\nMETHODS\nPatients with newly diagnosed MM who were less than 66 years old were treated with bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 to 12, and 17 to 20 (cycles 2, 4, and 6), followed by autologous stem-cell transplantation (ASCT). Responses were evaluated by modified European Bone Marrow Transplantation criteria. Random effects models were used to analyze the tumor response kinetics.\n\n\nRESULTS\nForty patients were enrolled. Partial response (PR) or greater was 65% (12.5% complete response [CR], 10% very good PR [VGPR], and 42.5% PR) plus 17.5% minor response. Time to response was rapid, with 82% serum M-protein reduction achieved within the first two cycles. The M-protein decrease was similar with dexamethasone and with bortezomib (P = .48). Chromosome 13 deletion, t(4;14), and t(14;16) did not have a negative impact on response. Toxicity was low, with no grade 3 to 4 peripheral neuropathy and no grade 2 to 4 thrombocytopenia. The response rate after ASCT was 88%, with 33% CR (negative immunofixation) plus 22% VGPR.\n\n\nCONCLUSIONS\nBortezomib alternating with dexamethasone is a highly effective induction regimen with low toxicity. The kinetic study has shown a high degree of heterogeneity in response and rapid effect from both agents, supporting the use of a short induction regimen before ASCT in MM.", "affiliations": "Hospital Clinic Barcelona, Barcelona, Spain.", "authors": "Rosiñol|Laura|L|;Oriol|Albert|A|;Mateos|Maria Victoria|MV|;Sureda|Anna|A|;García-Sánchez|Pedro|P|;Gutiérrez|Norma|N|;Alegre|Adrián|A|;Lahuerta|Juan José|JJ|;de la Rubia|Javier|J|;Herrero|Carlos|C|;Liu|Xiangyang|X|;Van de Velde|Helgi|H|;San Miguel|Jesús|J|;Bladé|Joan|J|", "chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone", "country": "United States", "delete": false, "doi": "10.1200/JCO.2007.12.3323", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "25(28)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012074:Remission Induction; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous", "nlm_unique_id": "8309333", "other_id": null, "pages": "4452-8", "pmc": null, "pmid": "17785704", "pubdate": "2007-10-01", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics.", "title_normalized": "phase ii pethema trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem cell transplantation in younger patients with multiple myeloma efficacy and clinical implications of tumor response kinetics" }

[ { "companynumb": "ES-TAKEDA-2017MPI007207", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "021602", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "021602", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROSINOL L, ORIOL A, MATEOS MV, SUREDA A, GARCIA-SANCHEZ P, GUTIERREZ N, ET AL.. PHASE II PETHEMA TRIAL OF ALTERNATING BORTEZOMIB AND DEXAMETHASONE AS INDUCTION REGIMEN BEFORE AUTOLOGOUS STEM-CELL TRANSPLANTATION IN YOUNGER PATIENTS WITH MULTIPLE MYELOMA: EFFICACY AND CLINICAL IMPLICATIONS OF TUMOR RESPONSE KINETICS.. JOURNAL OF CLINICAL ONCOLOGY.. 2007;25(28):4452-58", "literaturereference_normalized": "phase ii pethema trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem cell transplantation in younger patients with multiple myeloma efficacy and clinical implications of tumor response kinetics", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170905", "receivedate": "20170824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13903787, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "BACKGROUND\nCystinosis is a rare metabolic genetic disorder caused by a mutation in cystinosin lysosomal cystine transporter (CTNS). The diagnosis of nephropathic cystinosis (NC) is made by observing corneal cystine crystals and/or measuring the cystine content of leukocytes. CTNS mutation analysis confirms the diagnosis of cystinosis, but leukocyte cystine measurement and CTNS analysis have not been widely available, and cystine crystals in the cornea may not be apparent in the first months of life. Cystine crystal deposition can be seen in the bone marrow earlier than corneal deposition, in patients with NC.\n\n\nMETHODS\nTen patients with cystinosis diagnosis were enrolled in the study. Medical records were reviewed retrospectively to collect demographic and clinical data such as age at diagnosis, disease presentation, parental consanguinity, family history, corneal cystine deposition, leukocyte cystine level, bone marrow cystine deposition, presence of renal failure, follow-up time and prognosis.\n\n\nRESULTS\nCystine crystals were seen in all of the patients' fresh bone marrow aspiration samples. Eight patients had corneal cystine deposition. Leukocyte cystine measurement could have been performed in four patients who had come from another center. Complications such as pulmonary hypertension and idiopathic intracranial hypertension (IIH) were observed in two patients.\n\n\nCONCLUSIONS\nBone marrow aspiration might be an easy and short-cut diagnostic tool for NC especially when it is not possible to measure fibroblast cystine content. Additionally some rare complications such as pulmonary hypertension and IIH can be encountered during the course of NC.", "affiliations": "Department of Pediatric Nephrology, Mersin University Faculty of Medicine, Mersin, Turkey.;Department of Pediatric Nephrology, Mersin University Faculty of Medicine, Mersin, Turkey.;Department of Pediatrics, Mersin University Faculty of Medicine, Mersin, Turkey.;Department of Pediatric Hematology, Mersin University Faculty of Medicine, Mersin, Turkey.", "authors": "Sürmeli Döven|Serra|S|http://orcid.org/0000-0001-9109-859X;Delibaş|Ali|A|;Kayacan|Uğur Raşit|UR|;Ünal|Selma|S|", "chemical_list": "D003553:Cystine", "country": "Australia", "delete": false, "doi": "10.1111/ped.13416", "fulltext": null, "fulltext_license": null, "issn_linking": "1328-8067", "issue": "59(11)", "journal": "Pediatrics international : official journal of the Japan Pediatric Society", "keywords": "bone marrow aspiration; childhood; cystinosis; idiopathic intracranial hypertension; pulmonary hypertension", "medline_ta": "Pediatr Int", "mesh_terms": "D001853:Bone Marrow; D002648:Child; D002675:Child, Preschool; D003553:Cystine; D003554:Cystinosis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies", "nlm_unique_id": "100886002", "other_id": null, "pages": "1178-1182", "pmc": null, "pmid": "28871612", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Short-cut diagnostic tool in cystinosis: Bone marrow aspiration.", "title_normalized": "short cut diagnostic tool in cystinosis bone marrow aspiration" }

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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM CITRATE." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DOVEN SS, DELIBAS A, KAYACAN UR, UNAL S. SHORT-CUT DIAGNOSTIC TOOL IN CYSTINOSIS: BONE MARROW ASPIRATION. 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CITRATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM BICARBONATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM HYDROGEN CARBONATE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DOVEN SS, DELIBAS A, KAYACAN UR, UNAL S.. SHORT-CUT DIAGNOSTIC TOOL IN CYSTINOSIS: BONE MARROW ASPIRATION. PEDIATR INT.. 2017?59:1178-82", "literaturereference_normalized": "short cut diagnostic tool in cystinosis bone marrow aspiration", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20180320", "receivedate": "20180320", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14659912, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "TR-MYLANLABS-2018M1016880", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM HYDROGEN BICARBONATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTAMINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INDOMETHACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDOMETHACIN 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"drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCITRIOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYSTEAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYSTINOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTAMINE" } ], "patientagegroup": null, "patientonsetage": "96", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatosplenomegaly", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rales", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac murmur", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary hypertension", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SURMELI DS, RASIT U, KAYACAN, UNAL S.. SHORT-CUT DIAGNOSTIC TOOL IN CYSTINOSIS:BONE MARROW ASPIRATION.. PEDIATR INT.. 2017?59:1178-1182", "literaturereference_normalized": "short cut diagnostic tool in cystinosis bone marrow aspiration", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20180320", "receivedate": "20180320", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14660870, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Anaphylactic reaction to corticosteroids is an uncommon occurrence. Described is such a reaction resulting in cardiopulmonary collapse in a 66-year-old asthmatic treated with intravenous methylprednisolone. Awareness of this entity will allow for prompt and successful therapy.", "affiliations": null, "authors": "McNamara|R M|RM|", "chemical_list": "D008776:Methylprednisolone Hemisuccinate; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.1016/0736-4679(86)90044-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-4679", "issue": "4(3)", "journal": "The Journal of emergency medicine", "keywords": null, "medline_ta": "J Emerg Med", "mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D001249:Asthma; D004342:Drug Hypersensitivity; D004630:Emergencies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008775:Methylprednisolone; D008776:Methylprednisolone Hemisuccinate", "nlm_unique_id": "8412174", "other_id": null, "pages": "213-5", "pmc": null, "pmid": "3543111", "pubdate": "1986", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Anaphylaxis after intravenous corticosteroid administration.", "title_normalized": "anaphylaxis after intravenous corticosteroid administration" }

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{ "abstract": "BACKGROUND\nThis phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.\n\n\nMETHODS\nIn all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.\n\n\nRESULTS\nTwo patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade ≥3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.\n\n\nCONCLUSIONS\nAxitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug-drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.", "affiliations": "Section of Oncology/Hematology, Ingalls Hospital, Harvey, IL, USA. mfkozloff@aol.com", "authors": "Kozloff|M F|MF|;Martin|L P|LP|;Krzakowski|M|M|;Samuel|T A|TA|;Rado|T A|TA|;Arriola|E|E|;De Castro Carpeño|J|J|;Herbst|R S|RS|;Tarazi|J|J|;Kim|S|S|;Rosbrook|B|B|;Tortorici|M|M|;Olszanski|A J|AJ|;Cohen|R B|RB|", "chemical_list": "D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D016190:Carboplatin; D000077784:Axitinib; D017239:Paclitaxel; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1038/bjc.2012.406", "fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\nbjc2012406\n10.1038/bjc.2012.406\n22990652\nClinical Study\nPhase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours\nAxitinib plus platinum doublets for solid tumours\nKozloff M F 12*\nMartin L P 3\nKrzakowski M 4\nSamuel T A 5\nRado T A 6\nArriola E 7\nDe Castro Carpeño J 8\nHerbst R S 9\nTarazi J 10\nKim S 10\nRosbrook B 10\nTortorici M 10\nOlszanski A J 1011\nCohen R B 3\n1 Section of Oncology/Hematology, Ingalls Hospital, Harvey, IL, USA\n2 Department of Medicine, University of Chicago, Chicago, IL, USA\n3 Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA\n4 The Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland\n5 Department of Medical Oncology, Georgia Health Sciences University Cancer Center, Augusta, GA, USA\n6 Clinical Research Department, Columbia Basin Hematology and Oncology, Kennewick, WA, USA\n7 Medical Oncology Department, Hospital del Mar, Barcelona, Spain\n8 University Hospital La Paz, Madrid, Spain\n9 Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA\n10 Pfizer Oncology, San Diego, CA, USA\n* E-mail: mfkozloff@aol.com\n11 Current address: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA\n\n09 10 2012\n18 09 2012\n107 8 12771285\n24 02 2012\n30 07 2012\n15 08 2012\nCopyright © 2012 Cancer Research UK\n2012\nCancer Research UK\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/\nBackground:\n\nThis phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.\n\nMethods:\n\nIn all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.\n\nResults:\n\nTwo patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade⩾3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.\n\nConclusion:\n\nAxitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.\n\naxitinib\nchemotherapy\npharmacokinetics\nsolid tumours\nnon-small cell lung cancer\n==== Body\npmcNew therapeutic strategies are needed to improve the efficacy of chemotherapy regimens for advanced solid tumours. For patients with advanced non-small cell lung cancer (NSCLC), platinum-based doublets remain a standard of care (Stinchcombe and Socinski, 2009). However, these treatments result in only modest improvements in survival (Burris, 2009). Addition of targeted agents, which act on specific signalling pathways involved in tumour progression, to chemotherapy regimens may improve clinical outcomes.\n\nThe vascular endothelial growth factor (VEGF) pathway has a key role in tumour-related angiogenesis, and its deregulation is characteristic of many solid tumours (Brown et al, 1993; Ikeda et al, 1999; Berns et al, 2003; Saad et al, 2004; Keedy and Sandler, 2007). Novel agents have been developed to target the VEGF ligand or its receptor. In several phase III studies, inhibition of VEGF signalling by the anti-VEGF antibody bevacizumab in combination with chemotherapy improved patient outcomes compared with chemotherapy alone (Hurwitz et al, 2004; Sandler et al, 2006; Miller et al, 2007; Reck et al, 2010). In patients with advanced non-squamous NSCLC, bevacizumab prolonged overall survival (OS) when combined with paclitaxel and carboplatin compared with chemotherapy alone (median OS, 12.3 vs 10.3 months) (Sandler et al, 2006), and prolonged progression-free survival, but not OS, when combined with gemcitabine and cisplatin (Reck et al, 2010). Investigation of antiangiogenic agents with different mechanisms of action, such as tyrosine kinase inhibition, in combination with chemotherapy is warranted. Results from a phase III study showed that adding sorafenib, an inhibitor of multiple tyrosine kinases, to carboplatin/paclitaxel did not prolong OS compared with chemotherapy alone in patients with NSCLC (Scagliotti et al, 2010). Nevertheless, other tyrosine kinase inhibitors that selectively inhibit VEGF receptors may still offer clinical benefit when added to chemotherapy.\n\nAxitinib is an oral, potent and selective second-generation tyrosine kinase inhibitor of VEGF receptors 1, 2 and 3 (Hu-Lowe et al, 2008). When combined with docetaxel, carboplatin or gemcitabine in human tumour models, axitinib enhanced the antitumour efficacy of these agents (Hu-Lowe et al, 2008). In phase II studies of several tumour types, axitinib showed single-agent activity and was well tolerated (Rixe et al, 2007; Cohen et al, 2008; Rini et al, 2009; Schiller et al, 2009). In a phase II study of patients with advanced NSCLC receiving single-agent axitinib, median OS was 14.8 months (Schiller et al, 2009), which compares favourably with chemotherapy (Burris, 2009). These data suggest axitinib may enhance the efficacy of standard chemotherapy regimens for the treatment of selected solid tumours, including NSCLC.\n\nHere, we report safety, efficacy and pharmacokinetic findings from a phase I study of combination treatment with axitinib plus paclitaxel/carboplatin or gemcitabine/cisplatin in patients with advanced solid tumours, including squamous cell NSCLC.\n\nPatients and methods\n\nStudy design and end points\n\nThis was a phase I, open-label, multicentre, dose-finding study consisting of nine treatment cohorts, plus an expansion cohort of patients with squamous cell NSCLC who were enroled after determination of the maximum tolerated dose (MTD) of axitinib plus paclitaxel/carboplatin. Here, we report findings from cohorts that received axitinib in combination with either paclitaxel/carboplatin (cohorts 1, 2 and 3 plus expansion) or gemcitabine/cisplatin. Findings from other treatment cohorts are presented in an accompanying article (Martin et al, 2012). Primary end point was MTD of axitinib combined with either paclitaxel/carboplatin or gemcitabine/cisplatin. Secondary end points included safety, tumour response rates and plasma pharmacokinetic profiles.\n\nThis study was performed in accordance with the study protocol approved at each participating centre, International Conference on Harmonisation Guidelines on Good Clinical Practice and applicable local regulatory requirements and laws. All patients provided written informed consent. This trial is registered on ClinicalTrials.gov (NCT00454649).\n\nPatients\n\nPatients aged ⩾18 years with any histologically or cytologically proven advanced solid malignancy suitable for treatment with paclitaxel/carboplatin or gemcitabine/cisplatin were eligible. Inclusion criteria for all cohorts included an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; no pre-existing uncontrolled hypertension (antihypertensive medications were permitted); adequate organ function; and no prior chemotherapy with platinum salts or taxanes for metastatic disease except as noted below; adjuvant treatment with platinum salts or taxanes must have been completed ⩾12 months before enrolment. For patients receiving gemcitabine/cisplatin, any type of previous chemotherapy was allowed and, for patients in the expansion cohort, any type of previous treatment was allowed. Patients with NSCLC with squamous cell histology, or mixed histology that was predominantly squamous, were eligible for the expansion cohort, which received axitinib plus paclitaxel/carboplatin.\n\nExclusion criteria included myocardial infarction, congestive heart failure, cerebrovascular accident (including transient ischaemic attack) or pulmonary embolus <12 months before enrolment; haemoptysis (>0.5 teaspoon blood per day) within 1 week of enrolment; and at least one lung lesion with cavitation or any lesion invading and/or supporting large blood vessels.\n\nStudy treatments\n\nTreatment schedules are shown in Figure 1. All patients received axitinib twice daily (b.i.d.) with food. In vitro studies indicate axitinib noncompetitively inhibits the cytochrome P450 (CYP) 2C8 enzyme (unpublished data) involved in paclitaxel metabolism (Monsarrat et al, 1993; Steed and Sawyer, 2007). Owing to potential for drug–drug interactions between axitinib and paclitaxel, the axitinib lead-in dose was administered at 1, 3 and 5 mg b.i.d. for sequential cohorts 1, 2 and 3, respectively, started 3–5 days before the first dose of chemotherapy and continued for 2 days after the first chemotherapy dose. Cohorts 1, 2 and 3 were to enrol three to six patients, depending on the number of patients that experienced a dose-limiting toxicity (DLT) during the first cycle (Table 1). If none of the first three patients experienced a DLT during the first cycle, the lead-in dose of axitinib was escalated in the subsequent cohort. If one of the three patients experienced a DLT during the first cycle, the cohort was expanded to include a total of six patients, and if one of six patients experienced a DLT during the first cycle, the lead-in dose of axitinib was escalated in the next cohort. The lead-in dose of axitinib for the gemcitabine/cisplatin cohort was 5 mg b.i.d. After the lead-in period, axitinib 5 mg b.i.d. was administered continuously in all cohorts. Axitinib was interrupted 3 days before cycle 2 day 1 of chemotherapy administration and dosing was resumed on cycle 2 day 3; for cohorts 1 and 2, starting with cycle 2, axitinib was interrupted 1 day before chemotherapy infusion (day 21) and resumed on day 3 of each subsequent cycle. For the expansion cohort, axitinib was administered at the MTD defined in cohorts 1–3, beginning cycle 1 day 1. All patients continued treatment with axitinib until disease progression or unacceptable toxicity. After cycle 1, patients with no grade >2 adverse events (AEs) related to axitinib for consecutive 2-week periods could have their axitinib dose titrated to 7 mg b.i.d. and then to a maximum of 10 mg b.i.d., unless BP measured >150/100 mm Hg or the patient was receiving antihypertensive medication. The axitinib dose was reduced to 3 mg b.i.d., and then to 2 mg b.i.d. in patients with grade ⩾3 nonhaematologic treatment-related AEs. For patients who developed systolic BP >150 mm Hg or diastolic BP >100 mm Hg, new or additional antihypertensive therapy was started or the dose of existing medication increased. If patients developed haemoptysis (>0.5 teaspoon of bright red blood per day), axitinib was discontinued and a radiologic assessment was to be considered. For patients in the squamous cell NSCLC expansion cohort who developed cavitation after enrolment, axitinib was withheld and patients were assessed on a case-by-case basis. Patients who permanently discontinued axitinib because of toxicity could continue to receive chemotherapy as long as treatment was considered clinically beneficial.\n\nPatients in cohorts 1–3 and the expansion cohort received paclitaxel (200 mg m–2; 3-h infusion) followed by carboplatin (area under the plasma concentration–time curve (AUC) target of 6 mg min ml−1; 30-min infusion) every 3 weeks. Patients in the gemcitabine/cisplatin cohort received cisplatin (80 mg m−2 on day 1) and gemcitabine (1250 mg m−2 on days 1 and 8; 30-min infusion), followed by a 1-week rest period, in 3-week cycles. Chemotherapy regimens were modified on an individual basis according to patient tolerability at the discretion of the investigator. Paclitaxel/carboplatin was delayed in patients with absolute granulocyte counts <1500 cells mm−3or platelet counts <100 000 cells mm−3 and discontinued if recovery did not occur after 4 weeks. Paclitaxel/carboplatin was withheld in patients with grade ⩾3 haematologic or nonhaematologic toxicities and resumed at one lower dose level when the toxicity was grade ⩽1. Paclitaxel was reduced in patients with grade 2 neurotoxicity or withheld until neurotoxicity was grade ⩽1. The gemcitabine/cisplatin dose was reduced to 75% in patients with febrile neutropenia, grade 4 neutropenia for ⩾7 days, grade 4 thrombocytopenia, bleeding grade>2 with grade 3 thrombocytopenia or grade 3 nonhaematologic toxicities during the prior cycle. The gemcitabine/cisplatin dose was reduced to 50% or delayed in patients with grade 4 nonhaematologic toxicities during the prior cycle. Gemcitabine/cisplatin was delayed by 1 week if the absolute neutrophil count was <1.0 × 109 l−1 and/or the platelet count was <100 × 109 l−1. If on day 8, the absolute neutrophil count was <1.0 × 109 l−1 and/or the platelet count was <100 × 109 l−1, gemcitabine was not administered. Cisplatin was discontinued in patients with grade ⩾2 peripheral neurotoxicity, tinnitus or hearing loss during the prior cycle. Prophylactic use of colony-stimulating factors was permitted in patients who experienced infection or grade 4 neutropenia during the previous cycle. Patients who discontinued chemotherapy because of toxicity or because they completed the maximum number of cycles according to institutional practice could continue to receive axitinib as a single agent.\n\nAssessments\n\nThe MTD for axitinib plus paclitaxel/carboplatin or gemcitabine/cisplatin was defined as the dose level at which no more than one of the first six patients enroled in each cohort experienced a DLT during the first cycle of therapy, with two or more of the six patients experiencing a DLT at the next highest dose level. If the MTD was not exceeded within the planned dose levels, MTD was defined as the maximum dose tested. Dose-limiting toxicities were defined as grade 4 neutropenia or thrombocytopenia for ⩾14 days, or grade 4 febrile neutropenia; proteinuria ⩾2 g/24 h; haemoptysis (⩾ 0.5 teaspoon per day) for ⩾7 days; uncontrolled grade ⩾3 nonhaematologic toxicity for ⩾7 days; or inability to resume study treatment within 14 days after stopping because of axitinib-related toxicity.\n\nSafety was monitored throughout the study, and AE severity was graded according to the Common Terminology Criteria for Adverse Events, version 3.0 (Trotti et al, 2003). Physical examinations, assessment of ECOG PS, chest X-rays and laboratory tests were conducted at baseline, day 1 of each cycle and at follow-up (28 days after the last dose). Additional physical examinations and haematology tests were performed at days 8 and 15 of each cycle. For the squamous cell NSCLC expansion cohort, chest X-rays were performed to assess tumour cavitation on even-numbered cycles when other tumour assessments were not performed. BP was monitored at each clinic visit, and patients were issued a home BP monitoring device and diary and asked to record their BP at least twice daily before each axitinib dose. Patients were instructed to contact their physicians for systolic BP>150 mm Hg or diastolic BP>100 mm Hg. Home BP measurements were not used for DLT assessments. Tumours were radiologically assessed every two cycles, according to Response Evaluation Criteria in Solid Tumours (RECIST version 1.0) (Therasse et al, 2000).\n\nPharmacokinetic analysis\n\nThe pharmacokinetics of steady-state axitinib alone and chemotherapy alone, as well as the combination of steady-state axitinib plus chemotherapy, were evaluated in each patient in all cohorts except the expansion cohort. Pharmacokinetics of steady-state axitinib when administered alone were determined using blood samples collected pre-dose and 1, 2, 3, 4, 6 and 8 h after dosing on cycle 1 day –1. Pharmacokinetics of chemotherapy when administered alone were determined using blood samples collected on cycle 2 day 1. Pharmacokinetics of the combination of steady-state axitinib and chemotherapy were determined using blood samples collected on cycle 1 day 1. Samples for paclitaxel/carboplatin analysis were collected pre-dose and 1, 2, 3, 3.25, 3.5, 4, 5, 6, 8, 24 and 30 h after the start of paclitaxel infusion. Samples for gemcitabine analysis were collected pre-dose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3 and 4 h after the start of infusion in tubes containing tetrahydrouridine, which prevented continued metabolism of gemcitabine during the processing of samples. Samples for cisplatin analysis were collected pre-dose and 0.5, 1, 1.5, 2.5, 3.5, 5.5 and 7.5 h after the start of infusion.\n\nPlasma concentrations of axitinib were measured using a validated high-performance liquid chromatography with tandem mass spectrometric detection method (LC/MS/MS) (Charles River Discovery and Development Services; Shrewsbury, MA, USA) (Rugo et al, 2005). Concentrations of paclitaxel, gemcitabine and the gemcitabine metabolite 2′,2′-difluorodeoxyuridine (dFdU) in sodium heparin plasma were measured using a validated LC/MS/MS assay (Covance Bioanalytical Services; Indianapolis, IN, USA) with ranges of 10–2000 ng ml–1, 50–50 000 ng ml–1 and 500–50 000 ng ml–1 for paclitaxel, gemcitabine and dFdU, respectively. Concentrations of platinum from carboplatin and cisplatin in sodium heparin plasma and plasma ultrafiltrate (PUF) were measured using a validated inductively coupled plasma-MS assay (Covance Laboratories; Madison, WI, USA) with ranges of 2.0–1000 ng ml–1and 1.0–500 ng ml–1 in plasma and PUF, respectively. All pharmacokinetic analyses were conducted using WinNonlin Professional (version 4.01, Pharsight Corp.; Mountain View, CA, USA).\n\nStatistical analysis\n\nAll patients receiving at least one dose of study medication were included in the safety analysis. Patients having one or more target lesion according to RECIST and a baseline assessment of disease and who received at least one dose of study medication were included in the analysis of best objective response. Data were summarised using means, medians, s.d. and ranges for continuous data and frequencies and percentages for categorical data.\n\nResults\n\nPatient demographics and disposition\n\nIn all, 49 patients were enroled, including 28 patients in the paclitaxel/carboplatin cohorts and 21 patients in the gemcitabine/cisplatin cohort (Table 2). The most common tumour type was NSCLC in 17 patients (34.7%), all of whom were in the paclitaxel/carboplatin cohorts.\n\nStudy treatment duration for individual patients is shown in Figure 2. Patients received axitinib for a median of 174 days (range 10–656) and 89 days (range 5–992) in the paclitaxel/carboplatin and gemcitabine/cisplatin cohorts, respectively. The median daily axitinib dose was 9.8 mg (range 4.7–15.1) in patients receiving paclitaxel/carboplatin and 9.0 mg (range 6.0–10.0) in patients receiving gemcitabine/cisplatin. Dosing of axitinib was reduced in 16 patients (35.7% and 28.6% of patients in the paclitaxel/carboplatin and gemcitabine/cisplatin cohorts, respectively) and was interrupted in 24 patients (35.7% and 66.7% of patients in the paclitaxel/carboplatin and gemcitabine/cisplatin cohorts, respectively). Median number of paclitaxel/carboplatin cycles was 6, 5 and 4 (range 1–6) for cohorts 1, 2 and 3, respectively; median number of chemotherapy cycles was 4 (range 1–29) and 3 (range 1–9) for gemcitabine and cisplatin, respectively. A total of 26 patients receiving axitinib plus paclitaxel/carboplatin discontinued the study, including 14 patients because of insufficient clinical response, 4 patients because of AEs and 8 patients for other reasons. In the gemcitabine/cisplatin cohort, 20 patients discontinued, including 10 because of insufficient clinical response, 6 because of AEs and 4 for other reasons.\n\nDLTs and MTD\n\nOne of the first six patients in cohort 3 receiving axitinib/paclitaxel/carboplatin experienced a DLT of febrile neutropenia during the first cycle (Table 1), and the MTD was determined to be axitinib 5 mg b.i.d. continuously in combination with paclitaxel 200 mg m–2 and carboplatin (AUC 6 mg min ml–1). One of the first six patients receiving axitinib/gemcitabine/cisplatin experienced a DLT of fatigue during the first cycle; the MTD was determined to be axitinib 5 mg b.i.d. continuously in combination with cisplatin 80 mg m–2 (day 1) and gemcitabine 1250 mg m–2 (days 1 and 8). Dose titration to 10 mg b.i.d. was achieved in three patients receiving paclitaxel/carboplatin.\n\nSafety and tolerability\n\nSix patients discontinued the study because of treatment-related AEs, which were fatigue, cerebrovascular accident and haemoptysis (n=1 each) in the paclitaxel/carboplatin cohorts and hypertension (n=2) and cerebrovascular accident (n=1) in the gemcitabine/cisplatin cohort. Common treatment-related nonhaematologic AEs were hypertension (n=18; 36.7%), diarrhoea (n=17; 34.7%) and fatigue (n=14; 28.6%) (Table 3). Common grade ⩾3 treatment-related nonhaematologic AEs across both treatment arms were fatigue (n=5; 10.2%) and hypertension (n=5; 10.2%). In addition to the patient in cohort 3 receiving axitinib/paclitaxel/carboplatin who had a DLT of febrile neutropenia during the first cycle, one patient in cohort 2 experienced grade 4 febrile neutropenia; chemotherapy was reduced in this patient. In the paclitaxel/carboplatin cohorts, two patients (7.1%) developed treatment-related stomatitis; both cases were classified as grade 2. No cases of grade⩾3 haemoptysis or grade 5 treatment-related AEs were reported.\n\nHaematologic laboratory abnormalities occurred in most patients (Table 3). With the exceptions of lymphopenia in the gemcitabine/cisplatin cohort and neutropenia in both cohorts, the majority of abnormalities were grade ⩽2. Grade 3/4 treatment-related abnormalities reported as AEs were thrombocytopenia (n=4; 8.2%), neutropenia (n=2; 4.1%) and anaemia and leukopenia (n=1 each; 2.0%).\n\nClinical activity\n\nOf the evaluable patients, 15 (31.3%) achieved an objective response (Table 4), including 3 complete responses (6.3%). An additional 16 patients (33.3%) had stable disease for >8 weeks. Objective responses were observed in patients with NSCLC (n=5), ovarian cancer (n=3), melanoma (n=2) and other tumour types (n=5).\n\nPharmacokinetic results\n\nPlasma pharmacokinetic parameters (maximum plasma concentration, AUC, clearance and volume of distribution) for paclitaxel, carboplatin, gemcitabine and its metabolite dFdU and cisplatin were similar in the absence or presence of axitinib (Table 5; Figure 3). Axitinib pharmacokinetic parameters were similar in the absence or presence of co-administered paclitaxel/carboplatin or gemcitabine/cisplatin (Table 5; Figure 3).\n\nDiscussion\n\nCombination treatment with chemotherapy and an agent targeting the VEGF pathway has been shown to improve clinical outcome for several tumour types compared with chemotherapy alone (Hurwitz et al, 2004; Sandler et al, 2006; Miller et al, 2007; Reck et al, 2010). In this study, axitinib combined with paclitaxel/carboplatin or gemcitabine/cisplatin was well tolerated and demonstrated clinical efficacy without any overt pharmacokinetic interactions for various advanced solid tumours. The MTD for axitinib in combination with paclitaxel/carboplatin or gemcitabine/cisplatin was 5 mg b.i.d.; however, further dose escalation of axitinib was achieved in some patients tolerating 5 mg b.i.d.\n\nMost AEs reported in this study were of mild-to-moderate grade, and the most common treatment-related nonhaematologic, grade ⩾3 AEs (hypertension, diarrhoea and fatigue) were anticipated, based on results from prior phase II studies of axitinib (Rixe et al, 2007; Cohen et al, 2008; Spano et al, 2008; Rini et al, 2009; Schiller et al, 2009). Unlike DLTs observed with other VEGF receptor tyrosine kinase inhibitors, for example, sorafenib, where skin toxicities such as rash and hand–foot syndrome were predominant (Moore et al, 2005; Strumberg et al, 2005), DLTs associated with axitinib in combination with paclitaxel/carboplatin or gemcitabine/cisplatin were febrile neutropenia and fatigue. Potential overlapping toxicities between axitinib and the chemotherapeutic agents, such as fatigue, nausea, diarrhoea and stomatitis, did not appear to be appreciably exacerbated.\n\nPatients receiving anti-VEGF therapies have an increased risk of developing hypertension (Jain and Townsend, 2007; Zhu et al, 2007; Wu et al, 2008), and the incidence of hypertension in this study was consistent with previous axitinib trials (Rixe et al, 2007; Cohen et al, 2008; Rini et al, 2009; Schiller et al, 2009). Moreover, grade ⩾3 hypertension reported here was comparable to that reported in phase III studies in various advanced solid tumours treated with the VEGF inhibitor bevacizumab plus chemotherapy (4–14.8%) (Sandler et al, 2006; Miller et al, 2007; Saltz et al, 2008). These data favour the use of antihypertensive medication and suggest the possible need for axitinib dose adjustments in patients who develop hypertension while receiving axitinib plus chemotherapy.\n\nOf note, no cases of grade ⩾3 haemoptysis were reported in this study, although mild haemoptysis was reported in one patient who received axitinib plus paclitaxel/carboplatin. Bevacizumab is contraindicated in patients with squamous cell NSCLC because of the incidence of severe or fatal pulmonary haemorrhage (2004); thus, patients with squamous cell NSCLC were excluded from the phase III study evaluating bevacizumab combined with paclitaxel and carboplatin for NSCLC (Sandler et al, 2006). In this study, additional eligibility requirements, for example, exclusion of patients who had blood vessels with possible tumour involvement, may have mitigated, in part, the potential risk of haemoptysis. It will require further investigation in a larger study to confirm whether axitinib plus chemotherapy may be safely administered to patients with squamous cell NSCLC. A phase II trial (NCT00735904) evaluating axitinib combined with gemcitabine/cisplatin for squamous cell NSCLC was recently completed.\n\nData reported here suggest the ability to administer paclitaxel/carboplatin or gemcitabine/cisplatin with axitinib without altering pharmacokinetics of these agents. Axitinib metabolism is primarily mediated by CYP3A4 and to a lesser extent by CYP1A2, CYP2C19 and UDP-glucuronosyltransferase 1A1 as determined from in vitro studies with human liver microsomes (unpublished data). In vitro studies indicate that axitinib competitively inhibits CYP1A2 and non-competitively inhibits CYP2C8 with inhibitor constants of 0.7 μℳ (0.27 μg ml–1) and 0.5 μℳ (0.19 μg ml–1), respectively (unpublished data). Since paclitaxel is an established CYP2C8 substrate (Monsarrat et al, 1993; Steed and Sawyer, 2007) and axitinib inhibits CYP2C8 in vitro, increases in plasma concentrations of paclitaxel when administered in combination with axitinib were possible. Thus, patients were administered escalating lead-in doses of axitinib (starting at 1 mg b.i.d.) in sequential cohorts in combination with paclitaxel/carboplatin. Similar paclitaxel pharmacokinetics in the absence and presence of axitinib indicate that at clinically relevant plasma concentrations of axitinib, significant clinical CYP2C8 inhibition does not occur. In addition, there were no clinically apparent exacerbations of known paclitaxel toxicities.\n\nSimilarly, no overt changes in pharmacokinetics were observed between axitinib and cisplatin, carboplatin or gemcitabine and its metabolite dFdU, although interactions were not anticipated since axitinib is metabolised via pathways that are distinct from these agents. Both carboplatin and cisplatin are eliminated by glomerular filtration (Duffull and Robinson, 1997; Yao et al, 2007). Gemcitabine (2′,2′-difluorodeoxycytidine) is sequentially phosphorylated intracellularly by deoxycytidine kinase and converted to di- and triphosphate products. Observed plasma concentrations of axitinib in combination with either paclitaxel/carboplatin or gemcitabine/cisplatin were consistent with those reported in other phase I studies of axitinib as monotherapy or in combination with chemotherapy (Rugo et al, 2005; Sharma et al, 2010). Plasma exposures observed in this study of paclitaxel, carboplatin (PUF), cisplatin (PUF) and gemcitabine when administered alone were similar to those previously reported in the literature (Villalona-Calero et al, 2004; Kobayashi et al, 2007; Ricart et al, 2008; Okamoto et al, 2010).\n\nCombinations of bevacizumab with chemotherapy have shown promising results in phase III studies of different tumour types; however, randomised trials of tyrosine kinase inhibitors targeting VEGF receptors in combination with chemotherapy have not shown a benefit for these combinations. Although the efficacy data for axitinib in combination with chemotherapy reported here are encouraging, they are exploratory, as would be expected from any phase I trial. The number of patients in each cohort was small, making it difficult to draw any definitive conclusions about the utility of axitinib combined with paclitaxel/carboplatin or gemcitabine/cisplatin in these patient populations. Nevertheless, they offer direction for ongoing and future clinical studies with sufficient statistical power for comprehensive analysis of the safety and efficacy of these combinations for the treatment of various cancers.\n\nIn conclusion, axitinib at a starting dose of 5 mg b.i.d. may be combined with paclitaxel/carboplatin or gemcitabine/cisplatin at standard doses, with no apparent overlapping toxicities and no overt changes in plasma pharmacokinetic parameters. Both combinations showed antitumour activity in patients with advanced solid tumours, including squamous cell NSCLC. Phase II studies of axitinib in combination with paclitaxel/carboplatin, gemcitabine/cisplatin and pemetrexed/cisplatin for NSCLC were recently completed.\n\nThis study was sponsored by Pfizer Inc. Support was provided in part by National Institutes of Health grant P30 CA006927 to the Fox Chase Cancer Center. We thank the patients who participated in this study and the physicians who referred them, as well as the study coordinators and data managers, Shelley Mayfield and Carol Martins at Pfizer Inc. for support of the study conduct, and Gamal ElSawah, Pfizer Medical Affairs, for his review of the manuscript. Medical writing support was provided by Joanna Bloom, of UBC Scientific Solutions (Southport, CT, USA) and Christine Arris at ACUMED (Tytherington, UK) and was funded by Pfizer Inc.\n\nFigure 1 Treatment schedule for (A) paclitaxel/carboplatin cohorts and (B) gemcitabine/cisplatin cohort. aChemotherapy (CT)=paclitaxel/carboplatin for cohort 1, 2 and 3. C=cycle; Cis=cisplatin; Gem=gemcitabine; PK=pharmacokinetic.\n\nFigure 2 Duration of study treatment.\n\nFigure 3 Plasma concentration–time curves for (A) axitinib, paclitaxel and carboplatin and (B) axitinib, gemcitabine and cisplatin. Abbreviation: PUF=plasma ultrafiltrate.\n\nTable 1 Axitinib dose escalation in patients receiving paclitaxel/carboplatin\n\nCohort\tLead-in dose of axitinib (b.i.d.)\tPatients enroled (n)\tDose-limiting toxicities\t\n1\t1 mga\t3\tNone\t\n2\t3 mga\t5\tNone\t\n3\t5 mg\t20b\tFebrile neutropenia (n=1)\t\nAbbreviation: b.i.d.=twice daily.\n\na Lead-in dose of axitinib was started 3–5 days before the first dose of chemotherapy and continued for 2 days after the first chemotherapy dose (from day –5, –4 or –3 through cycle 1 day 2).\n\nb Includes patients enroled in the expansion cohort.\n\nTable 2 Patient baseline characteristics\n\n \tAxitinib +\t\n \tPaclitaxel/carboplatin, n=28\tGemcitabine/cisplatin, n=21\t\nMale/female, n\t21/7\t9/12\t\nAge, median (range), years\t60 (37–75)\t52 (40–79)\t\nECOG PS 0/1, n\t16/12\t9/12\t\n \t \t \t\nPrimary tumour type, n (%)\t\n NSCLC\t17 (60.7)\t0\t\n Melanoma\t4 (14.3)\t0\t\n Ovarian\t3 (10.7)\t1 (4.8)\t\n Pancreatic\t0\t4 (19.0)\t\n Breast\t0\t3 (14.3)\t\n Head and neck\t1 (3.6)\t1 (4.8)\t\n Cholangiocarcinoma\t0\t2 (9.5)\t\n CRC\t0\t2 (9.5)\t\n Other\t3 (10.7)a\t8 (38.1)b\t\n \t \t \t\nPrior therapy, n (%)\t\n Surgery\t14 (50.0)\t20 (95.2)\t\n Radiotherapy\t5 (17.9)\t9 (42.9)\t\n Drug therapyc\t8 (28.6)\t15 (71.4)\t\nAbbreviations: CRC=colorectal cancer; ECOG PS=Eastern Cooperative Oncology Group performance status; NSCLC=non-small cell lung cancer.\n\na Renal cell carcinoma, unknown primary tumour (n=2).\n\nb Bladder, cervical, ectopic hormone secretion syndrome associated with neoplasia, gastrointestinal, prostate, sarcoma, small intestine, unknown primary tumour.\n\nc Includes cytotoxic chemotherapy and targeted agents.\n\nTable 3 Safety and tolerability findings\n\n(A) Treatment-related nonhaematologic AEs,a n (%)\t\n \t \tAxitinib +\t\n \tTotal, N=49\tPaclitaxel/carboplatin, n=28\tGemcitabine/cisplatin, n=21\t\n \tAll grades\tAll grades\tGrade 3/4 b\tAll grades\tGrade 3/4 b\t\nHypertension\t18 (36.7)\t10 (35.7)\t1 (3.6)\t8 (38.1)\t4 (19.1)\t\nDiarrhoea\t17 (34.7)\t11 (39.3)\t1 (3.6)\t6 (28.6)\t1 (4.8)\t\nFatigue\t14 (28.6)\t9 (32.1)\t4 (14.3)\t5 (23.8)\t1 (4.8)\t\nProteinuria\t10 (20.4)\t7 (25.0)\t1 (3.6)\t3 (14.3)\t0\t\nHand–foot syndrome\t9 (18.4)\t8 (28.6)\t1 (3.6)\t1 (4.8)\t1 (4.8)\t\nEpistaxis\t8 (16.3)\t5 (17.9)\t0\t3 (14.3)\t0\t\nNausea\t8 (16.3)\t0\t0\t8 (38.1)\t0\t\nDecreased appetite\t7 (14.3)\t3 (10.7)\t0\t4 (19.1)\t0\t\nHeadache\t7 (14.3)\t1 (3.6)\t0\t6 (28.6)\t1 (4.8)\t\nRash\t7 (14.3)\t5 (17.9)\t1 (3.6)\t2 (9.5)\t1 (4.8)\t\nDysphonia\t7 (14.3)\t4 (14.3)\t0\t3 (14.3)\t0\t\nDysgeusia\t6 (12.2)\t4 (14.3)\t0\t2 (9.5)\t0\t\nDizziness\t5 (10.2)\t4 (14.3)\t0\t1 (4.8)\t0\t\n(B) Haematologic laboratory abnormalities, n (%)\t\n \t \tAxitinib+\t\n \tTotal, N=48\tPaclitaxel/carboplatin, n=27\tGemcitabine/cisplatin, n=21\t\n \tAll grades\tAll grades\tGrade 3/4 b\tAll grades\tGrade 3/4 b\t\nAnaemia\t48 (100)\t27 (100)\t0 (0)\t21 (100)\t2 (9.5)\t\nNeutropenia\t46 (95.8)\t26 (96.3)\t25 (92.6)\t20 (95.2)\t13 (61.9)\t\nLeukopenia\t46 (95.8)\t26 (96.3)\t10 (37.0)\t20 (95.2)\t10 (47.6)\t\nThrombocytopenia\t43 (89.6)\t25 (92.6)\t7 (25.9)\t18 (85.7)\t10 (47.6)\t\nLymphopenia\t40 (83.3)\t19 (70.4)\t5 (18.5)\t21 (100)\t14 (66.7)\t\nAbbreviation: AE=adverse event.\n\na Reported in⩾10% of patients.\n\nb No grade 5 AEs were reported.\n\nTable 4 Best response to therapy, by RECISTa\n\n \tn (%)\t\n \tAxitinib+\t\n \tPaclitaxel/carboplatin, n=27\tGemcitabine/cisplatin, n=21\t\nObjective response rateb\t10 (37.0)\t5 (23.8)\t\nComplete response\t2 (7.4)\t1 (4.8)\t\nPartial response\t8 (29.6)\t4 (19.0)\t\nStable disease\t11 (40.7)\t5 (23.8)\t\nDisease progression\t3 (11.1)\t3 (14.3)\t\nIndeterminate/missing\t3 (11.1)\t8 (38.1)\t\nAbbreviation: RECIST=Response Evaluation Criteria in Solid Tumours.\n\na Includes treated patients with at least one target lesion according to RECIST and a baseline assessment of disease.\n\nb Complete responses+partial responses.\n\nTable 5 Plasma pharmacokinetic parameters of (A) paclitaxel, carboplatin, gemcitabine and cisplatin in the absence or presence of axitinib and (B) axitinib in the absence or presence of paclitaxel, carboplatin, gemcitabine and cisplatin\n\nTreatment arm\tMean (%CV)\t\n(A) CT treatment with/without axitinib\tCmax (ng ml−1)\tAUC0–∞a (ng·h ml−1)\tCL (l h−1)\tV z (l)\tt½ (h)\t\nPaclitaxelb,c (n=12)\t\n (+Carboplatin)\t6182 (34)\t20 266 (28)\t21.6 (43)\t285 (82)\t8.36 (26)\t\n (+Carboplatin)+axitinib\t7182 (24)\t23 320 (34)\t18.2 (24)\t229 (31)\t8.64 (12)\t\n \t \t \t \t \t \t\nCarboplatinb,c (n=12)\t\n (+Paclitaxel)\t24 101 (29)\t57 519 (17)\t12.6 (32)\t45.2 (18)\t2.62 (21)\t\n (+Paclitaxel)+axitinib\t24 250 (32)\t52 768 (15)\t13.7 (31)\t44.8 (15)\t2.44 (29)\t\n \t \t \t \t \t \t\nGemcitabined (n=17)\t\n (+Cisplatin)\t22 445e (66)\t11 680e (31)\t224 (33)\t91.5 (35)\t0.29 (24)\t\n (+Cisplatin)+axitinib\t22 182 (34)\t12 270 (33)\t217 (36)\t95.5 (63)\t0.30 (33)\t\n dFdU (+cisplatin)\t48 981 (39)\t212 828 (39)\t–\t–\t3.32 (44)\t\n dFdU (+cisplatin)+axitinib\t47 024 (17)\t184 794 (20)\t–\t–\t3.12 (16)\t\n \t \t \t \t \t \t\nCisplatinf (n=13)\t\n (+Gemcitabine)\t1899g (30)\t3366g (25)\t46.3 (32)\t173 (53)\t2.61 (49)\t\n (+Gemcitabine)+axitinib\t1757 (33)\t3057 (30)\t52.8 (44)\t184 (96)\t2.27 (77)\t\n(B) Axitinib treatment with/without CT\tCmax(ng ml−1)\tAUC0-24(ng·h ml−1)\tCL/F (l h−1)\tV z /F (l)\tt½ (h)\t\nAxitinibh,i (n=12)\t\n Alone\t39 (40)\t404 (68)\t39 (87)\t108 (42)\t2.8 (53)\t\n +Paclitaxel/carboplatin\t46 (71)\t535 (76)\t37 (114)\t133 (126)\t2.7 (36)\t\n \t \t \t \t \t \t\nAxitinibj (n=20)\t\n Alone\t41 (81)\t416 (108)\t50.1 (113)\t157 (102)\t2.68 (41)\t\n +Gemcitabine/cisplatin\t41.7 (94)\t444 (84)\t46.7 (104)\t168 (116)\t2.66 (51)\t\nAbbreviations: AUC0–24=area under the plasma concentration–time curve (AUC) from time 0 to 24 h; AUC0–∞=AUC from time zero to infinity; b.i.d.=twice daily; CL=plasma clearance; CL/F=apparent oral plasma clearance; Cmax=maximum plasma concentration; CT=chemotherapy; CV=coefficient of variation; dFdU=2′,2′-difluorodeoxyuridine; PK=pharmacokinetic; PUF=plasma ultrafiltrate; t½=plasma terminal elimination half-life; Vz=volume of distribution of the drug during the elimination phase; Vz/F=apparent oral volume of distribution during the elimination phase.\n\na AUC reported for cisplatin is from time 0 to 8 h.\n\nb Pooled data from cohorts 1–3. PK parameters for carboplatin are in PUF.\n\nc Two patients excluded because PK samples were not collected on cycle 1 day 1.\n\nd Four patients excluded because matching cycle 1 and cycle 2 PK evaluations were not completed.\n\ne Cmax and AUC0–∞ on cycle 2 dose-normalised for patients who underwent gemcitabine dose reduction on cycle 2 compared with cycle 1.\n\nf Seven patients excluded because matching cycle 1 and cycle 2 PK evaluations were not completed; one patient excluded because of non-estimable half-life; one patient excluded because of dose infusion interruption. PK parameters for cisplatin are in PUF.\n\ng Cmax and AUC0–8 on cycle 2 dose-normalised for patients who underwent cisplatin dose reduction on cycle 2 compared with cycle 1.\n\nh Data were pooled from patients in cohorts 1, 2 and 3 who received 1, 3 and 5 mg b.i.d. doses of axitinib, respectively. Data were dose-normalised to 5 mg b.i.d.\n\ni For three patients, AUC0–24, CL/F, Vz/F and t1/2 were not reported because of non-estimable half-life.\n\nj One patient excluded because matching cycle 1 and cycle 2 PK evaluations were not completed; for five patients AUC0–24, CL/F, Vz/F, and t1/2 were not reported because of non-estimable half-life.\n\nThis work is published under the standard license to publish agreement. 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Am J Kidney Dis 49 : 186–19317261421\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0007-0920", "issue": "107(8)", "journal": "British journal of cancer", "keywords": null, "medline_ta": "Br J Cancer", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077784:Axitinib; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D005260:Female; D006801:Humans; D007093:Imidazoles; D007191:Indazoles; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome", "nlm_unique_id": "0370635", "other_id": null, "pages": "1277-85", "pmc": null, "pmid": "22990652", "pubdate": "2012-10-09", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "19010843;18514303;16006586;19680296;17261421;19940012;19652060;18160686;15447994;17334719;12684392;17959415;15613696;18421054;7912528;17686384;17167137;19760364;15175435;17892508;19597027;14657950;20150572;16027439;10188906;18541897;19047127;8238242;20212250;22996612;17638515;17700201;10655437;15184808;18221915;12903007;19349493;9314610", "title": "Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours.", "title_normalized": "phase i trial of axitinib combined with platinum doublets in patients with advanced non small cell lung cancer and other solid tumours" }

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{ "abstract": "Calciphylaxis is a rare syndrome of calcific microvascular occlusion, whereas non-uremic calciphylaxis (NUC) is a subset of this disease in which renal impairment is not observed. Recombinant human parathyroid hormone (rhPTH) (1-84) is a medication approved for the management of hypocalcemia in patients with hypoparathyroidism. We present a case report of a 38-year-old woman with postoperative hypoparathyroidism treated with rhPTH who subsequently developed calciphylactic lesions on her abdomen. Multidisciplinary interventions included intravenous and intralesional sodium thiosulfate therapy, laboratory monitoring, dermatological wound care, and pain management. Calciphylaxis can rarely be precipitated by rhPTH due to its effect on calcium and phosphorus balance even in the setting of normal renal function. The use of calcium and calcitriol supplementation, complicated by factors such as female sex and obesity, may have contributed in this patient's case. Hence, regular follow-up with tapering off of calcium and calcitriol supplementation is important in patients receiving rhPTH.", "affiliations": "Internal Medicine, University of Missouri, Columbia, USA.;Diabetes and Endocrinology, University of Missouri, Columbia, USA.;Diabetes and Endocrinology, University of Missouri, Columbia, USA.", "authors": "DeClue|Cory|C|;Chinnakotla|Bhavana|B|;Gardner|Michael J|MJ|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.15014", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.15014\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nPathology\nNon-Uremic Calciphylaxis: An Unexpected Complication With Recombinant Human Parathyroid Hormone\nMuacevic Alexander\nAdler John R\nDeClue Cory 1\nChinnakotla Bhavana 2\nGardner Michael J 2\n1 Internal Medicine, University of Missouri, Columbia, USA\n2 Diabetes and Endocrinology, University of Missouri, Columbia, USA\nCory DeClue ced538@health.missouri.edu\n13 5 2021\n5 2021\n13 5 e1501412 5 2021\nCopyright © 2021, DeClue et al.\n2021\nDeClue et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/44743-non-uremic-calciphylaxis-an-unexpected-complication-with-recombinant-human-parathyroid-hormone\nCalciphylaxis is a rare syndrome of calcific microvascular occlusion, whereas non-uremic calciphylaxis (NUC) is a subset of this disease in which renal impairment is not observed. Recombinant human parathyroid hormone (rhPTH) (1-84) is a medication approved for the management of hypocalcemia in patients with hypoparathyroidism. We present a case report of a 38-year-old woman with postoperative hypoparathyroidism treated with rhPTH who subsequently developed calciphylactic lesions on her abdomen. Multidisciplinary interventions included intravenous and intralesional sodium thiosulfate therapy, laboratory monitoring, dermatological wound care, and pain management. Calciphylaxis can rarely be precipitated by rhPTH due to its effect on calcium and phosphorus balance even in the setting of normal renal function. The use of calcium and calcitriol supplementation, complicated by factors such as female sex and obesity, may have contributed in this patient’s case. Hence, regular follow-up with tapering off of calcium and calcitriol supplementation is important in patients receiving rhPTH.\n\nnon uremic calciphylaxis\nrecombinant pth\nsodium thiosulfate\nhypoparathyroidism\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nCalciphylaxis is a rare syndrome of microvascular occlusion in the subcutaneous adipose tissue and dermis, resulting in painful skin lesions and poor prognosis. Lesions are composed of calcium and phosphate, and elevated levels of either of these elements increase the risk of calciphylaxis [1]. While calciphylaxis is primarily associated with end stage renal disease (ESRD), rarely it has been identified in patients with normal renal function due to a variety of reasons, collectively called non-uremic calciphylaxis (NUC).\n\nEven among patients with ESRD, calciphylaxis is quite uncommon, as evidenced by an estimated annual incidence rate of 0.04% in one registry of dialysis patients [2]. NUC is even rarer, accounting only for 5% of cases of calciphylaxis in a recent systematic review [3]. Another systematic review of NUC found that the most common risk factors were primary hyperparathyroidism, malignancy, warfarin use, and alcoholic liver disease [4]. It is interesting to note that the serum calcium and phosphate were normal in the majority of these cases reviewed.\n\nRecombinant human parathyroid hormone (rhPTH) may be a rare cause of calciphylaxis. This is evident from two cases of NUC resulting from use of Teriparatide, a form of PTH consisting of the first 34 amino acids [5-6]. Two cases of Teriparatide-associated uremic calciphylaxis have also been described [7-8]. The confounding risk factors in these cases include two patients with glomerular filtration rates of 37 and 46 mL/min, while the other two patients had autoimmune disease treated with corticosteroids. Additionally, three of the patients were obese, and two of the patients were treated with warfarin therapy.\n\nNatpara [rhPTH(1-84)] is an rhPTH injection approved as an adjunct to calcium and vitamin D to treat hypocalcemia in patients with hypoparathyroidism. It has been increasingly used by endocrinologists since its approval in 2015. Iatrogenic hyperparathyroidism resulting from rhPTH may cause devastating side effects. Here, we present a case of calciphylaxis in a woman treated with rhPTH(1-84).\n\nCase presentation\n\nA 38-year-old female was diagnosed with primary hyperparathyroidism with an intact PTH (iPTH) of 389 pg/mL (normal range: 15-65 pg/mL) after she developed a renal calculus with serum calcium of 9.9 mg/dL (normal range: 8.6-10.2 mg/dL). Past medical history included hypertension, gestational diabetes mellitus, obesity with BMI 34, depression, chronic osteomyelitis of the left foot, and migraine disorder. Surgical history consisted of multiple foot surgeries and two cesarean sections. Family history included lung cancer in her father and hypertension in her mother. There was no history of tobacco use, and she drank two glasses of wine monthly. Medication list included vitamin D3 2000 IU/day, topiramate 75 mg/day, amlodipine 5 mg/day, fluvoxamine 50 mg/day, gabapentin 300 mg/day, and as needed clonazepam 0.5 mg.\n\nDue to symptomatic hyperparathyroidism, she underwent parathyroidectomy of two out of four glands. Within days post-operatively, she developed symptomatic hypercalcemia of 12.8 mg/dL with an appropriately suppressed iPTH of 18.7 pg/mL. This was attributed to excess calcium supplementation, as extensive workup for hypercalcemia including repeat sestamibi scan, CT chest/abdomen, serum protein electrophoresis/urine protein electrophoresis (SPEP/UPEP), and bone marrow biopsy was unremarkable. She was started on cinacalcet 30 mg twice daily. After four doses, the patient developed muscle spasms and perioral paresthesia with hypocalcemia of 6.7 mg/dL despite calcitriol and calcium supplementation. Cinacalcet was stopped, and she was assumed to have postoperative hypoparathyroidism with an ionized calcium of 1.22 mmol/L (normal range: 1.15-1.25 mmol/L) and iPTH of 9.4 pg/mL two weeks after drug discontinuation. Serum calcidiol was 26 ng/mL (normal: 30-80 ng/mL) and 24-hour urine calcium was 327 mg (normal: 100-300 mg). rhPTH(1-84) 50 µg daily was started. Four months later, calcium was 9.2 mg/dL. Six months after this, her calcium was 7.6 mg/dL, phosphorus was 3.6 mg/dL (normal: 2.7-4.5 mg/dL), and iPTH was 12.6 pg/mL. She experienced muscle spasms, so rhPTH(1-84) was increased to 75 µg daily.\n\nSeventeen months following initiation of rhPTH(1-84), the patient developed a painful right breast lesion that had free air on ultrasound. Emergent surgical excision was done, and pathology showed necrotic tissue with calcification consistent with calciphylaxis. At that time, serum calcium was 9.9 mg/dL, phosphorus was 3.3 mg/dL, and iPTH was 44 pg/dL. Over the next two months, bilateral breast lesions erupted that required mastectomies. Following this, calcitriol was lowered to 0.5 µg twice daily, but rhPTH(1-84) was continued.\n\nTwo months later, she developed a new abdominal calciphylaxis lesion and presented to our center. Her lab results at admission, during hospital course, and at three-month post-discharge are illustrated in Table 1.\n\nTable 1 Laboratory values for the patient while on Natpara, off Natpara, and at three months post-discharge.\n\nLab Values\tAt admission (On Natpara)\tDuring hospitalization (Off Natpara)\tThree-month post-discharge\tReference range\t\nCalcium (mg/dL)\t9.5\t8.2\t9.2\t8.6-10.2\t\nPhosphorus (mg/dL)\t2.9\t2.5\t4\t2.7-4.5\t\nCalcium-Phosphorus product (mg/dL)\t27.55\t20.5\t36.8\t \t\nIonized Parathyroid Hormone (pg/dL)\t67.9\t66.7\t69.7\t15-65\t\nSodium (mmol/L)\t137\t139\t139\t136-145\t\nPotassium (mmol/L)\t3.5\t3.4\t4.3\t3.5-5.2\t\nChloride (mmol/L)\t96\t105\t102\t98-107\t\nCarbon Dioxide (mmol/L)\t24\t23\t25\t22-29\t\nAnion gap (mmol/L)\t17\t10\t12\t0-20\t\nBlood Urea Nitrogen (mg/dL)\t17\t6\t10\t6-20.0\t\nCreatinine (mg/dL)\t0.73\t0.47\t0.61\t0.5-1.2\t\nAlbumin (g/dL)\t4.1\t3.3\t4.2\t3.5-5.1\t\nVitamin D (ng/mL)\t \t31.6\t36\t30-80\t\nWhite Blood Cells (x109/L)\t15.1\t9.2\t13.7\t3.5-10.5\t\nPlatelets (x109/L)\t464\t409\t394\t150-450\t\nGlucose (mg/dL)\t87\t99\t104\t74-106\t\n\nAs noted in the table, renal function testing remained normal. Upon withholding the rhPTH(1-84), iPTH remained as high as 70 pg/mL, questioning her diagnosis of hypoparathyroidism. Calcitriol, calcium supplements, and rhPTH(1-84) were discontinued. A multidisciplinary treatment plan with sodium thiosulfate (STS) 25 g/100 mL IV three times per week along with pain management and wound care was initiated. The patient’s calcium and phosphorus remained normal throughout her course (Table 1). Her wounds progressed well on the STS infusions for five months (Figure 1), but due to incomplete closure, she was seen in dermatology clinic for intralesional STS injections.\n\nFigure 1 The calciphylaxis lesions over time. Lesions shown are at admission (top left), six months later (top right), seven months later (bottom left), and ten months later (bottom right).\n\nShe has continued to have new abdominal lesions despite discontinuation of Natpara for over one year. Due to significant pain, the patient continues to follow with palliative care clinic for opioid management.\n\nDiscussion\n\nThe pathogenesis of calciphylaxis is uncertain, despite growing work in this field as of late. Current theory suggests that local microvascular calcification leads to chronic ischemia, which then causes infarction via endothelial injury and microthrombus formation. This initial step appears to be due to a cell-mediated process involving a deficiency of calcification inhibitors. Matrix Gla protein (MGP) is an extracellular matrix protein that strongly inhibits calcification when carboxylated. This carboxylation step is dependent on vitamin K, leading many to speculate that this is the reason warfarin is a risk factor for calciphylaxis [9]. Another implicated inhibitor is fetuin-A, which leads to formation of calciprotein particles that help transport minerals through the body. Fetuin-A has been found to be downregulated in chronic inflammatory diseases, which may explain the increased calciphylaxis risk in people with uremia and autoimmune diseases [10].\n\nIn addition to a lack of calcification inhibition, there seems to be an increased pro-calcification response in calciphylaxis. Adipocytes have been shown to secrete cytokines that can lead to differentiation of vascular smooth muscle cells into procalcific cells, and this is one mechanism through which STS prevents calcification [11]. Additionally, this provocation of differentiation is stimulated by hyperphosphatemia, hypercalcemia, and hyperglycemia, explaining the increased risk in hyperparathyroidism and diabetes [12-13]. Despite all of these discoveries, there is still much to be learned about how and why calciphylaxis occurs.\n\nOur patient developed iatrogenic hyperparathyroidism from rhPTH(1-84) in the setting of intact parathyroid gland function. The calcium, calcitriol, and vitamin D supplements most likely contributed to imbalance in the calcium and phosphorous metabolism resulting in this devastating disease. Hence, careful diagnosis and patient selection are important prior to the initiation of rhPTH(1-84) therapy.\n\nUnlike the advancements in understanding the pathogenesis of calciphylaxis, treating this disease has not been as fruitful. Due to its complex nature, a multidisciplinary approach involving nephrologists, endocrinologists, plastic surgeons, dieticians, and wound care clinicians is paramount to success. In uremic calciphylaxis, elevated serum calcium and phosphate should be treated by increasing hemodialysis frequency and reducing intake [14]. Additionally, calcium-based phosphate binders should be avoided, and vitamin D supplements should be discontinued. Cinacalcet can be used for PTH suppression, and warfarin should be discontinued [15]. Bisphosphonates have been shown to improve pain and severity of skin lesions in retrospective studies but require controlled trials to determine true efficacy [16].\n\nIn addition to reducing vascular calcification, concurrent decalcification of vessels is also needed. STS has become the standard therapy due to the water-soluble thiosulfate chelation of calcium from the vessel wall, as well as antioxidant properties to reduce inflammation and thrombosis. In a recent meta-analysis of STS use in uremic calciphylaxis, improvement in lesions was observed in 70.1% of patients [17]. Another agent being used for treatment is vitamin K, which has been shown to reduce vascular calcification in animal models [18]. A newer agent, called SNF472 (intravenous myo-inositol hexaphosphate), blocks the formation of hydroxyapatite and has been assessed recently for treatment in calciphylaxis [19]. Finally, a change in medium such as double-filtration apheresis and hyperbaric oxygen therapy has reported some use in STS-refractory calciphylaxis cases.\n\nAs noted from the above discussion, most of the experience in diagnosing and treating calciphylaxis is evident from ESRD patients, while non-uremic calciphylaxis remains to be explored. Given the rarity of this phenomenon, there is currently a national registry for calciphylaxis which may be a potential tool for exploring its etiology, risk factors, and management. As we await more robust studies in NUC, we as endocrinologists must be aware of hyperparathyroidism, both primary and iatrogenic from rhPTH(1-84), as a risk given the associated morbidity and mortality.\n\nConclusions\n\nOur case highlights the need to monitor hypoparathyroid patients treated with rhPTH and calcitriol for calciphylaxis. Calcium and calcitriol supplementation should be adjusted, and patients should be closely followed to monitor for endogenous parathyroid function. The majority of calciphylaxis occurs in the setting of renal impairment, notably in dialysis patients. However, there can be a subset with normal renal function. Calciphylaxis, regardless of the renal function, still has poor outcomes. Gaining a better understanding of the precipitating factors for this disease process not only can establish effective therapies but can also lead to better treatment of calcium disorders when concomitantly present.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Calciphylaxis N Engl J Med Nigwekar SU Thadhani R Brandenburg VM 1704 1714 378 2018 29719190\n2 Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry Nephrol Dial Transplant Brandenburg VM Kramann R Rothe H 126 132 32 2017 26908770\n3 Calciphylaxis in patients with normal renal function: a case series and systematic review Mayo Clin Proc Bajaj R Courbebaisse M Kroshinsky D Thadhani RI Nigwekar SU 1202 1212 93 2018 https://pubmed.ncbi.nlm.nih.gov/30060958/#:~:text=In%20the%20literature%20review%2C%20median,with%20lesion%20improvement%20or%20survival. 30060958\n4 Calciphylaxis from nonuremic causes: a systematic review Clin J Am Soc Nephrol Nigwekar SU Wolf M Sterns RH Hix JK 1139 1143 3 2008 18417747\n5 Cutaneous vascular calcifications secondary to treatment with teriparatide Acta Dermosifiliogr Leis-Dosil VM Rubio Flores C Ruiz-Bravo E Diaz-Diaz RM 87 88 104 2013\n6 Nonuremic calciphylaxis in a patient with rheumatoid arthritis and osteoporosis treated with teriparatide J Am Acad Dermatol Dominguez AR Goldman BA 41 42 70 2014\n7 Development of multiorganic calciphylaxis during teriparatide, vitamin D, and calcium treatment Osteopor Int Monegal A Peris P Alsina M Colmenero J Guanabens N 2631 2634 27 2016\n8 Nonuremic calciphylaxis precipitated by teriparatide [rhPTH (1-34)] therapy in the setting of chronic warfarin and glucocorticoid treatment Osteopor Int Spanakis EK Sellmeyer DE 1411 1414 25 2014\n9 Vitamin K-dependent carboxylation of matrix Gla protein influences the risk of calciphylaxis J Am Soc Nephrol Nigwekar SU Bloch DB Nazarian RM 1717 1722 28 2017 28049648\n10 Serum fetuin-A concentration and fetuin-A-containing calciprotein particles in patients with chronic inflammatory disease and renal failure Nephrology (Carlton) Smith ER Cai MM McMahon LP Pedagogos E Toussaint ND Brumby C Holt SG 215 221 18 2013 23231493\n11 Adipocyte induced arterial calcification is prevented with sodium thiosulfate Biochem Biophys Res Commun Chen NX O'Neill K Akl NK Moe SM 151 156 449 2014 24824185\n12 Arterial calcification in chronic kidney disease: key roles for calcium and phosphate Circ Res Shanahan CM Crouthamel MH Kapustin A Giachelli CM Towler DA 697 711 109 2011 21885837\n13 Glucose stimulates chondrocyte differentiation of vascular smooth muscle cells and calcification: a possible role for IL‐1β FEBS Lett Bessueille L Fakhry M Hamade E Badran B Magne D 2797 2804 589 2015 26277062\n14 Calciphylaxis: diagnosis, pathogenesis, and treatment Adv Skin Wound Care Chang JJ 205 215 32 2019 31008757\n15 The successful use of apixaban in dialysis patients with calciphylaxis who require anticoagulation: a retrospective analysis Am J Nephrol Garza-Mayers AC Shah R Sykes DB Nigwekar SU Kroshinsky D 168 171 48 2018 30176675\n16 Clinical management of calcific uremic arteriolopathy before and after therapeutic inclusion of bisphosphonates Clin Nephrol Torregrosa JV Sanchez-Escuredo A Barros X Blasco M Campistol JM 231 234 83 2015 24075020\n17 Systematic review of sodium thiosulfate in treating calciphylaxis in chronic kidney disease patients Nephrology (Carlton) Peng T Zhuo L Wang Y Jun M Li G Wang L Hong D 669 675 23 2018 28603903\n18 Calciphylaxis in a dialysis patient successfully treated with high-dose vitamin K supplementation Clin Kidney J Christiadi D Singer RF 528 529 11 2018 30094016\n19 Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis J Nephrol Brandenburg VM Sinha S Torregrosa JV 811 821 32 2019 31401795\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(5)", "journal": "Cureus", "keywords": "hypoparathyroidism; non uremic calciphylaxis; recombinant pth; sodium thiosulfate", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e15014", "pmc": null, "pmid": "34150377", "pubdate": "2021-05-13", "publication_types": "D002363:Case Reports", "references": "22840755;26277062;21885837;29719190;24438979;23231493;28049648;18417747;24824185;24292108;26908770;31401795;30176675;24075020;31008757;30094016;30060958;27010647;28603903", "title": "Non-Uremic Calciphylaxis: An Unexpected Complication With Recombinant Human Parathyroid Hormone.", "title_normalized": "non uremic calciphylaxis an unexpected complication with recombinant human parathyroid hormone" }

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{ "abstract": "Children with lupus nephritis particularly, diffuse proliferative and membranous glomerulonephritis, may necessitate potent immunosuppressive medications and occasionally combined therapy.\nTo report the beneficial effects of tacrolimus (TAC) in children with refractory lupus nephritis from a single tertiary pediatric rheumatology clinic.\nThis is a retrospective case series of children with refractory lupus nephritis treated with TAC after failure of aggressive immunosuppressive treatment. All patients were evaluated at the time of initiation of TAC and at last follow-up visit by assessing the following response parameters: cSLE Disease Activity Index (SLEDAI), urine protein/creatinine ratio, urine sediments, serum albumin, complement (C3 and C4), anti-double-stranded DNA (dsDNA) antibody levels, and renal function assessed by glomerular filtration rate (eGFR).\nThree children (two girls and one boy) with lupus nephritis and persistent nephrotic-range proteinuria failed prednisone treatment as well as sequential treatment of cyclophosphamide, mycophenolate mofetil (MMF), and rituximab. When TAC was administered along with MMF and prednisone, all patients showed improvement in response parameters, namely, SLEDAI, serum albumin, and proteinuria, and prednisone doses were significantly weaned off and discontinued in two patients. However, eGFR remained stable during the treatment period. TAC was well tolerated, and no adverse effects were observed.\nTAC combined with MMF can be considered as an alternative therapeutic option for children with refractory lupus nephritis particularly those with persistent nephrotic-range proteinuria.", "affiliations": "Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.", "authors": "Almutairi|Abdulaziz|A|;Alkathiri|Ziyad|Z|;Al-Mayouf|Sulaiman M|SM|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijpam.2018.08.001", "fulltext": "\n==== Front\nInt J Pediatr Adolesc MedInt J Pediatr Adolesc MedInternational Journal of Pediatrics & Adolescent Medicine2352-6467King Faisal Specialist Hospital and Research Centre S2352-6467(18)30088-710.1016/j.ijpam.2018.08.001Original Research ArticleCombination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis Almutairi Abdulaziz Alkathiri Ziyad Al-Mayouf Sulaiman M. mayouf@kfshrc.edu.sa∗Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia∗ Corresponding author. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Alfaisal University, Po Box 3354, Riyadh 11211, Saudi Arabia. mayouf@kfshrc.edu.sa09 8 2018 9 2018 09 8 2018 5 3 99 102 11 6 2018 26 7 2018 5 8 2018 © 2018 Publishing services provided by Elsevier B.V. on behalf of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.2018King Faisal Specialist Hospital & Research Centre (General Organization), Saudi ArabiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nChildren with lupus nephritis particularly, diffuse proliferative and membranous glomerulonephritis, may necessitate potent immunosuppressive medications and occasionally combined therapy.\n\nObjective\nTo report the beneficial effects of tacrolimus (TAC) in children with refractory lupus nephritis from a single tertiary pediatric rheumatology clinic.\n\nMethods\nThis is a retrospective case series of children with refractory lupus nephritis treated with TAC after failure of aggressive immunosuppressive treatment. All patients were evaluated at the time of initiation of TAC and at last follow-up visit by assessing the following response parameters: cSLE Disease Activity Index (SLEDAI), urine protein/creatinine ratio, urine sediments, serum albumin, complement (C3 and C4), anti-double-stranded DNA (dsDNA) antibody levels, and renal function assessed by glomerular filtration rate (eGFR).\n\nResults\nThree children (two girls and one boy) with lupus nephritis and persistent nephrotic-range proteinuria failed prednisone treatment as well as sequential treatment of cyclophosphamide, mycophenolate mofetil (MMF), and rituximab. When TAC was administered along with MMF and prednisone, all patients showed improvement in response parameters, namely, SLEDAI, serum albumin, and proteinuria, and prednisone doses were significantly weaned off and discontinued in two patients. However, eGFR remained stable during the treatment period. TAC was well tolerated, and no adverse effects were observed.\n\nConclusion\nTAC combined with MMF can be considered as an alternative therapeutic option for children with refractory lupus nephritis particularly those with persistent nephrotic-range proteinuria.\n\nKeywords\nSystemic lupus erythematosusTacrolimusLupus nephritisNephrotic syndrome\n==== Body\n1 Introduction\nSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiorgan involvement; the onset and clinical features of childhood SLE (cSLE) are often aggressive and require an intensive therapy [1,2]. Lupus nephritis is one of the major clinical features of SLE, occurring in up to 60% of children with SLE. It can be subclinical but occasionally present with body edema due to nephrotic-range proteinuria, hypertension, and renal impairment [3,4].\n\nAlthough there is no available cure for SLE presently, several drugs are useful in controlling the disease and contributed to a favorable outcome. Children with lupus nephritis, especially diffuse proliferative and membranous glomerulonephritis, may necessitate potent immunosuppressive medications such as cyclophosphamide (CYC) or mycophenolate mofetil (MMF) and occasionally rituximab (RTX) [5,6]. However, one third of such patients might either have frequent disease flares or be resistant to the treatment with disease progression [7,8].\n\nTacrolimus (TAC) recently gained much attention in the treatment of adult patients with refractory lupus nephritis and children with a nephrotic syndrome [[9], [10], [11]]. However, the available published data in childhood lupus nephritis are limited [[12], [13], [14]].\n\nHerein, we present three children with refractory lupus nephritis who were treated successfully with TAC. Furthermore, we reviewed all published articles on the treatment of childhood lupus nephritis with TAC.\n\n2 Patients and methods\nThis is a retrospective case series of patients with refractory childhood lupus nephritis seen at King Faisal Specialist Hospital and Research Center (KFSH-RC), Riyadh. Medical records were reviewed for demographic data, clinical and laboratory parameters, histopathology and imaging findings, and response to TAC. All patients were evaluated at the time of initiation of TAC treatment, then after 3 and 6 months, and at the last follow-up visit by assessing the following response parameters: cSLE Disease Activity Index (SLEDAI), urine protein/creatinine ratio, urine sediments, serum albumin, complement (C3 and C4), anti-double-stranded DNA (dsDNA) antibody levels, and renal function assessed by estimated glomerular filtration rate (eGFR).\n\n3 Results\nTable 1 shows the clinical and laboratory findings of the three patients with refractory lupus nephritis.Table 1 Baseline clinical and laboratory findings of three patients with refractory lupus nephritis.\n\nTable 1\tCase I\tCase II\tCase III\t\nAge (Years)/Gender\t13/Female\t12/Female\t14/Male\t\nAge at onset (SLE) (Years)\t8\t11\t8\t\nLupus nephritis (ISN/RPS)\tIV\tIV\tIV/V\t\nExtra-renal\tMucocutaneous\tHematological\tMucocutaneous\t\nMusculoskeletal\tMusculoskeletal\t\nHematological\tHematological\t\nUrine Pr/Cr ratio (mg/mmol) a\t424\t120\t629\t\nUrine sediments\t5 RBC, 5 WBC+ Hyaline cast\tNegative\t>50 RBC, 5 WBC+ Granular cast\t\nC3 g/L (0.9–1.8)\t0.79\t1\t0.8\t\nC4 g/L (0.1–0.4)\t0.3\t0.4\t0.1\t\neGFR min/ml/1.73 m2\t157\t43\t162\t\nSerum albumin mg/L\t30\t34\t27\t\nAnti-dsDNA antibody (<200)\t1280\tNegative\t456\t\nDaily Steroid dose (mg)\t10\t5\t5\t\nPrevious medications\tMMF, RTX, CYC, IVIG\tMMF, RTX, CYC, IVIG\tMMF, RTX, CYC, IVIG\t\nSLEDAI\t9\t4\t14\t\nC3, complement 3; C4, Complement 4; dsDNA, double-stranded DNA; AZZ, azathioprine; CYC, cyclophosphamide; RTX, rituximab; MMF, mycophenolate mofetil; IVIG, intravenous immunoglobulin; SLEDAI, systemic lupus erythematosus disease activity index.\n\na Urine protein/creatinine ratio (<30 mg/mmol).\n\n\n\n3.1 First case\nA 13-year-old girl was diagnosed with SLE at the age of 8 years on the basis of constitutional symptoms, malar rash, oral ulceration, and arthritis. She had leukopenia, elevated antinuclear antibody (ANA), high anti-ds DNA antibody levels, and low complement (C3 and C4) levels. Other results revealed a high erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) 39 mm/h and 22 mg/L, respectively. She also had evidence of nephritis manifested with hematuria and nephrotic-range proteinuria. Renal biopsy proved lupus nephritis class IV. Interestingly, her mother is a known case of SLE with nephritis. She was started on prednisone (1 mg/kg/day), hydroxychloroquine (5 mg/kg/day), and azathioprine (AZA) (2 mg/kg/day).\n\nIn the early disease course, she developed heart failure due to moderate mitral valve regurgitation and required Lasix (2 mg/kg/day) and enalapril (0.2 mg/kg/day).\n\nBecause of cardiac involvement and persistent heavy proteinuria (632 mg/mmol), treatment was switched from AZA to CYC and RTX; she completed six doses of monthly CYC (750 mg/m2/dose), and two doses of RTX (350 mg/m2/dose), followed by MMF (600 mg/m2 12 h). She was maintained on hydroxychloroquine and variable of prednisone depending on the disease activity. Unfortunately, she had partial improvement with persistent heavy proteinuria, and then, oral TAC at 0.1 mg/kg/day was added to MMF, hydroxychloroquine, and prednisone. Three months later, she showed significant improvement in all parameters and allowed prednisone discontinuation.\n\n3.2 Second case\nA 13-year-old girl presented to the local hospital with features of nephrotic syndrome and was treated with prednisone 60 mg/m2/day for 4 weeks; she did not show improvement, and the renal biopsy performed proved lupus nephritis class IV. Interestingly, she did not have extra-renal manifestations of lupus, but laboratory investigations revealed positive ANA (1:160) and low C3 (0.8). Oral prednisone was continued, and MMF (600 mg/m2 12 h) was added along with hydroxychloroquine (5 mg/kg/day). Despite the treatment, she had progressive disease course with hypertension and impaired renal function. Accordingly, MMF was replaced with six doses of monthly CYC (750 mg/m2/dose) and two doses of RTX (350 mg/m2/dose). Proteinuria and hypoalbuminemia improved partially but with progressive renal impairment. Consequently, TAC (0.1 mg/kg/day) was added to her treatment regimen. Two months later, she showed good improvement in all parameters including renal function, and she was able to stop prednisone for the first time since her disease onset. During TAC treatment, she had urinary tract infection (UTI), wherein a proper oral antibiotic was administered for efficiently treating Escherichia coli.\n\n3.3 Third case\nA 14-year-old boy was diagnosed at the age of 11 years with SLE on the basis of mucocutaneous manifestations, leukopenia, autoimmune hemolytic anemia diagnosed by the direct Coombs test, thrombocytopenia, positive ANA, high anti-dsDNA antibody levels, and low C3 and C4 levels with hematuria and proteinuria. Renal biopsy proved lupus nephritis class III. He was treated with prednisone (2 mg/kg/day), hydroxychloroquine (5 mg/kg/day), and AZA (2 mg/kg/day). Owing to partial response, treatment was switched from AZA to MMF (600 mg/m2 12 h).\n\nTwo years later, he presented with nephritic/nephrotic manifestations; hence, renal biopsy was repeated and showed lupus nephritis class IV and V. Accordingly, MMF was replaced by CYC (750 mg/m2/dose), for six doses monthly, and then another six doses for every 3 months; then, he was maintained on MMF but showed partial response. He required two cycles of RTX (350 mg/m2/dose) but showed suboptimal improvement. Then, TAC (0.1 mg/kg/day) was added to MMF, and he showed good improvement.\n\n3.4 Clinical assessment\nAll patients showed improvement in response parameters, namely, SLEDAI, serum albumin, and urine protein/creatinine ratio (Fig. 1). However, eGFR remained stable during the treatment period. Prednisone was weaned gradually and was stopped in two patients. TAC was well tolerated, and no significant adverse effects were observed except in one patient who had simple UTI. Table 2 summarizes the results of response to TAC during the follow-up period.Fig. 1 Changes in urine protein/creatinine ratio during the treatment period.\n\nFig. 1Table 2 Summarized results of response to tacrolimus during the follow-up period.\n\nTable 2\tBaseline\t3 months\t6 months\tLast follow-up visit\t\nUrine Pr/Cr ratio\t\nCase I\t424\t127\t18\t70\t\nCase II\t126\t69\t23\t37\t\nCase III\t629\t76\t62\t49\t\nC3/C4\t\nCase I\t0.76/0.3\t0.76/0.28\t0.9/0.39\t0.9/0.2\t\nCase II\t1.0/0.46\t1.1/0.48\t0.9/0.37\t1.0/0.4\t\nCase III\t0.8/0.1\t1.05/0.1\t1.22/0.13\t1.37/0.21\t\neGFR\t\nCase I\t157\t130\t–\t165\t\nCase II\t43\t51\t49\t52\t\nCase III\t206\t260\t230\t239\t\nSerum albumin\t\nCase I\t30\t36.8\t40\t40\t\nCase II\t34\t39\t43\t44\t\nCase III\t19\t28\t41\t42\t\nAnti-dsDNA antibody\t\nPatient I\t1280\t–\t–\t348\t\nPatient II\t–\t–\t–\t–\t\nPatient III\t456\t–\t296\t–\t\nSLEDAI\t\nCase I\t9\t6\t0\t0\t\nCase II\t4\t0\t0\t0\t\nCase III\t14\t0\t0\t0\t\nPrednisone daily dose\t\nCase I\t10\t5\t0\t0\t\nCase II\t5\t0\t0\t0\t\nCase III\t5\t5\t5\t5\t\nC3, complement 3; C4, Complement 4; eGFR, estimated glomerular filtration rate; dsDNA, double-stranded DNA; SLEDAI, systemic lupus erythematosus disease activity index.\n\n\n\n4 Discussion\nManagement of lupus nephritis remains a great challenge particularly in children with active nephritis and persistent heavy proteinuria [14]. CYC and MMF are still considered as the induction therapy for proliferative lupus nephritis, but MMF is considered as a suitable maintenance therapy. Additionally, MMF might be the preferred induction and maintenance therapy for membranous lupus nephritis [15]. By this approach, the disease relapse rate reduced and the outcome improved significantly. Despite that, renal flare can occur in up to 50% during the maintenance treatment. Thus, in active nephritis or persistent proteinuria, immunosuppressive drugs can be switched to another agent within 3–6 months of treatment [15,16]. Although, evidence is limited, combination of RTX and MMF or CYC might provide efficacious therapeutic effect for refractory cases of SLE including nephritis. However, it was associated with a high rate of infection [17,18].\n\nTAC recently showed encouraging results suggesting its efficacy in adult patients with refractory lupus nephritis, especially in reducing proteinuria [9,19].\n\nThe available data in childhood lupus nephritis are limited. Almost all published data came from one institution. Tanaka et al. followed a cohort of children with lupus nephritis treated with TAC; the results suggest that TAC is beneficial with low cytotoxicity [12,13]. A new treatment option in patients who were refractory to the standard treatment is the multitarget treatment such as a combination of TAC and MMF [20,21].\n\nOur patients had refractory lupus nephritis with persistent heavy proteinuria showing partial response to sequential CYC, MMF, and RTX treatment. Fortunately, combined treatment of TAC and MMF showed beneficial therapeutic effect within 3 months of treatment. This regimen led to complete remission of proteinuria and constant improvement in eGFR. Furthermore, prednisone was discontinued in two patients. Interestingly, none of them had relapses after initiation of this regimen until the last follow-up visit.\n\nEvidence is limited for the use of TAC for treating childhood lupus nephritis. However, if a patient with cSLE with heavy proteinuria resists the standard induction treatment within 6 months, it is worth considering TAC as an alternative therapeutic option. This work had several limitations; it included a small number of patients. Moreover, it is an open uncontrolled study with patients treated in an unblinded manner.\n\nConflicts of interest\nThe authors have nothing to disclose related to this work. This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nPeer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.\n==== Refs\nReferences\n1 Morgan T. Watson L. McCann L. Beresford M. Children and adolescents with SLE: not just little adults Lupus 22 2013 1309 1319 24098003 \n2 Kamphuis S. Silverman E. Prevalence and burden of pediatric-onset systemic lupus erythematosus Nat Rev Rheumatol 6 2010 38 46 \n3 Wu J. Yeh K. Huang J. Early predictors of outcomes in pediatric lupus nephritis: focus on proliferative lesions Semin Arthritis Rheum 43 2014 513 520 23972330 \n4 Sato V. Marques D. Goldenstein P. Carmo L. Jorge L. Titan S. Lupus nephritis is more severe in children and adolescents than in older adults Lupus 21 2012 978 983 22451604 \n5 Boneparth A. Radhakrishna S. Greenbaum L. Yen E. Okamura D. Cooper J. Approach to membranous lupus nephritis: a survey of pediatric nephrologist and pediatric rheumatologists J Rheumatol 44 2017 1619 1623 28916546 \n6 Hogan J. Godron A. Baudouin V. Kwon T. Harambat J. Deschenes G. Combination therapy of rituximab and mycophenolate mofetil in childhood lupus nephritis Pediatr Nephrol 33 2018 111 116 28780657 \n7 Groot N. de Graeff N. Marks S. Brogan P. Avcin T. Bader-Meunier B. Dolezaova P. European evidence-based recommendation for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative Ann Rheum Dis 76 2017 1965 1973 28877866 \n8 Chen Y. Korbet S. Katz R. Schwartz M. Lewis E. Value of a complete or partial remission in severe lupus nephritis Clin J Am Soc Nephrol 3 2008 46 53 18003764 \n9 Hannah J. Casian A. D’Cruz D. Tacrolimus use in lupus nephritis: a systematic review and meta-analysis Autoimmun Rev 15 2016 93 101 26427983 \n10 Choi C. Won S. Bae S. Outcome of multitarget therapy using mycophenolate mofetil and tacrolimus for refractory or relapsing lupus nephritis Lupus 27 2018 1007 1011 29448881 \n11 Chatzidmitriou A. Trachana M. Prasidou-Gerts P. The role of tacrolimus in the step-up induction therpay of refractory childhood-onset lupus nephritis Hippokratia 19 2015 378 27703317 \n12 Tanaka H. Oki E. Tsugawa K. Nonaka K. Suzuki K. Ito E. Effective treatment of young patients with pediatric-onset, long-standing lupus nephritis with tacrolimus given as a single daily dose: an open-label pilot study Lupus 16 2007 896 900 17971363 \n13 Tanaka H. Watanabe S. Aizawa-Yashiro T. Oki E. Kumagai N. Tsuruga K. Long-Term tacrolimus-based immunosuppressive treatment for young patients with lupus nephritis: a prospective study in daily clinical practice clinical practice Nephron Clin Pract 121 2013 165 173 \n14 Tanaka H. Joh K. Imaizumi T. Treatment of pediatric-onset lupus nephritis: a proposal of optimal therapy Clin Exp Nephrol 2 2017 755 763 \n15 Groot N. de Graeff N. Marks S. Brogan P. Avcin T. Bader-Meunier B. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative Ann Rheum Dis 76 2017 1965 1973 28877866 \n16 Elmougy A. Sarhan A. Hammad A. El-Refaey A. Zedan M. Eid R. Lupus nephritis in Egyptian children: a 16-year experience J Nephrol 28 2015 557 562 25491938 \n17 Ale’ed A. Alsonul A. Al-Mayouf S.M. Safety and efficacy of combined cyclophosphamide and rituximab treatment in recalcitrant childhood lupus Rheumatol Int 34 2014 529 533 24218286 \n18 Hogan J. Godron A. Baudouin V. Kwon T. Harambat J. Deschenes G. Combination therapy of rituximab and mycophenolate mofetil in childhood lupus nephritis Pediatr Nephorl 33 2018 111 116 \n19 Yap D. Ma M. Mok M. Kwan L. Chan G. Chan T. Long-term data on tacrolimus treatment in lupus nephritis Rheumatology 53 2014 2232 2237 24996908 \n20 Tanaka H. Aizawa T. Watanabe S. Oki E. Tsuruga K. Imaizumi T. Efficacy of mizoribine-tarcolimus-based induction therapy for pediatric lupus nephritis Lupus 23 2014 8130 8818 \n21 Choi C. Won S. Bae S. Outcomes of mutlitarget therapy using mycophenolate mofetil and tracolimus for refractory or relapsing lupus nephritis Lupus 27 2018 1007 1011 29448881\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2352-6467", "issue": "5(3)", "journal": "International journal of pediatrics & adolescent medicine", "keywords": "Lupus nephritis; Nephrotic syndrome; Systemic lupus erythematosus; Tacrolimus", "medline_ta": "Int J Pediatr Adolesc Med", "mesh_terms": null, "nlm_unique_id": "101670718", "other_id": null, "pages": "99-102", "pmc": null, "pmid": "30805542", "pubdate": "2018-09", "publication_types": "D016428:Journal Article", "references": "17971363;18003764;20683438;22451604;23327881;23972330;24098003;24218286;24651669;24996908;25491938;26427983;27703317;28258497;28780657;28877866;28916546;29448881", "title": "Combination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis.", "title_normalized": "combination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": 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COMBINATION OF TACROLIMUS AND MYCOPHENOLATE MOFETIL IN PERSISTENT PROTEINURIA DUE TO REFRACTORY CHILDHOOD LUPUS NEPHRITIS. INT J PEDIATR ADOLESC MED. 2018?5(3):99-102", "literaturereference_normalized": "combination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20181127", "receivedate": "20181127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15659706, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "SA-MYLANLABS-2018M1089128", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" 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null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "350", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", 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"drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALMUTAIRI A, ALKATHIRI Z, AL-MAYOUF SM. COMBINATION OF TACROLIMUS AND MYCOPHENOLATE MOFETIL IN PERSISTENT PROTEINURIA DUE TO REFRACTORY CHILDHOOD LUPUS NEPHRITIS. INTERNET-DOC 2018?5(3):99-102.", "literaturereference_normalized": "combination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20181130", "receivedate": "20181130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15677472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "SA-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-192007", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", 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COMBINATION OF TACROLIMUS AND MYCOPHENOLATE MOFETIL IN PERSISTENT PROTEINURIA DUE TO REFRACTORY CHILDHOOD LUPUS NEPHRITIS. 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COMBINATION OF TACROLIMUS AND MYCOPHENOLATE MOFETIL IN PERSISTENT PROTEINURIA DUE TO REFRACTORY CHILDHOOD LUPUS NEPHRITIS. INTERNET-DOC 2018?5(3):99-102.", "literaturereference_normalized": "combination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20181130", "receivedate": "20181130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15677471, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "Torsades de pointes (TdP) is a rapid, polymorphic and usually self-terminating ventricular tachycardia associated with the long QT syndrome. Many drugs may cause prolongation of QT interval and be the trigger for TdP occurrence. We present the case of 52-year-old male who was treated with clarithromycin due to bilateral atypical pneumonia. However, on the fourth day of hospitalization he deteriorated, developed pulmonary edema and short cardiac arrest. After successful resuscitation, unfortunately amiodarone and co-trimoxazole were given causing the arrhythmic storm which required many defibrillations. The case highlights the importance of careful QT measurement, appropriate TdP treatment and difficulties resulting from the patient's disagreement for invasive treatment. We think, that knowledge of drug-induced long QT syndrome and its consequences should be widely spread not only in cardiologists, but also in others doctors.", "affiliations": null, "authors": "Bienias|Piotr|P|;Ciurzyński|Michał|M|;Paczyńska|Marzanna|M|;Pruszczyk|Piotr|P|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D017291:Clarithromycin; D000638:Amiodarone", "country": "Poland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1426-9686", "issue": "37(221)", "journal": "Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego", "keywords": null, "medline_ta": "Pol Merkur Lekarski", "mesh_terms": "D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D017291:Clarithromycin; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006323:Heart Arrest; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D011654:Pulmonary Edema; D016171:Torsades de Pointes; D015662:Trimethoprim, Sulfamethoxazole Drug Combination", "nlm_unique_id": "9705469", "other_id": null, "pages": "285-8", "pmc": null, "pmid": "25546990", "pubdate": "2014-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cardiac arrest and electrical storm due to recurrent torsades de pointes caused by concomitant clarithromycin, cotrimoxazole and amiodarone treatment.", "title_normalized": "cardiac arrest and electrical storm due to recurrent torsades de pointes caused by concomitant clarithromycin cotrimoxazole and amiodarone treatment" }

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"reactionmeddrapt": "Ventricular tachycardia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BIENIAS P, CIURZYNSKI M, PACZYNSKA M, PRUSZCZYK P. CARDIAC ARREST AND ELECTRICAL STORM DUE TO RECURRENT TORSADES DE POINTES CAUSED BY CONCOMITANT CLARITHROMYCIN, COTRIMOXAZOLE AND AMIODARONE TREATMENT. POL MERKUR LEKARSKI. 2014;37(221):285-8", "literaturereference_normalized": "cardiac arrest and electrical storm due to recurrent torsades de pointes caused by concomitant clarithromycin cotrimoxazole and amiodarone treatment", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20150310", "receivedate": "20150310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10902559, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "PL-ROXANE LABORATORIES, INC.-2015-RO-00528RO", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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"drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MAGNESIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugadministrationroute": "065", "drugauthorizationnumb": "065178", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRYL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "POTASSIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ventricular tachycardia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ventricular arrhythmia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypomagnesaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BIENIAS P,CIURZYNSKI M,PACZYNSKA M,PRUSZCZYK P. CARDIAC ARREST AND ELECTRICAL STORM DUE TO RECURRENT TORSADES DE POINTES CAUSED BY CONCOMITANT CLARITHROMYCIN, COTRIMOXAZOLE AND AMIODARONE TREATMENT. POLSKI MERKURIUSZ LEKARSKI 2014 NOV;37:221:285-288.", "literaturereference_normalized": "cardiac arrest and electrical storm due to recurrent torsades de pointes caused by concomitant clarithromycin cotrimoxazole and amiodarone treatment", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "PL", "receiptdate": "20150327", "receivedate": "20150327", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10960490, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "OBJECTIVE\nTo assess the efficacy and safety of preoperative intravitreal bevacizumab (IVB) before vitrectomy for diabetic tractional retinal detachment (TRD).\n\n\nMETHODS\nUsing ICD-9 codes, we located all patients with diabetic TRD who underwent 3-port 20-gauge vitrectomy primarily performed by one surgeon between January 2004 and January 2009. Eyes receiving IVB were compared with those not. The following outcomes were compared: visual acuity (VA), duration of surgery, and complication rates.\n\n\nRESULTS\nA total of 99 eyes of 90 patients were included in the analysis. In all, 34 patients received IVB on an average of 11.5 (range, 3-30) days previtrectomy. Age was 46.5 and 51.6 in the IVB and non-IVB groups, respectively. VA was improved significantly in both groups: from 20/617 to 20/62 in the IVB group, and from 20/443 to 20/86 in the non-IVB group (P=0.11 between groups). Operating time and postoperative complications (glaucoma, RD, and revitrectomy rate) were similar in both groups. On comparing IVB and non-IVB eyes in younger patients (≤ 40), operating time was shorter (P=0.02) and a trend to better VA in the IVB group was seen.\n\n\nCONCLUSIONS\nPreoperative IVB may be a useful adjunct to vitrectomy for severe PDR complicated by TRD, particularly in younger diabetics.", "affiliations": "Department of Ophthalmology and Eye Care Services, Henry Ford Hospital, Detroit, MI 48202, USA. pokroyr@yahoo.com", "authors": "Pokroy|R|R|;Desai|U R|UR|;Du|E|E|;Li|Y|Y|;Edwards|P|P|", "chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab", "country": "England", "delete": false, "doi": "10.1038/eye.2011.149", "fulltext": null, "fulltext_license": null, "issn_linking": "0950-222X", "issue": "25(8)", "journal": "Eye (London, England)", "keywords": null, "medline_ta": "Eye (Lond)", "mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003930:Diabetic Retinopathy; D006801:Humans; D058449:Intravitreal Injections; D007902:Length of Stay; D008875:Middle Aged; D011300:Preoperative Care; D012163:Retinal Detachment; D015861:Retinal Neovascularization; D012189:Retrospective Studies; D015983:Selection Bias; D016896:Treatment Outcome; D014792:Visual Acuity; D014821:Vitrectomy", "nlm_unique_id": "8703986", "other_id": null, "pages": "989-97", "pmc": null, "pmid": "21738230", "pubdate": "2011-08", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "18547539;19039332;15992755;19208678;20135139;18942219;4000644;19787608;18286296;17965108;19205502;19584650;19699531;17891057;18696095;18631336;15030802;19269033;16829817;19284326", "title": "Bevacizumab prior to vitrectomy for diabetic traction retinal detachment.", "title_normalized": "bevacizumab prior to vitrectomy for diabetic traction retinal detachment" }

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{ "abstract": "Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder that mainly affects middle-aged patients with human immunodeficiency virus (HIV) infection. However, HIV-negative patients can also be affected representing a small proportion of the total MCD cases. Of note, recent studies from China in HIV-negative patients with MCD have suggested that the onset of the disease can be observed in younger age than previously thought. If undiagnosed and untreated, the MCD has a poor prognosis and may progress to lymphoma. We present an 82-year-old immunocompetent male patient who was admitted to our department because of low-grade fever, cachexia, anasarca, hepatosplenomegaly, and generalized lymphadenopathy. Laboratory findings showed anemia and increased markers of inflammation including hyperferritinemia and polyclonal hyperglobulinemia. Infectious causes including HIV were ruled out. Histological examination of a cervical lymph-node revealed lesions supportive of MCD diagnosis. Of note, the outer-zone plasmablasts' nuclei stained positive for human herpesvirus-8 (HHV8). The patient received 4 cycles of cyclophosphamide, vincristine, and dexamethasone with regression of all symptoms. This case underlines that HHV8-associated MCD should be considered as a rare cause of generalized lymphadenopathy even in HIV-negative immunocompetent patients when other causes have been appropriately excluded because a timely diagnosis can be life-saving.", "affiliations": "Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece.;Department of Pathology, Medical School, University of Thessaly, 41110 Larissa, Greece.;Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece.;Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece.", "authors": "Azariadis|Kalliopi|K|https://orcid.org/0000-0002-4218-9847;Ioannou|Maria|M|;Zachou|Kalliopi|K|;Dalekos|George N|GN|https://orcid.org/0000-0001-7075-8464", "chemical_list": null, "country": "Egypt", "delete": false, "doi": "10.1155/2021/6614208", "fulltext": "\n==== Front\nCase Rep Infect Dis\nCase Rep Infect Dis\nCRIID\nCase Reports in Infectious Diseases\n2090-6625\n2090-6633\nHindawi\n\n10.1155/2021/6614208\nCase Report\nAn Immunocompetent HIV-Negative Elderly Patient with Low-Grade Fever, Generalized Lymphadenopathy, Splenomegaly, and Acute Phase Response: Do Not Forget Castleman Disease\nhttps://orcid.org/0000-0002-4218-9847\nAzariadis Kalliopi 1\nIoannou Maria 2\nZachou Kalliopi 1\nhttps://orcid.org/0000-0001-7075-8464\nDalekos George N. dalekos@med.uth.gr\n1\n1Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece\n2Department of Pathology, Medical School, University of Thessaly, 41110 Larissa, Greece\nAcademic Editor: Larry M. Bush\n\n2021\n11 3 2021\n2021 661420822 12 2020\n19 2 2021\n2 3 2021\nCopyright © 2021 Kalliopi Azariadis et al.\n2021\nThis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nMulticentric Castleman disease (MCD) is a rare lymphoproliferative disorder that mainly affects middle-aged patients with human immunodeficiency virus (HIV) infection. However, HIV-negative patients can also be affected representing a small proportion of the total MCD cases. Of note, recent studies from China in HIV-negative patients with MCD have suggested that the onset of the disease can be observed in younger age than previously thought. If undiagnosed and untreated, the MCD has a poor prognosis and may progress to lymphoma. We present an 82-year-old immunocompetent male patient who was admitted to our department because of low-grade fever, cachexia, anasarca, hepatosplenomegaly, and generalized lymphadenopathy. Laboratory findings showed anemia and increased markers of inflammation including hyperferritinemia and polyclonal hyperglobulinemia. Infectious causes including HIV were ruled out. Histological examination of a cervical lymph-node revealed lesions supportive of MCD diagnosis. Of note, the outer-zone plasmablasts' nuclei stained positive for human herpesvirus-8 (HHV8). The patient received 4 cycles of cyclophosphamide, vincristine, and dexamethasone with regression of all symptoms. This case underlines that HHV8-associated MCD should be considered as a rare cause of generalized lymphadenopathy even in HIV-negative immunocompetent patients when other causes have been appropriately excluded because a timely diagnosis can be life-saving.\n==== Body\n1. Introduction\n\nCastleman disease (CD) was first described in 1954 in a series of patients with localized mediastinal lymphadenopathy and characteristic histopathological features [1]. Currently, the term CD is applied to diverse polyclonal B-cell lymphoproliferative entities with distinct clinicopathologic features based on the number of affected lymph nodes. The disease is classified in two general forms: the unicentric CD (UCD) and the multicentric CD (MCD) [2–5]. The UCD form refers to 75% of all cases, with histological features of either hyaline vascular proliferation (90%) or mature plasma cell proliferation (10%) [6, 7]. The MCD is subclassified to (a) the human herpes virus 8 (HHV8 or Kaposi Sarcoma- (KS-)associated herpes virus, KSV) positive MCD seen predominantly in human immunodeficiency virus- (HIV-) infected or otherwise immunocompromised individuals [2, 4, 5, 8] and (b) the idiopathic MCD (iMCD) with histological features of both hyaline vascular and plasma cell proliferation with relatively preserved nodal architecture [3, 9]. In addition, two clinical syndromes have been described in association with iMCD: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes) [10, 11] and TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) [10, 12].\n\nThe estimated annual incidence of MCD ranges between 2.4 and 6.25 per million person-years in Western population [12–14]. However, HHV8-associated MCD prevalence is practically unknown and probably underestimated, being underdiagnosed especially in HIV-negative patients who represent only a small proportion of cases [15–17]. The reasons for underdiagnosis is the high level of suspicion required from clinicians and pathologists, as the clinical features of HHV8-associated MCD overlap significantly with those of uncontrolled infections and lymphoid malignancies. The clinical and laboratory characteristics include systemic manifestations such as fever, sweating, fatigue, cachexia, generalized lymphadenopathy, splenomegaly, anasarka, cytopenias, and hypoalbuminemia [18–21]. Furthermore, patients with MCD are at high risk of developing non-Hodgkin lymphomas (NHL) [11, 21, 22]. Risk assessment and estimation of survival is difficult because of the rarity of the disease. However, a 5-year survival of about 80% has been recorded after treatment in small case series from France and South Korea [11, 23].\n\nHerein, we present a case of an elderly immunocompetent patient with HHV8-associated MCD and highlight the crucial steps for establishing the diagnosis in conjunction with approach to treatment.\n\n2. Case Presentation\n\nAn 82-year-old male was admitted to the Department of Medicine because of low-grade fever (37.8oC) over the past 24 hours and cachexia, occipital headache, and pain in the cervical spine over the past 72 hours. His medical history included ischemic heart failure under furosemide and bisoprolol, atrial fibrillation under dabigatran, ocular cataract, and a single episode of herpes zoster in the left abdominal wall four months ago. The patient resided in an agricultural area, owned poultry, and reported frequent consumption of nonpasteurized dairy products. On clinical examination, the patient was hemodynamically stable, and he had anasarka and tenderness at the cervical spine without stiffness, restriction to movement or Kerning and Brudzinski signs. The rest neurologic examination was also normal. The liver and spleen were palpable in combination with multiple nontender, mobile lymph nodes in the cervical, supraclavicular, axillary, and inguinal areas.\n\nLaboratory work-up on admission revealed hypochromic normocytic anemia, with normal leukocytes and platelets count, hypoalbuminemia, polyclonal hyperglobulinemia with increased immunoglobulin G and increased inflammatory markers such as erythrocyte sedimentation rate, C-reactive protein, ferritin, and fibrinogen (Supplementary Table S1). The rest of the laboratory tests were within normal limits (Supplementary Table S1). The chest X-ray revealed bilateral pleural effusions. Because of the presence of low-grade fever, headache, and tenderness at the cervical spine, a cerebrospinal fluid paracentesis was performed which was not contributory (Supplementary Table S1). To further assess the generalized peripheral lymphadenopathy, a computer tomography (CT) of the cervix, thorax, and abdomen was performed. The results showed several lymph nodes (maximum diameter 3.8 cm) with non-necrotizing centers in all anatomical spaces (cervix, supraclavicular and axillary areas, mediastinum, and retroperitoneal, femoral, and inguinal areas). A work-up for zoonosis based on local endemicity [24–29] that included serological tests for Brucella, Leishmania, Leptospira, Coxiella species, Rickettsia conorii and typhi, Bartonella, and Toxoplasma was unrevealing (Supplementary Table S1). Furthermore, serological testing for several viruses including Epstein Barr Virus, cytomegalovirus, HIV, and hepatitis B and C viruses was also negative. Multiple sets of blood cultures incubated for 21 days for slowly growing bacteria were also negative. Tuberculosis was ruled out based on a negative skin tuberculin test and negative sputum examination (direct Ziehl-Neelsen staining and long-term culture of 6 weeks). Peripheral blood and bone marrow smears were negative for neoplastic cells while the bone marrow biopsy revealed granulocyte left shift, small T and B cells, and 8% polyclonal plasma cells.\n\nFinally, a right supraclavicular lymph node of 3.8 cm diameter was biopsied. The histological examination revealed mildly deranged nodal architecture, multiple lymphoid follicles with vascular proliferation and perivascular hyalinization of the blast centers, increased follicular dendritic cells (CD21+), and mantle lymphocytes in onion-skin layers surrounded by polyclonal plasma cells without monoclonal proliferation of κ- and λ-light chains. Staining for CD3, CD4, CD68, ALK, EMA, CD23, and cyclin D1 was nonsupportive of lymphoma. Of note, anosoblasts/plasmablasts (MUM1+, CD30+, and CD15-) in the outer zone showed positive nuclear staining for HHV8.\n\nAs most of the causes of generalized lymphadenopathy in combination with hepatosplenomegaly, anasarka, high markers of acute phase response, and polyclonal hyperglobulinemiahad been excluded, the differential diagnosis included sarcoidosis and miscellaneous lymphoproliferative disorders. However, sarcoidosis was unlikely based on the lack of abnormal findings in the lung imaging, absence of respiratory symptoms, and nontypical lymph node lesions on histology. In addition, no arthritis was mentioned or was evident on physical examination. In contrast, the histological findings of the lymph node biopsy revealed a benign lymphoproliferative disorder characterized by increased plasma cells that stained positive for HHV8 along with vascular proliferation and perivascular hyalinization supporting the diagnosis of CD (Figures 1–3).\n\nThe patient received four cycles of cyclophosphamide (1000 mg/cycle), vincristine (10 mg/cycle), and dexamethasone (16 mg/day for days 1–5/cycle) in 21-day intervals. Resolution of symptoms and all physical findings was achieved after the third cycle. Normalization of the acute phase inflammatory markers and resolution of anemia was evident at the end of the fourth cycle indicating complete response at 12 weeks of treatment (Supplementary Table S1). Complete remission of the disease was further confirmed on 18F-FDG positron emission tomography. Regarding side effects, the patient experienced only a single episode of neutropenia after the second cycle of treatment which required administration of granulocyte colony-stimulating factor (GCSF). Till the time of this writing, the patient remains asymptomatic having completed 6 months of follow-up without any clinical or laboratory sign of recurrence.\n\n3. Discussion\n\nHHV8-associated MCD is a rare clinical entity, especially in HIV-negative immunocompetent individuals. The incidence of HHV8-associated MCD is highly related to the HHV8 endemicity in the general population (1.4–1.9% in Japan, 4% in north Europe, and 10–20% in the Mediterranean basin and Balkans) [30–36]. Furthermore, the demographic characteristics of HIV-negative, HHV8-assosciated MCD patients differ according to the population studied with European and American studies reporting higher incidence in males in the sixth decade [10, 12, 23, 31]. However, a recent retrospective study from China in 185 CD patients including 64 with MCD has shown that the onset of the disease can be observed in younger age, even though precise demographic data on the 11/64 HIV-negative, HHV8-associated MCD patients was not given [32].\n\nThe clinical characteristics of the disease include the presence of generalized lymphadenopathy, splenomegaly, and systemic inflammatory manifestations such as fever, fatigue, night sweats, weight loss, volume overload (sometimes with ascites and pulmonary effusions), skin abnormalities (including hyperpigmentation and cherry hemangiomas), and nonspecific neurologic, respiratory, and gastrointestinal symptoms. Secondary hemophagocytic lymphohistiocytosis (sHLH), autoimmune cytopenias, renal involvement (including secondary amyloidosis and membranoproliferative glomerulonephritis), peripheral neuropathy, lymphoid interstitial pneumonitis, and bronchiolitis obliterans have also been described [33, 35, 37]. Of note, patients with HHV8-associated MCD are at high risk of developing HHV8-associated lymphomas and KS even years after the initial diagnosis [22, 38].\n\nRegarding MCD pathogenesis, overproduction and dysregulation of circulating cytokines like interleukin-6 (IL-6), interleukin-10, tumor necrosis factor-alpha, and interleukin-1 are thought to play a pivotal role, with IL-6 being the key playmaker [2, 39]. In addition to its apparent role as a growth and differentiation factor for lymphocytes and plasma cells leading to lymph node enlargement, hepatosplenomegaly, and bone marrow polyclonal plasmacytosis with the accompanying B-symptoms (fever, night sweats, weight loss, and cachexia), IL-6 exhibits many pleiotropic actions [40]. Hepatocytes respond to IL-6 by diminishing albumin production and producing several acute phase proteins and hepcidin, which in turn leads to reduced intestinal iron absorption, impaired release of iron stored in the macrophages, and anemia [40, 41]. In addition, the endothelium responds by increasing vascular endothelial growth factor secretion which induces angiogenesis and increased vascular permeability. The latter, in combination with the hypoalbuminemia, precipitates extravascular fluid accumulation (ascites, pleural and pericardial effusion, and anasarka). Furthermore, increased fibrinogen and tissue factor production can cause hypercoagulopathy, thromboembolic phenomena, and thrombotic microangiopathy leading to multiorgan failure [40].\n\nHIV infection or other immunosuppressive state enables HHV8 to escape the host's immune system and replicate in lymph node plasmablasts. Lytic activation of infected B-cells results in release of cytokines which in turn gives rise to the clinical syndrome [2]. Interestingly, HHV8-associated MCD can also occur in HIV-infected patients with preserved CD4 counts and low HIV-RNA [42]. In immunocompetent individuals, the cause that drives HHV8 escape is largely unknown, as it is not clear why individuals infected with HHV8 only rarely develop MCD [2]. In more detail, HHV8 has tropism for B cells, monocytes, dendritic cells, keratinocytes, and epithelial and endothelial cells [8]. Several HHV8 viral proteins enhance the production of human IL-6 (hIL-6) or independently activate hIL-6 pathways [2, 8]. HHV8-encoded viral IL-6 (vIL-6), which is mainly released during the lytic replication of the virus, bears a 25% sequence homology with hIL-6 and can bind directly to the IL-6 receptor (gp130) irrespectively of its co-receptor p80 [8, 43]. Therefore, it is possible that vIL6 enhances IL-6 signaling in a wider range of tissues compared to hIL-6. In HHV8-associated MCD, vIL-6 plasma levels correlate with disease activity and collaboration of both viral and endogenous IL-6 may be crucial for the clinical expression of MCD [2, 8].\n\nA thorough investigation and exclusion of several infectious diseases based on local epidemiology, autoimmune diseases, sHLH [44], and hematological neoplasms, as we performed in our patient, is essential for the differential diagnosis of the disease. HIV serology is mandatory in all patients, since management and prognosis differ in the case of HIV-positive HHV8-associated MCD. Finally, a lymph node biopsy is mandatory in order to exclude NHL and guide the diagnosis and treatment. Positive immunohistochemical staining for HHV8 and/or PCR for HHV8 establishes the diagnosis of HHV8-associated MCD in a patient with generalized lymphadenopathy and CD histopathology.\n\nIf untreated, HHV8-associated MCD bares a dismal prognosis and can be lethal within two years [44]. However, due to the rarity of the disease, there is no established treatment [5, 45]. For this reason, the outstanding Castleman Disease Collaborative Network (CDCN) was founded in 2012 by Drs Frits van Rhee and David Fajgenbaum, in order to advance research on pathophysiology, diagnosis, and especially treatment. In the premonoclonal antibody era, therapy was based on cytotoxic chemotherapy, extrapolated from the treatment of B-cell lymphomas. Agents used in different anecdotal cases and small series include etoposide, interferon-alpha, thalidomide, cyclophosphamide, vincristine, and doxorubicin with or without corticosteroids in various combinations [37, 38, 45]. Conclusions regarding efficacy, response, and relapse rates cannot be drawn safely due to the lack of randomized trials, established response criteria, and the heterogeneity of patients. The role of antivirals (ganciclovir, foscarnet, cidofovir, and valanciclovir) is controversial, and remissions have been described only with the use of ganciclovir in one small retrospective study [45, 46].\n\nBreakthrough in MCD treatment was the discovery of the biological agents. Several studies in HIV-positive HHV8-associated MCD patients support the use of rituximab, whereas efficacy in HIV-negative patients relies mostly on anecdotal cases or small case series [4, 5, 47–50]. Treatment with rituximab has also been associated with a substantially lower risk of progression to NHL, although bearing the risk for KS exacerbation in patients with concurrent KS [5, 45]. Biological agents targeting the pathogenetic IL-6 pathway have shown efficacy in iMCD, but the clinical experience with these agents in HHV8-associated MCD is scarce [45]. Actually, tocilizumab, a humanized monoclonal antibody against the IL-6 receptor has shown efficacy and long-term safety in two HIV-negative HHV8-associated MCD cases [51]. As of September 2011, an open-label clinical trial to assess efficacy of tocilizumab in HHV8-associated MCD (NCT01441063) has been running in the USA, with 8 patients enrolled and estimated completion date in 2023.\n\nNevertheless, the treatment of HHV8-associated MCD should be individualized keeping in mind the lack of consensus on response-to-treatment criteria and optimal treatment duration [5, 45]. Our patient was symptomatic with increased inflammatory markers, and he received four cycles of cyclophosphamide, vincristine, and dexamethasone. We have chosen this treatment option because of the potential high risk of rituximab toxicity in a patient older than 80 years of age keeping also in mind, that in the case series of rituximab administration in patients with HHV8-associated MCD, the patients were much younger than our patient. The response was spectacular, since all symptoms and signs resolved and laboratory values returned to normal after four months of treatment. In addition, the patient experienced only a single episode of neutropenia after the third circle that required treatment with GCSF. Complete treatment response was confirmed by 18F-FDG PET, and the patient remains on remission six months after treatment completion.\n\nIn conclusion, our case highlights the importance for clinicians to keep in mind and recognizes this rare syndrome even in immunocompetent patients with generalized lymphadenopathy and systemic symptoms when other common causes have been appropriately excluded because a prompt and timely diagnosis can be life-saving as in our case. Lymph node histology is the backbone for a firm diagnosis and exclusion of other pathologies. HHV8-associated MCD should not be overlooked as this disorder carries a malignant course and unfavorable prognosis if undiagnosed and untreated.\n\nData Availability\n\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to disclose.\n\nSupplementary Materials\n\nSupplementary Materials Table S1: laboratory data of the patient on admission and after remission (12 weeks after treatment initiation).\n\nClick here for additional data file.\n\nFigure 1 Hematoxylin and eosin stain, original magnification ×10. Germinal centers traversed by penetrating vessels (arrow 1) and thickened mantle zones with lymphocytes arranged in layers with onion skin appearance (arrow 2). In the interfollicular areas, there is extensive vascular proliferation with perivascular hyalinization (arrow 3).\n\nFigure 2 Hematoxylin and eosin stain, original magnification ×40. Sheets of mature plasma cells and a few plasmablasts with large nuclei, vesicular chromatin, and prominent nucleoli (arrows) are also seen in the interfollicular areas.\n\nFigure 3 HHV-8 immunohistochemical stain, original magnification ×40. Cells with plasmablastic morphology are HHV8-infected cells (brown nuclei). These cells were polytypic (immunostaining for kappa and lambda light chains (data not shown)). In order to exclude the possibility of random positive counting, the immunostaining section was split into four fields and cells positive for HHV8 were counted in each of these four quartiles. The measurements were grouped for each quartile. Pairwise comparisons among groups using the student t test showed p values >0.05 in all cases. In addition, repeating procedures concerning immunohistochemical staining for HHV8 were performed in other two different histological sections producing finally similar results.\n==== Refs\n1 Castleman B. Towne V. W. 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Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease Blood 2005 106 8 2627 2632 10.1182/blood-2004-12-4602 2-s2.0-27144488346 15998837\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2021()", "journal": "Case reports in infectious diseases", "keywords": null, "medline_ta": "Case Rep Infect Dis", "mesh_terms": null, "nlm_unique_id": "101573243", "other_id": null, "pages": "6614208", "pmc": null, "pmid": "33777463", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "12667236;18955561;31708515;29157618;15764213;22791417;26805758;24174627;30995501;18397911;24387011;29157621;26087799;25743761;26867490;13356266;29223447;14615380;28087540;25120049;27847886;22729151;19008139;17664482;17385692;15998837;29157613;22223822;25903208;21555697;23223599;31766018;11835348;10729121;27029894;20569167;25548759;19264784;32106302;27063975;13111435;31750324;28333859;30181172;31829070;28699668;29124835;15896845;31305183;25331113;29143319", "title": "An Immunocompetent HIV-Negative Elderly Patient with Low-Grade Fever, Generalized Lymphadenopathy, Splenomegaly, and Acute Phase Response: Do Not Forget Castleman Disease.", "title_normalized": "an immunocompetent hiv negative elderly patient with low grade fever generalized lymphadenopathy splenomegaly and acute phase response do not forget castleman disease" }

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{ "abstract": "We report a case of a 15-year-old male who developed severe left-sided hemiplegia and hemi-sensory loss 20 minutes after arrival in post anaesthetic care unit following an uneventful general anaesthesia for removal of a cannulated screw of left hip. Initial CT and MRI/MRA with diffusion-weighted imaging were unremarkable. The patient was transferred to The Royal Children's Hospital Melbourne and was commenced on heparin infusion pending investigation results. Complete recovery occurred within 36 hours. Eventually, hemiplegic migraine was diagnosed on the basis of negative investigations and a retrospective history of the patient's migraine. This case demonstrates that the management of peri-operative neurological deficits must be approached in a systematic fashion. Hemiplegic migraine is a well-defined clinical syndrome. It is not merely a diagnosis of exclusion.", "affiliations": "Department of Anaesthesia, Box Hill Hospital, Melbourne, Victoria, Australia. linl@ausdoctors.net", "authors": "Lin|L|L|;Adey|C|C|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/0310057X0703500318", "fulltext": null, "fulltext_license": null, "issn_linking": "0310-057X", "issue": "35(3)", "journal": "Anaesthesia and intensive care", "keywords": null, "medline_ta": "Anaesth Intensive Care", "mesh_terms": "D000293:Adolescent; D000768:Anesthesia, General; D006429:Hemiplegia; D006801:Humans; D006987:Hypesthesia; D008297:Male; D008881:Migraine Disorders", "nlm_unique_id": "0342017", "other_id": null, "pages": "418-22", "pmc": null, "pmid": "17591140", "pubdate": "2007-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Presentation of hemiplegic migraine--hemiplegia and hemi-sensory loss following general anaesthesia.", "title_normalized": "presentation of hemiplegic migraine hemiplegia and hemi sensory loss following general anaesthesia" }

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{ "abstract": "Cutaneous nocardiosis is an infrequent infection which has been increasingly reported in immunocompromised patients. Although trimethoprim-sulfamethoxazole is considered to be the agent of choice for treatment of nocardiosis, newer antimicrobials such as tigecycline have been proven to be effective in vitro, as well. We report the first case of primary cutaneous nocardiosis in a renal transplant recipient having corresponded well to treatment with tigecycline.", "affiliations": "5th Department of Medicine, Division of Infectious Diseases, Evangelismos Hospital, Athens, Greece.;5th Department of Medicine, Division of Infectious Diseases, Evangelismos Hospital, Athens, Greece.;Department of Nephrology, Evangelismos Hospital, Athens, Greece.;Department of Microbiology, Evangelismos Hospital, Athens, Greece.;Department of Microbiology, Evangelismos Hospital, Athens, Greece.;5th Department of Medicine, Division of Infectious Diseases, Evangelismos Hospital, Athens, Greece.", "authors": "Mylona|Eleni|E|;Papastamopoulos|Vasilios|V|;Giannopoulou|Myrto|M|;Perivolioti|Efstathia|E|;Psaroudaki|Zoi|Z|;Skoutelis|Athanasios|A|", "chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D000078304:Tigecycline", "country": "Saudi Arabia", "delete": false, "doi": "10.4103/1319-2442.243954", "fulltext": null, "fulltext_license": null, "issn_linking": "1319-2442", "issue": "29(5)", "journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia", "keywords": null, "medline_ta": "Saudi J Kidney Dis Transpl", "mesh_terms": "D000900:Anti-Bacterial Agents; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008206:Lymphatic Diseases; D008297:Male; D008875:Middle Aged; D009617:Nocardia Infections; D009894:Opportunistic Infections; D017192:Skin Diseases, Bacterial; D000078304:Tigecycline; D016896:Treatment Outcome", "nlm_unique_id": "9436968", "other_id": null, "pages": "1207-1210", "pmc": null, "pmid": "30381521", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": null, "title": "Lymphocutaneous nocardiosis in a kidney transplant patient successfully treated with tigecycline.", "title_normalized": "lymphocutaneous nocardiosis in a kidney transplant patient successfully treated with tigecycline" }

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LYMPHOCUTANEOUS NOCARDIOSIS IN A KIDNEY TRANSPLANT PATIENT SUCCESSFULLY TREATED WITH TIGECYCLINE. 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"drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EZETIMIBE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous nocardiosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201704" } }, "primarysource": { "literaturereference": "MYLONA E, PAPASTAMOPOULOS V, GIANNOPOULOU M, PERIVOLIOTI E, PSAROUDAKI Z, SKOUTELIS A. LYMPHOCUTANEOUS NOCARDIOSIS IN A KIDNEY TRANSPLANT PATIENT SUCCESSFULLY TREATED WITH TIGECYCLINE. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION. 2018?29(5):1207-1210.", "literaturereference_normalized": "lymphocutaneous nocardiosis in a kidney transplant patient successfully treated with tigecycline", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20191218", "receivedate": "20191218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17172652, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "Background: The goal of this study was to relate diffusion MR measures of white matter integrity of the retinofugal visual pathway with prolactin levels in a patient with downward herniation of the optic chiasm secondary to medical treatment of a prolactinoma. Methods: A 36-year-old woman with a prolactinoma presented with progressive bilateral visual field defects 9 years after initial diagnosis and medical treatment. She was diagnosed with empty-sella syndrome and instructed to stop cabergoline. Hormone testing was conducted in tandem with routine clinical evaluations over 1 year and the patient was followed with diffusion magnetic resonance imaging (dMRI), optical coherence tomography (OCT), and automated perimetry at three time points. Five healthy controls underwent a complementary battery of clinical and neuroimaging tests at a single time point. Results: Shortly after discontinuing cabergoline, diffusion metrics in the optic tracts were within the range of values observed in healthy controls. However, following a brief period where the patient resumed cabergoline (of her own volition), there was a decrease in serum prolactin with a corresponding decrease in visual ability and increase in radial diffusivity (p < 0.001). Those measures again returned to their baseline ranges after discontinuing cabergoline a second time. Conclusions: These results demonstrate the sensitivity of dMRI to detect rapid and functionally significant microstructural changes in white matter tracts secondary to alterations in serum prolactin levels. The inverse relations between prolactin and measures of white matter integrity and visual function are consistent with the hypothesis that prolactin can play a neuroprotective role in the injured nervous system.", "affiliations": "Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States.;Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY, United States.;University of Rochester School of Medicine and Dentistry, Rochester, NY, United States.;University of Rochester School of Medicine and Dentistry, Rochester, NY, United States.;Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY, United States.;Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States.;Department of Psychology, Carnegie Mellon University, Pittsburgh, PA, United States.;Department of Endocrinology and Metabolism, University of Rochester Medical Center, Rochester, NY, United States.;Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States.;Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States.;Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States.", "authors": "Paul|David A|DA|;Strawderman|Emma|E|;Rodriguez|Alejandra|A|;Hoang|Ricky|R|;Schneider|Colleen L|CL|;Haber|Sam|S|;Chernoff|Benjamin L|BL|;Shafiq|Ismat|I|;Williams|Zoë R|ZR|;Vates|G Edward|GE|;Mahon|Bradford Z|BZ|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fmed.2021.680602", "fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.680602\nMedicine\nOriginal Research\nEmpty Sella Syndrome as a Window Into the Neuroprotective Effects of Prolactin\nPaul David A. 1\n\nStrawderman Emma 2\n\nRodriguez Alejandra 3\n\nHoang Ricky 3\nSchneider Colleen L. 234\n\nHaber Sam 1\nChernoff Benjamin L. 4\nShafiq Ismat 5\nWilliams Zoë R. 167\n\nVates G. Edward 1\nMahon Bradford Z. 1478*\n1Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States\n2Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY, United States\n3University of Rochester School of Medicine and Dentistry, Rochester, NY, United States\n4Department of Psychology, Carnegie Mellon University, Pittsburgh, PA, United States\n5Department of Endocrinology and Metabolism, University of Rochester Medical Center, Rochester, NY, United States\n6Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, United States\n7Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States\n8Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, United States\nEdited by: Holly Bridge, University of Oxford, United Kingdom\n\nReviewed by: Valentina Di Iorio, University of Campania Luigi Vanvitelli, Italy; Shweta Singhal, Singapore National Eye Center, Singapore\n\n*Correspondence: Bradford Z. Mahon bmahon@andrew.cmu.edu\nThis article was submitted to Ophthalmology, a section of the journal Frontiers in Medicine\n\n08 7 2021\n2021\n8 68060215 3 2021\n14 6 2021\nCopyright © 2021 Paul, Strawderman, Rodriguez, Hoang, Schneider, Haber, Chernoff, Shafiq, Williams, Vates and Mahon.\n2021\nPaul, Strawderman, Rodriguez, Hoang, Schneider, Haber, Chernoff, Shafiq, Williams, Vates and Mahon\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: The goal of this study was to relate diffusion MR measures of white matter integrity of the retinofugal visual pathway with prolactin levels in a patient with downward herniation of the optic chiasm secondary to medical treatment of a prolactinoma.\n\nMethods: A 36-year-old woman with a prolactinoma presented with progressive bilateral visual field defects 9 years after initial diagnosis and medical treatment. She was diagnosed with empty-sella syndrome and instructed to stop cabergoline. Hormone testing was conducted in tandem with routine clinical evaluations over 1 year and the patient was followed with diffusion magnetic resonance imaging (dMRI), optical coherence tomography (OCT), and automated perimetry at three time points. Five healthy controls underwent a complementary battery of clinical and neuroimaging tests at a single time point.\n\nResults: Shortly after discontinuing cabergoline, diffusion metrics in the optic tracts were within the range of values observed in healthy controls. However, following a brief period where the patient resumed cabergoline (of her own volition), there was a decrease in serum prolactin with a corresponding decrease in visual ability and increase in radial diffusivity (p < 0.001). Those measures again returned to their baseline ranges after discontinuing cabergoline a second time.\n\nConclusions: These results demonstrate the sensitivity of dMRI to detect rapid and functionally significant microstructural changes in white matter tracts secondary to alterations in serum prolactin levels. The inverse relations between prolactin and measures of white matter integrity and visual function are consistent with the hypothesis that prolactin can play a neuroprotective role in the injured nervous system.\n\ndiffusion MRI\npituitary tumor\nprolactin\noptical coherence tomography\nneuro-glial interactions\nneuroprotection\nNational Institutes of Health10.13039/100000002\n==== Body\nIntroduction\n\nCrush and stretch injuries to the optic nerve, tract and chiasm in animals reveal that demyelination is a primary process in the progression of delayed axonal degeneration (1–4). Human studies looking at compression of the optic chiasm have confirmed those findings and also suggested the possibility of rapid vision recovery (5, 6). Unlike primary axotomy, in which axonal connections are immediately severed, delayed axonal degeneration is a potentially reversible process. Several mechanisms likely contribute to recovery, including remyelination (7), microtubule reorganization, shifts in ion channel permeability and restoration of glial-neuronal connections at the paranodes (8). Left unhindered, delayed axonal degeneration and its associated sequela lead to irreversible cell death (1–3, 9–11). Prolactin, a hormone synthesized in and released by the anterior pituitary gland with well-established roles in lactation, demonstrates promise as a mediator of delayed axonal degeneration and is known to control important mechanisms in the central nervous system (12, 13). In the retina, prolactin serves as a neurotrophic factor required for maintaining homeostasis during both injury (14) and physiologic aging (15), with receptors prominent in the ganglion cell layer as well as the outer and inner nuclear layers (16). In white matter, high prolactin levels signal oligodendrocyte proliferation, modulate neurotransmission (17) and promote white matter repair after demyelination in mice (18).\n\nA specific disease model – compression of retinofugal fibers by large prolactin-secreting pituitary tumors (i.e., prolactinomas) offers a “natural experiment” with which to observe the potential mechanisms through which prolactin exerts a neuroprotective role in the injured human brain (19). Patients with prolactinomas often experience a stereotyped loss of vision in the temporal hemifields secondary to the mass (i.e., compressive effect) of the tumor on the retinofugal pathway, in addition to multiple endocrinopathies (20). Treatment using dopamine agonists (e.g., cabergoline) increases the available substrate capable of binding D2 receptors on lactotroph cells in the anterior pituitary gland and inhibits prolactin release (21). A secondary effect of cabergoline is reduction in tumor size (21). As such, it is used as a first line treatment for prolactinomas. Surgical decompression is reserved for cases of dopamine agonist-resistant prolactinomas or acute changes in tumor size that necessitate immediate intervention to prevent blindness. Dopamine agonist therapy for large prolactinomas can, in rare circumstances, cause symptomatic empty-sella syndrome. Empty-sella syndrome is characterized by both downward herniation of the optic chiasm into an empty sella turcica (the bony cave that houses the pituitary gland) and delayed secondary vision loss. To our knowledge, only 21 cases have been reported in the literature; the large majority of them were treated by reducing or completely stopping dopamine agonist therapy (22–27), or with surgical management to untether or elevate the optic apparatus (28–34). With cessation of dopamine agonist therapy, all reported patients demonstrated improvement of visual outcomes without any changes in either the level of herniation or macrostructural properties of the optic chiasm. How vision returns, despite persistent downward herniation of the chiasm in this small cohort of patients, has not previously been studied.\n\nHere we investigate mechanistic hypotheses of the effect of prolactin on glial-neuronal function in an observational study of a rare patient with symptomatic empty sella syndrome. Both delayed axonal injury and retinal health were studied longitudinally at three time points over a year, using a combination of diffusion magnetic resonance imaging (dMRI) and optical coherence tomography (OCT), respectively. Measures of axonal injury and retinal health for our case study were compared with a cohort of healthy control participants. Diffusion MRI offers a tool with which to non-invasively measure myelin integrity (3, 35–38). Specifically, an increase in radial diffusivity (RD) without changes in axial diffusivity (AD) indicates a breakdown in myelin, while decreased AD indicates axonal degeneration (37). These properties have been leveraged in human subjects to characterize microstructural changes occurring across the length of the optic tract for numerous pathologies that include pituitary macroadenomas (5), optic neuritis (39), and glaucoma (40). Additionally, retrograde degeneration of retinal ganglion cells can be characterized as a function of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness as measured by OCT (41–43).\n\nAs noted, the standard clinical treatment for symptomatic empty sella syndrome is to discontinue cabergoline. The patient that is the focus of the current investigation temporarily resumed, on her own volition, cabergoline in between her first and second research visits. That event provided a unique opportunity to test how serum prolactin levels affect the structure-function relations between white matter integrity, retinal health, and visual ability. More broadly, this investigation also provided an opportunity to demonstrate that MRI metrics are sensitive to detect early changes in white matter associated with varying levels of serum prolactin.\n\nMethods\n\nParticipant Recruitment\n\nThis research was conducted as part of an ongoing pituitary tumor research study approved by the Research Subjects Review Board at the University of Rochester (RSRB00071763). Patient AJ, a 36-year-old nulliparous woman with a large prolactinoma was recruited as part of this study (see Supplementary Material 1 for a detailed clinical history). Five healthy control participants (n = 10 total hemifields, mean age 35.8 ± 11.88 SD) were also recruited and reviewed by an ophthalmologist (ZW) to confirm eligibility. Exclusion criteria included glaucoma, diabetic retinopathy, history of central retinal artery occlusion, optic disc drusen, multiple sclerosis, stroke, and previous head trauma. Supplementary Table 1 displays basic demographic information for all study participants. All participants gave written consent for participation in the study.\n\nMeasurement of Serum Prolactin Levels\n\nSerum prolactin was obtained via laboratory blood draw by a trained phlebotomist and analyzed by the University of Rochester Clinical Laboratories as part of the patient's routine clinical care. The prolactin was measured via Electrochemiluminescence Immunoassay with a reference range of 4.8–23.3 ng/ml. Approximately 10 laboratory draws were performed over the course of a year (see Supplementary Figure 1) and data from each research visit was paired with the closest obtained laboratory value for analysis. Control participants each had a one-time blood draw obtained at a single University of Rochester Medical Center outpatient clinic and analyzed by the same clinical laboratory as patient, AJ.\n\nOphthalmologic Evaluation\n\nFormal Ophthalmologic Testing\n\nAutomated 24–2 Humphrey perimetry (Zeiss HFA II-i series) and three-dimensional macular cube OCT (Zeiss Cirrus HD-OCT model 5000, 512 × 128 scan protocol with 6 × 6 × 2 mm volumes) were performed for each eye – right eye (OD) and left eye (OS). Peripapillary retinal nerve fiber layer thickness (pRNFL) was additionally obtained using an optic disc cube 200 × 200 protocol. Testing was performed three times over a year for patient AJ, and at a single time point for all control participants. Crawford and Howell's modified t-test was used to compare retinal thickness measurements and mean deviation for each eye at each time point for patient AJ to the control population (44). Intraocular pressure and fundus examination were also performed as part of the routine ophthalmologic assessment; results are reported in Supplementary Table 8.\n\nGanglion Cell Complex Thickness and Hemiretina Data\n\nMacular central subfield (CST), ganglion cell layer (GCL), inner plexiform layer (IPL) and pRNFL thickness measurements were processed independently by Carl Zeiss Meditec, Inc. Ganglion cell complex (GCC) thickness was calculated using the sum of GCL and IPL layers. Measures of retinal thickness were subsequently mapped onto visual space using an in-house pipeline implemented in MATLAB (45) and analyzed with respect to visual hemi-field (i.e., the averaged thickness of homonymous hemiretinas) for comparison with optic tract integrity. To account for contributions from nasal vs. temporal halves, retinal measures were weighted 53% contribution from nasal hemi-retina and 47% for temporal hemi-retina (46). The relations between weighted retinal thickness by hemi-field and corresponding optic tract diffusion metrics across all participants were evaluated using linear regression. Processed OCT data from Zeiss was unavailable for one healthy control due to acquisition artifact and thus excluded from the GCC analyses (controls n = 8 total hemifields).\n\nMagnetic Resonance Imaging Acquisition and Processing\n\nMRI Acquisition and Analysis\n\nScanning was performed at the University of Rochester Center for Advanced Brain Imaging and Neurophysiology on a 3T Siemens MAGNETOM Prisma scanner with a 64-channel head coil. T1 weighted images were acquired at the start of each session with a MPRAGE pulse sequence (TR = 2,530 ms, TE = 3.44 ms, flip angle = 71°, FOV = 256 × 256 sq mm, matrix = 256 × 256, resolution = 1 cu mm, 192 sagittal slices). Diffusion MRI data were acquired using a single-shot echo-planar sequence (65 diffusion directions, echo spacing = 0.66 ms, EPI factor = 172, b = 0, 1,000, 3,000 s/sq mm, 96 slices, resolution = 1.5 cu mm, 68 non-diffusion weighted volumes). Three non-diffusion weighted volumes were collected at the same resolution with reversed phase-encode blips to estimate the susceptibility-induced off-resonance field as implemented in FMRIB software library, or FSL (47, 48). FSL utilities were used to reduce motion artifacts and eddy current distortions and perform brain extraction (49). Probabilistic tractography of the optic tracts was performed on the preprocessed b = 1,000 files, using two fibers per voxel and Bayesian estimation (50–52), following techniques previously described (5, 53). All data in the main text are reported at a threshold of 2% for radial (RD) and axial (AD) diffusivity. See Supplementary Material 2 for additional discussion on tractography, threshold determination, and supplemental analyses related to fractional anisotropy and mean diffusivity.\n\nStructural Analysis of the Optic Tracts\n\nOptic tract cross-sectional area (CSA) was approximated using T1-MPRAGE scans of both patient AJ and controls, assuming an elliptical shape. Measurements were made using Horos, an open source DICOM viewer, freely available for download at: https://horosproject.org/. Height and width were evaluated just posterior to the optic chiasm. One trained researcher (RH) obtained measurements for all participants. A Welch's t-test was used to compare right and left optic tract CSA of this study's controls with the respective CSA measured by Andrews et al. (54); there were no statistically significant differences between the data sets. Crawford and Howell's (44) modified t-test was subsequently used to compare the patient's right and left optic tract CSA at each time point with the healthy controls. Linear regression analyses were used to relate CSA with prolactin and diffusion MRI metrics.\n\nStudy Timeline\n\nDiffusion MRI studies were performed every 4–5 months for patient AJ, in tandem with routine clinical care over the course of a year. Serial laboratory, HVF and OCT assessments were driven by the patient's clinical care team – with AJ0 representing the patient's last clinical evaluation prior to discontinuing cabergoline and enrolling in the study. All testing for each control participant was completed over the span of 3 weeks. See Table 1 for the full study timeline.\n\nTable 1 Study timeline for dMRI, laboratory evaluation and ophthalmologic exam.\n\n\tdMRI scan\tLaboratory evaluation\tHVF\tOCT\t\nAJ0\t\t11/14/2018\t10/08/2018\t10/08/2018\t\nAJ1\t01/15/2019\t02/02/2019\t03/08/2019\t03/08/2019\t\nAJ2\t05/19/2019\t05/05/2019\t05/20/2019\t07/10/2019\t\nAJ3\t10/18/2019\t11/13/2019\t11/13/2019\t–\t\nControl 1\t03/05/2019\t03/05/2019\t02/25/2019\t02/25/2019\t\nControl 2\t04/10/2019\t04/18/2019\t05/13/2019\t05/13/2019\t\nControl 3\t06/25/2019\t06/25/2019\t06/03/2019\t06/03/2019\t\nControl 4\t08/07/2019\t08/22/2019\t08/05/2019\t08/05/2019\t\nControl 5\t08/15/2019\t08/12/2019\t08/12/2019\t08/12/2019\t\nDates of evaluation for patient AJ and control participants. AJ0 represents the patient's first clinical encounter prior to study enrollment and discontinuation of medical therapy.\n\nResults\n\nClinical Presentation: Patient AJ, a 36-Year-Old Woman With Empty Sella Syndrome\n\nPatient AJ presented to the UR Medicine Pituitary Program at the University of Rochester with complaints of progressive bilateral visual field defects, photosensitivity and bilateral ocular pain 9 years after initial diagnosis and subsequent medical treatment of a large prolactin-secreting pituitary tumor (Figures 1A,B). Prior to study enrollment, a clinical MRI was obtained demonstrating both a significant reduction in tumor size compared with initial diagnosis (9 years earlier) and downward herniation of the chiasm into an empty sella turcica (Figure 1C). Ophthalmologic examination revealed a normal pRNFL (OD, 74 μm; OS 87 μm) (AJ0, Figure 2A) and bitemporal visual field defects on Humphrey perimetry (AJ0, Figure 3A) with intact visual acuity (20/20 in both OS and OD). Prolactin levels were measured at 17.9 ng/mL, consistent with continued use of cabergoline. In keeping with previously published treatment recommendations (22–27), AJ's cabergoline dose was reduced to 0.25 mg every other week and eventually discontinued. She was enrolled in the current study and serum prolactin and cabergoline dosage continued to be monitored as standard of care. At AJ's first research visit (AJ1), her prolactin level was 86.6 ng/ml (normal reference range 4.8–23.3 ng/ml for non-pregnant females at our institution), consistent with treatment recommendations. As noted, she resumed taking cabergoline on her own volition between the first and second research visit; her prolactin level dropped to 23.5 ng/ml when measured at the time of the second research visit (AJ2). Between the second and third research visits she then (on medical advice) discontinued cabergoline a second time, and her prolactin level rose to 179 ng/ml at the time of the third research visit (AJ3). These clinical observations confirm established relations between cabergoline use and serum prolactin. See Supplementary Figure 1 for a historical timeline of serum prolactin levels as a function of cabergoline dose and Supplementary Material 1 for a detailed clinical history.\n\nFigure 1 Clinical T1-weighted MRI scan with contrast demonstrating patient AJ's pituitary macroadenoma in 2009 prior to (A), and after initiation of treatment with cabergoline (B), with progressive herniation of the optic chiasm into an empty sella (C) that was present at the time of study enrollment in 2018. Initial imaging of the mass in 2009 (A) demonstrated significant contrast enhancement with expansion of the sella-turcica, asymptomatic extension of the tumor into the left cavernous sinus, and suprasellar extension with some deviation, but no outright compression of the optic chiasm. The normal pituitary gland and stalk were pushed to the right and superiorly.\n\nFigure 2 Spectral domain optical coherence tomography showing near normal average peripapillary retinal nerve fiber layer thickness (74 microns) in the right eye and normal average peripapillary retinal nerve fiber layer thickness (87 microns) in the left eye (A). OCT RNFL shows borderline thinning superiorly, nasally and temporally in the right eye. The ganglion cell complex shows loss of the nasal fibers bilaterally (B).\n\nFigure 3 Humphrey 24-2 visual field automated perimetry of AJ prior to discontinuation of cabergoline (AJ0; A), at the time of study enrollment (AJ1; B) illustrating a single temporal defect in OD, mean deviation −6.15 dB, and supratemporal defect in OS, mean deviation −6.57 dB. Following cabergoline use (AJ2; C), ophthalmologic evaluation was notable for OD supratemporal and nasal defects (mean deviation −9.51 dB) and OS temporal-greater-than-nasal defects (mean deviation −13.35 dB), reflecting worsening of visual function. Further evaluation after final cessation of cabergoline (AJ3; D), demonstrates subtle worsening of the temporal defect extending infratemporally (mean deviation −9.65) and significantly improved supratemporal and nasal defects (mean deviation −6.05), reflective of overall improvement in visual function. (E) demonstrates a positive correlation between GCC thickness and mean deviation.\n\nOphthalmologic Evaluation of Visual Function and Retinal Thickness\n\nVisual Function\n\nAt all three time points our patient demonstrated significantly reduced visual function compared with healthy control participants, as measured by mean deviation (all p < 0.05, using Crawford and Howell's modified t-test; Table 2). This difference is most pronounced at AJ2 relative to the other time points and overlaps with the period in which the patient resumed cabergoline. Figures 3A–D display Humphrey 24-2 visual automated perimetry data for patient AJ at each time point, demonstrating a transient worsening of vision during the period when she (on her own volition) resumed taking cabergoline.\n\nTable 2 Mean deviation in AJ compared with healthy controls.\n\n\tHealthy controls\tAJ0\tAJ1\tAJ2\tAJ3\t\nOD mean deviation (dB)\t−1.99 ± 0.69\t−7.63†\t−6.57†\t−9.51†\t−9.65†\t\nOS mean deviation (dB)\t−2.19 ± 1.44\t−10.05†\t−6.15*\t−13.35†\t−6.05*\t\nDemonstrated here is the average perimetric mean deviation (in decibels, dB) for both healthy control participants (n = 10 total eyes) and patient AJ across all time points, with AJ0 representing visual field data acquired on initial presentation just prior to study enrollment. Error measurements for the cohort of healthy controls are reported as standard deviation;\n\n* p < 0.05,\n\n† p < 0.01. Refer to Supplementary Tables 4, 5 for individual mean deviation values of all participants in the study reported both by eye and hemiretina.\n\nRetinal Thickness\n\nOptical Coherence Tomography was used to segment the retinal layers in all healthy control participants (n = 8 total eyes) and patient AJ at each time point. There was a trend of reduced retinal thickness across all layers in patient AJ compared with healthy controls (Supplementary Table 4). Notably, this pattern was not significant (all p > 0.05), and thus consistent with the independent observation that the values of retinal thickness for AJ were at the border of what is considered normal thickness (74 μm for pRNFL). Her normal OCT RNFL in the left eye predicted full recovery of her visual field defects following decompression of the chiasm. It is therefore unlikely that her bitemporal visual field defects at the time of the current investigation are residual from her chiasmal compression 9 years prior (42, 55). This line of reasoning suggests that her bitemporal visual field defects are likely secondary to chiasmal herniation causing optic chiasm traction in the setting of continued cabergoline treatment. This is further supported by interval worsening of her bitemporal visual field defects in October 2018 compared with HVF testing from May 2018. Reduced thickness was primarily in the nasal hemiretinas bilaterally (Figure 2).\n\nGCC data were also correlated with mean deviation, demonstrating a significant relation between retinal thickness and visual function across all study participants (r = 0.69 and p = 0.006; Figure 3E). These data indicate a causal relation between GCC and Humphrey perimetry. It is important however, to note that the stability of retinal thickness measures for patient AJ observed over the duration of the study, suggests that the transient decline in visual function at time point 2 (AJ2) cannot be primarily explained by macrostructural changes within the retina. Raw data for all retinal layers is provided in the Supplementary Material.\n\nDiffusion MRI Is Sensitive to Alternations in Serum Prolactin Levels\n\nDiffusion MRI was obtained on all study participants in tandem with ophthalmologic and laboratory evaluations; and micro-structural properties of the optic tracts were measured within the analytic approach of probabilistic tractography, see Figure 4. At the onset of the study (AJ1), and shortly after initial discontinuation of cabergoline, AJ's diffusion metrics for the optic tracts were within the range established by the healthy controls sample (Figures 5A,B). This was supported by non-significant Welch's t-tests (all p > 0.4) comparing AJ's average diffusion metrics for the optic tracts with those of the control sample (n = 10) optic tracts. With decreasing levels of prolactin at the patient's second visit (AJ2), related to the use of cabergoline, there was a significant increase in average RD compared to the control population (two tailed; p < 0.001) with no change in axial diffusivity (p = 0.52). This difference is apparent in the distribution of voxel-based diffusion measures, as displayed in Figures 5A,B. After following medical advice to again discontinue cabergoline at the third time point (AJ3), diffusion metrics again no longer differed from controls (all p > 0.3). Notably, the pattern relating measures of diffusion in the optic tracts to serum levels of prolactin in patient AJ suggests that higher levels of prolactin are associated with reduced RD. This trend is not present for AD, as demonstrated in Figures 5C,D.\n\nFigure 4 Tractography Results of the optic tract for patient AJ at each time point; (A) AJ1, (B) AJ2, (C) AJ3, and for a representative control participant (D) demonstrating the course of the optic tract from just posterior the chiasm to the lateral geniculate nucleus. Supplementary Figure 3 shows tractography results for each control participant.\n\nFigure 5 (A,B) Distribution of diffusion MRI metrics for the optic tracts of AJ at three time-points, and healthy control participants (n = 10 total optic tracts) at one time point each. AJ scan 1 (AJ1) was completed after initial discontinuation of cabergoline (high PRL); AJ scan 2 (AJ2) was completed after cabergoline was resumed of the patient's own volition (normal PRL); AJ scan 3 was completed 5 months after final termination of cabergoline treatment (high PRL). Diffusion metrics include axial diffusivity (AD) and radial diffusivity (RD). (C,D) Averaged diffusion metrics for patient AJ as a function of prolactin, demonstrating a negative relation between prolactin and both RD and MD. *p < 0.05.\n\nDiffusion MRI Indices Correlate With Ganglion Cell Complex Thickness\n\nGCC thickness was inversely related to the diffusion MRI index of RD in the optic pathways across all study participants (Pearson correlation, r = −0.68 and p = 0.015), whereas there were no relations for AD and GCC thickness (r = −0.16 and p = 0.62; Figure 6). Some clustering of data points is expected, due to the fact that AJ's GCC values are expected to be lower than those of the healthy controls. Recognizing that inclusion of patient AJ across time points could potentially introduce unwanted variability in measures of diffusion around a relatively stable GCC thickness, the analyses were repeated for only healthy control participants. Results from those analyses demonstrate the relation remains between measures of diffusion and GCC thickness, for RD (r = −0.69 and p = 0.066), but not between AD and GCC among healthy control participants (r = −0.28 and p = 0.50). These patterns suggest that the identified relations between GCC and diffusion indices represent a baseline structure-function relation between the retina and white matter tract integrity.\n\nFigure 6 Hemifield GCC thickness measurements are related to indexed diffusion MRI metrics within the corresponding optic tracts. (A) No correlation was identified between GCC and AD (r = −0.0235, p = 0.937). All relations evaluated using linear regression. (B) Significant correlations were identified between GCC and RD (r = −0.595, p = 0.0247).\n\nOptic Tract Size Does Not Correlate With Measures of Diffusion or Hormonal Function\n\nA core finding described above is that diffusion indices of myelination track prolactin levels in patient AJ. In order to rule out the possibility that the observed effects on diffusion indices are derivative of macrostructural changes, such as thinning of the optic tracts secondary to increasing traction on the chiasm, we measured optic tract size for all healthy controls (n = 10 optic tracts) and patient AJ across all time points. The range of right optic tract CSA values was 6.22–9.96 mm2 (mean = 8.47 mm2) for healthy controls and 9.56–10.02 mm2 (mean = 9.81 mm2) for patient AJ. In the left optic tract, values ranged from 6.27 to 11.00 mm2 (mean = 9.18 mm2) for controls and 9.83–10.35 mm2 (mean = 10.08 mm2) for patient AJ. These data are consistent with previously published studies (54) and there were no left/right differences. No statistical differences were identified between optic tract CSA in patient AJ (at any time point) and healthy control participants (p = 0.14, using Welch's t-test). The tight range of CSA values at each time point demonstrates stability of optic tract size and suggests that increased traction or physical deformation of the optic tract is not the primary factor in the patient's worsened clinical exam at AJ2. This is further supported by the fact that no correlations were identified between optic tract size and measures of AD, RD, prolactin or GCC, all p > 0.34. Additionally, at the level of the optic chiasm, there were no observable macrostructural changes in patient AJ over the course of the study (see Figure 7).\n\nFigure 7 Coronal images at the level of the optic chiasm obtained from the T1-MPRAGE MRI sequence associated with each diffusion MRI scan for patient AJ at all time points; (A) AJ1, (B) AJ2, (C) AJ3, and for a representative control participant (D). Notably, there are no macrostructural differences observed across time for patient AJ, who demonstrates stable downward herniation of the chiasm compared with controls. Supplementary Figure 4 reports coronal images of each control participant.\n\nDiscussion\n\nThe current investigation demonstrates a stereotyped pattern of diffusion MRI changes in response to varying levels of serum prolactin in a rare, isolated, model of nerve traction injury. This study—while limited in scope to a single patient—provides a natural experiment for observing the effects of varying levels of serum prolactin on measures of visual function, white matter integrity, and retinal health that would otherwise not be possible to observe in-vivo. Specifically, increased RD indexed a significant decrease in serum prolactin. Important to this finding, is that no relations were present between axial diffusivity, levels of prolactin, retinal thickness or visual function. These data confirm the suite of diffusion MRI signals that have been shown to index the integrity of myelin (3, 35–38) and are consistent with the proposed neuroprotective role of prolactin in the human brain (12, 13, 17, 18, 56).\n\nAdding to the specificity of the diffusion MRI changes we have reported is the demonstration of concordant changes in visual ability, indicating that serum levels of prolactin modulate the tightly coupled structure-function relationship between vision and white matter integrity. Notably, these patterns were present in the absence of macrostructural changes to the optic tracts, as assessed by CSA, and their specificity is further supported by stable measures of retinal thickness and axial diffusivity. Given the specificity of these findings, it is reasonable to infer that serum levels of prolactin physiologically modulate the relation between white matter integrity (i.e., myelination) and visual ability. Additionally, these data support the use of diffusion MRI as an independent index of the effects of prolactin on white matter in the human brain, both for future observational studies and for future interventional studies.\n\nRadial Diffusivity as an Index for Glial-Neuronal Interactions That Support Myelin Health\n\nPrior work has documented a pattern of reduced RD after surgical decompression of the optic chiasm that is disproportionate to changes in AD (5). This pattern is thought to characterize rapid remyelination in the human brain (i.e., days to weeks) following chiasmatic decompression. The current study demonstrates this same pattern of diffusion changes following periods of hyperprolactinemia rather than decompression – and does so in the setting of chronic injury from persistent traction. These data suggest that in the setting of an isolated stretch injury, radial diffusivity indexes the glial-neuronal interactions that support myelin sheath integrity and preservation of function. Key to this conclusion is that despite persistent traction on the optic chiasm throughout the study, white matter injury, as assessed with diffusion MRI, was only made apparent after AJ resumed cabergoline on her own volition – an event that resulted in decreased levels of serum prolactin. This is an important distinction given what is currently known about both neuronal stretch injury (8, 57) and prolactin's role in neural recovery (13, 17, 18). Once a nerve is stretched, a stereotyped pattern of microstructural changes leads to the development of axonal swelling and correlated changes in the microtubular component of the axonal cytoskeleton, particularly microtubule loss at nodes of Ranvier and at internodal regions (8). More severe injury models describe diffuse patterns of injury with permeabilization of the axolemma and subsequent formation of peri-axonal spaces, myelin inclusions, and reactive axonal swellings culminating in secondary axotomy (57).\n\nThere is a growing body of evidence in both in-vitro and in-vivo models demonstrating prolactin's role in mediating glial-neuronal interactions, including improved astrocyte viability and decreased astrogliosis (12). Critical for inferring microstructural properties from diffusion MRI data is the b-value used during image acquisition: in our case b = 1,000. At this b-value, diffusion patterns are most sensitive to changes in the extra-axonal compartment (58). Recruitment of oligodendrocyte precursor cells to the injured optic tract can effectively decrease radial diffusivity and is consistent with known properties of prolactin (18). Recovery of both the number and density of microtubules, which has been shown to occur as quickly as 4 h after an optic nerve stretch injury (8) can also reduce radial diffusivity and represents a potential area of future interest with respect to possible associations with prolactin. These physical changes, which can be measured in the extra-axonal space, likely accompany upregulation of neurotransmission that improves signal conduction and information transfer to the striate cortex. Increased signal conduction alone would be unlikely to provide microstructural changes large enough to be measured at the resolution of diffusion tensor imaging. Data from this study, therefore, add to the argument that prolactin influences a complex network of interactions important for maintaining the health of oligodendrocytes, cytoskeletal structures, and levels of myelination – which would otherwise be susceptible to secondary axonal injury.\n\nStability of Retinal Thickness Measures\n\nRecovery after retinal thinning, as measured by OCT varies with pathology (41–43, 45, 55, 59, 60). Optic neuritis patients experience recovery of visual function with increasing VEP amplitudes despite continued loss of pRNFL thickness and significant optic nerve atrophy over 12 months (61). Klistorner et al. suggest that this discrepancy is driven by a combination of both remyelination and neural reorganization. When used to measure recovery following nerve decompression (e.g., resulting from treatment of a pituitary macroadenoma), pRNFL and photopic negative response are sensitive to detect changes at 3 months (41–43, 55). These changes lag behind both improvements in visual function and diffusion MRI indices and are relatively stable at the individual level. In chiasmal compression by pituitary tumors, GCC thickness analysis had greater correlation to mean deviation, a measure of visual defect, than RNFL analysis (62). Additionally, some patients had GCC thinning but no abnormalities in RNFL or mean deviation of visual defect on perimetry testing (63), suggesting increased sensitivity of GCC to injury. As such, this study primarily focused on GCC.\n\nHere, we demonstrate preservation of retinal ganglion cell thickness despite persistent traction injury to the optic nerves, chiasm and tracts over the course of a year, including a transient period (AJ2) of worsening white matter injury and decreased vision. Only one other case with a similar pattern of preserved pRNFL thickness despite recorded deficits on Humphrey perimetry and injury to the optic chiasm has been reported in the literature – a patient with a large, compressive prolactinoma and hyperprolactinemia that was evaluated prior to starting cabergoline (64). While it is possible that the stability of retinal thickness measurements in patient AJ is secondary to exposure to high levels of prolactin – this pattern is complicated by a known delay (~6–8 weeks) in measurable response to pathology, which warrants further investigation. Our findings indicate that radial diffusivity is a sensitive marker that is dynamically modulated in the central nervous system coincident with rapidly changing serum prolactin levels.\n\nThe Role of Cabergoline\n\nGiven that the transient normal prolactin level measured in patient AJ was precipitated by use of cabergoline, it is possible that cabergoline has an independent effect on radial diffusivity and visual function. Chuman et al. suggest that cabergoline drug toxicity directly results in vision loss, and that cessation of therapy subsequently leads to vision recovery (22). While plausible, this pattern of delayed vision loss is not typically seen in patients treated with high doses of cabergoline (65), and has not been reported in the absence of empty sella syndrome. Further investigation in animal models relating the impact of cabergoline on D2 receptors in white matter may help to better separate differences between the changes related to prolactin vs. those related to dopamine agonists alone. A second hypothesis proposes that in the absence of cabergoline, undetectable tumor regrowth leads to untethering of the of the optic chiasm and a subsequent return of visual function. Two issues arise in this context. First, no patient has been reported to demonstrate a reduction in the amount of optic chiasm herniation, at least across all case reports of which we are aware, and for which cessation of medical therapy was the treatment strategy (22–27). Second, the amount of deformation of the optic chiasm poorly correlates with visual function, as demonstrated in both compressive pituitary tumor patients (66), and individuals with an incidental finding of primary empty sella syndrome as an anatomic variant (67). As such, we suggest that it is unlikely that an “undetectable” change in tethering is responsible for the significant reduction in radial diffusivity and improved visual function observed with hyperprolactinemia in this study.\n\nConclusions\n\nIn summary, we demonstrate in a single patient with empty sella syndrome secondary to dopamine agonist therapy, that increasing serum levels of prolactin correlate with improved visual function and an increase in myelination of the optic tracts. These data support, in-vivo, a neuro-protective role for prolactin in the injured human brain, confirming previous work in animal models, and establishes radial diffusivity as an important index for tracking the white matter impact of varying levels of serum prolactin. These findings offer a non-invasive means of measuring the effectiveness of novel therapies targeting prolactin as a mediator of neuroprotection in the human brain.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Research Subjects Review Board at the University of Rochester (RSRB00071763). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nData collection and analysis were performed by DP, ES, AR, RH, CS, SH, and ZW. The manuscript was written and prepared by DP. All authors made substantial contributions to the conception or design of the work, commented on manuscript drafts, read, and approved the final manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors are grateful to Frank Yeh and Arun Venkataraman for their contributions to the development of the diffusion MRI acquisition and analysis pipeline, and for their comments on earlier drafts, and to Tod Romo for assistance with computing resources.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.680602/full#supplementary-material\n\nClick here for additional data file.\n\nAbbreviations\n\ndMRI Diffusion magnetic resonance imaging\n\nOCT Optical coherence tomography\n\nRNFL Retinal nerve fiber layer\n\npRNFL Peripapillary retinal nerve fiber layer thickness\n\nGCC Ganglion Cell Complex\n\nIPL Inner plexiform layer\n\nCST Macular central subfield\n\nGCL Ganglion cell layer\n\nOD Right eye\n\nOS Left eye\n\nCSA Cross sectional area\n\ndB Decibels\n\nAD Axial diffusivity\n\nRD Radial diffusivity.\n\nFunding. This work was supported by NIH Grants R01NS089069 and R01EY028535 to BM, P30EY001319 to the Center for Visual Sciences at the University of Rochester, a grant for Research to Prevent Blindness to ZW, NIH grant F30EY027988 to CS, and resources provided by the Program for Translational Brain Mapping at the University of Rochester. The Program for Translational Brain Mapping was established, in part, with support from Norman and Arlene Leenhouts (see: www.tbm.urmc.edu). DP was supported by a UL1 TR002001 grant via the NIH/National Center for Advancing Translational Sciences at the University of Rochester. AR was supported by a CTSI TL1 TR000096 grant via the National Center for Advancing Translational Sciences at the University of Rochester.\n==== Refs\nReferences\n\n1. Crowe MJ Bresnahan JC Shuman SL Masters JN Beattie MS . Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. (1997) 3 :73–6. 10.1038/nm0197-73 8986744\n2. 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(1998) 12 :905–6. 10.1038/eye.1998.235 10325982\n\n", "fulltext_license": "CC BY", "issn_linking": "2296-858X", "issue": "8()", "journal": "Frontiers in medicine", "keywords": "diffusion MRI; neuro-glial interactions; neuroprotection; optical coherence tomography; pituitary tumor; prolactin", "medline_ta": "Front Med (Lausanne)", "mesh_terms": null, "nlm_unique_id": "101648047", "other_id": null, "pages": "680602", "pmc": null, "pmid": "34307410", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "29421446;17065494;25504884;16446103;10400201;10711689;6051727;24776630;30963844;22593708;9257661;10325982;9247275;8956160;9337123;17557778;16736739;18096157;17314279;23314935;14642481;15274075;24252319;28192385;11276097;28170483;21896856;19381817;18756587;12131469;8986744;20042660;10541870;24478366;27322457;21799043;18263812;12391568;15862213;14568458;29378204;18673461;8683606;9092607;30537563;18812485;17070705;16127264;26339851;30660127;30315973;18578635;24758841;30097827;31698287;11012580;31467999;26481672;15846782;9743562;29569513;23658616;10404830;12414282;21960556", "title": "Empty Sella Syndrome as a Window Into the Neuroprotective Effects of Prolactin.", "title_normalized": "empty sella syndrome as a window into the neuroprotective effects of prolactin" }

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null, "drugstructuredosagenumb": "0.25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CABERGOLINE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "CABERGOLINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "20664", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.25 MG, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "0.25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CABERGOLINE" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hemianopia heteronymous", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Empty sella syndrome", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Panic attack", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Balance disorder", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130101" } }, "primarysource": { "literaturereference": "Paul, D.. Empty Sella Syndrome as a Window Into the Neuroprotective Effects of Prolactin.. Frontiers in Medicine. 2021;8:10.3389/fmed.2021.680602", "literaturereference_normalized": "empty sella syndrome as a window into the neuroprotective effects of prolactin", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220426", "receivedate": "20220426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20749891, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]

{ "abstract": "Pyoderma gangrenosum (PG)-like ulcerations are a rare clinical manifestation of methylenetetrahydrofolate reductase (MTHFR) mutation. We describe a patient considered to have PG who was treated with long-term high doses of systemic corticosteroids and multiple immunosuppressive agents for several years. In spite of this continuous aggressive therapy, the lesions did not improve but continued to get worse. She developed many significant and catastrophic side effects to them. When referred to our dermatology centre, on investigation, it was discovered that she has an MTHFR mutation. It seemed reasonable to presume that PG-like lesions were related to it. Treatment with a biologically active form of folate-[6S]-5-MTHF-with vitamins B6 and B12 was initiated. It was considered to be beneficial and capable of reducing hyperhomocysteinaemia and endothelial damage consequent from it. Since the institution of this treatment, the patient has begun to show very gradual but slow and incremental improvement.", "affiliations": "Center for Blistering Diseases, Boston, Massachusetts, USA.;The Center for Wound Care and Hyperbaric Medicine, Elliot Hospital, Manchester, New Hampshire, USA.;Department of Dermatology, Center for Blistering Diseases, Boston, Massachusetts, USA.", "authors": "Turkowski|Yana|Y|;Razvi|Syed|S|;Ahmed|Abdul Razzaque|AR|", "chemical_list": "D013763:Tetrahydrofolates; D014803:Vitamin B Complex; D025101:Vitamin B 6; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12; C005984:5-methyltetrahydrofolate", "country": "England", "delete": false, "doi": "10.1136/bcr-2018-228403", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(4)", "journal": "BMJ case reports", "keywords": "dermatology; genetics", "medline_ta": "BMJ Case Rep", "mesh_terms": "D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D020138:Hyperhomocysteinemia; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009154:Mutation; D017511:Pyoderma Gangrenosum; D035583:Rare Diseases; D012883:Skin Ulcer; D013763:Tetrahydrofolates; D016896:Treatment Outcome; D014805:Vitamin B 12; D025101:Vitamin B 6; D014803:Vitamin B Complex", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31015243", "pubdate": "2019-04-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "24898196;16858047;23116396;17133733;23158641;28913208;14985224;19917061;21472223;21482894", "title": "Pyoderma gangrenosum-like lesion secondary to methylenetetrahydrofolate reductase mutation: an unusual presentation of a rare disease.", "title_normalized": "pyoderma gangrenosum like lesion secondary to methylenetetrahydrofolate reductase mutation an unusual presentation of a rare disease" }

[ { "companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201905-001422", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "B6?4MONTHS AGO", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "B12?4MONTHS AGO", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED TO 3G DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYODERMA GANGRENOSUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSES WERE REDUCED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INCREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "009768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYODERMA GANGRENOSUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4MONTHS AGO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYODERMA GANGRENOSUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rebound effect", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pyoderma gangrenosum", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Discharge", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Excessive granulation tissue", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TURKOWSKIL Y, AHMED A, RAZVI S. PYODERMA GANGRENOSUM-LIKE LESION SECONDARY TO METHYLENETETRAHYDROFOLATE REDUCTASE MUTATION: AN UNUSUAL PRESENTATION OF A RARE DISEASE. BMJ CASE REP.. 2019 APR 23?12(4):. DOI:L0.L I36/BCR-2018-228403", "literaturereference_normalized": "pyoderma gangrenosum like lesion secondary to methylenetetrahydrofolate reductase mutation an unusual presentation of a rare disease", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190520", "receivedate": "20190520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16335054, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "Little is known about the impact of Epstein-Barr virus (EBV) infection on clinical outcomes in adults with inflammatory bowel disease (IBD).\n\n\n\nTo evaluate seroprevalence, seroconversion rate and complications associated with EBV infection in an adult IBD cohort attending a tertiary care hospital in Spain between 2006 and 2016.\n\n\n\nEBV serological status was determined. In seronegative patients, the seroconversion rate was evaluated. The complications associated with primary and latent EBV infection are described.\n\n\n\nOne thousand four hundred and eighty-three patients over the age of 17 were included in the study (mean age at EBV serological status determination was 48.3). Overall seroprevalence of EBV was 97.4% (95% CI: 96.6%-98.2%). The seroconversion rate was 29.7% (95% CI: 16.2-45.9) after a mean of 47.5 months. There were no differences in seroconversion rates between patients 35 years or younger and patients older than 35 years. A 66-year-old man, on treatment with thiopurines, developed lymphoma and a hemophagocytic syndrome during a primary EBV infection. Overall, six patients (one with primary infection and five with prior EBV infection) developed lymphoma. In three of five patients with lymphoma and thiopurine use, EBV was associated to the development of lymphoma.\n\n\n\nThere is a small percentage of adults with IBD at risk of primary EBV infection. The risks of seroconversion and its complications remain through adulthood. Our results suggest that, when considering the use of thiopurines in IBD, the information on EBV serological status should be taken into account at any age.", "affiliations": "Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Pathology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Pediatrics Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Statistics Department, Universidad de Oviedo, Oviedo, Spain.;Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.;Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.", "authors": "de Francisco|Ruth|R|;Castaño-García|Andrés|A|;Martínez-González|Susana|S|;Pérez-Martínez|Isabel|I|;González-Huerta|Ana J|AJ|;Morais|Lucía R|LR|;Fernández-García|María S|MS|;Jiménez|Santiago|S|;Díaz-Coto|Susana|S|;Flórez-Díez|Pablo|P|;Suárez|Adolfo|A|;Riestra|Sabino|S|0000-0002-9383-3698", "chemical_list": "D000914:Antibodies, Viral; D007166:Immunosuppressive Agents", "country": "England", "delete": false, "doi": "10.1111/apt.14933", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "48(7)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral; D015331:Cohort Studies; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016036:Seroepidemiologic Studies; D013030:Spain; D055815:Young Adult", "nlm_unique_id": "8707234", "other_id": null, "pages": "723-730", "pmc": null, "pmid": "30095176", "pubdate": "2018-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Impact of Epstein-Barr virus serological status on clinical outcomes in adult patients with inflammatory bowel disease.", "title_normalized": "impact of epstein barr virus serological status on clinical outcomes in adult patients with inflammatory bowel disease" }

[ { "companynumb": "ES-MYLANLABS-2018M1077870", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2001", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemophagocytic lymphohistiocytosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE FRANCISCO R, CASTANO-GARCIA A, MARTINEZ-GONZALEZ S, PEREZ-MARTINEZ I, GONZALEZ-HUERTA AJ, MORAIS LR, ET AL. IMPACT OF EPSTEIN-BARR VIRUS SEROLOGICAL STATUS ON CLINICAL OUTCOMES IN ADULT PATIENTS WITH INFLAMMATORY BOWEL DISEASE. ALIMENT-PHARMACOL-THER 2018?48(7):723-730.", "literaturereference_normalized": "impact of epstein barr virus serological status on clinical outcomes in adult patients with inflammatory bowel disease", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181025", "receivedate": "20181025", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15552229, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "BACKGROUND\nMiller Fisher syndrome (MFS) is a rare variant of Guillain-Barre syndrome characterized by ataxia, areflexia, and ophthalmoplegia. We present a case of MFS following Pfizer COVID-19 vaccine.\n\n\nMETHODS\nA previously healthy 24-year-old female presented with binocular horizontal diplopia 18 days after receiving the first dose of Pfizer COVID-19 vaccine (Comirnaty®). Anti-ganglioside testing revealed positive anti-GQ1b antibodies. Intravenous immunoglobulins were administered, in a dose of 2 g per kg of body weight over 5 days. On a follow-up exam 3 weeks after the treatment, clinical improvement was noted with normal bulbomotor examination.\n\n\nCONCLUSIONS\nPatients with acute ophthalmoplegia occurring after COVID-19 vaccination should be screened for the presence of anti-GQ1b antibody. If the antibody is present, intravenous immunoglobulin should be administered as it may hasten clinical improvement.", "affiliations": "General Hospital Zabok, Zabok, Croatia.;Department of Neurology, University Hospital Center Zagreb, Referral Center for Autonomic Nervous System Disorders, Zagreb, Croatia. ivan.adamec@yahoo.com.;Department of Neurology, University Hospital Center Zagreb, Referral Center for Autonomic Nervous System Disorders, Zagreb, Croatia.", "authors": "Abičić|Ana|A|;Adamec|Ivan|I|http://orcid.org/0000-0003-3873-6526;Habek|Mario|M|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.1007/s10072-021-05776-0", "fulltext": null, "fulltext_license": null, "issn_linking": "1590-1874", "issue": null, "journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology", "keywords": "COVID-19; Miller Fisher syndrome; Pfizer vaccine", "medline_ta": "Neurol Sci", "mesh_terms": null, "nlm_unique_id": "100959175", "other_id": null, "pages": null, "pmc": null, "pmid": "34817727", "pubdate": "2021-11-24", "publication_types": "D016428:Journal Article", "references": "23219950;33710649;17657801;23677659;34432976;11118247;18678825;16403531;33758714;33677662", "title": "Miller Fisher syndrome following Pfizer COVID-19 vaccine.", "title_normalized": "miller fisher syndrome following pfizer covid 19 vaccine" }

[ { "companynumb": "HR-LUPIN PHARMACEUTICALS INC.-2022-03628", "fulfillexpeditecriteria": "2", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "4", "drugadministrationroute": "042", "drugauthorizationnumb": "209097", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Miller Fisher syndrome", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "3", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Abicic A, Adamec I, Habek M. Miller Fisher syndrome following Pfizer COVID-19 vaccine. Neurological Sciences. 2022;43(3):1495-1497", "literaturereference_normalized": "miller fisher syndrome following pfizer covid 19 vaccine", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20220316", "receivedate": "20220316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20603247, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" } ]

{ "abstract": "There is a documented association between drug exposure and sarcoidosis-like reactions. In this study, we used the largest pharmacovigilance database to describe drug-induced sarcoidosis.\n\n\n\nData were collected from the World Health Organization (WHO) pharmacovigilance database (VigiBase). We excluded steroids and vaccines from the analysis. The primary end-point was the lower end-point of the 95% credibility interval for the information component (IC025 ).\n\n\n\nA total of 127 reports had significant IC025 values for drug-induced sarcoidosis, and 110 were included in the final analysis, accounting for 2425 adverse drug reactions. Overall, 2074 (85.5%) reactions were considered 'serious' and 86 (3.5%) were fatal. Most of the drugs that led to sarcoidosis adverse reactions were TNF-alpha antagonists, interferon or peg-interferon therapeutics, and immune checkpoint inhibitors. Other biologic drugs were less frequently associated with sarcoidosis adverse events. Cancer-targeted therapies such as BRAF or MEK inhibitors were associated with sarcoidosis reactions in 37 cases. Pulmonary hypertension drugs were also reported for drug-induced sarcoidosis. Amongst the 55 drugs considered as potential sarcoidosis inducers, 25 (45.4%) were never reported in Medline as drug-induced sarcoidosis.\n\n\n\nWe provide a detailed list of suspected drugs associated with drug-induced sarcoidosis that will improve the recognition of this drug-induced adverse event.", "affiliations": "Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.;Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.;Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.;Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Bobigny, France.;Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.;Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.;Assistance Publique-Hôpitaux de Paris, Service de Pharmacovigilance de la pitié-Salpêtrière, Paris, France.", "authors": "Cohen Aubart|F|F|;Lhote|R|R|;Amoura|A|A|;Valeyre|D|D|;Haroche|J|J|;Amoura|Z|Z|;Lebrun-Vignes|B|B|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/joim.12991", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-6820", "issue": "288(3)", "journal": "Journal of internal medicine", "keywords": "drugs; granuloma; sarcoidosis", "medline_ta": "J Intern Med", "mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D006801:Humans; D012507:Sarcoidosis; D014944:World Health Organization", "nlm_unique_id": "8904841", "other_id": null, "pages": "356-362", "pmc": null, "pmid": "31612562", "pubdate": "2020-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Drug-induced sarcoidosis: an overview of the WHO pharmacovigilance database.", "title_normalized": "drug induced sarcoidosis an overview of the who pharmacovigilance database" }

[ { "companynumb": "FR-UCBSA-2020040056", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CERTOLIZUMAB PEGOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CERTOLIZUMAB PEGOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary sarcoidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sarcoidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AUBART FC, LHOTE R, AMOURA A, VALEYRE D, HAROCHE J, AMOURA Z, ET AL. DRUG-INDUCED SARCOIDOSIS: AN OVERVIEW OF THE WHO PHARMACOVIGILANCE DATABASE. JOURNAL OF INTERNAL MEDICINE. 2020?288(3):356-62", "literaturereference_normalized": "drug induced sarcoidosis an overview of the who pharmacovigilance database", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20201012", "receivedate": "20201012", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18373574, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "NVSC2019FR031361", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "761071", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary sarcoidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "AUBART FC, LHOTE R, AMOURA A, VALEYRE D, HAROCHE J, AMOURA Z ET AL.. DRUG-INDUCED SARCOIDOSIS: AN OVERVIEW OF THE WHO PHARMACOVIGILANCE DATABASE. JOURNAL OF INTERNAL MEDICINE. 2019?1-7", "literaturereference_normalized": "drug induced sarcoidosis an overview of the who pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191114", "receivedate": "20191114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17029841, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "We report two cases of louse-borne relapsing fever (LBRF) in young Somali asylum seekers having recently arrived to Finland. They had sought medical attention for a febrile illness. Blood smears were examined for suspected malaria, but instead, spirochete shaped bacteria were observed. The bacteria were confirmed as Borrelia recurrentis by PCR and sequencing. The patients survived, but their treatment was complicated by Jarisch-Herxheimer reaction. We conclude that LBRF must be considered as a diagnostic option in febrile refugees also in the northernmost parts of Europe.", "affiliations": "Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.;Helsinki University Central Hospital, Helsinki, Finland.;Microbiology and Genetics Department, Turku University Hospital, Turku, Finland.;Department of Bacteriology and Immunology, Haartman Institute, Helsinki, Finland.;Department of Bacteriology and Immunology, Haartman Institute, Helsinki, Finland.;University of Turku and Turku University Hospital, Turku, Finland.", "authors": "Hytönen|Jukka|J|;Khawaja|Tamim|T|;Grönroos|Juha O|JO|;Jalava|Anna|A|;Meri|Seppo|S|;Oksi|Jarmo|J|", "chemical_list": null, "country": "Denmark", "delete": false, "doi": "10.1111/apm.12635", "fulltext": null, "fulltext_license": null, "issn_linking": "0903-4641", "issue": "125(1)", "journal": "APMIS : acta pathologica, microbiologica, et immunologica Scandinavica", "keywords": "Borrelia recurrentis; Louse-borne relapsing fever; refugee", "medline_ta": "APMIS", "mesh_terms": "D000328:Adult; D000818:Animals; D001769:Blood; D001898:Borrelia; D005387:Finland; D006801:Humans; D010373:Lice Infestations; D008297:Male; D016133:Polymerase Chain Reaction; D012036:Refugees; D012061:Relapsing Fever; D017422:Sequence Analysis, DNA; D012998:Somalia; D016896:Treatment Outcome", "nlm_unique_id": "8803400", "other_id": null, "pages": "59-62", "pmc": null, "pmid": "27859692", "pubdate": "2017-01", "publication_types": "D002363:Case Reports", "references": null, "title": "Louse-borne relapsing fever in Finland in two asylum seekers from Somalia.", "title_normalized": "louse borne relapsing fever in finland in two asylum seekers from somalia" }

[ { "companynumb": "FI-TEVA-762370ROM", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFUROXIME" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "62497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Jarisch-Herxheimer reaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HYTONEN J, KHAWAJA T, GRONROOS JO, JALAVA A, MERI S, OKSI J. LOUSE-BORNE RELAPSING FEVER IN FINLAND IN TWO ASYLUM SEEKERS FROM SOMALIA. APMIS 2017;125(1):59-62.", "literaturereference_normalized": "louse borne relapsing fever in finland in two asylum seekers from somalia", "qualification": "3", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20170427", "receivedate": "20170427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13490887, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "FI-MYLANLABS-2017M1023659", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFUROXIME" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "062337", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Jarisch-Herxheimer reaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HYTONEN J, KHAWAJA T, GRONROOS JO, JALAVA A, MERI S, OKSI J. LOUSE-BORNE RELAPSING FEVER IN FINLAND IN TWO ASYLUM SEEKERS FROM SOMALIA. APMIS 2017;125(1):59-62.", "literaturereference_normalized": "louse borne relapsing fever in finland in two asylum seekers from somalia", "qualification": "3", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20170418", "receivedate": "20170418", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13452597, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "FI-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-139394", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65053", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "100 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NOREPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOREPINEPHRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Jarisch-Herxheimer reaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HYTONEN J, KHAWAJA T, GRONROOS JO, JALAVA A, MERI S, OKSI J. LOUSE-BORNE RELAPSING FEVER IN FINLAND IN TWO ASYLUM SEEKERS FROM SOMALIA. APMIS. 2016;125:59-62", "literaturereference_normalized": "louse borne relapsing fever in finland in two asylum seekers from somalia", "qualification": "3", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20170428", "receivedate": "20170428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13494288, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "OBJECTIVE\nThe MIRACLE I pilot study was designed as a preliminary investigation of safety and efficacy of Embozene TANDEM microspheres loaded with doxorubicin for treatment of locally untreatable (i.e., unresectable and not suitable for local thermal ablation) hepatocellular carcinoma (HCC).\n\n\nMETHODS\nPatients with locally untreatable HCC (mono- or bilobar disease, ECOG performance status 0-2, Child-Pugh score < 11) were eligible for this single-arm multicenter study. DEB-TACE was performed with 75 µm Embozene TANDEM loaded with 150 mg of doxorubicin.\n\n\nRESULTS\nTwenty-five subjects with 41 tumors were treated (mean age 65 years); 16, 52, and 32% had BCLC A, B, and C status, respectively. Child-Pugh status was A for 64%, B for 32%, and C for 4%; 40% had ascites. About 92% had disease localized to one liver lobe. Most (72%) underwent ≤ 2 DEB-TACE procedures. Average doxorubicin dose was 124.5 ± 36.1 mg (median 150 mg) per procedure. Two patients had procedure-related SAE (liver necrosis, worsening of liver insufficiency) within 30 days of the first DEB-TACE procedure. Six-month freedom from procedure-related SAE or death was 68% (one hepatic encephalopathy, five deaths). Tumor response or stable disease was achieved in 95% (20/21) of subjects. Freedom from tumor progression or death at 6 months was 76%. The one-year survival rate was 56% overall and 73% among patients without ascites at baseline.\n\n\nCONCLUSIONS\nMIRACLE I results suggest that Embozene TANDEM microspheres loaded with doxorubicin can provide good local tumor control in a heterogeneous group of patients with locally untreatable HCC.\n\n\nMETHODS\nLevel 2b, Individual cohort study.", "affiliations": "1st Siemens Reference Center for Interventional Radiology and Oncology, Klinikum Stuttgart, Kriegsbergstr 60, 70174, Stuttgart, Germany. G.richter@klinikum-stuttgart.de.;Klinikum der Universität Heidelberg, Heidelberg, Germany.;Klinikum der Universität Regensburg, Regensburg, Germany.;SLK-Kliniken Heilbronn GmbH, Heilbronn, Germany.;Klinikum Bogenhausen, Munich, Germany.;Celonova Biosciences, San Antonio, TX, USA.;Klinikum Darmstadt, Darmstadt, Germany.", "authors": "Richter|Götz|G|;Radeleff|Boris|B|;Stroszczynski|Christian|C|;Pereira|Philippe|P|;Helmberger|Thomas|T|;Barakat|Mark|M|;Huppert|Peter|P|", "chemical_list": "D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin", "country": "United States", "delete": false, "doi": "10.1007/s00270-017-1839-2", "fulltext": "\n==== Front\nCardiovasc Intervent RadiolCardiovasc Intervent RadiolCardiovascular and Interventional Radiology0174-15511432-086XSpringer US New York 183910.1007/s00270-017-1839-2Clinical InvestigationSafety and Feasibility of Chemoembolization with Doxorubicin-Loaded Small Calibrated Microspheres in Patients with Hepatocellular Carcinoma: Results of the MIRACLE I Prospective Multicenter Study Richter Götz (+49)711 278 34401G.richter@klinikum-stuttgart.de 1Radeleff Boris 2Stroszczynski Christian 3Pereira Philippe 4Helmberger Thomas 5Barakat Mark 6Huppert Peter 71 1st Siemens Reference Center for Interventional Radiology and Oncology, Klinikum Stuttgart, Kriegsbergstr 60, 70174 Stuttgart, Germany 2 0000 0001 0328 4908grid.5253.1Klinikum der Universität Heidelberg, Heidelberg, Germany 3 0000 0000 9194 7179grid.411941.8Klinikum der Universität Regensburg, Regensburg, Germany 4 SLK-Kliniken Heilbronn GmbH, Heilbronn, Germany 5 0000 0000 8973 0691grid.414523.5Klinikum Bogenhausen, Munich, Germany 6 Celonova Biosciences, San Antonio, TX USA 7 grid.419810.5Klinikum Darmstadt, Darmstadt, Germany 22 11 2017 22 11 2017 2018 41 4 587 593 24 5 2017 13 11 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nThe MIRACLE I pilot study was designed as a preliminary investigation of safety and efficacy of Embozene TANDEM microspheres loaded with doxorubicin for treatment of locally untreatable (i.e., unresectable and not suitable for local thermal ablation) hepatocellular carcinoma (HCC).\n\nMaterials and Methods\nPatients with locally untreatable HCC (mono- or bilobar disease, ECOG performance status 0–2, Child–Pugh score < 11) were eligible for this single-arm multicenter study. DEB-TACE was performed with 75 µm Embozene TANDEM loaded with 150 mg of doxorubicin.\n\nResults\nTwenty-five subjects with 41 tumors were treated (mean age 65 years); 16, 52, and 32% had BCLC A, B, and C status, respectively. Child–Pugh status was A for 64%, B for 32%, and C for 4%; 40% had ascites. About 92% had disease localized to one liver lobe. Most (72%) underwent ≤ 2 DEB-TACE procedures. Average doxorubicin dose was 124.5 ± 36.1 mg (median 150 mg) per procedure. Two patients had procedure-related SAE (liver necrosis, worsening of liver insufficiency) within 30 days of the first DEB-TACE procedure. Six-month freedom from procedure-related SAE or death was 68% (one hepatic encephalopathy, five deaths). Tumor response or stable disease was achieved in 95% (20/21) of subjects. Freedom from tumor progression or death at 6 months was 76%. The one-year survival rate was 56% overall and 73% among patients without ascites at baseline.\n\nConclusion\nMIRACLE I results suggest that Embozene TANDEM microspheres loaded with doxorubicin can provide good local tumor control in a heterogeneous group of patients with locally untreatable HCC.\n\nLevel of Evidence\nLevel 2b, Individual cohort study.\n\nKeywords\nChemoembolizationDoxorubicinDrug carriersHepatocellular carcinomaMicrospheresCeloNova BioSciences Inc., San Antonio, USAissue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2018\n==== Body\nIntroduction\nPatients with locally untreatable HCC (i.e., unresectable and not suitable for local thermal ablation) have few treatment options [1]. Systemic sorafenib has been shown to modestly prolong survival in patients with advanced stage disease [1, 2], and transarterial chemoembolization (TACE) is recommended for patients with intermediate stage disease [1]. Meta-analyses have shown that TACE performed with doxorubicin-loaded beads has similar efficacy but fewer side effects than conventional TACE [3, 4].\n\nIn a preliminary single-center study of 52 patients with locally untreatable HCC who underwent TACE with doxorubicin-loaded Embozene TANDEM™ microspheres (CeloNova Biosciences/Boston Scientific, Marlborough, MA), more than 60% of patients had an objective tumor response, and the one-year survival rate was more than 90% [5]. All patients in the study were treated with microspheres of nominal diameter ≤ 100 µm and were randomized to one of two doxorubicin doses. The MIRACLE I pilot study was a multicenter study designed to further evaluate safety and efficacy of Embozene TANDEM microspheres loaded with doxorubicin for DEB-TACE treatment of locally untreatable hepatocellular carcinoma, specifically the 75 µm size and 150 mg doxorubicin dose.\n\nMaterials and Methods\nStudy Design\nMicroparticle Enhanced Cytotoxic Transarterial Embolization Therapy in Hepatocellular Carcinoma (MIRACLE I) was a prospective, single-arm multicenter feasibility study of chemoembolization with 75 µm doxorubicin-loaded Embozene TANDEM microspheres to treat locally unresectable HCC.\n\nThe trial was conducted according to the guidelines established in the Declaration of Helsinki, ICH/135/95 Good Clinical Practice (GCP), and local ethical and legal requirements. Ethics committee and competent authority approvals were obtained prior to study initiation. All patients provided written informed consent. The trial was registered at clinicaltrials.gov (identifier NCT01798134).\n\nStudy Patients\nPatients eligible for the study were adults with confirmed diagnosis of HCC according to European Association of the Study of the Liver (EASL) criteria [6] and were staged according to BCLC criteria [1]. Eastern Cooperative Oncology Group (ECOG) [7] performance status of 0, 1, or 2, and Child–Pugh score of < 11 points (i.e., A, B, or C 10) [8] were required. Tumors were to be ≥ 3–10 cm (multinodular or single node). Mono- or bilobar disease was allowed. Lack of main portal vein trunk or common bile duct invasion was to be confirmed by MRI. Patients were required to have laboratory values in the following ranges: white blood cell count > 3000/mL, absolute neutrophil count > 1500 cells/mL, INR < 2.0, partial thromboplastin time < 40 s, platelet number > 5 × 104 mL, blood bilirubin < 3.0 mg/dL, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) within five times of normal range of each organ, serum creatinine < 2.5 mg/dL, hemoglobin > 8.0 g/dL, and alkaline phosphatase < 630 IU/L. Key exclusion criteria were metastatic disease or diffuse HCC, the presence of an untreatable arteriovenous or arterioportal shunt, known hepatofugal blood flow, previous treatment with anthracyclines, previous embolotherapy to treat primary liver cancer, and treatment with sorafenib within the previous 4 weeks. Patients with unstable coronary artery disease, myocardial infarction within the previous 4 weeks, or an abnormal electrocardiogram (QT < 480 ms) within the previous 12 months were excluded.\n\nTreatment Plan and Embolization Procedure\nEmbozene TANDEM microspheres have a negatively charged hydrogel core and biocompatible perfluorinated polymer coating. They can be loaded with anthracyclines, such as doxorubicin, or other chemotherapeutic drugs, such as irinotecan [5, 9–11]. Patients in MIRACLE I were treated with 75 µm diameter Embozene TANDEM microspheres, which are calibrated to ± 15 µm. One 3-mL syringe of microspheres can be loaded with up to 150 mg of doxorubicin-HCl, with little shrinkage (~ 9%) observed after drug loading [9]. Doxorubicin loading was performed according to the manufacturer’s instructions.\n\nA procedural doxorubicin dose of 75 mg/m2 body surface area was targeted. A minimum of two treatments per lesion, separated by 4 weeks, was planned. Thus, patients with bilobar hepatic disease were to have at least four treatment sessions (two per liver lobe).\n\nChemoembolization procedures were performed with antibiotic prophylaxis, analgesic, and antiemetic medications at the physician’s discretion. Angiography of the hepatic and mesenteric arteries was performed prior to chemoembolization to confirm anatomical eligibility and identify tumor feeder arteries. The hepatic segmental or subsegmental arteries supplying the lesion were selectively catheterized with a microcatheter while ensuring sufficient flow to the tumor, and a mixture of 75-µm doxorubicin-loaded microspheres and non-ionic contrast agent was slowly injected. The protocol encouraged a super-selective approach to reduce non-target embolization. Bland microspheres could also be used at the treating physician’s discretion if blood flow stasis was not achieved after delivery of the desired drug dose.\n\nSafety and Efficacy Endpoints\nThe primary study endpoints were safety (serious adverse events) at 30 days and 6 months, and freedom from primary tumor progression at 6 months. Secondary endpoints included the rate of local tumor control and 12-month survival. Survival among subgroups of patients with Child–Pugh class A or B/C liver function and with or without ascites was examined in a post hoc analysis.\n\nAdverse event monitoring occurred throughout the treatment and follow-up phases. Adverse event seriousness and potential causal relationships with the DEB-TACE procedure or Embozene TANDEM microspheres were assessed by the site investigator. Grading according to CTCAE criteria was not mandated in the study protocol, but was completed retrospectively (CTCAE v 4.03) for serious adverse events occurring within 30 days post-procedure based on information collected about the events.\n\nTumor imaging (contrast-enhanced CT or MRI) was performed, and measurements were taken within 2 weeks prior to the first DEB-TACE procedure (baseline) and 2 weeks following the first and again following the second procedure (for a patient with monolobar disease intended to be treated with a minimum of two procedures). Repeat DEB-TACE procedures were performed when follow-up imaging studies showed residual enhancement and patients continued to be willing to undergo additional procedures. Imaging was repeated at 4- to 6-week intervals to determine need for additional DEB-TACE procedures and was scheduled to be performed 3 and 6 months following the last DEB-TACE procedure and 12 months from the initial treatment. Clinical and laboratory assessments were also repeated at each of these visits.\n\nTumor response was assessed based on mRECIST criteria [12]. “Best overall response” was defined as the smallest measurement of hypervascularized tumor tissue recorded from the start of study treatment until disease progression/recurrence and took into account non-target and new lesions [6]. Images were evaluated by the investigator/radiologist at each site.\n\nResults\nPatients\nFrom January 2013 to March 2014, 25 patients with 41 lesions were enrolled and treated at six German sites. Patient and lesion characteristics are summarized in Table 1. Most patients (92%) had monolobar disease, and 32% had advanced HCC (BCLC stage C). Thirteen (52%) patients had at least one tumor with largest diameter > 5 cm and eight more patients (32%) had at least one tumor with largest diameter 3–5 cm. As shown in Table 1, Child–Pugh classification of B (Child–Pugh score of 7–9) or C (Child–Pugh score of 10) was noted for 36% of patients at baseline, and many (64%) presented with symptoms of advanced liver disease, including ascites, hepatic encephalopathy, esophageal varices, or splenomegaly. Five patients had radiofrequency ablation or surgical resection prior to enrollment; none had systemic chemotherapy. Several patients had comorbidities preventing surgery, and two were on the liver transplant list at enrollment. One patient was withdrawn from the study two days after the initial treatment in order to undergo systemic treatment outside the trial; this patient was followed for safety but was excluded from the efficacy analysis. Four other patients withdrew consent (one at 5 days, one at 2 weeks, and two at 5 months from the initial treatment), and one patient was withdrawn after suffering a fall and broken vertebrae 2 weeks following the initial treatment.Table 1 Baseline patient characteristics (N = 25)\n\nCharacteristic\t\nN (%)\t\nSex (male/female)\t18/7\t\nAge, years (median, range)\t65 (39–85)\t\nRace/ethnicity\t\n Caucasian\t24 (96)\t\n Asian\t1 (4)\t\nEtiology of cirrhosis\t\n Alcohol abuse\t12 (48)\t\n HCV\t3 (12)\t\n HBV\t3 (12)\t\n HBV, HCV, and alcohol abuse\t1 (4)\t\n NASH\t1 (4)\t\n Unknown/other\t5 (20)\t\nChild–Pugh classification\t\n A\t16 (64)\t\n B\t8 (32)\t\n C\t1 (4)\t\nECOG performance status\t\n 0\t19 (76)\t\n 1\t5 (20)\t\n 2\t1 (4)\t\nBCLC classification\t\n A\t4 (16)\t\n B\t13 (52)\t\n C\t8 (32)\t\n Prior radiofrequency ablation therapy\t1 (4)\t\n Prior surgery\t4 (16)\t\n INR < 1.5\t24 (96)\t\n Platelets < 100,000\t7 (28)\t\n Bilirubin ≤ 2\t22 (88)\t\n AST < 100\t22 (88)\t\n ALT < 100\t25 (100)\t\n Ascites\t10 (40)\t\n Hepatic encephalopathy\t2 (8)\t\n Esophageal varices\t9 (36)\t\n Splenomegaly\t9 (36)\t\n Portal vein thrombosis\t2 (8)\t\n Diabetes\t11 (44)\t\n Anemia\t5 (20)\t\n Renal insufficiency\t4 (16)\t\nLiver lobes involved\t\n 1 (Monolobar HCC)\t23 (92)\t\n 2 (Bilobar HCC)\t2 (8)\t\nTumor size (largest diameter; n = 41)\t\n <3 cm\t15 (37)\t\n 3 − < 5 cm\t12 (29)\t\n ≥ 5 − < 10 cm\t13 (32)\t\n ≥ 10 cm\t1 (2)\t\n Range\t1–13 cm\t\n\nALT alanine aminotransferase, AST aspartate aminotransferase, HBV hepatitis B virus, HCV hepatitis C virus, HCC hepatocellular carcinoma, and NASH non-alcoholic steatohepatitis\n\n\n\n\nEmbolization with Drug-loaded Microspheres\nAll enrolled patients underwent at least one DEB-TACE procedure successfully; most had one (24%) or two (48%) procedures; five (20%) had three; and two (8%) had four or more. The six patients who underwent only one procedure all had monolobar disease; the second planned procedure was not performed because of early withdrawal from the study in four cases, as described above. One of the remaining two experienced liver necrosis and underwent hemihepatectomy approximately 1 week following treatment, and the other one died approximately 2 months following the first treatment. The administered doxorubicin dose averaged 124.5 ± 36.1 mg per procedure (median 150 mg, range 44–150 mg), with a mean cumulative dose of 227.4 ± 142.1 mg (median 180 mg, range 45–600 mg).\n\nSafety\nBy 30 days from their first embolization procedure with drug-loaded microspheres, 88% (n = 22) of patients remained free from procedure-related serious adverse events. The two procedure-related serious adverse events (worsening of liver insufficiency and liver necrosis) were experienced by two patients. The worsening liver insufficiency was experienced by a patient while hospitalized for a lumbar vertebrae fracture following a fall which occurred 2 weeks after the first DEB-TACE procedure. The patient had a history of cirrhosis of the liver, portal hypertension, liver insufficiency, ascites, macrocytic anemia, chronic erosive gastritis, diverticulosis, alcohol abuse, cholecystolithiasis, dyspnea, leg edema, and presented with BCLC stage C HCC. During the hospitalization (1 week later), the patient’s liver function was moderately worsened and was treated with medical treatment and prolonged hospitalization. The patient recovered and was discharged 1 week later.\n\nThe second procedure-related serious adverse event was experienced by a 60-year-old man with a history of liver cirrhosis with portal hypertension, diabetes mellitus, partial portal vein thrombosis (noted on MRI prior enrollment), hypertension, bronchial asthma, and a multifocal hepatocellular carcinoma of the right liver lobe. Two days after the first DEB-TACE procedure, the patient collapsed due to low blood pressure (60/40 mmHg) and was transferred to the intensive care unit for treatment and observation. His laboratory assessments revealed electrolyte imbalance, elevation of liver enzymes, and elevation of C-reactive protein and leukocytes. CT of the abdomen and pelvis 8 days later revealed liver necrosis around the treated segments. The patient was diagnosed to have liver cell necrosis and electrolyte imbalance. He was treated with fluid replacement, antibiotics, and prophylactic anticoagulation. His spironolactone medication was stopped due to hyponatremia. Three days later, the patient laboratory assessments were back to normal, and the next day the patient had hemihepatectomy due to the necrosis. The treating investigator reported that the patient collapse and electrolyte imbalance were due to multifactorial causes, including liver cirrhosis and necrosis, loss of volume, and concomitant medication (spironolactone), while liver cell necrosis was a result of excess volume of the microspheres and patient anatomy factors that led to embolizing the tumor and the surrounding liver tissue.\n\nNo deaths or alopecia occurred within 30 days (Table 2). Occurrence of post-embolization syndrome symptoms after sequential embolization procedures is summarized in Table 3. Post-embolization syndrome events were grade 1 or 2.Table 2 Serious adverse event occurrence within 6 months of the initial embolization\n\n\t30 Days N (%)a\n\t6 Months N (%)\t\nBack pain\t1 (4)\t–\t\nAcute cholecystitis\t1 (4)\t–\t\nWorsening liver insufficiency\t1 (4)\t–\t\nLiver necrosisb\n\t1 (4)\t–\t\nHypotension\t1 (4)\t–\t\nUrinary tract infection\t1 (4)\t–\t\nGastritis\t1 (4)\t–\t\nElevated creatinine\t1 (4)\t1 (4)\t\nAscites/worsening ascites\t–\t3 (12)\t\nAngina\t–\t2 (8)\t\nHepatic encephalopathy\t–\t1 (4)\t\nHepatic abscessc\n\t–\t1 (4)\t\nAlopecia\t–\t1 (4)\t\nSepsis\t–\t1 (4)\t\nCardiac insufficiency\t–\t1 (4)\t\nBleeding of esophageal varices\t–\t1 (4)\t\nAnemia\t–\t1 (4)\t\nMelena\t–\t1 (4)\t\nUlcus lower extremity\t–\t1 (4)\t\nHemiataxia\t–\t1 (4)\t\nMortality\t0 (0)\t5 (20)\t\n\naGrade 2 unless otherwise noted\n\n\nbGrade 3 necrosis was observed in liver tissue surrounding the tumor and was not considered immediately life-threatening\n\n\ncGrade 3 asymptomatic and noted incidentally on abdomen CT scan performed during hospitalization due to fall\n\n\nTable 3 Occurrence of post-embolization syndrome following DEB-TACE procedures\n\n\t1st DEB-TACE (N = 25)\t2nd DEB-TACE (N = 18)\t3rd DEB-TACE (N = 7)\t4th DEB-TACE (N = 2)\t\nPost-embolization syndrome, n (%)\t13 (52)\t9 (50)\t6 (86)\t1 (50)\t\nAbdominal pain\t8 (32)\t7 (39)\t2 (29)\t1 (50)\t\nNausea/vomiting\t4 (16)\t2 (11)\t1 (14)\t1 (50)\t\nFever\t1 (4)\t2 (11)\t4 (57)\t0 (0)\t\n\n\n\nBy 6 months from their first DEB-TACE procedure, 68% (n = 17) of patients were free from procedure-related serious adverse events or death. One additional patient had hepatic encephalopathy reported as a possible procedure-related serious adverse event, and five patients died by 6 months. One of these deaths was the patient with the worsening liver insufficiency serious adverse event at 30 days. One was a Child–Pugh class C patient who withdrew from the study after receiving only one treatment. The other three were known to be due to comorbidities: one cardiac, one 3 days after liver transplant (documented partial response prior to transplant), and one due to decompensated liver cirrhosis (documented partial response). One patient was lost to follow-up.\n\nEfficacy\nImaging to evaluate tumor response was available for 21 patients (of the remaining four patients, three withdrew from the study prior to having follow-up imaging performed, and one died before response was assessed). According to mRECIST criteria for best response, complete response was achieved in 10 patients (48%), partial response in 4 (19%), stable disease in 6 (29%), and progressive disease in 1 (5%). Among these 21 patients, the median time to maximum observed radiographic response was 28 days (range 10–127 days). At 6 months, 76% of patients were free from tumor progression or death. The one patient with tumor progression had three embolization procedures before progression was observed.\n\nThe one-year survival rate was 56% (14/25); 14 patients were known alive, nine died, one was lost to follow-up, and one was not included in the efficacy analysis due to early withdrawal from the study as noted above (i.e., the patient was not treated according to the protocol). A total of four of the deaths were attributable to comorbidities: In addition to the three noted above which occurred within 6 months, a later death was caused by sepsis followed by liver failure. Survival rates were higher for patients with less advanced liver disease: The one-year survival for patients with Child–Pugh A (n = 16) and B/C (n = 9) classification was 75 and 44%, respectively, and for patients without ascites (n = 15) or with ascites (n = 10), it was 73 and 50%, respectively. Four patients received liver transplants while in the study; these occurred between 4 and 11 months following the initial DEB-TACE procedure and at a minimum of 89 days following the patient’s last procedure (each of these four patients had two study procedures). Three of the four patients who received liver transplants were alive through 12 months, the fourth died soon after their transplant as described above.\n\nDiscussion\nMIRACLE I study results demonstrated a high rate of tumor control and few serious adverse events among patients treated with doxorubicin-loaded microspheres. Incidence of serious adverse events or Grade 3–4 toxicities following doxorubicin-eluting embolic therapy for HCC has generally been low in previous studies [13–15] and was comparably low in MIRACLE I. For example, Prajapati et al. [13] reported an overall adverse event rate of 30% within 30 days of embolization, with the majority of complications Grade 1–2 and no Grade 4 toxicities in a retrospective study of 121 patients. In a randomized study, approximately 24% of 93 patients treated with a drug-eluting embolic agent reported serious adverse events within 30 days, and two patients died [14]. In MIRACLE I, no deaths or systemic toxicities occurred within 30 days, and only 2 of the 25 patients had procedure-related serious adverse events. The small 75 µm microsphere size used here was not associated with specific safety concerns. One patient developed mild alopecia in the longer term, but no myelosuppression was reported. Compared with MIRACLE I, the studies noted above included greater proportions of patients with Child–Pugh class A (> 75% in two of the studies [14, 15]) and lower proportions with ascites. Ascites was observed in 40% of MIRACLE I patients at baseline, but in only 23% of patients in one of the comparable studies [13] and excluded or not present in the other comparable study samples [14, 15]. Although the heterogeneous nature of HCC patient characteristics, variable treatment regimens, and evaluation criteria across studies limit comparisons between studies, results from previous studies of doxorubicin-loaded microsphere treatment of HCC provide background for the findings observed in the MIRACLE I study.\n\nPost-embolization syndrome, or symptoms such as abdominal pain, nausea, vomiting, and fever, has been reported in 5–100% of patients in previous studies [5, 13–17]. In a recent study of the same type of microspheres used in MIRACLE I, post-embolization syndrome occurred in 13–46% of patients across embolization sessions [5], and approximately half of patients in MIRACLE I had mild symptoms following embolization procedures.\n\nTumor response rates compare favorably with previous studies, with complete or partial tumor responses observed in 67% of MIRACLE I patients and only one patient (5%) displaying tumor progression during study follow-up. Objective response rates in previous studies range from 40 to 64%, with disease progression observed in 5–32% of patients [5, 14, 15]. The one-year survival rate was 56% in the current study, with a greater rate among patients with liver function classified as Child–Pugh A (75%) or without ascites (73%). Four of the nine deaths in the MIRACLE I study were known to be attributable to comorbidities rather than to disease progression. Previously reported overall one-year survival rates range from 58 to 92% [5, 15, 18], with stratifying factors such as the presence of ascites and Child–Pugh classification of B or C associated with poorer survival [13, 18, 19]. The proportions of patients with liver function classified as Child–Pugh B or C or ascites (indicative of liver cirrhosis) were relatively high in MIRACLE I compared with these previous studies (i.e., no patients with ascites or Child–Pugh C liver disease were included in the studies by Reyes et al. [15] or Malagari et al. [5]) and may explain the lower survival rate. In the study by Dhanasekaran et al. [18], in which half of patients had Child–Pugh class B or C, one-year survival for patients who underwent TACE with drug-eluting beads was 58% overall, but decreased to 32% among patients with Child–Pugh class C.\n\nSpecific reasons for choosing to treat the study patients with TACE with drug-eluting microspheres, rather than ablation or surgery, were not collected. The presence of severe comorbidities, failed prior treatment, and multiple tumors likely limited the patients’ surgical options, thereby characterizing their disease as “locally untreatable” as defined by the study eligibility criteria. Limitations also included the lack of central review of tumor response and adverse events and the lack of systematic CTCAE grading at the time of data collection.\n\nNotwithstanding study limitations including a relatively small sample size and heterogeneous clinical characteristics of the study sample, MIRACLE I study results suggest that Embozene TANDEM microspheres loaded with doxorubicin can provide good local tumor control in a heterogeneous group of patients with unresectable intermediate and locally advanced HCC.\n\nAcknowledgements\nThe authors thank Elizabeth J. Davis, PhD (Boston Scientific, Maple Grove, MN), for medical writing assistance. Findings from the MIRACLE I study were presented at CIRSE 2016, September 10–14, Barcelona, Spain.\n\nMIRACLE I was sponsored by CeloNova BioSciences Inc., San Antonio, USA.\n\nCompliance with Ethical Standards\nConflict of interest\nGötz Richter declares no conflict of interest with respect to design, conduct, and organization of the MIRACLE I study. Boris Radeleff declares no conflict of interest. Christian Stroszczynski declares no conflict of interest. Philippe Pereira has received speaker’s honoraria or grants or participated as a consultant or advisory board member or participated in symposia sponsored by the following companies: Bayer Global and Bayer Germany, Biocompatibles and BTG, Celonova, Cook Medical, Pharmacept, SIRTEX, Terumo. Thomas Helmberger declares no conflict of interest. Mark Barakat is an employee of Celonova Biosciences. Peter Huppert declares no conflict of interest.\n\nEthical Approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed Consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\n1. Bruix J Sherman M Management of hepatocellular carcinoma: an update Hepatology 2011 53 1020 1022 10.1002/hep.24199 21374666 \n2. Llovet JM Ricci S Mazzaferro V Sorafenib in advanced hepatocellular carcinoma N Engl J Med 2008 359 378 390 10.1056/NEJMoa0708857 18650514 \n3. Hui Y Ruihua T Jing L Meta-analysis of doxorubicin-eluting beads via transcatheter arterial chemoembolization in the treatment of unresectable hepatocellular carcinoma Hepatogastroenterology 2015 62 1002 1006 26902045 \n4. Zou J Zhang L Ren Z Ye SL Efficacy and safety of cTACE versus DEB-TACE in patients with hepatocellular carcinoma: a meta-analysis J Dig Dis 2016 17 8 510 517 10.1111/1751-2980.12380 27384075 \n5. Malagari K Kiakidis T Pomoni M Pharmacokinetics, safety, and efficacy of chemoembolization with doxorubicin-loaded tightly calibrated small microspheres in patients with hepatocellular carcinoma Cardiovasc Intervent Radiol 2016 39 1379 1391 10.1007/s00270-016-1382-6 27393274 \n6. EASL-EORTC clinical practice guidelines Management of hepatocellular carcinoma J Hepatol 2012 56 908 943 10.1016/j.jhep.2011.12.001 22424438 \n7. Oken MM Creech RH Tormey DC Toxicity and response criteria of the Eastern cooperative oncology group Am J Clin Oncol 1982 5 649 655 10.1097/00000421-198212000-00014 7165009 \n8. Pugh RN Murray-Lyon IM Dawson JL Pietroni MC Williams R Transection of the oesophagus for bleeding oesophageal varices Br J Surg 1973 60 646 649 10.1002/bjs.1800600817 4541913 \n9. de Baere T Plotkin S Yu R Sutter A Wu Y Cruise GM An In vitro evaluation of four types of drug-eluting microspheres loaded with doxorubicin J Vasc Interv Radiol 2016 27 1425 1431 10.1016/j.jvir.2016.05.015 27402527 \n10. Tanaka T Nishiofuku H Hukuoka Y Pharmacokinetics and antitumor efficacy of chemoembolization using novel 40-μm irinotecan-loaded microspheres (Embozene® TANDEM™) in a rabbit liver tumor model J Vasc Intervent Radiol 2014 25 1037 1044 10.1016/j.jvir.2014.04.005 \n11. Gnutzmann DM Mechel J Schmitz A Evaluation of the plasmatic and parenchymal elution kinetics in a domestic pig model using irinotecan-loaded drug-eluting beads J Vasc Intervent Radiol 2015 26 746 752 10.1016/j.jvir.2014.12.016 \n12. Lencioni R Llovet JM Modified RECIST (mRECIST) assessment for hepatocellular carcinoma Semin Liver Dis 2010 30 52 60 10.1055/s-0030-1247132 20175033 \n13. Prajapati HJ Dhanasekaran R El-Rayes BF Safety and efficacy of doxorubicin drug-eluting bead transarterial chemoembolization in patients with advanced hepatocellular carcinoma J Vasc Interv Radiol 2013 24 307 315 10.1016/j.jvir.2012.11.026 23375519 \n14. Lammer J Malagari K Vogl T Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study Cardiovasc Intervent Radiol 2010 33 41 52 10.1007/s00270-009-9711-7 19908093 \n15. Reyes DK Vossen JA Kamel IR Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States Cancer J 2009 15 526 532 10.1097/PPO.0b013e3181c5214b 20010173 \n16. Malagari K Chatzimichael K Alexopoulou E Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients Cardiovasc Intervent Radiol 2008 31 269 280 10.1007/s00270-007-9226-z 17999110 \n17. Malagari K Pomoni M Spyridopoulos TN Safety profile of sequential transcatheter chemoembolization with DC Bead: results of 237 hepatocellular carcinoma (HCC) patients Cardiovasc Intervent Radiol 2011 34 774 785 10.1007/s00270-010-0044-3 21184228 \n18. Dhanasekaran R Kooby DA Staley CA Kauh JS Khanna V Kim HS Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC) J Surg Oncol 2010 101 476 480 20213741 \n19. Hsin IF Hsu CY Huang HC Liver failure after transarterial chemoembolization for patients with hepatocellular carcinoma and ascites: incidence, risk factors, and prognostic prediction J Clin Gastroenterol 2011 45 556 562 10.1097/MCG.0b013e318210ff17 21666547\n\n", "fulltext_license": "CC BY", "issn_linking": "0174-1551", "issue": "41(4)", "journal": "Cardiovascular and interventional radiology", "keywords": "Chemoembolization; Doxorubicin; Drug carriers; Hepatocellular carcinoma; Microspheres", "medline_ta": "Cardiovasc Intervent Radiol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D004317:Doxorubicin; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "8003538", "other_id": null, "pages": "587-593", "pmc": null, "pmid": "29167967", "pubdate": "2018-04", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": "21374666;21184228;19908093;20213741;24861663;27384075;20175033;26902045;18650514;17999110;21666547;27393274;7165009;20010173;4541913;23375519;25704223;27402527;22424438", "title": "Safety and Feasibility of Chemoembolization with Doxorubicin-Loaded Small Calibrated Microspheres in Patients with Hepatocellular Carcinoma: Results of the MIRACLE I Prospective Multicenter Study.", "title_normalized": "safety and feasibility of chemoembolization with doxorubicin loaded small calibrated microspheres in patients with hepatocellular carcinoma results of the miracle i prospective multicenter study" }

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{ "abstract": "BACKGROUND\nApatinib is a novel anti-angiogenic agent targeting vascular endothelial growth factor receptor-2, which is effective in patients with chemotherapy-refractory gastric cancer. There are no reports of concurrent apatinib with local radiation therapy in elderly patients with advanced gastric cancer. PATIENT CONCERNS AND DIAGNOSES:: we present the first published report of a 70-year-old male patient with advanced gastric cancer who received concurrent apatinib and local radiation therapy after failure of oxaliplatin and S-1 chemotherapy.\n\n\nRESULTS\nThe patient received concurrent apatinib and local radiation therapy and was followed up 7 months after therapy without disease progress, 14 months later indicated extensive metastasis and this patient died of pulmonary infection.\n\n\nCONCLUSIONS\nElderly patients with advanced gastric cancer may benefit from concurrent apatinib with local radiation therapy when chemotherapy is not tolerated or successful. Further studies are needed to investigate the clinical outcomes and toxicities associated with concurrent apatinib and radiation therapy in gastric cancer.", "affiliations": "Department of Radiation Oncology, Hebei General Hospital, Shijiazhuang, China Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health at Houston, Houston, TX Department of Gastrointestinal Surgery Department of Pathology, Hebei General Hospital, Shijiazhuang, China.", "authors": "Zhang|Ming|M|;Deng|Weiye|W|;Cao|Xiaoci|X|;Shi|Xiaoming|X|;Zhao|Huanfen|H|;Duan|Zheping|Z|;Lv|Bonan|B|;Liu|Bin|B|", "chemical_list": "D011725:Pyridines; C553458:apatinib", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000006241", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28248891MD-D-16-0620210.1097/MD.0000000000006241062414500Research ArticleClinical Case ReportConcurrent apatinib and local radiation therapy for advanced gastric cancer A case report and review of the literatureZhang Ming MDa∗Deng Weiye MDbcCao Xiaoci MDaShi Xiaoming MDdZhao Huanfen MDeDuan Zheping MDaLv Bonan MDdLiu Bin MDa∗Gurzu. Simona a Department of Radiation Oncology, Hebei General Hospital, Shijiazhuang, Chinab Department of Radiation Oncology, The University of Texas MD Anderson Cancer Centerc Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health at Houston, Houston, TXd Department of Gastrointestinal Surgerye Department of Pathology, Hebei General Hospital, Shijiazhuang, China.∗ Correspondence: Ming Zhang and Bin Liu, Department of Radiation Oncology, Hebei General Hospital, Shijiazhuang, China (e-mails: Zhangming096@163.com [MZ]; 13111582843@163.com [BL]); Bin Liu, MD, Department of Radation Oncology, Hebei General Hospital, Shijiazhuang, 050051, China (e-mail: 13111582843@163.com).3 2017 03 3 2017 96 9 e624111 10 2016 5 2 2017 6 2 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-No Derivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nApatinib is a novel anti-angiogenic agent targeting vascular endothelial growth factor receptor-2, which is effective in patients with chemotherapy-refractory gastric cancer. There are no reports of concurrent apatinib with local radiation therapy in elderly patients with advanced gastric cancer.\n\nPatient concerns and Diagnoses:\nwe present the first published report of a 70-year-old male patient with advanced gastric cancer who received concurrent apatinib and local radiation therapy after failure of oxaliplatin and S-1 chemotherapy.\n\nInterventions and Outcomes:\nThe patient received concurrent apatinib and local radiation therapy and was followed up 7 months after therapy without disease progress, 14 months later indicated extensive metastasis and this patient died of pulmonary infection.\n\nLessons:\nElderly patients with advanced gastric cancer may benefit from concurrent apatinib with local radiation therapy when chemotherapy is not tolerated or successful. Further studies are needed to investigate the clinical outcomes and toxicities associated with concurrent apatinib and radiation therapy in gastric cancer.\n\nKeywords\nantiangiogenic therapyapatinibgastric cancerradiation therapyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe gastric cancer is the fifth leading cause of cancer in the world and China accounts for approximately 40% of global gastric cancer incidence annually.[1] Patients diagnosed with advanced gastric cancer usually have a poor prognosis, with a median overall survival (OS) of 1 year when treated with chemotherapy.[2,3] Gastric cancer frequently occurs in elder individuals, and conventional cancer therapies are difficult to administer due to challenges associated with age, comorbidities, and cancer-related debilitation. In order to avoid the toxicity associated with conventional therapies and improve outcomes in this patient population, many research studies have focused on the application of novel molecular targeted agents.\n\nIn the 1970s, angiogenesis was reported to play a key role in tumor growth.[4] Since this initial research, multiple antiangiogenic agents have been developed and studied in clinical trials. Although these agents show promising antitumor effects, their efficacy when used as monotherapy is limited. Therefore, these agents have been integrated with conventional cancer therapies, including chemotherapy and radiotherapy, in order to enhance antitumor activity.\n\nApatinib is a novel oral antiangiogenic agent that shows efficacy in the inhibition of tumor angiogenesis.[5] Phase II and III clinical trials suggest apatinib can improve OS and progression-free survival (PFS) in advanced gastric cancer patients who have experienced treatment failure on 2 or more prior chemotherapy regimens. Apatinib was approved and launched in the People's Republic of China in 2014 as a second-line treatment for gastric cancer patients.\n\nHere, we report the case of a 70-year-old male patient with advanced gastric cancer, who received concurrent apatinib and local radiation therapy.\n\n2 Case report\nOn December 28, 2014, a 70-year-old man complaining of abdominal pain, dizziness, and nausea was referred to the Hebei General Hospital, Hebei, China. Gastroscopy showed irregular hemorrhagic ulcerative lesions extending from the gastric body to the lesser curvature and pyloric stenosis of the stomach. Gastric biopsy revealed adenocarcinoma. On January 7, 2015, palliative gastrectomy plus Roux-en-Y near esophagojejunostomy were performed. Diffuse enlarged para-aortic and anterior superior pancreatic lymph nodes, as well as lymph nodes around the common hepatic artery, could not be resected. Postoperative pathology demonstrated moderately differentiated gastric adenocarcinoma (Fig. 1A). Immunohistochemistry showed the following: human epidermal growth factor receptor 2 (HER-2) (+), vascular endothelial growth factor (VEGF) (+), CD31 (+), CD105 (+) (Fig. 1B–E), triple positive (TP) (+), glutathione S-transferase π (GST-π) (+++), topoisomerase enzyme II α (TOPOII α), P53 (–), and Ki-67 (70%). The diagnosis was stage IV gastric adenocarcinoma with multiple lymphnodes metastases (T4N2M1).\n\nFigure 1 Postoperative pathology: (A) hematoxylin and eosin staining indicating moderately differentiated gastric adenocarcinoma (100×). (B) Immunohistochemistry showing the expression of HER2 (+) (100×). (C) Immunohistochemistry showing the expression of VEGF (+) (100×). (D) Immunohistochemistry showing the expression of CD31 (+) (100×). (E) Immunohistochemistry showing the expression of CD105 (+) (100×). HER-2 = human epidermal growth factor receptor 2, VEGF = vascular endothelial growth factor.\n\nThe patient was administered 1 cycle of chemotherapy with oxaliplatin and S-1; however, the treatment was terminated, as the patient could not tolerate the associated gastrointestinal disturbances. On February 2, 2015, adjuvant radiotherapy was administered. Before radiotherapy, positron-emission tomography computed tomography (PET-CT) showed extensive distant metastasis (left supraclavicular and mediastinal lymph nodes, and lymph nodes throughout the abdominal cavity). The patient's Eastern Cooperative Oncology Group (ECOG) performance status was 2, and his body mass index (BMI) was 19; therefore, he was considered to be at risk of malnutrition. Oral apatinib 850 mg once a day combined with and following radiotherapy was prescribed. Informed consent was obtained from the patient prior to treatment. In an attempt to improve tolerance to treatment, palliative intensity modulated radiation therapy (IMRT) was used. The patient received a dose of 64 Gy in 30 fractions to the mediastinum and doses of 52 Gy in 26 fractions to the other abdominal metastatic lesions (n = 5). The left supraclavicular lymph node was treated with apatinib alone (Figs. 2 and 3A–C).\n\nFigure 2 PET-CT scans: (A) left supraclavicular metastasis (arrow) before apatinib treatment; (B) left supraclavicular metastasis (arrow) after apatinib treatment; (C) mediastinum metastasis (arrow) before concurrent apatinib and radiotherapy; (D) mediastinum metastasis (arrow) after concurrent apatinib and radiotherapy; (E) abdominal metastasis (arrow) before concurrent apatinib and radiotherapy; (F) abdominal metastasis (arrow) after concurrent apatinib and radiotherapy. PET-CT = positron-emission tomography computed tomography.\n\nFigure 3 Pre- and postoperative imaging: (A) clinical target volume (red) of the left supraclavicular region; (B) clinical target volume (red) of the mediastinum; (C) clinical target volume (red) of the abdominal cavity (A–C) gross tumor volume and planning target volume contours omitted for clarity); (D) gastric endoscopy showing anastomotic stenosis due to gastric cancer with intragastric hemorrhage; (E) PET-CT showing extensive distant metastasis in supraclavicular lymph nodes (arrow), the mediastinum (arrow), and multiple parts of the abdominal cavity (circle and arrow) before concurrent apatinib and radiotherapy; (F) PET-CT showing a partial response in the supraclavicular lymph nodes, mediastinum, and multiple parts of the abdominal cavity after concurrent apatinib and radiotherapy. PET-CT = positron-emission tomography computed tomography.\n\nA PET-CT scan performed 2 weeks after radiotherapy showed an 80% reduction in the maximum standardized uptake value (SUVmax) of 2-deoxy-2-[[18]F]fluoro-D-glucose (FDG). FDG uptake was higher in the left supraclavicular lymph node compared to the metastatic regions treated with concurrent apatinib and radiation therapy. According to Response Evaluation Criteria in Solid Tumors (RECIST), the clinical effect was partial response (Fig. 2). The patient received further radiotherapy (66 Gy in 28 fractions) to the left supraclavicular lymph node due to residual metastasis.\n\nTumor markers and biochemical analyses were evaluated every 2 months. Two months after therapy, chest, and abdominal CT scans indicated stable disease; anemia and gastrointestinal symptoms had improved, ECOG performance status was 0, and BMI was 22. Hematologic toxicity, hypertension, renal dysfunction, proteinuria, and hand–foot syndrome were not observed during apatinib therapy.\n\nIn September 2015, a follow-up examination showed increased carbohydrate antigen (CA) 125 and ferritin; however, gastroscopy and abdominal CT revealed no abnormalities. In November 2015, the patient had difficulty swallowing and experienced intermittent hematochezia. Apatinib was terminated due to gastrointestinal bleeding. Gastroscopy revealed anastomotic stenosis due to gastric cancer and intragastric hemorrhage (Fig. 3D–F). The patient and his family refused chemoradiotherapy. Symptomatic treatment with a hemostatic drug and best supportive care were prescribed. After 1 week of therapy, hemorrhaging was resolved. One month later, the patient again experienced intermittent hematochezia. On December 20, 2015, PET-CT demonstrated extensive metastasis. The patient and his family requested best supportive care. On April 16, 2016, the patient died due to pulmonary infection.\n\n3 Discussion\nThis study reports the case of a 70-year-old male patient with advanced gastric cancer who received concurrent apatinib and local radiation therapy after failure of oxaliplatin and S-1 chemotherapy. Chemotherapy, radiation therapy, and chemoradiotherapy are recommended for metastatic gastric cancer; however, relapses are frequent and prognosis is poor.\n\nMolecular targeted therapies have the potential to improve oncological outcomes. The recently published multinational Phase III randomized TOGA trial of trastuzumab, a monoclonal antibody that targets HER2,[6] is the first to show benefit of a targeted agent in gastric cancer. The addition of trastuzumab to a standard cisplatin/fluoropyrimidine chemotherapy doublet resulted in significant improvements in the overall response rate, PFS and OS, compared to chemotherapy alone. However, the survival benefit of trastuzumab is limited to the few patients whose esophagogastric cancers are HER2 (+++) or fluorescence in situ hybridization (FISH) positive. The gastric cancer of the patient in the current study was HER2 (+); therefore, he was not eligible for trastuzumab therapy.\n\nNew blood vessel formation or neovascularization is crucial for tumor growth and metastasis. VEGF is the most potent mediator of this process. VEGF binds to high-affinity receptors (VEGFR type 1 and 2) and leads to endothelial cell migration and proliferation.[7] Antiangiogenesis strategies using monoclonal antibodies and tyrosine kinase inhibitors have improved OS in colon, renal, non-small-cell lung cancer and hepatocellular carcinoma,[8] and have been extensively assessed in gastric cancer. Interesting, antiangiogenesis strategies seem to be more effective in intestinal-type than diffuse-type gastric cancer.[9]\n\nApatinib targets the intracellular ATP-binding site of VEGFR-2.[10] It was the first agent to show a clear survival benefit compared with placebo in a phase III trial in patients with advanced gastric cancer refractory to 2 or more lines of prior chemotherapy. OS was 6.5 months in the apatinib group and 4.7 months in the placebo group. PFS was 2.6 months in the apatinib group and 1.8 months in the placebo.[11] To our knowledge, the current study is the first to show that apatinib combined with radiotherapy may achieve a better clinical outcome that apatinib alone in metastatic gastric cancer.\n\nAlthough several trials have shown that the addition of conventionally fractionated radiation therapy to antiangiogenic agents is well tolerated,[12,13] some reports suggest increased luminal gastrointestinal toxicity in combination therapy, especially when stereotactic body radiation therapy is combined with antiangiogenic agents.[14,15] Gastrointestinal organs are regenerative organs. However, acute radiation toxicity may selectively kill stem cells, resulting in an insufficient supply to replace sloughed villi.[16,17] Chronic radiation toxicity can cause fibrosis and endothelial abnormalities.[18] Furthermore, radiation therapy is associated with a decrease in vascular density, leading to ischemia, telangiectasia, and a predisposition for bleeding. VEGF plays an important role in the gastrointestinal mucosa and ulcer healing, and it may be protective against small bowel injury after irradiation. Infusion of VEGF inhibitors delays healing of gastric erosions.[19] Additionally, excessive VEGF inhibition can cause regression of normal blood vessels and reduced vascular density in the small intestinal villi, affecting recovery of damaged tissue.[20]\n\nThe schedule of radiotherapy and the timing, duration, dosage and selection of VEGF inhibitor may determine the extent of treatment-related toxicity. In the current study, we used fractionated radiation therapy. Our patient presented with intermittent gastrointestinal hemorrhage 7 months after radiation therapy; however, gastroscopy confirmed that the hemorrhagic lesions were not radiation-associated.\n\nPostoperative adjuvant radiotherapy or chemoradiotherapy is beneficial for gastric cancer patients. However, some elderly patients with resected gastric adenocarcinoma may not gain a survival benefit from administration of adjuvant chemo radiotherapy.[21] The patient in the current study refused chemoradiotherapy after termination of apatinib. The PFS of this patient reached 7 months and he experienced good quality of life. After disease progression, best supportive care was prescribed.\n\nFuture studies investigating treatment regimens for advanced gastric cancer should focus on target validation, the development of biomarkers of gastrointestinal toxicity, and stratify patients by age in order to better understand the impact of treatment regimens on older patients. There is a need for more data to create treatment guidelines that can be refined to maximize treatment benefit and minimize toxicity.\n\n4 Conclusion\nElderly patients with advanced gastric cancer may benefit from concurrent apatinib and local radiation therapy when chemotherapy is not tolerated or successful. Further studies are needed to investigate the clinical outcomes and toxicities associated with concurrent apatinib and radiation therapy in gastric cancer.\n\nAbbreviation: BMI = body mass index, ECOG = Eastern Cooperative Oncology Group, FISH = fluorescence in situ hybridization, GST-π = glutathione S-transferase π, HER-2 = human epidermal growth factor receptor 2, IMRT = intensity modulated radiation therapy, OS = overall survival, PET-CT = positron-emission tomography computed tomography, PFS = progression-free survival, RECIST = Response Evaluation Criteria in Solid Tumors, SUV = standardized uptake value, TOPOII α = topoisomerase enzyme II α, VEGF = vascular endothelial growth factor.\n\nMZ and WD contributed equally to this work.\n\nFunding: This work was supported by The fund of HeBei Food and Drug Administration (ZD2015035).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Lu S Zhu Z \nClinical and prognostic features of surgical treatment in gastric cancer in aged patients . Zhonghua Wei Chang Wai Ke Za Zhi \n2016 ;19 :596 –600 .27215533 \n[2] Cunningham D Okines AF Ashley S \nCapecitabine and oxaliplatin for advanced esophagogastric cancer . N Engl J Med \n2010 ;362 :858 –9 .20200397 \n[3] Ajani JA Buyse M Lichinitser M \nCombination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study . Eur J Cancer \n2013 ;49 :3616 –24 .23899532 \n[4] Folkman J \nTumor angiogenesis: therapeutic implications . N Engl J Med \n1971 ;285 :1182 –6 .4938153 \n[5] Geng R Li J \nApatinib for the treatment of gastric cancer . Expert Opin Pharmacother \n2015 ;16 :117 –22 .25420417 \n[6] Bang YJ Van Cutsem E Feyereislova A \nTrastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial . Lancet \n2010 ;376 :687 –97 .20728210 \n[7] Ferrara N Kerbel RS \nAngiogenesis as a therapeutic target . Nature \n2005 ;438 :967 –74 .16355214 \n[8] Cheng AL Kang YK Chen Z \nEfficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial . Lancet Oncol \n2009 ;10 :25 –34 .19095497 \n[9] Gurzu S Kadar Z Sugimura H \nGastric cancer in young vs old Romanian patients: immunoprofile with emphasis on maspin and mena protein reactivity . APMIS \n2015 ;123 :223 –33 .25556597 \n[10] Zhang H \nApatinib for molecular targeted therapy in tumor . Drug Des Devel Ther \n2015 ;9 :6075 –81 .\n[11] Li J Qin S Xu J \nRandomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction . J Clin Oncol \n2016 ;34 :1448 –54 .26884585 \n[12] Small WJr Mulcahy MF Rademaker A \nPhase II trial of full-dose gemcitabine and bevacizumab in combination with attenuated three-dimensional conformal radiotherapy in patients with localized pancreatic cancer . Int J Radiat Oncol Biol Phys \n2011 ;80 :476 –82 .20598452 \n[13] Spigel DR Hainsworth JD Yardley DA \nTracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab . J Clin Oncol \n2010 ;28 :43 –8 .19901100 \n[14] Lordick F Geinitz H Theisen J \nIncreased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases . Int J Radiat Oncol Biol Phys \n2006 ;64 :1295 –8 .16503384 \n[15] Barney BM Markovic SN Laack NN \nIncreased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT) . Int J Radiat Oncol Biol Phys \n2013 ;87 :73 –80 .23920388 \n[16] Potten CS \nExtreme sensitivity of some intestinal crypt cells to X and gamma irradiation . Nature \n1977 ;269 :518 –21 .909602 \n[17] Brown M \nWhat causes the radiation gastrointestinal syndrome?: overview . Int J Radiat Oncol Biol Phys \n2008 ;70 :799 –800 .18262092 \n[18] Brush J Lipnick SL Phillips T \nMolecular mechanisms of late normal tissue injury . Semin Radiat Oncol \n2007 ;17 :121 –30 .17395042 \n[19] Yoshida M Wakabayashi G Ishikawa H \nA possible defensive mechanism in the basal region of gastric mucosa and the healing of erosions . Clin Hemorheol Microcirc \n2003 ;29 :301 –12 .14724355 \n[20] Pollom EL Deng L Pai RK \nGastrointestinal toxicities with combined antiangiogenic and stereotactic body radiation therapy . Int J Radiat Oncol Biol Phys \n2015 ;92 :568 –76 .26068491 \n[21] Hoffman KE Neville BA Mamon HJ \nAdjuvant therapy for elderly patients with resected gastric adenocarcinoma: population-based practices and treatment effectiveness . Cancer \n2012 ;118 :248 –57 .21692071\n\n", "fulltext_license": "CC BY-ND", "issn_linking": "0025-7974", "issue": "96(9)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D059248:Chemoradiotherapy; D006801:Humans; D008297:Male; D011725:Pyridines; D050397:Radiotherapy, Intensity-Modulated; D013274:Stomach Neoplasms", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e6241", "pmc": null, "pmid": "28248891", "pubdate": "2017-03", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "18262092;21692071;17395042;20200397;23899532;4938153;14724355;909602;16355214;25556597;20728210;26068491;19901100;27215533;19095497;26884585;26622168;16503384;23920388;25420417;20598452", "title": "Concurrent apatinib and local radiation therapy for advanced gastric cancer: A case report and review of the literature.", "title_normalized": "concurrent apatinib and local radiation therapy for advanced gastric cancer a case report and review of the literature" }

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{ "abstract": "A 77-year-old woman, who had a history of rheumatic mitral stenosis with atrial fibrillation (AF), was referred and admitted to our hospital because of a transient ischemic attack at 4: 55 p.m.. She had taken warfarin for over 10 years, but her condition was not well controlled on admission. At 8: 30 p.m., she had acute ischemic stroke with right facial palsy, right hemiparesis and slurred speech. At 10: 35 p.m., she was treated with intravenous tissue plasminogen activator (t-PA) and her neurological deficits almost fully recovered by 0: 05 a.m. (90 min after t-PA started). At 0: 08 a.m., she collapsed due to sudden pulseless arrest. Using advanced life support, she soon recovered with no complications. After mitral valve replacement and left atrial appendectomy, she was discharged with a modified Rankin scale 0 at day 40. To the best of our knowledge, this is the first case report showing pulseless arrest immediately after treatment with t-PA in an elderly patient with ischemic stroke. Left insular injury seemed to be a crucial mechanism of pulseless arrest in this case.", "affiliations": "Department of Cardiology, Ehime Prefectural Central Hospital.", "authors": "Yamamoto|Yuki|Y|;Suzuki|Makoto|M|;Kawada|Yoshitaka|Y|;Kamogawa|Kenji|K|;Okamoto|Kensho|K|;Okuda|Bungo|B|", "chemical_list": "D010959:Tissue Plasminogen Activator", "country": "Japan", "delete": false, "doi": "10.3143/geriatrics.46.352", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-9173", "issue": "46(4)", "journal": "Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics", "keywords": null, "medline_ta": "Nihon Ronen Igakkai Zasshi", "mesh_terms": "D000368:Aged; D002544:Cerebral Infarction; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007275:Injections, Intravenous; D010959:Tissue Plasminogen Activator", "nlm_unique_id": "7507332", "other_id": null, "pages": "352-7", "pmc": null, "pmid": "19713669", "pubdate": "2009-07", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Pulseless arrest in an elderly patient treated with intravenous tissue plasminogen activator for cardioembolic ischemic stroke.", "title_normalized": "pulseless arrest in an elderly patient treated with intravenous tissue plasminogen activator for cardioembolic ischemic stroke" }

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{ "abstract": "Syphilis is an overlooked cause of hepatitis. Syphilitic hepatitis should be a differential diagnosis in all patients with abnormal liver biochemical marker levels. Syphilitic hepatitis has been defined as the combination of increased liver enzymes, positive serology for syphilis, the absence of alternative causes for hepatobiliary injury, and liver enzyme improvement with proper antibiotic therapy.", "affiliations": "Gastroenterology Department Centro Hospitalar de Leiria Leiria Portugal.;Gastroenterology Department Centro Hospitalar de Leiria Leiria Portugal.;Dermatology Department Centro Hospitalar de Leiria Leiria Portugal.;Gastroenterology Department Centro Hospitalar de Leiria Leiria Portugal.", "authors": "Marcos|Pedro|P|https://orcid.org/0000-0002-0367-1702;Eliseu|Liliana|L|;Henrique|Martinha|M|;Vasconcelos|Helena|H|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2588", "fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2588CCR32588Case ReportCase ReportsSyphilitic hepatitis: Case report of an overlooked condition MARCOS et al.Marcos Pedro https://orcid.org/0000-0002-0367-1702\n1\npedromarcos1ster@gmail.com Eliseu Liliana \n1\nHenrique Martinha \n2\nVasconcelos Helena \n1\n\n1 \nGastroenterology Department\nCentro Hospitalar de Leiria\nLeiria\nPortugal\n\n2 \nDermatology Department\nCentro Hospitalar de Leiria\nLeiria\nPortugal\n* Correspondence\n\nPedro Miguel Ribeiro Marcos, Serviço de Gastrenterologia, Centro Hospitalar de Leiria, Rua das Olhalvas, 2410‐197 Leiria, Portugal.\n\nEmail: pedromarcos1ster@gmail.com\n04 12 2019 1 2020 8 1 10.1002/ccr3.v8.1123 126 24 6 2019 24 10 2019 30 10 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nSyphilis is an overlooked cause of hepatitis. Syphilitic hepatitis should be a differential diagnosis in all patients with abnormal liver biochemical marker levels. Syphilitic hepatitis has been defined as the combination of increased liver enzymes, positive serology for syphilis, the absence of alternative causes for hepatobiliary injury, and liver enzyme improvement with proper antibiotic therapy.\n\nSyphilis is an overlooked cause of hepatitis. Syphilitic hepatitis should be a differential diagnosis in all patients with abnormal liver biochemical marker levels. Syphilitic hepatitis has been defined as the combination of increased liver enzymes, positive serology for syphilis, the absence of alternative causes for hepatobiliary injury, and liver enzyme improvement with proper antibiotic therapy.\n\n\nSyphilisSyphilitic hepatitisTreponema pallidum source-schema-version-number2.0cover-dateJanuary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:25.01.2020\n\n\nMarcos \nP \n, \nEliseu \nL \n, \nHenrique \nM \n, \nVasconcelos \nH \n. Syphilitic hepatitis: Case report of an overlooked condition . Clin Case Rep . 2020 ;8 :123 –126 . 10.1002/ccr3.2588 \n\n\n\n\nStatements: The authors obtained signed informed consent from the patient for the publication of his case.\n==== Body\n1 INTRODUCTION\nSyphilis is a sexually and vertically transmitted infection that is caused by the bacterium, Treponema pallidum (T pallidum), an obligate human pathogen well‐known for its invasiveness and immune‐evasive properties.1 Syphilis was first described at the end of the fifteenth century, and it remains a major public health problem worldwide.2 According to the most recent global estimation of the World Health Organization, approximately 19.9 million individuals had syphilis in 2016, and an estimated 6.3 million new cases occur every year.3\n\n\nDuring its natural course, syphilis progresses from early (including primary, secondary, and early latent syphilis) to late stages (including late latent and tertiary syphilis) if left untreated. Primary syphilis classically presents with a single ulcer (chancre) or multiple lesions at the site of inoculation; these are typically painless, they resolve spontaneously, and they may go unnoticed by patients. Secondary syphilis, also known as the dissemination phase, is commonly characterized by a non‐itchy skin rash that can mimic other infectious and non‐infectious conditions, but the rash can spontaneously disappear even without treatment. When left untreated, the infection enters a latent stage, which is asymptomatic and can last for years (early latent stage, infection with a duration of ≤1 year; late latent stage, infection with a duration of >1 year). Tertiary syphilis is characterized by the development of major complications during the latent phase, such as gumma, cardiosyphilis, or late neurosyphilis.1, 4\n\n\nSyphilis can involve multiple organs and produce diverse and often subtle clinical manifestations that can mimic other infectious and non‐infectious conditions.1 Liver involvement associated with syphilis is not observed in daily clinical practice. Here, we presented the uncommon case of a man with syphilitic hepatitis, which is an overlooked entity that warrants attention.\n\n2 CASE REPORT\nA 48‐year‐old Caucasian man with a 2‐week history of epigastric tenderness and asthenia was referred to our hospital owing to abnormal hepatic and biochemical test results (alanine aminotransferase [ALT] at 324 IU/L [normal, 3–45]; aspartate aminotransferase [AST] at 154 IU/L [normal, 15–50]; gamma‐glutamyl transferase [GGT] at 1384 IU/L [normal < 55]; and alkaline phosphatase at 390 IU/L [normal, 30–120]). The patient did not have a past medical history of liver disease or abnormal liver tests. Essential arterial hypertension under prolonged treatment with olmesartan was the only known medical condition and medication, respectively. He denied significant alcohol intake, as well as the use of acetaminophen, herbals, over‐the‐counter products, recreational drugs, or other potentially toxic substances. He also had no family history of gastrointestinal or hepatic diseases. He was single and frequently traveled for work. The patient mentioned a casual unprotected heterosexual intercourse 2 months prior to his present condition. He showed no signs and symptoms, and he had no history of sexually transmitted infections.\n\nThe admission physical examination was unremarkable. He was fully alert and oriented, with good reflexes and no flapping; his sclerae were anicteric; he had no skin lesions; his vital signs, heart, and lung sounds were normal; his abdomen was soft, without tenderness or appreciable hepatosplenomegaly.\n\nThe admission blood tests revealed normal complete blood counts and coagulation tests; a high C‐reactive protein at 30.6 mg/L (<5.0 mg/L); levels of creatinine, albumin, amylase, lipase, and bilirubin within the normal ranges; and increased ALT (342 IU/L [3–45]), AST (93 IU/L [15–50]), GGT (1503 IU/L [<55]), and alkaline phosphatase (591 IU/L [30–120]). An abdominal ultrasound revealed normal liver parenchyma, biliary tract, gallbladder, pancreas, and spleen and the absence of lithiasis.\n\nWe admitted the patient for further investigation and surveillance. The consecutive blood tests showed a progressive increase in the liver enzymes (ALT, 844 IU/L; AST, 387 IU/L; GGT, 1763 IU/L; alkaline phosphatase, 763 IU/L) with normal liver function parameters. Two days after being hospitalized, the patient developed non‐itchy, erythematous, maculopapular rashes on the palms of both hands (Figure 1). He showed no signs of liver failure. Serological test results were negative for hepatitis A, B, C, and E viruses, cytomegalovirus, Epstein‐Barr virus, herpes simplex virus, and human immunodeficiency virus (HIV). The usual liver autoantibodies were also negative. The levels of serum immunoglobulins were normal. Given the dermal findings, we tested him for syphilis and found a reactive venereal disease research laboratory (VDRL) titer of 1:64, a T pallidum hemagglutination assay of 1:640, and a positive IgM fluorescent T pallidum antibody absorbance (FTA‐Abs IgM).\n\nFigure 1 Erythematous maculopapular rashes on the palms of both hands\n\nTaking the clinical and laboratory findings together, the patient was diagnosed with syphilitic hepatitis and initiated his intake of benzathine penicillin G 2.4 million units intramuscularly once weekly, for 3 weeks. Two days after the first dose, he was discharged. A month later, he was completely asymptomatic, the skin lesions had disappeared, the liver biochemical marker levels had completely normalized, and the VDRL was already nonreactive (seroconversion), which confirmed the clinical cure (Table 1).\n\nTable 1 Blood test changes before and after treatment\n\n \tNormal range\tHospital admission\tBefore treatment\tOne month after treatment\t\nINR (ratio)\t0.50–3.00\t1.11\t1.10\t1.09\t\nAlbumin (g/L)\t35–52\t44\t42\t44\t\nBilirubin (µmol/L)\t5.0–21.0\t20.6\t38.3\t18.1\t\nALT (IU/L)\t3–45\t342\t844\t41\t\nAST (IU/L)\t15–50\t93\t387\t35\t\nGGT (IU/L)\t<55\t1503\t1782\t53\t\nAlkaline phosphatase (IU/L)\t30–120\t591\t763\t118\t\nVDRL (titer)\t–\t–\t1:64\tNonreactive\t\nNote\nAbbreviations: INR, international normalized ratio; ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma‐glutamyl transferase; VDRL, venereal disease research laboratory.\n\nJohn Wiley & Sons, Ltd3 DISCUSSION\nSyphilitic hepatitis is a rare clinical presentation of syphilis, with an incidence ranging from 0.25% to 38%.5, 6 It occurs relatively more frequently among men who engaged in sexual intercourse with men or with patients with HIV infection, but the disease can emerge in any individual who gets infected.7 Even though a local inflammatory response elicited by spirochetes is believed to be the cause of all clinical manifestations of syphilis, the precise mechanisms by which T pallidum causes liver damage and the reason behind certain patients with infection developing hepatitis while others do not remain unclear.1, 6\n\n\nHepatic involvement in syphilis can be observed during any phase of the disease. A systematic review that includes 144 patients found that 89% of cases develop during early syphilis and 6% during late stages.7 According to the same review, the most frequently occurring signs and symptoms in patients with syphilitic hepatitis are rashes involving the palms of both hands, soles, or any other body part (78%), followed by fatigue/poor appetite (57%), hepatomegaly (54%), jaundice (35%), lymphadenopathy (31%), fever (26%), weight loss (23%), abdominal pain (22%), and splenomegaly (14%).7\n\n\nOn the basis of other studies, syphilitic hepatitis can be diagnosed when all the following criteria are present: abnormal liver biochemical marker levels, serological evidence of syphilitic infection, exclusion of other etiologies of liver disease, and successful response to the antibiotic treatment with normalization of the liver enzymes.5, 8, 9 The patient in the present case met all these criteria.\n\nThe pattern of abnormal liver test results in syphilitic hepatitis is typically cholestatic, but it can also be hepatocellular or mixed. Disproportionally high serum alkaline phosphatase and GGT levels with slight raised or normal serum transaminases and bilirubin are common. 7, 8, 9, 10, 11, 12\n\n\nSerologic testing for the diagnosis of syphilis should include the use of both nontreponemal and treponemal tests. Either test can be used as the initial screening test. In our patient, we were still using the traditional approach (initial screening with nontreponemal test). This algorithm has shown a high positive predictive value when both tests are reactive, although very early primary and previously treated syphilis can be overlooked due to the lower sensitivity of nontreponemal tests. Nowadays, in numerous institutions including ours, the reverse algorithm is used (initial screening with treponemal tests). This approach is associated with higher costs, but it permits the detection and treatment of 99% of cases compared with the traditional algorithm in a low‐prevalence setting.1\n\n\nLiver biopsies performed in patients with syphilitic hepatitis often show portal and lobular inflammatory cell infiltrates, hepatocellular necrosis, cholestasis, and/or noncaseating granulomas. Since these findings are non‐specific and spirochete recognition in liver specimens is difficult, even after immunohistochemical or Warthin‐Starry staining, liver biopsy is not considered essential for the diagnosis of syphilitic hepatitis when there is a positive response to therapy.7, 8, 9\n\n\nPenicillin remains the treatment of choice for patients in all stages of syphilis, with different regimens suggested based on the disease stage. In our case, as we could not be sure of the timing of the infection because the patient did not notice a chancre or any other primary lesion, we preferred to prescribe a 3‐week course of intramuscular administration of benzathine penicillin G at 2.4 million units once weekly (as recommended for latent syphilis) rather than a single dose (used to treat early syphilis).2\n\n\nAntibiotic treatment shows rapid improvement in the majority of cases of syphilitic hepatitis.6, 7, 8, 13 Very rarely, syphilitic hepatitis can result in fulminant liver failure, as shown in the case of a patient who required a liver transplantation.14\n\n\nIn summary, this case report highlights syphilis as an overlooked etiology of hepatitis that should always be excluded during the evaluation of patients with abnormal liver biochemical marker levels of unknown etiology. Its diagnosis is usually straightforward, and a liver biopsy is not generally necessary for a positive response to antibiotic therapy. Timely diagnoses and prompt treatments are important for limiting clinical effects and preventing progression to tertiary syphilis.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nPedro Marcos: revised the literature and drafted the manuscript. Liliana Eliseu: revised the manuscript. Martinha Henrique and Helena Vasconcelos: revised the manuscript and approved the final version.\n==== Refs\nREFERENCES\n1 \n\nPeeling \nRW \n, \nMabey \nD \n, \nKamb \nML \n, \nChen \nXS \n, \nRadolf \nJD \n, \nBenzaken \nAS \n. Syphilis . Nat Rev Dis Primers . 2017 ;3 :17073 .29022569 \n2 \n\nClement \nME \n, \nOkeke \nNL \n, \nHicks \nCB \n. Treatment of syphilis: a systematic review . JAMA . 2014 ;312 (18 ):1905 ‐1917 .25387188 \n3 \n\nRowley \nJ \n, \nVander Hoorn \nS \n, \nKorenromp \nE \n, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016 . Bull World Health Organ . 2019 ;97 (8 ):548 ‐562 .31384073 \n4 \n\nJanier \nM \n, \nHegyi \nV \n, \nDupin \nN \n, et al. 2014 European guideline on the management of syphilis . J Eur Acad Dermatol Venereol: JEADV . 2014 ;28 (12 ):1581 ‐1593 .25348878 \n5 \n\nAdachi \nE \n, \nKoibuchi \nT \n, \nOkame \nM \n, et al. Liver dysfunction in patients with early syphilis: a retrospective study . J Infect Chemother . 2013 ;19 (1 ):180 ‐182 .22692597 \n6 \n\nPizzarossa \nAC \n, \nRebella \nM \n. Hepatitis in patients with syphilis: an overlooked association . BMJ Case Rep . 2019 ;12 (1 ).\n7 \n\nHuang \nJ \n, \nLin \nS \n, \nWan \nB \n, \nZhu \nY \n. A systematic literature review of syphilitic hepatitis in adults . J Clin Transl Hepatol . 2018 ;6 (3 ):306 ‐309 .30271743 \n8 \n\nGerman \nMN \n, \nMatkowskyj \nKA \n, \nHoffman \nRJ \n, \nAgarwal \nPD \n. A case of syphilitic hepatitis in an HIV‐infected patient . Hum Pathol . 2018 ;79 :184 ‐187 .29505766 \n9 \n\nLee \nM \n, \nWang \nC \n, \nDorer \nR \n, \nFerguson \nL \n. A great masquerader: acute syphilitic hepatitis . Dig Dis Sci . 2013 ;58 (4 ):923 ‐925 .22833383 \n10 \n\nMulder \nCJ \n, \nCho \nRS \n, \nHarrison \nSA \n, \nCebe \nK \n, \nFrancis \nJM \n. Syphilitic hepatitis uncommon presentation of an old scourge . Mil Med . 2015 ;180 (5 ):e611 ‐e613 .25939121 \n11 \n\nAggarwal \nSK \n, \nRadhakrishnan \nS \n. Syphilitic hepatitis: Look for raised alkaline phosphatase level . Med J Armed Forces India . 2016 ;72 (2 ):192 ‐193 .27257335 \n12 \n\nMandache \nC \n, \nCoca \nC \n, \nCaro‐Sampara \nF \n, et al. A forgotten aetiology of acute hepatitis in immunocompetent patient: syphilitic infection . J Intern Med . 2006 ;259 (2 ):214 ‐215 .16420551 \n13 \n\nBronstein \nFN \n, \nMeyer \nB \n, \nCondat \nB \n, \nLoria \nA \n, \nBronstein \nJA \n. Secondary syphilitic hepatitis in a fifteen‐year‐old boy . Med Mal Infect . 2019 ;49 (8 ):625 –627 .31611136 \n14 \n\nLo \nJO \n, \nHarrison \nRA \n, \nHunter \nAJ \n. Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation . J Infect . 2007 ;54 (3 ):e115 ‐e117 .16939692\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2050-0904", "issue": "8(1)", "journal": "Clinical case reports", "keywords": "Syphilis; Syphilitic hepatitis; Treponema pallidum", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "123-126", "pmc": null, "pmid": "31998501", "pubdate": "2020-01", "publication_types": "D002363:Case Reports", "references": "30271743;25939121;31384073;16939692;22692597;31611136;30696640;29505766;27257335;22833383;25348878;16420551;29022569;25387188", "title": "Syphilitic hepatitis: Case report of an overlooked condition.", "title_normalized": "syphilitic hepatitis case report of an overlooked condition" }

[ { "companynumb": "PT-DSJP-DSE-2020-109288", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021286", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN MEDOXOMIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis syphilitic", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARCOS P, ELISEU L, HENRIQUE M, VASCONCELOS H. SYPHILITIC HEPATITIS: CASE REPORT OF AN OVERLOOKED CONDITION. CLINICAL CASE REPORTS. 2020?8.1:123-126", "literaturereference_normalized": "syphilitic hepatitis case report of an overlooked condition", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20200319", "receivedate": "20200319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17563864, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "PT-MYLANLABS-2020M1038557", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078276", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN MEDOXOMIL." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis syphilitic", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARCOS P, ELISEU L, HENRIQUE M, VASCONCELOS H.. SYPHILITIC HEPATITIS: CASE REPORT OF AN OVERLOOKED CONDITION.. CLINICAL CASE REPORTS. 2020?8.1:123-126", "literaturereference_normalized": "syphilitic hepatitis case report of an overlooked condition", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20200420", "receivedate": "20200420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17684415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]

{ "abstract": "We present a case of increased fluid-attenuated inversion recovery signal intensity in the subarachnoid spaces on 6-hour delayed enhanced MR imaging in a patient with posterior reversible encephalopathy syndrome (PRES) in the setting of acute hypertensive encephalopathy. This hyperintensity was believed due to CSF gadolinium enhancement, a finding that would be anticipated in light of the suspected pathogenesis of increased microvascular permeability in PRES.", "affiliations": "Department of Diagnostic Radiology, Oregon Health & Science University, Portland, OR 97239, USA. hamiltob@ohsu.edu", "authors": "Hamilton|B E|BE|;Nesbit|G M|GM|", "chemical_list": "D003287:Contrast Media; D005682:Gadolinium", "country": "United States", "delete": false, "doi": "10.3174/ajnr.A0926", "fulltext": null, "fulltext_license": null, "issn_linking": "0195-6108", "issue": "29(3)", "journal": "AJNR. American journal of neuroradiology", "keywords": null, "medline_ta": "AJNR Am J Neuroradiol", "mesh_terms": "D000368:Aged; D002555:Cerebrospinal Fluid; D003287:Contrast Media; D005260:Female; D005682:Gadolinium; D006801:Humans; D020343:Hypertensive Encephalopathy; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging; D054038:Posterior Leukoencephalopathy Syndrome; D013997:Time Factors", "nlm_unique_id": "8003708", "other_id": null, "pages": "456-7", "pmc": null, "pmid": "18184835", "pubdate": "2008-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12594563;16611776;9367319;11990808;15814928;15472105;10669233;15454616;14716235;10344507;16224930;11159107", "title": "Delayed CSF enhancement in posterior reversible encephalopathy syndrome.", "title_normalized": "delayed csf enhancement in posterior reversible encephalopathy syndrome" }

[ { "companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1507L-0153", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GADOLINIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GADOLINIUM (UNSPECIFIED)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GADOLINIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "DOSE NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GADOLINIUM (UNSPECIFIED)" } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nuclear magnetic resonance imaging brain abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAMILTON B,NESBIT G. DELAYED CSF ENHANCEMENT IN POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME. AMERICAN JOURNAL OF NEURORADIOLOGY. 2008 MAR 01;29:456-457.", "literaturereference_normalized": "delayed csf enhancement in posterior reversible encephalopathy syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150714", "receivedate": "20150714", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11270522, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Indications for the administration of vancomycin in the perioperative period have expanded in recent years. Used in this situation, vancomycin has caused adverse reactions, the most serious of which is hypotension. We describe five patients who had adverse reactions to vancomycin perioperatively. Vancomycin-induced hypotension usually results from a negative inotropic and vasodilator effect produced in part by a histamine-release phenomenon, which occurs most commonly with rapid intravenous infusion of the drug. Such a release of histamine may also produce an acute urticarial flushing of the upper torso (the \"red neck syndrome\") and symptoms of pain and muscle spasm in the chest or paraspinal muscles, which may mimic myocardial infarction. These effects usually abate promptly when the infusion of vancomycin is discontinued, and their resolution may be expedited by administration of an antihistamine.", "affiliations": null, "authors": "Southorn|P A|PA|;Plevak|D J|DJ|;Wright|A J|AJ|;Wilson|W R|WR|", "chemical_list": "D014640:Vancomycin", "country": "England", "delete": false, "doi": "10.1016/s0025-6196(12)62773-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0025-6196", "issue": "61(9)", "journal": "Mayo Clinic proceedings", "keywords": null, "medline_ta": "Mayo Clin Proc", "mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007022:Hypotension; D007432:Intraoperative Period; D008297:Male; D008875:Middle Aged; D012871:Skin Diseases; D014640:Vancomycin", "nlm_unique_id": "0405543", "other_id": null, "pages": "721-4", "pmc": null, "pmid": "3747614", "pubdate": "1986-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Adverse effects of vancomycin administered in the perioperative period.", "title_normalized": "adverse effects of vancomycin administered in the perioperative period" }

[ { "companynumb": "US-BAXTER-2017BAX037070", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDICATION DILUTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISOTONIC SALINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050671", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "1 GRAM IN 200 ML OF ISOTONIC SALINE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN INJECTION, USP" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SOUTHORN P, PLEVAK D, WRIGHT A, WILSON W. ADVERSE EFFECTS OF VANCOMYCIN ADMINISTERED IN THE PERIOPERATIVE PERIOD. MAYO CLINIC PROCEEDINGS. 1986 SEP;61(9):721-724.", "literaturereference_normalized": "adverse effects of vancomycin administered in the perioperative period", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171114", "receivedate": "20171114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14188880, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "The case involved a 52-year-old man. He was diagnosed with sigmoid colon cancer and multiple liver and lung metastases. After placement of a metallic stent for circumferential stricture, 5-fluorouracil/Leucovorin/oxaliplatin (FOLFOX4) plus bevacizumab therapy was introduced. After 17 courses, gastrointestinal perforation was noted at the site of stent placement, but this was alleviated with conservative therapy. Although gastrointestinal perforation is known to be a serious complication that occurs during chemotherapy combined with bevacizumab, further studies are needed to investigate the incidence of gastrointestinal perforation after stent placement more fully.", "affiliations": "Dept. of Organ Regulatory Surgery, Fukushima Medical University.", "authors": "Chida|Shun|S|;Matsumoto|Susumu|S|;Inoue|Norio|N|;Takenoshita|Seiichi|S|", "chemical_list": "D000068258:Bevacizumab", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "42(12)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D006801:Humans; D007416:Intestinal Perforation; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D012811:Sigmoid Neoplasms; D015607:Stents", "nlm_unique_id": "7810034", "other_id": null, "pages": "2148-50", "pmc": null, "pmid": "26805293", "pubdate": "2015-11", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A Case of Gastrointestinal Perforation in a Patient with Colon Cancer and Stent Placement during Bevacizumab Treatment, Alleviated with Conservative Therapy.", "title_normalized": "a case of gastrointestinal perforation in a patient with colon cancer and stent placement during bevacizumab treatment alleviated with conservative therapy" }

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A CASE OF GASTROINTESTINAL PERFORATION IN A PATIENT WITH COLON CANCER AND STENT PLACEMENT DURING BEVACIZUMAB TREATMENT, ALLEVIATED WITH CONSERVATIVE THERAPY.. CANCER + CHEMOTHERAPY. 2015;42 (12):2148-2150.", "literaturereference_normalized": "a case of gastrointestinal perforation in a patient with colon cancer and stent placement during bevacizumab treatment alleviated with conservative therapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160630", "receivedate": "20160427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12312018, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-ROCHE-1615083", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE IS UNCERTAIN.", "drugenddate": "2014", "drugenddateformat": "602", "drugindication": "COLON CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5-FU" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOLEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, 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null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TS-1" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE IS UNCERTAIN.", "drugenddate": "2014", "drugenddateformat": "602", "drugindication": "COLON CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELPLAT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "DOSAGE IS UNCERTAIN.", "drugenddate": "2014", "drugenddateformat": "602", "drugindication": "COLON CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AVASTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE IS UNCERTAIN.", "drugenddate": "2014", "drugenddateformat": "602", "drugindication": "COLON CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5-FU" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal perforation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device occlusion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neoplasm", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201405" } }, "primarysource": { "literaturereference": "CHIDA T, CHIDA TAKASHI, TAKENOSHITA SEIICHI, MATSUMOTO SUSUMU, ET AL. A CASE OF GASTROINTESTINAL PERFORATION IN A PATIENT WITH COLON CANCER AND STENT PLACEMENT DURING BEVACIZUMAB TREATMENT, ALLEVIATED WITH CONSERVATIVE THERAPY. G07/JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY/(ISSN:0385-0684)?()/ ?:-.", "literaturereference_normalized": "a case of gastrointestinal perforation in a patient with colon cancer and stent placement during bevacizumab treatment alleviated with conservative therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160114", "receivedate": "20160114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11915306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "JP-PFIZER INC-2016227733", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (17 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008107", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (17 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM FOLINATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (17 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK(17 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal perforation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHIDA, S.. A CASE OF GASTROINTESTINAL PERFORATION IN A PATIENT WITH COLON CANCER AND STENT PLACEMENT DURING BEVACIZUMAB TREATMENT, ALLEVIATED WITH CONSERVATIVE THERAPY. JAPANESE JOURNAL OF CANCER + CHEMOTHERAPY. 2015;42(12):2148-2150", "literaturereference_normalized": "a case of gastrointestinal perforation in a patient with colon cancer and stent placement during bevacizumab treatment alleviated with conservative therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160627", "receivedate": "20160516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12372309, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016JP066451", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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"medicinalproduct": "5 FLUORO URACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "78812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "78812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "78812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5 FLUORO URACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal perforation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHIDA S, MATSUMOTO S, INOUE N, TAKENOSHITA S.. [A CASE OF GASTROINTESTINAL PERFORATION IN A PATIENT WITH COLON CANCER AND STENT PLACEMENT DURING BEVACIZUMAB TREATMENT, ALLEVIATED WITH CONSERVATIVE THERAPY]. [JAPANESE]. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY. 2015;42(12):2148-50", "literaturereference_normalized": "a case of gastrointestinal perforation in a patient with colon cancer and stent placement during bevacizumab treatment alleviated with conservative therapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160519", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12387481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-ACTAVIS-2016-08520", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "78803", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK UNK, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM FOLINATE" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal perforation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHIDA S, MATSUMOTO S, INOUE N, TAKENOSHITA S. A CASE OF GASTROINTESTINAL PERFORATION IN A PATIENT WITH COLON CANCER AND STENT PLACEMENT DURING BEVACIZUMAB TREATMENT, ALLEVIATED WITH CONSERVATIVE THERAPY. GAN TO KAGAKU RYOHO. 2015;42(12):2148-50.", "literaturereference_normalized": "a case of gastrointestinal perforation in a patient with colon cancer and stent placement during bevacizumab treatment alleviated with conservative therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160624", "receivedate": "20160422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12295273, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "A 73-year-old female with a past medical history of breast cancer, who 10 years earlier experienced complete remission, complained of bilateral visual field disturbances and photopsia, 2 months prior. Tumour recurrence and metastatic lesions were not found during the medical examination, but antibodies against recoverin were detected in her serum. Despite immunosuppressive treatment with prednisolone and plasmapheresis, rapid and diffuse degeneration of the patient's photoreceptors and deterioration of her visual field were observed. This is a rare case of cancer-associated retinopathy with a long interval (10 years) between the diagnosis of the malignancy and visual loss.", "affiliations": "Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.", "authors": "Igarashi|Nozomi|N|;Sawamura|Hiromasa|H|;Kaburaki|Toshikatsu|T|;Aihara|Makoto|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/01658107.2018.1460761", "fulltext": null, "fulltext_license": null, "issn_linking": "0165-8107", "issue": "43(1)", "journal": "Neuro-ophthalmology (Aeolus Press)", "keywords": "Cancer-associated retinopathy; breast cancer; recoverin", "medline_ta": "Neuroophthalmology", "mesh_terms": null, "nlm_unique_id": "8408966", "other_id": null, "pages": "36-42", "pmc": null, "pmid": "30723523", "pubdate": "2019-02", "publication_types": "D002363:Case Reports", "references": "10206574;10766180;11222531;12208243;12559325;1310001;15183799;16019671;18408929;19168157;19887879;20370338;20473029;21674222;22218149;23860756;23969019;24225966;24646664;24945598;25754855;26172160;8110675;9176775", "title": "Cancer-associated Retinopathy Developing After 10 Years of Complete Breast Cancer Remission.", "title_normalized": "cancer associated retinopathy developing after 10 years of complete breast cancer remission" }

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{ "abstract": "BACKGROUND\nCaudal epidural sacral injection is one of the most common conservative treatments for chronic low back pain with radiculopathy. Neurological deficit after injection is a rare complication that must be identified and treated properly.\n\n\nMETHODS\nWe report a case of cauda equina syndrome that persisted until 3 months after injection. A 63-year-old man came to our department with severe lumbar canal stenosis who experienced motor weakness, buttocks numbness and voiding difficulties immediately after injection. His lower extremities improved after 24 h, but his neurogenic bladder problems and perianal numbness still persisted. We collaborated with our interdisciplinary teams to do a rehabilitation program, and the symptoms were alleviated and he fully recovered within three months.\n\n\nCONCLUSIONS\nPatients with severe stenosis can be best described from magnetic resonance imagery scans, and clinicians should be careful about the risks after injection ranging from transient complications to persistent spinal cord injury.", "affiliations": "Orthopaedic Traumatology Department, Soeradji Tirtonegoro General Hospital, Indonesia; Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia.;Orthopaedic Traumatology Department, Soeradji Tirtonegoro General Hospital, Indonesia; Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia. Electronic address: doktergustomrhatomy@yahoo.com.", "authors": "Wibowo|Hastomo Agung|HA|;Rhatomy|Sholahuddin|S|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijscr.2020.10.100", "fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30978-0\n10.1016/j.ijscr.2020.10.100\nCase Report\nCauda equina syndrome after caudal epidural sacral injection in severe lumbar spinal stenosis: Case report\nWibowo Hastomo Agung ab Rhatomy Sholahuddin doktergustomrhatomy@yahoo.comab⁎ a Orthopaedic Traumatology Department, Soeradji Tirtonegoro General Hospital, Indonesia\nb Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia\n⁎ Corresponding author at: Sport and Adult Reconstruction Division, Orthopaedics and Traumatology Department, Soeradji Tirtonegoro Hospital, Indonesia. doktergustomrhatomy@yahoo.com\n25 10 2020 \n2020 \n25 10 2020 \n77 12 14\n17 9 2020 20 10 2020 21 10 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Cauda Equina Syndrome.\n\n• Caudal Epidural Sacral Injection.\n\n• Severe Lumbal Spinal Stenosis.\n\n• Complication.\n\n\n\nIntroduction\nCaudal epidural sacral injection is one of the most common conservative treatments for chronic low back pain with radiculopathy. Neurological deficit after injection is a rare complication that must be identified and treated properly.\n\nPresentation of case\nWe report a case of cauda equina syndrome that persisted until 3 months after injection. A 63-year-old man came to our department with severe lumbar canal stenosis who experienced motor weakness, buttocks numbness and voiding difficulties immediately after injection. His lower extremities improved after 24 h, but his neurogenic bladder problems and perianal numbness still persisted. We collaborated with our interdisciplinary teams to do a rehabilitation program, and the symptoms were alleviated and he fully recovered within three months.\n\nConclusion\nPatients with severe stenosis can be best described from magnetic resonance imagery scans, and clinicians should be careful about the risks after injection ranging from transient complications to persistent spinal cord injury.\n\nKeywords\nEpidural steroid injectionCauda equina syndromeTreatment complications\n==== Body\n1 Introduction\nThe prevalence of lumbar spinal stenosis is estimated at about 200,000 adults in the United States. This problem is the most common reason for >65 years old patients to undergo spinal surgery. Some patients refuse to have the operation [1,2]. Instead, epidural steroid injections have been widely used to treat lumbar spinal stenosis. Corticosteroids including local anesthetic agents can reduce inflammation and improve symptoms when delivered directly into the epidural space. There are three ways to approach the lumbar epidural space: cauda, transforaminal and interlaminar. This injection is reported safe, but sometimes leads to complications including headache, hiccups, fatigue, infection, bleeding, dural puncture, and nerve damage [3,4].\n\nCauda equina syndrome is a rare condition which has symptoms characterized by low back pain followed by sciatica, saddle and/or genital sensory disturbance with bladder, bowel and sexual dysfunction. It occurs following disc herniation, epidural hematoma, post trauma or surgical, infections, neoplasms, or after spinal anesthesia [5]. Some studies have shown that caudal sacral steroid injection can induce complications ranging from transient to persistent cauda equina syndrome [6,7].\n\nOur case report describes a patient whose cauda equina syndrome suddenly developed after undergoing caudal sacral steroid injection for severe lumbar stenosis and who spontaneously recovered within 3 months with follow-up and rehabilitation. This case is reported according to the SCARE 2018 guidelines published by Agha et al. [8].\n\n2 Case report\nA 63-year-old man came to our spine clinic with chronic low back pain for 2 years. He also complained of radiating pain in both of his legs when standing or walking about 50 m. There was no history of neurological deficit, urination problems, drug allergy or family history. The lumbar magnetic resonance imagery (MRI) revealed low grade spondylolisthesis with severe canal stenosis at L4-L5. We advised to do a sacral caudal steroid injection to relieve the pain. The procedure involved image guided placement using 23-gauge syringe needle below the S3 to avoid the risk of dural puncture. We used 10 mL normal saline, 40 mg of triamcinolone and 8 mL of 0.25% bupivacaine. Suddenly after injection, the patient suffered more severe radiating pain with motor weakness in his both legs. He also complained about numbness in both buttocks. We planned to do an emergency decompression operation after these symptoms happened, but unfortunately, the patient refused (Fig. 1).Fig. 1 Magnetic resonance T2-weighted imaging of the lumbosacral spine. A. Sagittal: low grade spondylolisthesis of L4-L5. B. Axial: severe central canal stenosis.\n\nFig. 1\n\nThe patient had analgesic injection intravenous every 8 h to reduce the pain. After 12 h, the patient complained of difficulty to void his bladder, so we inserted an indwelling catheter. Subsequently, the patient could move his legs 20 h after injection and started to walk after 24 h. The pain had significantly decreased. We took out the catheter and the patient was discharged. About 12 h after he was discharged from the hospital, he came back to the emergency department with voiding difficulty and tingling sensation with pain in his buttocks. Then, we reinserted another catheter and consulted him to our rehabilitation team. After 3 months of the patient receiving medication, and bladder training in the rehabilitation program, the pain was improved and he could void spontaneously (Table 1).Table 1 Neurological examination.\n\nTable 1\tGrade motor power\tSaddle anesthesia\tVoiding Dysfunction\t\nImmediately after injection\t0 (complete paralysis)\t(+)\t(+)\t\n20 h after injection\t3 (lower movement is possible against gravity)\t(+)\t(+)\t\n24 h after injection\t4 (can against some resistance, able to walk using walker)\t(+)\t(+)\t\n1 month rehabilitation program\t5 (normal strength)\tdiminished\t(+)\t\n3 months rehabilitation program (Final follow up)\t5 (normal strength)\t(−)\t(−)\t\n\n\n3 Discussion\nCaudal sacral steroid injection is a safer procedure for treating lumbar stenosis which can provide significant pain relief and offer an alternative to surgery. Several reviews have reported about the risk of rare complications after the injection procedure. One of the most dangerous complications is neurological deficit that can be transient or permanent. This complication can be due to several possible causes such as spinal infarction, chemotoxicity, vascular occlusion and epidural hematoma. The onset is also variable from within 1 h after injection, until 8 days after injection, but most often happens within 6–24 h [3].\n\nTackle et al. reported a patient with conus medullaris syndrome after undergoing transforaminal lumbar steroid injection who recovered within 1 month after injection. They suggested the possibility of vascular injury of either the artery of Adamkiewicz or collateral radiculomedullary artery branches after the injection procedure. Some studies suggested performing a MRI study if neurologic function fails to recover within 2–3 h time period after injection to exclude an epidural hematoma [1].\n\nDrasner et al. reported cauda equina syndrome after an epidural injection using 5% lidocaine which entered the subarachnoid space accidentally. That can be ruled out in our case because there was no dural puncture or draining of cerebrospinal fluid after injection [9]. Kim and Kim, also reported temporary cauda equina syndrome following epidural adhesiolysis using 0.25% bupivacaine 10 mL and triamcinolone 40 mg injection. The patient finally recovered 1 month after the procedure following medication and physical therapy. They suggested the causative factors were osmotic damage produced by subarachnoid injection of large doses of hypertonic saline solution [10].\n\nSeo et al. reported persistent cauda equina syndrome over 1 year after caudal epidural injection. They suggested two possibilities for the cause. The first was drug induced neurotoxicity by local anesthetics and the second was the possibility of mechanical compression which could cause ischemic damage [6]. Spinal infections can also be the causative agent of neurological deficit after injection. It will be presented with back pain and systemic signs in most cases. Median time to onset of spinal infections is 7 days, with reports as early as 72 h [11].\n\nIn our case, it happened suddenly after injection so we considered some mechanical problem after injection which can lead to neurological damage. The amount of fluid that was injected can highly increase the epidural pressure in a patient with severe spinal stenosis. Usubiga et al. also reported that in elderly patients, there was age-related degeneration causing decrease in dural membrane elasticity and an increase in epidural pressure [12]. Bloodworth et al. recommend decompressive surgery within 8 h when neurological deficits progress due to intraspinal hematoma after a systematic review of 33 cases of sudden paralysis after injection [3]. Stoll et al. mentioned that epidural hematoma is a common complication after epidural injection in patients with coagulation disorders [13].\n\n4 Conclusions\nDespite caudal steroid injection being one of most common conservative treatments in lumbar canal stenosis problems, several uncommon complications have been reported. Especially in a patient with severe stenosis that can be best described from MRI, we recommend the clinicians careful consider the risks after injection such as transient until persistent spinal cord injury. If there was history of neurological deficit prior to injection we suggest considering an operative procedure. The patient should also be well informed concerning the risk of paralysis before the injection procedure. If the complication does happen, it is recommended to identify the probable causative factors and coordinate with the interdisciplinary teams to determine the next appropriate treatment.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nFunding\nThere is no funding for this study.\n\nEthical approval\nMedical and health research ethics committee, faculty of medicine,public health and nursing, Universitas Gadjah Mada :KE/0946/09/2020.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of written consent is available for review by Editor-in-Chief of this journal on request.\n\nAuthor contribution\nSholahuddin Rhatomy and Hastomo Agung Wibowo: writing the manuscript, study design, data collector, final review.\n\nRegistration of research studies\n1. Name of the registry: Research Registry.\n\n2. Unique identifying number or registration ID: researchregistry6078.\n\n3. Hyperlink to your specific registration (must be publicly accessible and will be checked): https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5f78da2caf6da50015468bbf/.\n\n\n\nGuarantor\nSholahuddin Rhatomy.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nAcknowledgement\nWe thank the staff of Klinik Bahasa for their help during manuscript preparation.\n==== Refs\nReferences\n1 Tackla R.D. Keller J.T. Ernst R.J. Farley C.W. Conus medullaris syndrome after epidural steroid injection: case report Int. J. Spine Surg. 1 6 2012 29 33 \n2 Wu A. Zou F. Cao Y. Xia D. He W. Zhu B. Lumbar spinal stenosis: an update on the epidemiology, diagnosis and treatment lumbar spinal stenosis: an update on the epidemiology, diagnosis and treatment AME Med. J. 2 63 2017 1 14 \n3 Bloodworth Donna M. Perez-Toro Marco R. Kent H. Nouri M. Neurological deficits after epidural steroid injection: time course, differential diagnoses, management, and prognosis suggested by review of case reports Pain Med. 9 S1 2008 9 11 \n4 Kaydu A. Kılıç E.T. Gökçek E. Akdemir M.S. Unexpected complication after caudal epidural steroid injection: hiccup Anesth. Essays Res. 11 3 2017 776 777 28928587 \n5 Gardner A. Gardner E. Morley T. Cauda equina syndrome: a review of the current clinical and medico-legal position Eur. Spine J. 20 5 2011 690 697 21193933 \n6 Seo Y.T. Kong H.H. Lee G.J. Bang H.J. Persistent cauda equina syndrome after caudal epidural injection under severe spinal stenosis: a case report J. Pain Res. 10 2017 1425 1429 28652808 \n7 Somanchi B.V. Mohammad S. Ross Raymond An unusual complication following caudal epidural steroid injection: a case report Acta Orthop. Belg. 74 5 2008 720 722 19058714 \n8 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Dennis P. The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) Guidelines Riaz Int. J. Surg. 60 2018 132 136 30342279 \n9 Drasner K. Rigler M.L. Sessler D.I. Stoller M.L. Cauda equina syndrome following intended epidural anesthesia Anesthesiology 77 3 1992 5820585 \n10 Dh K. Hj K. Cauda equina syndrome following epidural adhesiolysis in a patient with spinal stenosis J. Korean Cont. Soc. 7 1 2003 46 49 \n11 Huang R.C. Shapiro G.S. Lim M. Sandhu H.S. Lutz G.E. Herzog R.J. Cervical epidural abscess after epidural steroid injection Spine (Phila Pa 1976) 29 1 2004 E7 E9 14699291 \n12 Usubiaga J.E. Wikinski J.A. Usubiaga L.E. Epidural pressure and its relation to spread of anesthetic solutions in epidural space Anesth. Analg. 46 4 1967 440 446 4952222 \n13 Stoll A. Sanchez Modesto Epidural hematoma after epidural block: implications for its use in pain management Surg. Neurol. 57 4 2002 235 240 12173390\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2210-2612", "issue": "77()", "journal": "International journal of surgery case reports", "keywords": "Cauda equina syndrome; Epidural steroid injection; Treatment complications", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "12-14", "pmc": null, "pmid": "33137663", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "4952222;25694868;12173390;19058714;28652808;1519794;28928587;30342279;21193933;14699291", "title": "Cauda equina syndrome after caudal epidural sacral injection in severe lumbar spinal stenosis: Case report.", "title_normalized": "cauda equina syndrome after caudal epidural sacral injection in severe lumbar spinal stenosis case report" }

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{ "abstract": "Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs.\n\n\n\nFive patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.\n\n\n\nConcurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.", "affiliations": "Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.;Harvard Medical School, Boston, MA, 02115, USA.;Harvard Medical School, Boston, MA, 02115, USA.;Harvard Medical School, Boston, MA, 02115, USA.;Harvard Medical School, Boston, MA, 02115, USA.;Harvard Medical School, Boston, MA, 02115, USA. mldougan@partners.org.", "authors": "Badran|Yousef R|YR|;Cohen|Justine V|JV|;Brastianos|Priscilla K|PK|;Parikh|Aparna R|AR|;Hong|Theodore S|TS|;Dougan|Michael|M|0000-0001-9266-2009", "chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha", "country": "England", "delete": false, "doi": "10.1186/s40425-019-0711-0", "fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 71110.1186/s40425-019-0711-0Short ReportConcurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events Badran Yousef R. 12Cohen Justine V. 23Brastianos Priscilla K. 23Parikh Aparna R. 23Hong Theodore S. 24http://orcid.org/0000-0001-9266-2009Dougan Michael mldougan@partners.org 251 0000 0004 0386 9924grid.32224.35Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA 2 000000041936754Xgrid.38142.3cHarvard Medical School, Boston, MA 02115 USA 3 0000 0004 0386 9924grid.32224.35Division of Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA 4 0000 0004 0386 9924grid.32224.35Department of Radiation Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA 5 0000 0004 0386 9924grid.32224.35Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA 22 8 2019 22 8 2019 2019 7 22627 6 2019 14 8 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nImmune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs.\n\nCase presentations\nFive patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.\n\nConclusions\nConcurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.\n\nKeywords\nCheckpoint inhibitorPD-1CTLA-4TNFαInfliximabImmune related enterocolitisImmune related adverse eventshttp://dx.doi.org/10.13039/100000062National Institute of Diabetes and Digestive and Kidney Diseases1K08DK114563-01Dougan Michael http://dx.doi.org/10.13039/100009560American Gastroenterological AssociationResearch Scholars AwardDougan Michael issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMonoclonal antibodies targeting the immune regulatory “checkpoint” receptors programmed death receptor 1 (PD-1), its ligand, PD-L1, and cytotoxic T cell associated antigen 4 (CTLA-4) have demonstrated remarkable efficacy against advanced cancers [1]. The natural roles of these immune checkpoints include preventing T cell over-activation, inducing anergy, maintaining peripheral immune tolerance, and contributing to T cell exhaustion in local inflammatory environments [2, 3]. By inhibiting these regulatory receptors, immune checkpoint inhibitors (ICIs) boost the anti-tumor effector functions of T cells [2]. Simultaneously, ICI-induced loss of tolerance leads to off-target immune related adverse events (irAEs) [4]. The frequency and severity of these events are an important limitation of immunotherapy, leading to treatment interruption and even discontinuation [5].\n\nImmune related (entero) colitis (irEC) is among the most common severe irAEs leading to the discontinuation of immunotherapy [6–9]. High dose glucocorticoids are the first line management of immune mediated enterocolitis [10–13]. Current guidelines recommend continuation for at least 4 to 6 weeks after resolution of irEC [10–13]. Not infrequently, patients are intolerant to steroid tapers or require prolonged courses of glucocorticoids for symptom control. Prolonged use of glucocorticoids is associated with multiple complications that include serious infections, hyperglycemia, osteoporosis, and altered mental status. In patients with irEC who fail steroid tapers or are steroid unresponsive, inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to suppress mucosal inflammation [14, 15]. Retrospective studies of patients who received anti-TNFα agents for irEC have shown that compared to steroids, these agents lead to more rapid symptomatic improvement and a shorter duration of steroids without affecting time to ICI treatment failure or overall survival [6, 14–16]. For patients who require anti-TNFα agents to control irEC, ICIs are generally discontinued out of concern for recurrent, potentially treatment refractory, colitis. Recent work in mouse models of cancer has shown that co-administration of ICI and anti-TNFα upfront led to improved tumor responses and decreased colitis severity, an approach that has not yet be studied in prospective trials in humans [17, 18]. In this report, we present our institutional experience on patients with different malignancies who were treated concurrently with anti-TNFα and single or combination ICIs.\n\nPatients and methods\nIncluded in this series are patients evaluated and treated at the Massachusetts General Hospital who were referred to the gastroenterology service for new gastrointestinal complaints (abdominal pain, protracted nausea and vomiting, or diarrhea) that arose during treatment with one or more ICIs. ICIs were administered as standard-of-care or as a part of a clinical trial. Details of the patients’ medical history, malignancy, and prior cancer therapeutics were reviewed in the chart. Data pertaining to ICI use and irEC development and management include doses of ICI, presenting grades of diarrhea and colitis, glucocorticoid dose and number of steroid taper attempts, infliximab dose and frequency, doses of infliximab to clinical remission, and doses of ICI concurrently administered with infliximab. Diarrhea and colitis were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at disease onset [19]. Upper endoscopy and/or colonoscopy/flexible sigmoidoscopy were performed as clinically indicated at the Massachusetts General Hospital Endoscopy Unit. Consent was obtained from all patients. Pathology was reviewed by board certified pathologists. Radiologic imaging data were obtained as indicated by the treatment protocol. This retrospective study was approved by the institutional review board of the Massachusetts General Hospital.\n\nResults\nPatient 1\nPatient 1 is a 70-year-old man with a past medical history of segmental colitis associated with diverticulosis (SCAD) who was diagnosed at the age of 73 with a right vestibular schwannoma and a large bifrontal atypical meningioma. At diagnosis, he was treated with subtotal resection and postoperative proton therapy. Two years later, he presented with recurrent bitemporal extra-cranial soft tissue meningioma treated with resection and radiation therapy. He was then started on pembrolizumab (PD-1 inhibitor) monotherapy and received two doses (Table 1). After receiving his second dose of pembrolizumab, he developed intermittent rectal bleeding without urgency, diarrhea, abdominal pain, cramping or bloating. He underwent a colonoscopy that showed endoscopic and histologic features of active colitis (Fig. 1). Based on these findings, he was treated with prednisone 60 mg, azithromycin, and metronidazole for a 7-day course that led to symptomatic improvement. With tapering of the steroids, his rectal bleeding recurred which prompted a repeat flexible sigmoidoscopy that demonstrated persistent inflammation. He then received infliximab (5 mg/kg) concurrently with prednisone 50 mg which led to resolution of his symptoms after one infusion and successful rapid tapering of prednisone. Staging imaging after 2 months off pembrolizumab therapy (due to irEC) showed progression of his intracranial tumor and extracranial metastases. After an interruption of ICI for 4 months, it was decided to restart pembrolizumab with concurrent infliximab therapy. He subsequently received a total of twelve doses of pembrolizumab concurrently with infliximab (5mg/kg every 6 weeks, Table 2) over the course of 10.5 months. He did not experience any other irAEs or worsening rectal bleeding and a repeat flexible sigmoidoscopy showed mild active chronic colitis. Staging scans at that point showed stable intracranial and extracranial disease. Then, he developed Clostridium difficile colitis. He was treated with oral vancomycin to which he appropriately responded. However, after a few days of normal bowel movements, he started having loose bloody bowel movements and abdominal pain prompting an admission to the hospital. During that admission, he tested negative for Clostridium difficile and underwent a flexible sigmoidoscopy that showed severe colonic inflammation thought to be due to irEC. He received vancomycin, high dose intravenous steroids followed by oral steroids, and one infusion of infliximab (10 mg/kg) leading to symptom improvement. His steroids were tapered but therapy with pembrolizumab was discontinued. One month later, he developed retroperitoneal bleeding and was transitioned to hospice care.\nTable 1 Patient characteristics, ICI treatment history, symptomatology, and endoscopy findings\n\nPatient\tAge\tSex\tMalignancy\tHistory of other ICI exposure\tICI type and dose\tDays (doses) to onset of symptoms post ICI\tDiarrhea grade\tOther symptoms\tColitis grade\tEndoscopic features\tHistopathologic features\t\n1\t75\tM\tMeningioma\tNone\tPembrolizumab\n\n\nDose: 3 mg/kg\n\n\nFrequency: every 3 weeks\n\n\t39 days (2)\t1\tNone\t2\tColonoscopy:\n\nSigmoid colon: localized moderate inflammation characterized by altered vascularity, congestion (edema), friability and granularity\n\n\tColonoscopy:\n\n- Ileum: mucosa with hyperplastic Peyer’s patches and no diagnostic abnormality\n\n- Ascending colon: mucosa with lymphoid aggregate and no diagnostic abnormality\n\n- Sigmoid colon: moderately active colitis with neutrophilic cryptitis and crypt abscesses\n\n\t\n2\t58\tF\tColon\t- Pembrolizumab (stopped 2 years prior to current ICI): no adverse effects but disease progression\tIpilimumab/Nivolumab\n\n\nDose:\n\n\nIpilimumab-1 mg/kg, Nivolumab- 240 mg (3 mg/kg)\n\nFrequency: combined every 6 weeks (4 doses total) followed by nivolumab alone every 2 weeks\n\n\t8 days (1)\t2\tAbdominal pain\t2\tUpper endoscopy:\n\n- Gastric antrum: diffuse moderately erythematous mucosa without bleeding\n\n- Duodenum: an acquired benign-appearing, intrinsic moderate stenosis in the first portion of the duodenum\n\n\tUpper endoscopy:\n\n- Gastric antrum/fundus/body:\n\nactive chronic gastritis\n\n- Duodenum: mucosa with ulceration, crypt dropout, marked expansion of lamina propria with prominent eosinophils and acute inflammation\n\n- Duodenal stricture: mucosa with mild expansion of the lamina propria\n\n\t\n3\t70\tF\tMelanoma\t- PD-L1 inhibitor (as a part of a clinical trial): for a total of 1 year (stopped 3 years prior to current ICI). No adverse events but disease recurrence\n\n- Pembrolizumab: 200 mg 3 (mg/kg) every 3 weeks for total of 8 doses (stopped 1 year prior to current ICI): no adverse events but disease progression\n\n\tIpilimumab\n\nDose: 3 mg/kg\n\nFrequency: every 3 weeks\n\n\t35 days (2)\t2\tNausea, vomiting\t2\tUpper Endoscopy:\n\n- Stomach: normal\n\n- Duodenum: diffuse moderately scalloped mucosa\n\nFlexible Sigmoidoscopy:\n\n- Colon: examined portion was normal\n\n\tUpper Endoscopy:\n\n- Duodenum: diffuse active duodenitis with villous blunting, expansion of the lamina propria with mixed inflammation, and reactive epithelial changes\n\n- Stomach: antral mucosa with edema and mild patchy inflammation\n\nFlexible Sigmoidoscopy:\n\n- Colon: normal\n\n\t\n4\t73\tM\tMelanoma\tAtezolizumab (in combination with cobimetinib): total of 13 cycles (stopped 2 weeks prior to current ICI)\tIpilimumab/Nivolumab\n\n\nDose:\n\n\nIpilimumab-3 mg/kg, Nivolumab-1 mg/kg\n\nFrequency: combined every 3 weeks\n\n\t11 days (1)\t2\tNausea, vomiting, abdominal pain\t2\tUpper Endoscopy:\n\n- Stomach: non-bleeding erosive gastropathy\n\n- Duodenum: diffuse mildly congested mucosa without active bleeding\n\nColonoscopy:\n\n- Sigmoid and descending colon: discontinuous areas of nonbleeding ulcerated mucosa with no stigmata of recent bleeding\n\n\tUpper Endoscopy:\n\n- Stomach: active gastritis with small stromal granuloma in antrum. Active gastritis with stromal histiocytes in the body\n\n- Duodenum: active duodenitis with villous injury\n\nColonoscopy:\n\n- Descending colon: focal active colitis with stromal histiocytes\n\n- Colon and sigmoid ulcers: severely active colitis with ulceration\n\n\t\n5\t79\tF\tSCC\tNone\tCemiplimab\n\nDose: 350 mg\n\nFrequency: every 3 weeks\n\n\t14 (1 dose)\t1\tNausea, vomiting\t2\tUpper Endoscopy:\n\n- Stomach: Non-bleeding erosive gastropathy\n\n- Duodenum: normal\n\nFlexible Sigmoidoscopy:\n\n- Colon: Inflammation characterized by congestion (edema), erythema and granularity\n\n\tUpper Endoscopy:\n\n- Stomach: reactive gastropathy and intestinal metaplasia\n\n- Duodenum: normal\n\nFlexible Sigmoidoscopy:\n\n- Colon: mucosa with mildly increased cellularity of the lamina propria and epithelial injury. Focal acute inflammation is also noted, but there is no increase in apoptosis.\n\n\t\n\nFig. 1 Infliximab and pembrolizumab for segmental colitis in meningioma. a – d (Images taken from the sigmoid colon during endoscopic evaluation. a Diagnosis of recurrent SCAD. b After completion of antibiotics and on prednisone. c Infliximab and prednisone co-treatment. d Infliximab and pembrolizumab co-treatment\n\n\nTable 2 IrEC management and outcomes\n\nPatient\tICI type/dose\tInitial management\tNumber of steroid tapering attempts\tInfliximab\nDose-frequency\tDoses of infliximab to clinical remission\tDoses of ICI concurrently administered with infliximab\tFollow up endoscopy on concurrent treatment (months)\tRecurrence\t# of months of follow-up on ICI/on concurrent therapy\tDisease progression/Follow up\t\n1\tPembrolizumb\n\n\nDose: 3 mg/kg\n\n\nFrequency: every 3 weeks\n\n\tPrednisone 40 mg > 60 mg PO daily> taper failure\n\n+azithromycin + metronidazole\n\n\t2\t5 mg/kg\n\n- every 2 weeks for first 2 doses then every 6 weeks\n\n\t1\t12\tFlexible Sigmoidoscopy (4 months):\n\nEndoscopic: erythematous mucosa in sigmoid, normal colon for 40 cm\n\nHistologic: Mild active chronic colitis\n\n\tPatient developed Clostridium difficile colitis then flare of irEC.\n\n\nTreatment:\n\n\n- Infliximab 10 mg/kg\n\n- Methylprednisolone 1 mg/kg BID then prednisone 75 mg PO BID followed by a taper\n\n- PO vancomycin\n\n- Immunotherapy was discontinued\n\n\t14.5/10.5\t- Staging scans after concurrent therapy (12 doses) showed stable disease\n\n- Developed retroperitoneal bleed and was transitioned to hospice care\n\n\t\n2\tIpilimumab/Nivolumab\n\n\nDose:\n\n\nIpilimumab-1 mg/kg, Nivolumab- 240 mg (3 mg/kg)\n\nFrequency: combined every 6 weeks (4 doses total) followed by nivolumab alone every 2 weeks\n\n\tPrednisone 60 mg PO daily>taper\t1\t5 mg/kg\n\n- every 2 weeks for first 2 doses then every 4 weeks\n\n\t1\t3 doses of (ipilimuab+Nivolumab) and 12 doses of nivolumab alone\tUpper endoscopy (3 months):\n\nEndoscopic:\n\n- Gastric body: localized mild inflammation characterized by erythema and friability\n\n- Duodenum: an acquired benign-appearing, intrinsic moderate stenosis was found in the second portion of the duodenum associated with a small erosion\n\nHistologic:\n\n- Gastric body: lymphocytic involvement of gastric pits\n\n- Duodenum: no diagnostic abnormality\n\n- Duodenal stricture: ulceration and expansion of lamina propria by mononuclear cells\n\n\tNo\t12/7.5\t- Staging scans after concurrent therapy (15 doses) showed stable disease and patient continues concurrent therapy\n\n- Developed mucositis/stomatitis that is being managed conservatively\n\n\t\n3\tIpilimumab\n\nDose: 3 mg/kg\n\nFrequency: every 3 weeks\n\n\tMethylprednisolone 1 mg/kg IV twice daily >taper failure\t1\t5 mg/kg\n\n- every 4 weeks\n\n\t1\t2\tNot done\tNo\t6.5/3.5\t- Staging scans showed stable bulk of disease after concurrent therapy (2 doses) with ongoing slight progression in one metastatic lesion in the lung\n\n- Developed skin rash (ipilimumab cutaneous toxicity) that was managed successfully with topical steroids\n\n\t\n4\tIpilimumab/Nivolumab\n\n\nDose:\n\n\nIpilimumab-3 mg/kg, Nivolumab-1 mg/kg\n\nFrequency: combined every 3 weeks\n\n\tPrednisone 60 mg daily>taper failure\t1\t5 mg/kg\n\n- every 4 weeks\n\n\t1\t3\tUpper endoscopy (1 month):\n\nEndoscopic/histologic\n\n- Stomach: normal/chronic inactive gastritis\n\n- Duodenum Normal/normal\n\nColonoscopy (1 month):\n\n- Sigmoid/transverse colon ulcers: fragments of colonic mucosa with crypt architectural disarray and mildly increased cellularity of the lamina propria.\n\nColonoscopy\n\n(3 months)\n\n- Colonic mucosa with scattered crypt epithelial apoptosis and minimal crypt architectural distortion\n\n\tNo\t5/3\t- Staging scans showed interval progression of his disease in the chest, abdomen and pelvis.\t\n5\tCemiplimab\n\nDose: 350 mg\n\nFrequency: every 3 weeks\n\n\tPrednisone 60 mg daily>taper failure\t1\t5 mg/kg\n\n- once\n\n\t1\t2\tNot done\tNo\t4/2.5\t- Staging scans demonstrated interval decrease in the disease burden in the chest and lymph nodes\n\n- Patient developed radiation/checkpoint pneumonitis and was treated with high dose oral steroids\n\n\t\n\n\nPatient 2\nPatient 2 is a 58-year-old woman with stage 4 microsatellite instability (MSI) high colon cancer who was diagnosed at the age of 50. At diagnosis, she underwent a right total colectomy and was treated with 12 cycles of folinic acid, fluorouracil and oxaliplatin (FOLFOX). Two years later she was found to have metastatic disease in the ovaries and underwent bilateral salpingo-oophorectomy. This was followed by 18 cycles of folinic acid, fluorouracil, irinotecan hydrochloride, and avastin (FOLFIRI/Avastin) for metastatic foci in the abdomen. Subsequently she was treated with pembrolizumab for a total of 5 months without adverse events but then stopped due to disease progression. She underwent cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Afterwards, she was on two clinical trials using targeted therapies for advanced colon cancer but had no response to therapy. She then entered a clinical trial testing combination therapy with ipilimumab (CTLA-4 inhibitor), nivolumab (PD-1 inhibitor), and radiation therapy. Eight days after receiving the first dose, she developed epigastric pain, grade 2 diarrhea, abdominal distention, urgency, and stomatitis. She underwent an upper endoscopy that showed active chronic gastritis and a duodenal stricture with active duodenal inflammation (Table 1). Based on these findings, she was initially treated with prednisone 60 mg that was tapered successfully and her ICIs were held for a total of 7 weeks. Due to fear of recurrent duodenitis and the need for continued immunotherapy for disease control she was treated with infliximab (5 mg/kg every 4 weeks, Table 2) and continued to receive three further doses of ipilimumab/nivolumab then biweekly nivolumab. Over the past 7.5 months of concurrent therapy, she has had no further sustained diarrhea and only had occasional episodes of epigastric abdominal pain and nausea. She developed no other irAEs. A follow up upper endoscopy showed improvement of the inflammatory findings (Table 2). Staging imaging for colon cancer showed stable disease without further progression.\n\nPatient 3\nPatient 3 is a 70-year-old woman who was first diagnosed with melanoma at the age of 40 and underwent a surgical resection at the time. At the age of 62, she was diagnosed with recurrent metastatic melanoma to the bone and lungs. Over the past 9 years, she has been treated with multiple surgical resections, adjuvant radiation, adjuvant interferon, and talimogene laherparepvec (TVEC). Next, she was enrolled in two clinical trials and one of them included an anti PD-L1 agent as a part of the treatment regimen but had no response or side effects to either trial. She received eight cycles of pembrolizumab without adverse events but with continued disease progression. Next, she was treated with ipilimumab. Two weeks after the second cycle of ipilimumab, the patient developed diarrhea, vomiting, abdominal pain, and poor oral intake. She was admitted to the hospital and underwent an upper endoscopy that demonstrated patchy gastritis and diffuse active duodenitis with villous blunting (Table 1). A flexible sigmoidoscopy demonstrated no abnormalities grossly and histologically. Based on these findings, she was treated with methylprednisolone 1 mg/kg twice daily to which her symptoms improved but on transitioning to high dose oral glucocorticoids her symptoms recurred and did not respond to another challenge of intravenous steroids. She was administered one dose of infliximab (5 mg/kg) and her steroids were tapered subsequently. Restaging imaging at that point revealed stable disease on ipilimumab. She had been off ICI for 8 weeks due to irEC and it was determined that she would benefit from continued immunotherapy with concurrent infliximab (5 mg/kg every 4 weeks, Table 2). The patient subsequently received 2 cycles of ipilimumab (to complete a total planned course of 4 cycles) with monthly infliximab infusions (total of 4 doses). She had no further diarrhea or abdominal pain through her treatment. While on concurrent therapy, she developed a pruritic skin rash that was biopsied and thought to be a cutaneous manifestation of ipilimumab toxicity. This was managed successfully with topical steroids. Restaging scans after completion of a total of 4 planned cycles of ipilimumab showed stability in the majority of her disease with slight progression in one metastatic lesion in the lung.\n\nPatient 4\nPatient 4 is a 73-year-old man who was diagnosed with metastatic melanoma to the peritoneum and lungs at the age of 72. At diagnosis he was treated with 13 cycles of atezolizumab (anti-PD-L1) and cobimetinib (MEK inhibitor) as well as radiation therapy to the abdomen. He tolerated these therapies well with no adverse events however his disease continued to progress. Next, he was treated with ipilimumab and nivolumab (Table 1). Eleven days after receiving his first cycle, he developed worsening abdominal pain, nausea, vomiting and decreased oral intake. He underwent an upper endoscopy that demonstrated active gastritis and active duodenitis with villous injury. A flexible sigmoidoscopy showed mucosal ulceration with biopsies demonstrating severe active colitis with ulceration. He was then treated with prednisone 60 mg daily with difficulty tapering due to symptom recurrence. Further doses of ipilimumab and nivolumab were held for a total of 2.5 months. Restaging scans were obtained at the time and showed ongoing progression of disease burden in the abdomen. The severity of his irEC and the risk of colonic perforation prompted the decision to initiate concurrent treatment with infliximab. The patient received three more cycles of ipilimumab and nivolumab with infliximab (5 mg/kg every 4 weeks, Table 2). He had no further diarrhea, abdominal pain, nausea, vomiting, or other manifestation of irAEs. Follow-up upper endoscopy after two doses of concurrent therapy showed chronic inactive gastritis and a normal duodenal mucosa, and a flexible sigmoidoscopy showed a mucosal ulcer that demonstrated crypt architectural disarray but with improvement from previously seen active colitis. A follow up colonoscopy after completion of a total of three doses of concurrent therapy showed scattered crypt epithelial apoptosis and minimal crypt architectural distortion. Staging scans after completion of a total of 4 cycles of ipilimumab and nivolumab (3 of which were on concurrent therapy) demonstrated interval progression of his metastatic disease burden in the chest, abdomen, and pelvis. He is being considered for surgical debulking to reduce the metastatic disease burden in the abdomen.\n\nPatient 5\nPatient 5 is a 79-year-old woman who was diagnosed with a cutaneous squamous cell carcinoma with metastasis to the lungs and lymph nodes. She underwent surgical resection of the primary lesion as well as radiation therapy to involved lymph nodes. Simultaneously, she was treated with cemiplimab (PD-1 inhibitor). Two weeks after receiving the first dose of cemiplimab, she developed significant nausea, vomiting, and diarrhea. She was admitted to the hospital and underwent an upper endoscopy which demonstrated reactive gastropathy and intestinal metaplasia in the gastric mucosa. A flexible sigmoidoscopy was performed and showed increased cellularity of the lamina propria and epithelial injury with focal acute inflammation (Table 1). She was treated with high dose oral glucocorticoids, received a dose of infliximab (5 mg/kg, Table 2), and cemiplimab therapy was held for 6 weeks. Her nausea, vomiting, and diarrhea resolved. Subsequently, she received a total of 2 cycles of cemiplimab without recurrence of her gastrointestinal symptoms. She developed worsening shortness of breath and chest imaging revealed evidence of pneumonitis. This was thought to be secondary to radiation and exacerbated by immunotherapy. She was treated with prednisone 60 mg that was tapered successfully; however, further cemiplimab doses were held. Restaging scans demonstrated interval decrease in the size of metastatic foci in the lymph nodes and the chest.\n\nDiscussion\nThe biological rationale for combining anti-TNFα therapies with ICIs comes from recent insights into the role of TNFα in tumor immunology. TNFα produced in the setting of anti-PD-1 blockage leads to impaired CD8+ tumor infiltrating T lymphocyte responses [17]. Additionally, TNFα increases activation-induced cell death in T cells, limiting their viability in the tumor microenvironment [18, 20]. In a mouse model of melanoma, concurrent treatment with anti-PD-1 and anti-TNFα led to improved anti-tumor responses [17]. More recently, in a murine colon cancer model, concurrent treatment with anti-TNFα and combined anti-CTLA-4 and anti-PD-1 improved survival when compared with double checkpoint inhibition treatment alone [18]. When colitis was concomitantly induced in the tumor bearing mice through dextran sodium sulfate (DSS), the mice that received anti-TNFα and double checkpoint inhibition had better colitis amelioration and improved overall survival [18]. By blocking TNFα both studies showed an increase in CD8+ T cells numbers and viability in the tumor microenvironment and draining lymph nodes [17, 18]. These findings add to a growing body of literature that implicates innate inflammation in tumor promotion [21–23].\n\nTNFα plays as essential role in the pathogenesis of irEC. Patients with irEC have up-regulated mucosal TNFα and a local activation of the TNFα gene signature [18]. Additionally, mucosal TNFα levels predict irEC steroid responsiveness with higher mucosal TNFα levels predicting lower steroid responsiveness [24]. Multiple groups have previously reported on treatment of severe irEC with TNFα blokecrs [8, 14, 15, 25]. However, after receiving anti-TNFα, patients’ ICI therapy was usually discontinued. In this case series, we report our institutional experience with patients who received immunotherapy and anti-TNFα concurrently.\n\nPatients 2 and 4 were both treated with a combination of ipilimumab and nivolumab while Patients 1, 3, and 5 received monotherapy with pembrolizumab, ipilimumab, or cemiplimab, respectively. Patients 2, 3, and 4 all received a different ICI months to years prior to the regimen immediately associated with colitis. Given that the irAE to some ICI may manifest up to 2 years after therapy [26], the irEC they experienced may have a mixed component due to previous exposure to multiple ICIs. The onset of symptoms was sooner and the severity was worse in the patients who received a combination of ipilimumab and nivolumab compared to those receiving a single agent ICI, consistent with findings reported in the literature previously [6, 26].\n\nPatient 1 had a history of segmental colitis associated with diverticulitis (SCAD) prior to initiation of ICI. Overlapping features of ICI and SCAD were seen on the colonic biopsy. The pathophysiology of SCAD is incompletely understood but the syndrome is thought to overlap with IBD [27]. Some retrospective studies reported increased risk of irEC in patients with baseline active inflammatory and autoimmune diseases, placing the patient at a higher risk of irEC [7, 28].\n\nOn presentation with symptoms, all patients were initiated on glucocorticoid therapy for irEC and achieved good control. Patients 1, 3, 4, and 5 were unable to maintain symptom control with glucocorticoid tapering. The decision to resume ICI after irEC carries a serious risk of relapse and is often done on an individual basis [29]. Some studies have shown that 50–60% of these patients have relapse of irEC [14, 29]. In one study, after irEC resolution, ICIs were restarted concomitantly with vedolizumab, an α4β7 integrin inhibitor that blocks T cell trafficking to the gut, only one out of eight patients had recurrence of irEC [14]. Although vedolizumab is a reasonable approach for treatment of glucocorticoid refractory irEC, inhibition of T cell trafficking into the gut may be risky in patients with gastrointestinal malignancies (e.g. patient 2) where antitumor T cells would also require access to the gastrointestinal mucosa. Similarly, vedolizumab could inhibit responses to gastrointestinal metastases, which are found in approximately 5% of patients with melanoma and are often not seen on surveillance imaging [30, 31]. We favor infliximab as initial biologic therapy for irEC for these reasons, as well as the potential antitumor benefit associated with TNFα blockade.\n\nThe decision to initiate concurrent ICI and anti-TNFα therapy in our cohort was driven by an inability to taper steroids and concern for irEC recurrence. Infliximab was administered at a dose of 5 mg/kg. The frequency of infliximab infusions varied depending on ICI regimen and irEC severity. In general, patients were loaded on infliximab using standard dosing at weeks 0, 2, and 6. Maintenance therapy frequency was selected based on the assumption that patients receiving ongoing immunotherapy in the setting of irEC would behave like patients with severe IBD, and that they may require more frequent infliximab administration than the standard 8 week interval. In addition, for patient convenience, infliximab was infused on the same schedule as the immunotherapy, with infusions occuring on the same day, though the drugs were not given simultaneously.\n\nAfter initiation of concurrent anti-TNFα and ICI therapy, all patients continued to receive ICI without recurrence of symptoms. Follow up endoscopies in Patients 1, 2, and 4 showed resolution of acute inflammatory features. Staging scans in Patients 1, 2, 3, and 5 after concurrent therapy demonstrated overall disease stability. Patient 4 had progression of his disease despite targeted therapy, immunotherapy, and radiation. He is currently being considered for surgical management for symptom control. After receiving anti-TNFα and 12 further doses of ICI with no disease progression, Patient 1 developed a Clostridium difficile infection after which he had recurrence of irEC. After treatment with immunotherapies, gastrointestinal disruption (e.g., due to infection) may cause alteration in the gut microbiota and the local immune compartment, resulting in a breach in tolerance leading to irEC [4, 7].\n\nOur experience adds to the growing animal literature showing that concurrent anti-TNFα and ICI therapy is safe, does not negatively impact tumor control and is associated with a better side effect profile. Importantly, patients were able to continue on immunotherapy. We suggest that concurrent anti-TNFα be considered in patients who develop severe irECs early in their immunotherapy course where additional immunotherapy is likely to provide a benefit, and where other treatment alternatives are either unavailable or have a low likelihood of providing benefit. Prospective data will be necessary, however, to clearly define populations where anti-TNFα concurrent with immunotherapy is both safe, and leads to improved tumor outcomes.\n\nAn ongoing phase I clinical trial (NCT03293784) is evaluating the safety and tolerability of treating metastatic melanoma with ICIs combined with either infliximab or certolizumab, a similar anti-TNFα agent. Our experience helps provide evidence of the safety of combination treatment with anti-TNFα and ICI, which we propose should accelerate the initiation of a phase II clinical trial to examine the impact of TNFα blockade on both irAEs and antitumor immunity.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNA\n\nAuthors’ contributions\nYRB compiled and reviewed all of the data. JVC, PKB, AP and TSH assessed and confirmed the accuracy of the details relating to the patients’ oncologic history and treatment. MD assessed and confirmed the accuracy of the patients’ gastroenterological history, treatment, and endoscopy results. YRB and MD wrote the manuscript with contributions from all of the authors. All authors read and approved the final manuscript.\n\nFunding\nFunding was provided by National Institutes of Health Mentored Clinical Scientist Development Award 1K08DK114563–01 and the American Gastroenterological Association Research Scholars Award (M.D.).\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNA\n\nConsent for publication\nPatient records were accessed and analyzed through a protocol approved by the Partners Institutional Review Board that waved patient consent.\n\nCompeting interests\nJ.V.C. has received consulting fees from Sanofi-Genzyme. P.K.B. receives consulting fees from Lilly, Angiochem, Tesaro, Genentech-Roche, speaker’s honoraria from Genentech-Roche and Merck and grant funding from Merck and BMS (institutional). A.R.P. is a consultant/advisory board member for Puretech, Driver, Foundation Medicine and Eisai; and has institutional research funding from Array, Plexxikon, Guardant, BMS, MacroGenics, Genentech-Roche, Novartis, OncoMed, and Tolero. T.S.H. receives research funding (Clinical Trials) from BMS, Taiho, Tesaro, IntraOp, Astra-Zeneca, and Novartis, and an advisory board honorarium from Merck. M.D. receives research funding from Novartis, and has received consulting fees from Genentech-Roche and Tillotts. All other authors declare no competing interests.\n==== Refs\nReferences\n1. Ribas A Wolchok JD Cancer immunotherapy using checkpoint blockade Science 2018 359 1350 1355 10.1126/science.aar4060 29567705 \n2. Wei SC Duffy CR Allison JP Fundamental mechanisms of immune checkpoint blockade therapy Cancer Discov 2018 8 1069 1086 10.1158/2159-8290.CD-18-0367 30115704 \n3. 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Ridker PM Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial Lancet Lond Engl 2017 390 1833 1842 10.1016/S0140-6736(17)32247-X \n23. Dougan M Dranoff G Dougan SK Cancer immunotherapy: beyond checkpoint blockade Annu Rev Cancer Biol 2019 3 55 75 10.1146/annurev-cancerbio-030518-055552 \n24. Coutzac C Colon immune-related adverse events: anti-CTLA-4 and anti-PD-1 blockade induce distinct Immunopathological entities J Crohns Colitis 2017 11 1238 1246 10.1093/ecco-jcc/jjx081 28967957 \n25. Som A Immune checkpoint inhibitor-induced colitis: a comprehensive review World J Clin Cases 2019 7 405 418 10.12998/wjcc.v7.i4.405 30842952 \n26. Boutros C Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination Nat Rev Clin Oncol 2016 13 473 486 10.1038/nrclinonc.2016.58 27141885 \n27. Schembri J Bonello J Christodoulou DK Katsanos KH Ellul P Segmental colitis associated with diverticulosis: is it the coexistence of colonic diverticulosis and inflammatory bowel disease? Ann Gastroenterol 2017 30 257 261 28469355 \n28. Menzies AM Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab Ann Oncol Off J Eur Soc Med Oncol 2017 28 368 376 \n29. Marthey L Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease J Crohns Colitis 2016 10 395 401 10.1093/ecco-jcc/jjv227 26783344 \n30. Blecker D Abraham S Furth EE Kochman ML Melanoma in the gastrointestinal tract Am J Gastroenterol 1999 94 3427 3433 10.1111/j.1572-0241.1999.01604.x 10606298 \n31. Bello E Cohen JV Mino-Kenudson M Dougan M Antitumor response to microscopic melanoma in the gastric mucosa mimicking ipilimumab-induced gastritis J Immunother Cancer 2019 7 41 10.1186/s40425-019-0524-1 30744698\n\n", "fulltext_license": "CC BY", "issn_linking": "2051-1426", "issue": "7(1)", "journal": "Journal for immunotherapy of cancer", "keywords": "CTLA-4; Checkpoint inhibitor; Immune related adverse events; Immune related enterocolitis; Infliximab; PD-1; TNFα", "medline_ta": "J Immunother Cancer", "mesh_terms": "D000911:Antibodies, Monoclonal; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005767:Gastrointestinal Diseases; D006801:Humans; D008297:Male; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "101620585", "other_id": null, "pages": "226", "pmc": null, "pmid": "31439050", "pubdate": "2019-08-22", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "10606298;21537082;26783344;27141885;27687304;28469355;28855077;28967957;29162153;29230210;29273790;29320654;29387476;29517954;29567705;29747688;29784734;29917046;30115704;30131322;30290139;30305177;30744698;30842952;30940209;31043740;31053497;31286682;7566090", "title": "Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events.", "title_normalized": "concurrent therapy with immune checkpoint inhibitors and tnf blockade in patients with gastrointestinal immune related adverse events" }

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CONCURRENT THERAPY WITH IMMUNE CHECKPOINT INHIBITORS AND TNF BLOCKADE IN PATIENTS WITH GASTROINTESTINAL IMMUNE-RELATED ADVERSE EVENTS. 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{ "abstract": "Oritavancin is a lipoglycopeptide antibiotic with in vitro bactericidal activity against gram-positive pathogens indicated for use in adults with acute bacterial skin and skin structure infections (ABSSSI). Its concentration-dependent activity and prolonged half-life provide a convenient single-dose alternative to multi-dose daily therapies for ABSSSI. This retrospective cohort study was conducted to quantify the clinical and economic advantages of using oritavancin compared to other antibiotic agents that have been historically effective for ABSSSI.\n\n\n\nSeventy-nine patients received oritavancin who had failed previous outpatient antibiotic therapy (OPAT) for cellulitis or abscess and were subsequently readmitted to the hospital as an inpatient between 2016 and 2018. These patients were compared to a cohort of 28 patients receiving other antibiotics following OPAT failure and subsequent hospitalization for these two infection types. The primary clinical end point was average length of stay (aLOS) and secondary endpoints included readmission rates for the same indication at 30 and 90 days after discharge and the average hospital cost (aHC).\n\n\n\nA total of 107 patients were hospitalized for treatment of cellulitis or abscess. Demographic characteristics of both the oritavancin and comparator groups were similar except for the presence of diabetes. The primary clinical endpoint showed a non-significant decrease in aLOS between the oritavancin group versus comparator (2.12 days versus 2.59 days; p = 0.097). The secondary endpoints revealed lower readmission rates associated with oritavancin treatment at 30 and 90 days; the average hospital cost was 5.9% lower for patients that received oritavancin.\n\n\n\nThe results of this study demonstrate that oritavancin provides not only a single-dose alternative to multi-day therapies for skin and skin structure infections, but also a clinical and economic advantage compared to other antibiotic agents.", "affiliations": "Department of Pharmacy, DeTar Healthcare System, Victoria, Texas, United States of America.;Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas, United States of America.;Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas, United States of America.;DeTar Family Medicine Residency Program, DeTar Healthcare System, Victoria, Texas, United States of America.;Facultad de Ciencias Medicas, Hospital Escuela Universitario, Universidad Nacional Autonoma de Honduras, Boulevard Suyapa, Tegucigalpa, Honduras, United States of America.;Texas A&M College of Medicine affiliated DeTar Family Medicine Residency, Victoria, Texas, United States of America.;DeTar Healthcare System, Victoria, Texas, United States of America.;University of Texas at Austin, Austin, Texas, United States of America.;Texas A&M College of Medicine affiliated DeTar Family Medicine Residency, Victoria, Texas, United States of America.", "authors": "Saddler|Kimberly|K|0000-0001-9673-4241;Zhang|Jason|J|;Sul|Jennifer|J|;Patel|Pruthvi|P|;Castro-Lainez|Miriams|M|;Stevens|Mark L|ML|0000-0002-1813-6403;Kosler|Sheryl|S|;Lowery|Emily|E|;Sierra-Hoffman|Miguel|M|", "chemical_list": "D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; C100708:oritavancin", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0248129", "fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nplosone\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0248129\nPONE-D-20-39053\nResearch Article\nMedicine and Health Sciences\nPharmacology\nDrugs\nAntimicrobials\nAntibiotics\nBiology and Life Sciences\nMicrobiology\nMicrobial Control\nAntimicrobials\nAntibiotics\nMedicine and Health Sciences\nHealth Care\nHealth Care Facilities\nHospitals\nMedicine and Health Sciences\nMedical Conditions\nSkin Diseases\nSkin Infections\nMedicine and Health Sciences\nDermatology\nSkin Diseases\nSkin Infections\nMedicine and Health Sciences\nMedical Conditions\nInfectious Diseases\nSkin Infections\nMedicine and Health Sciences\nHealth Care\nPatients\nOutpatients\nMedicine and Health Sciences\nHealth Care\nPatients\nInpatients\nEngineering and Technology\nElectronics Engineering\nElectronics\nComparators\nMedicine and Health Sciences\nMedical Conditions\nInfectious Diseases\nBacterial Diseases\nCellulitis\nMedicine and Health Sciences\nClinical Medicine\nSigns and Symptoms\nAbscesses\nImproved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital\nImproved economic and clinical outcomes with oritavancin versus comparator group for bacterial skin infection\nhttps://orcid.org/0000-0001-9673-4241\nSaddler Kimberly Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Software Supervision Validation Visualization Writing – original draft Writing – review & editing 1*\nZhang Jason Conceptualization Data curation Formal analysis Investigation Methodology Software Validation Writing – original draft Writing – review & editing 2\nSul Jennifer Conceptualization Data curation Formal analysis Methodology Resources Validation Writing – original draft 2\nPatel Pruthvi Data curation Resources Writing – original draft 3\nCastro-Lainez Miriams Conceptualization Data curation Formal analysis Investigation Methodology Resources Supervision Validation Visualization Writing – original draft Writing – review & editing 4\nhttps://orcid.org/0000-0002-1813-6403\nStevens Mark L. Data curation Investigation Methodology Resources Writing – original draft 5\nKosler Sheryl Conceptualization Data curation Resources Writing – original draft 6\nLowery Emily Data curation Investigation Methodology Resources 7\nSierra-Hoffman Miguel Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Software Supervision Validation Visualization Writing – original draft Writing – review & editing 5\n1 Department of Pharmacy, DeTar Healthcare System, Victoria, Texas, United States of America\n2 Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas, United States of America\n3 DeTar Family Medicine Residency Program, DeTar Healthcare System, Victoria, Texas, United States of America\n4 Facultad de Ciencias Medicas, Hospital Escuela Universitario, Universidad Nacional Autonoma de Honduras, Boulevard Suyapa, Tegucigalpa, Honduras, United States of America\n5 Texas A&M College of Medicine affiliated DeTar Family Medicine Residency, Victoria, Texas, United States of America\n6 DeTar Healthcare System, Victoria, Texas, United States of America\n7 University of Texas at Austin, Austin, Texas, United States of America\nDi Gennaro Francesco Editor\nNational Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, ITALY\nCompeting Interests: DeTar Healthcare System provided support in the form of a salary for author KS. Miguel Sierra-Hoffman M.D. is a member of the speaker bureau for Melinta Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: kim.saddler@detar.com\n18 3 2021\n2021\n16 3 e024812911 12 2020\n22 2 2021\n© 2021 Saddler et al\n2021\nSaddler et al\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nBackground\n\nOritavancin is a lipoglycopeptide antibiotic with in vitro bactericidal activity against gram-positive pathogens indicated for use in adults with acute bacterial skin and skin structure infections (ABSSSI). Its concentration-dependent activity and prolonged half-life provide a convenient single-dose alternative to multi-dose daily therapies for ABSSSI. This retrospective cohort study was conducted to quantify the clinical and economic advantages of using oritavancin compared to other antibiotic agents that have been historically effective for ABSSSI.\n\nMethods\n\nSeventy-nine patients received oritavancin who had failed previous outpatient antibiotic therapy (OPAT) for cellulitis or abscess and were subsequently readmitted to the hospital as an inpatient between 2016 and 2018. These patients were compared to a cohort of 28 patients receiving other antibiotics following OPAT failure and subsequent hospitalization for these two infection types. The primary clinical end point was average length of stay (aLOS) and secondary endpoints included readmission rates for the same indication at 30 and 90 days after discharge and the average hospital cost (aHC).\n\nResults\n\nA total of 107 patients were hospitalized for treatment of cellulitis or abscess. Demographic characteristics of both the oritavancin and comparator groups were similar except for the presence of diabetes. The primary clinical endpoint showed a non-significant decrease in aLOS between the oritavancin group versus comparator (2.12 days versus 2.59 days; p = 0.097). The secondary endpoints revealed lower readmission rates associated with oritavancin treatment at 30 and 90 days; the average hospital cost was 5.9% lower for patients that received oritavancin.\n\nConclusion\n\nThe results of this study demonstrate that oritavancin provides not only a single-dose alternative to multi-day therapies for skin and skin structure infections, but also a clinical and economic advantage compared to other antibiotic agents.\n\nDeTar Healthcare System provided support in the form of a salary for author KS but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Data AvailabilityData cannot be shared publicly because of associated PHI. Data are available from the DeTar Ethics Committee (contact via Kim Saddler) for researchers who meet the criteria for access to confidential data. An alternate non-author contact for data access would be Petrina Lowery, Facility Compliance Officer (petrina.lowery@detar.com).\nData Availability\n\nData cannot be shared publicly because of associated PHI. Data are available from the DeTar Ethics Committee (contact via Kim Saddler) for researchers who meet the criteria for access to confidential data. An alternate non-author contact for data access would be Petrina Lowery, Facility Compliance Officer (petrina.lowery@detar.com).\n==== Body\nIntroduction\n\nThe therapeutic management of acute bacterial infections of the skin and skin structures (ABSSSIs) has been identified as a clinical area of infectious disease focus with vast opportunity for improvement for both hospital policy makers and front-line clinicians [1,2]. New pharmacological treatments are needed, but of major importance is improving cost effectiveness and efficient use of resources. In the era of value-based care, there are strong incentives to develop patient-centric treatment approaches that improve quality of care and increase efficiency while utilizing resources judiciously [2,3].\n\nThe challenge of managing ABSSSIs is complicated by its common diagnosis and healthcare burden. Miller et al examined ambulatory and inpatient data from the HealthCore Integrated Research Database between 2005 and 2010 and found that the incidence of ABSSSIs is substantial; it is approximately double the prevalence of UTI and tenfold that of pneumonia. Persons aged 45 to 64 years had the highest incidence of both ambulatory-treated and inpatient-treated ABSSSIs [4]. Tun et al performed a cross-sectional analysis of nationally representative data from the Medical Expenditure Panel Survey and found a total of 2.4 million patients experienced an ABSSSI in 2000 compared to 3.3 million in 2012, representing a 40% increase. From 2000 to 2012, the incidence of patients with at least one hospital visit for ABSSSIs increased 22%, ambulatory care visits increased 30%, and emergency department visits increased 40%. In 2012, ambulatory based ABSSSI visits accounted for the majority of all ABSSSI visits (76%), or 2.5 million visits annually–a 30% increase since 2000, followed by increases in ED visits (17%) and inpatient visits (7%) [5].\n\nWhile there is sparse data on the incidence after 2012 in the U.S., a recent study by Morgan et al showed a decline of 8.0% in emergency room encounters for ABSSSIs between 2009 and 2014 [6]. Recently, Fritz et al used a nationally representative dataset from 2000–2015 and demonstrated a rise in the incidence of outpatient visits for purulent skin infections in adults, peaking in 2010–2013, followed by a plateau or slight decline [7]. Temporal trends in MRSA-related hospital-onset and community-onset infections (between 2012 and 2017) decreased by 20.5% [8]. According to our local antibiograms, produced yearly, MRSA infections have not decreased in the last three years, but continue to represent approximately 50% of Staphylococcus aureus infections. Due to continued rise in healthcare costs across the board, it is not surprising that although the rate of infection may not be increasing, the cost to treat continues to rise. These combined trends likely result in some stabilization or slight decrease in ABSSSI incidence and MRSA-related ABSSSIs.\n\nAs the incidence of ABSSSIs has remained stable over the past decade, costs have increased. Kaye et al explored data from the US Healthcare Cost and Utilization Project National Inpatient Sample between 2005 and 2011. They found that average costs and length of stay in 2011 for an adult ABSSSI inpatient were $9,895.31 and 5.0 days, respectively, primarily composed of abscess and cellulitis in 73% of patients [2]. Tun et al added further information on the impact of ABSSSI on the US healthcare system. The total estimated direct healthcare costs of ABSSSIs increased 3-fold from $4.8 billion in 2000 to $15.0 billion in 2012. Direct healthcare costs of ED visits doubled ($200 million in 2000 to $400 million in 2012) and that of inpatient visits increased 1.6-fold ($3.5 billion to $5.5 billion) [5].\n\nThis retrospective study collected data during a three-year calendar period (2016 to 2018) at DeTar Healthcare System, a 219-bed community hospital with an average daily census of 95 located in outh Texas. An oritavancin protocol was developed and approved for treatment of patients with skin and skin structure infections (see Fig 1); utilization began in August 2015.The pathway at our institution reflects a suggested practice and is not mandatory. It provides guidance on infusion requirements, pre-medication, and diluent. The pathway was not used a priori to select patients for this study. We measured the real-world experience including length of stay, readmission rate, and economic impacts of a cohort of patients who received oritavancin in an infusion center compared to a cohort of patients who received other antibiotic agents effective for cellulitis and abscess. The hypothesis of this study was that incorporation of oritavancin into hospital pathways would be associated with a reduction in hospital costs as a result of decreased average length of stay and/or decreased readmission rates for ABSSSI patients.\n\n10.1371/journal.pone.0248129.g001 Fig 1 Hospital protocol for administration of oritavancin.\n\nMethods\n\nThis study was based on a retrospective chart review. Medical charts of 506 patients administered oritavancin in 2015 to 2018 were examined to identify patients with a clinical diagnosis of either cellulitis or abscess who were hospitalized and exhibited none of the exclusions. Patients were excluded from the study for any of the following: osteomyelitis, endocarditis, primary or secondary bacteremia, age <18 years, length of inpatient stay exceeding 7 days, any ICU stay during hospital admission, infections that required major surgical debridement and/or wound care, and incomplete data for length of stay, readmission data to 90 days, and hospital costs. Following application of these exclusions, 79 patients remained and were the source of this analysis. These 79 patients had failed previous outpatient antibiotic therapy (OPAT) following a prior hospitalization and were treated with a single intravenous (IV) dose of oritavancin 1200 milligrams infused over 3 hours at hospital discharge and included in cohort A. These patients were compared with a cohort of 28 unique patients screened from a database of 216 patients admitted during the same period and who did not receive oritavancin (cohort B). Exclusion criteria noted above were also applied to patients in cohort B during the identification process. As with cohort A, patients in cohort B were required to have failed non-oritavancin therapy prior to hospital admission. Demographic data and clinical outcomes were obtained by chart abstraction. This study was approved by DeTar Healthcare System Ethics Committee and Chief Compliance Officer. Informed consents were waived by the Ethics Committee as Protected Health Information was not included and data was collected retrospectively. Patient data was collected via electronic medical records in May of 2019 for patients treated during the time period of August 2015 thru December of 2018. Patient data was anonymized following completion of data collection. This case study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Waivers were approved by the hospital IRB. Hospitalization costs were obtained from medical records and hospital finance. Failure of a recent course of antibiotic therapy, either oritavancin or another course of other antibiotic(s), was defined as patients who returned to the hospital due to worsening infection symptoms or lack of improvement within 30 days or 90 days, and for oritavancin specifically within 14 days post-dose.\n\nThe evaluable safety cohort consisted of 107 patients who received oritavancin or other antibiotic therapies. Medical records were reviewed to identify drug-related treatment-emergent adverse event (TEAE) considered by the physician to be definitely related or possibly related to oritavancin or other antibiotics.\n\nThe primary endpoint was average length of stay (aLOS). The secondary endpoints included readmission rates for the same indication at 30 and 90 days after discharge and the average hospital cost (aHC). The average cost of hospitalization for patients within each cohort was derived from non-ICU medical-surgical bed charges adjusted using the hospital’s cost-to-charge ratio. Cost avoidance included differences in costs of the index hospitalization plus readmissions in each cohort. The cost of readmissions was based on the greater aLOS observed in cohort B (2.59 hospital days). Cost avoidance used an average cost per hospital stay of $3,879.43 (Detar Healthcare System) and was normalized for 100 patients treated with oritavancin to compare against non-oritavancin treatments.\n\nData were summarized using descriptive statistics to characterize patient demographics and clinical conditions. Due to positive skewing, continuous variables for outcome measures were log-transformed to calculate average lengths of stay (aLOS) and average hospital costs (aHC) in each cohort and retransformed thereafter. Where necessary, actual costs are used for comparison. The statistical analysis plan included calculation of level of significance for aLOS comparing cohort A and cohort B cumulatively and for each year of the study. Similarly, aHC data were analyzed over the entire study period. Furthermore, the Chi-square test was used to compare the two cohorts regarding readmission status at 30 and 90 days. A significance level of 0.05 was used throughout.\n\nResults\n\nA total of 107 patients were retrospectively identified and which were admitted to the inpatient medical service for failed treatment of ABSSSIs as outpatients. Treatment post-discharge was retrospectively identified as oritavancin in patients admitted for recurrent or failed ABSSSI therapy (cohort A, n = 79), or recurrent episode of ABSSSI treated with alternative agents (cohort B, n = 28), at discharge. Patient identification and cohort assignments are shown in Fig 2. All patients suffered from cellulitis or abscess.\n\n10.1371/journal.pone.0248129.g002 Fig 2 Flow diagram of patient allocation into cohorts based on treatment regimen.\n\nDemographic characteristics of both the oritavancin and comparator groups were similar (Table 1) except for greater age in cohort B (median 61 years versus 51 years). Males predominated in both cohorts. The majority of patients were obese. Hypertension was observed in at least half of patients in each cohort. Cellulitis was the predominant infection with the remaining patients hospitalized for recurring or failed treatment of abscess. Staphylococcus aureus was the predominant pathogen in 77 percent of positive cultures; methicillin-susceptible and methicillin-resistant phenotypes were similar. Diagnosis-Related Group 603 was the discharge diagnosis for all patients in cohort B while it was the primary DRG in 53 percent of patients in cohort A.\n\n10.1371/journal.pone.0248129.t001 Table 1 Patient demographics.\n\nCharacteristic\tOritavancin (n = 79)\tComparator (n = 28)\t\nAge\t\t\t\n Mean, yr (SD)\t51.3 (17.2)\t57.6 (21.3)\t\n Median, yr\t51\t61\t\n Range, yr\t21–93\t25–92\t\n Age ≥ 65, no. (%)\t19 (24.1)\t10 (35.7)\t\nSex, no. (%)\t\t\t\n Male\t49 (62)\t17 (61)\t\nRace, no. (%)\t\t\t\n Caucasian\t46 (58.2)\t15 (53.6)\t\n Hispanic\t32 (40.5)\t13 (46.4)\t\n African-American\t1 (1.3)\t0 (0.0)\t\nBMI (SD), kg/m2\t\t\t\n Mean\t35.3 (10.8)\t36.4 (13.6)\t\n Median\t33.3\t32.7\t\n Range\t17.7–72.4\t24.6–76.2\t\nBMI Category, no. (%), kg/m2\t\t\t\n < 25\t9 (11.4)\t2 (7.1)\t\n 25 to < 30\t23 (29.1)\t8 (28.6)\t\n ≥ 30\t47 (59.5)\t18 (64.3)\t\nCo-morbidities, no. (%)\t\t\t\n Hypertension\t46 (58.2)\t16 (57.1)\t\n Diabetes\t28 (35.4)\t11 (39.3)\t\n Dyslipidemia\t27 (34.2)\t10 (35.7)\t\n≥ 2 co-morbidities, no. (%)\t31 (39.2)\t12 (42.9)\t\nInfection type, no. (%)\t\t\t\n Cellulitis\t68 (86.1)\t22 (78.6)\t\n Abscess\t11 (13.9)\t6 (21.4)\t\nPositive infection site cultures, no. (%)\t26 (32.9)\t13 (46.4)\t\nSpecific pathogen from positive cultures\t\t\t\n MRSA\t10 (12.7)\t5 (17.9)\t\n MSSA\t11 (13.9)\t4 (14.3)\t\n Other Gram-positive\t5 (6.3)\t1 (3.6)\t\nPrimary DRG, no. (%)\t\t\t\n 603\t42 (53.2)\t28 (100)\t\n 602\t1 (1.2)\t0\t\n Other\t36 (45.6)\t0\t\n\nPrimary and secondary endpoints showed improvement in the oritavancin group (Table 2). The primary clinical endpoint showed a non-significant decrease in aLOS with the oritavancin group versus comparator (2.12 days versus 2.59 days; p = 0.097). Actual average ($3,959.05 versus $4,256.28, respectively; P = 0.55) and log-transformed average hospital costs ($3,376.57 versus $3,588.68; P = 0.63) were lower in the oritavancin cohort compared to cohort B, but did not reach statistical significance. The average hospital cost was lower for patients that received oritavancin (7.0% for average costs and 5.9% for log-transformed average costs). Another secondary endpoint was significant for lower readmission rates associated with oritavancin treatment within 30 and 90 days: 10.1% (8/79) and 12.7% (10/79), respectively; for the comparator group the readmission rate was 60.7% (17/28) at both timepoints. The difference in readmission rates between the oritavancin and comparator cohorts was statistically significant for 30 days and 90 days (p<0.001 and p<0.001, respectively).\n\n10.1371/journal.pone.0248129.t002 Table 2 Primary and secondary outcomes.\n\nParameter\tOritavancin (n = 79)\tComparator (n = 28)\tSignificance\t\nLog-Transformed Length of Stay (days), 2016–2018 (mean, SD) a\nLog-Transformed Length of Stay (days) by year (mean, no. of patients) a\n 2016\n 2017\n 2018\t2.12 (0.086)\n\n3.52, 9\n1.89, 29\n2.06, 41\t2.59 (0.078)\n\n2.00, 2\n2.92, 9\n2.51, 17\tp = 0.097\n\np = 0.146\np = 0.037\np = 0.177\t\nReadmission Rate, no. (%)\n Within 30 days\n Within 90 days\t\n8 (10.1)\n10 (12.7)\t\n17 (60.7)\n17 (60.7)\t\np < 0.001\np < 0.001\t\nAverage Cost per Hospitalization\n Actual cost, $ (SD)\n Log-transformed cost, $\t\n\n3,959.05 (2,377.34)\n3,376.54\t\n\n4,256.28 (1,752.34)\n3,588.68\t\n\np = 0.55\np = 0.63\t\nCost avoidance (index case plus readmission) b ($)\t207,423.64\t\na Oritavancin was adopted in DeTar formulary in August 2015 and data is omitted for this year.\n\nb Cost avoidance per 100 patients treated with oritavancin is the sum of difference in hospital cost of index hospitalization based on log-transformed value of $212.11 plus difference in 90-day readmission rates using $3,879.43 average cost per hospitalization.\n\nAbbreviation: SD, standard deviation.\n\nOnly 6 of 79 (7.6%) patients required reevaluation within 14 days following a single intravenous (IV) dose of oritavancin 1200 milligrams delivered at discharge. Characteristics and medical narratives are described in Table 3. Two patients received a second dose of oritavancin 1200 milligrams as outpatients with subsequent resolution of infection. Two additional patients were readmitted to an inpatient medical service for unsatisfactory clinical response; one patient was discharged on non-oritavancin antibiotics but eventually required toe amputation and the second patient finally required several days of meropenem administered at a nearby long-term acute care facility. The final two patients were evaluated as outpatients accordingly: oritavancin failure followed by oral therapy with doxycycline plus ciprofloxacin as an outpatient, and post-discharge referral to a dermatology service for a non-infectious lesion.\n\n10.1371/journal.pone.0248129.t003 Table 3 Characteristics, diagnosis and management of 6 patients without resolution of infection within 14 days post-dose oritavancin.\n\nNo. of patients\tDescription of infection at time of follow-up visit\tReadmitted as Inpatient within 14 days (Yes/No) a\t\n1\tUnsatisfactory clinical response and was prescribed an oral combination of doxycycline and ciprofloxacin\tNo\t\n1\tUnsatisfactory clinical response to oritavancin; oral antibiotic therapy initiated in clinic also without resolution leading to amputation of 4th toe 14 days after oritavancin\tYes\t\n2\tReturned for a second dose of oritavancin, administered as outpatients, with resolution of lesion\tNo\t\n1\tReadmitted for additional parenteral antibiotic therapy for post-traumatic wound infection culture-positive for MSSA; patient responded to meropenem and additional gram-positive therapy, subsequently transferred to LTACH for completion of meropenem\tYes\t\n1\tReferred to dermatology for a non-infectious lesion\tNo\t\na Infection-related readmissions are described for 2 patients within 14 days following administration of oritavancin. Not included in this table, an additional 6 patients requiring readmission to the hospital within 30 days (Table 2) post-dose oritavancin were managed for non-infectious reasons.\n\nPrior antibiotics leading to clinical failure are provided for both groups (Table 4). Almost 70% of antibiotic failures in cohort A prior to oritavancin treatment involved four oral agents commonly used for treatment of ABSSSIs (n, % of failures): trimethoprim/sulfamethoxazole (n = 19, 24.1%), clindamycin (n = 15, 19.0%), doxycycline (n = 11, 13.9%), and cephalexin (n = 9, 11.4%). In cohort B, patients failed the same four oral agents at a similar rate (n = 17, cumulative 60.7%; cohort A, n = 54, cumulative 68.4%).\n\n10.1371/journal.pone.0248129.t004 Table 4 Previous antibiotic failures in order of occurrence in oritavancin group.\n\nAntibiotic\tOritavancin (n = 79) a\tComparator (n = 28) b\t\nOral antibiotics\t\t\t\n Trimethoprim/sulfamethoxazole\t19\t6\t\n Clindamycin\t15\t2\t\n Doxycycline\t11\t4\t\n Cephalexin\t9\t5\t\n Ciprofloxacin/levofloxacin\t6\t1\t\n Minocycline\t3\t1\t\n Cefdinir\t2\t0\t\n Amoxicillin/clavulanate\t1\t2\t\n Penicillin\t1\t0\t\n Amoxicillin\t0\t3\t\nIntravenous antibiotics\t\t\t\n Ceftriaxone\t2\t0\t\n Vancomycin\t2\t0\t\n Meropenem\t1\t0\t\n Ertapenem\t1\t0\t\nNot recorded in medical chart/EHR\t21\t7\t\na All 79 patients who received oritavancin failed prior outpatient treatment with oral or intravenous antibiotics; 73 antibiotic courses were recorded in 58 patients at discharge.\n\nb Includes 28 patients who failed prior outpatient treatment with oral antibiotics; 24 antibiotic courses were recorded in 21 patients at discharge.\n\nThere were 107 patient records available to review safety. There were no safety issues identified during the retrospective analysis in patients receiving oritavancin or alternative agents. There were no reports of infusion-related treatment-related adverse events or infusion discontinuations. There were no in-hospital deaths. Benefit derived from pre-medication with diphenhydramine 50 milligrams could not be evaluated since this practice was initiated from inception of the institutional protocol.\n\nWe conducted a simplified hospital cost avoidance analysis based on the difference in average cost per hospitalization (log-transformed) over the course of the 3-year time period between cohorts ($212.11, Table 2). For 100 patients, treatment with oritavancin based on our selective treatment strategy of early discharge and administration of oritavancin in an outpatient setting was associated with a cost avoidance of $21,211. The difference in observed 90-day readmission rates (oritavancin, 12.7%; comparator, 60.7%) multiplied by the average medical/surgical hospital stay per patient of $3,879.43 (DeTar Healthcare System) led to an additional cost avoidance of $186,212.64 per 100 patients. A total conservative cost avoidance with use of oritavancin was estimated as $207,423.64. The contribution of costs from diphenhydramine premedication to oritavancin therapy were not included as these were nominal.\n\nDiscussion\n\nOritavancin is a long-acting lipoglycopeptide antibiotic that was studied in two Phase III randomized controlled trials. The Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections (SOLO I and SOLO II) trials demonstrated that a single 1200 mg intravenous (IV) dose of oritavancin was non-inferior to 7 to 10 days of IV vancomycin (1 g or 15 mg/kg twice daily) [9–11]. Furthermore, the pooled SOLO studies revealed similar patient outcomes of single-dose oritavancin (n = 392) compared to multidose vancomycin (n = 400) used to treat ABSSSIs entirely in the outpatient setting [12]. Efficacy response rates using a primary composite endpoint of early clinical evaluation were 80.4% and 77.5% for oritavancin and vancomycin, respectively.\n\nThe use of healthcare resources and costs associated with ABSSSI are largely driven by decision-making in the emergency department. A key study by Talan et al. highlights opportunities for transition of care to the outpatient arena in selected cases. In a prospective study of 12 US emergency departments in 2008 enrolling 619 adult patients with ABSSSI, 15.2% were admitted to an inpatient medical service. Common reasons for admission were need for intravenous antibiotics in 85.1% (and the only reason in 41.5%), surgery in 24.5%, and underlying disease in 11.7% [13]. Several studies have suggested that the Charlson Comorbidity Index (CCI), Eron Severity Score, and other well-defined criteria, based on the presence of comorbid conditions and infection severity, can identify patients who may be candidates for effective and safe treatment as outpatients [14–19]. Use of such pathways for managing resource utilization in ABSSSIs can lead to cost savings through avoidable hospitalization.\n\nTreatment failure is common with ABSSSIs, which subsequently adds significant healthcare costs. Lee et al conducted a prospective, observational study among 14 primary care clinics within the South Texas Ambulatory Research Network between 2007 and 2014; the primary outcome was treatment failure within 90 days of the initial visit. Overall, 21% (22/106) patients with S. aureus ABSSSIs experienced treatment failure [20]. Treatment failure with disease recurrence is multifactorial including non-adherence to prescribed antibiotics. Eells et al found that patient adherence with oral antibiotic therapy for an ABSSSI after hospital discharge was low (57%) and associated with poor clinical outcome in 46% of patients [21]. The combination of appropriate outpatient prescribing and the long acting effect of oritavancin may also contribute to decreased rates of antimicrobial resistance (AMR) by reducing antimicrobial pressure seen during hospitalization. As noted in a survey of young physicians by Gennero et al, it is widely recognized that AMR is a growing global issue but healthcare systems are lacking in addressing it at the local level [22]. In developing our local protocol, part of the aim was providing adequate education to providers on appropriate prescribing of oritavancin to promote antimicrobial stewardship (AS). Transitioning care to the outpatient setting reduces AMR well documented to occur with extended and frequent hospitalizations; while the long acting molecule affords assurance of completion of therapy, therefore, drastically reducing compliance as a cause for treatment failure.\n\nIn this study, the option of prescribing oritavancin in the appropriate patient with cellulitis or abscess led to shorter length of stay and lower hospital cost. While aLOS was non-significantly lower for years 2017 and 2018, the first 2016 year included only 11 patients. Over the study period, the aLOS was almost half a day shorter in cohort A. The lower 90-day readmission rate observed with oritavancin is even more remarkable compared with non-oritavancin antibiotics (12.7% versus 60.7%, respectively). The use of 90-day readmission served as a conservative estimate, although a 30-day readmission rate may be more reflective of antibiotic failure. However, cost avoidance was heavily weighted towards the excess costs of readmission observed in patients who received non-oritavancin antibiotics. We cannot account for physician decisions made at the point of care regarding hospital admission of patients in either treatment cohort.\n\nOpportunities to decrease cost are invaluable to hospital administrators who observe increasing rates of ABSSSI and lack of consistent clinical management. The average length of stay prior to the advent of oritavancin utilization coupled with the allotted payment by most third-party payers decreases operating margins for hospitals. As reported by Ektare et al, hospital bed cost and average length of stay were the predominant factors in driving the total direct hospital costs for treating ABSSSI patients. In their analysis, the ability to move treatment of these patients to the outpatient setting demonstrated a potential cost savings of $13,090 to $13,473 by avoiding inpatient admission [23]. The results from this study represent a small community hospital in which Medicare is a large payer source, critical for small community hospitals. The results from this study demonstrate a benefit associated with the addition of oritavancin for the management of ABSSSI. Our findings lend further support to other non-academic community hospitals which do not serve as referral or tertiary care centers. As skin infections represent 2% of all US hospital admissions, increased use of oritavancin may represent an opportunity to recover several hundred thousand bed days for use with other patients [24].\n\nThis study has important limitations, including a retrospective methodology reliant on accurate medical record documentation and abstraction. Although categorization of diagnoses of skin infection by clinical type were made, the accuracy of these designations is unclear. Severity of illness measurements and purulence of cellulitis cases were not available which could have served to differentiate between uncomplicated and complicated ABSSSIs. While assessment of disease severity may be more variable in real-world studies than in controlled ABSSSI clinical trials, abscess and cellulitis size restricted to ≥75 cm2 is expected to be less stringently applied in this study [14]. Specific causes of antibiotic failure, such as medication adherence to oral and multi-dose therapies, could not be ascertained and antibiotic agents were not evaluated for either appropriate spectrum of in vitro activity according to confirmed microbiological cultures or appropriate dose. Therefore, we emphasize caution when interpreting these findings. Cohorts did not differ with respect to incidence of diabetes, and the use of one liter of 5% Dextrose in water required for admixture and infusion of oritavancin did not influence the selection of therapy in diabetics in this study. The failure rate and subsequent need for hospitalization in these patients reflect the ongoing observations at DeTar Healthcare System after 2018. However, future subset analyses could be valuable. The study protocol relied on medical chart abstraction to identify adverse events noted by caregivers but cannot preclude that treatment-emergent adverse events due to either oritavancin or other therapies were omitted, missed, or were deemed minor and not recorded. While diphenhydramine premedication is included in the protocol, there is no data to suggest if this practice should be adopted widely. Finally, there may be limited generalizability to other regions outside of South Texas. To our knowledge, this is the first study performed in a small community hospital comparing the impact of oritavancin against other historically accepted treatment options in patients who failed initial treatment.\n\nMore than 85% of US hospitals in 2019 are community-based, the majority of which have less than 200 beds and an average occupancy rate of 45 to 60% [25]. Our broad patient demographics present advantages to management of ABSSSIs which are not encountered in phase 3 clinical studies which often prevent a large and substantial number of patients eligible for enrollment. Real-world evidence (RWE) studies provide a bridge for validation or dispute between randomized controlled trials (RCTs) and clinical practice and filling current gaps in clinical knowledge. While RCTs provide evidence of efficacy, real-world studies produce evidence of comparative effectiveness, safety and economic performance in a naturalistic setting. Real-world studies are increasingly recognized by regulatory bodies such as the US Food and Drug Administration (FDA) [26]. Our data reflects the economic, efficacy and logistical impact of an oritavancin pathway seen by progressive reductions in average length of stay, readmission rates, and hospital costs. The results demonstrate the increased adoption of our institutional pathway in a small community hospital by healthcare providers over the 3 years of our study with realization of cumulative benefits over time.\n\nAll coauthors were responsible for data interpretation and writing of this report. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.\n\nAdditional contributions\n\nWe would like to thank Mark Redell PharmD for his contribution to this publication. The expertise he provided in regards to the oritavancin molecule was a valuable addition to our study.\n\n10.1371/journal.pone.0248129.r001\nDecision Letter 0\nDi Gennaro Francesco Academic Editor\n© 2021 Francesco Di Gennaro\n2021\nFrancesco Di Gennaro\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version0\n7 Jan 2021\n\nPONE-D-20-39053\n\nImproved Economic and Clinical Outcomes with Oritavancin Versus A Comparator Group for Treatment of Acute Bacterial Skin and Skin Structure Infections in a Community Hospital\n\nPLOS ONE\n\nDear Dr. Kimberly Saddler,\n\nThank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. 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Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n3. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: In this work Authors analyzed the economic and clinical impact of a long-acting anti-gram positive antibacterial for the treatment of ABSSSIs.\n\nTo do this, they compared 79 patients received oritavancin who had failed previous outpatient antibiotic therapy (OPAT) with 28 patients receiving other antibiotics following OPAT failure and subsequent hospitalization.\n\nThis work is well performed and interesting to read. Attached there are several comments to improve the manuscript.\n\nIntroduction:\n\nLines 101 – 110: this is an interesting point. Authors should briefly describe the reason of this increase in healthcare costs of SSTIs despite the decrease of MRSA infections\n\nMethods:\n\nAuthors use alternatively the acronyms ABSSSI and SSTI, however they refer to two different classification. I suggest defining better and clearly type of infections included in this study.\n\nResults:\n\nIn this study the costs associated to antibiotics were not evaluated. However, if possible, I suggest also to consider costs associated with comparator antibiotics.\n\nDiscussion:\n\nUse of long acting antibiotics that lead to early discharge of patients allows to reduce antimicrobial pressure in hospital setting. Reducing causes of antibiotic resistance is another important benefit of long-acting antibiotics. In my opinion this point and the need of including competencies in antibiotic use in all medical specialties should be briefly discussed (accordingly, this recent survey could be cited on this topic: “Italian young doctors' knowledge, attitudes and practices on antibiotic use and resistance: A national cross-sectional survey; J Glob Antimicrob Resist . 2020 Dec;23:167-173. doi: 10.1016/j.jgar.2020.08.022.”)\n\nReviewer #2: This article has some research value, but the scope of the topic is too large, or the scope of the research object is too small, it needs to be supplemented.The article only has the statistics data of hospitalized patients who had failed treatment.\n\n**********\n\n6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files.]\n\nWhile revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.\n\nAttachment Submitted filename: minor modifications.pdf\n\nClick here for additional data file.\n\n10.1371/journal.pone.0248129.r002\nAuthor response to Decision Letter 0\nSubmission Version1\n9 Feb 2021\n\nThank you for your review of our manuscript. Please see attached document \"Response to Reviewers\" for complete response.\n\nAttachment Submitted filename: Response to Reviewers (1).docx\n\nClick here for additional data file.\n\n10.1371/journal.pone.0248129.r003\nDecision Letter 1\nDi Gennaro Francesco Academic Editor\n© 2021 Francesco Di Gennaro\n2021\nFrancesco Di Gennaro\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version1\n22 Feb 2021\n\nImproved Economic and Clinical Outcomes with Oritavancin Versus A Comparator Group for Treatment of Acute Bacterial Skin and Skin Structure Infections in a Community Hospital\n\nPONE-D-20-39053R1\n\nDear Dr. Saddler,\n\nWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.\n\nWithin one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.\n\nAn invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.\n\nIf your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.\n\nKind regards,\n\nFrancesco Di Gennaro\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (optional):\n\ndear authors congratulations\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your \"Accept\" recommendation.\n\nReviewer #1: All comments have been addressed\n\nReviewer #2: All comments have been addressed\n\n**********\n\n2. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n6. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: (No Response)\n\nReviewer #2: Thank you for your replies and hard work on the manuscript. I accept your interpretations, and also hope your future publications will have more considerations.\n\n**********\n\n7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n10.1371/journal.pone.0248129.r004\nAcceptance letter\nDi Gennaro Francesco Academic Editor\n© 2021 Francesco Di Gennaro\n2021\nFrancesco Di Gennaro\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n25 Feb 2021\n\nPONE-D-20-39053R1\n\nImproved Economic and Clinical Outcomes with Oritavancin Versus A Comparator Group for Treatment of Acute Bacterial Skin and Skin Structure Infections in a Community Hospital\n\nDear Dr. Saddler:\n\nI'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.\n\nIf your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nIf we can help with anything else, please email us at plosone@plos.org.\n\nThank you for submitting your work to PLOS ONE and supporting open access.\n\nKind regards,\n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nDr. Francesco Di Gennaro\n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n\n1 Kaye KS , Patel DA , Stephens JM , et al . Rising United States hospital admissions for acute bacterial skin and skin structure infections: recent trends and economic impact. PLoS One. 2015;10 (11 ):e0143276. 10.1371/journal.pone.0143276 26599005\n2 Kaye KS , Petty LA , Shorr AF , Zilberberg MD . Current epidemiology, etiology, and burden of acute skin infections in the United States. Clin Infect Dis. 2019;68 (S3 ):S193–9.30957165\n3 The Patient Protection and Affordable Care Act (PPACA), Pub. L. No. 111–148, 124 Stat. 119. 2010.\n4 Miller LG , Eisenberg DF , Liu H , et al . Incidence of skin and soft tissue infections in ambulatory and inpatient settings, 2005–2010. BMC Infect Dis. 2015;15 :362. 10.1186/s12879-015-1071-0 26293161\n5 Tun K , Shurko JF , Ryan L , Lee GC . Age-based health and economic burden of skin and soft tissue infections in the United States, 2000 and 2012. PLoS One. 2018;13 (11 ):e0206893. 10.1371/journal.pone.0206893 30383858\n6 Morgan E , Hohmann S , Ridgway JP , et al . Decreasing incidence of skin and soft-tissue infections in 86 US emergency departments, 2009–2014. Clin Infect Dis. 2019;68 :453–459. 10.1093/cid/ciy509 29912305\n7 Fritz SA , Shapiro DJ , Hersh AL . National trends in incidence of purulent skin and soft tissue infections in patients presenting to ambulatory and emergency department settings, 2000–2015. Clin Infect Dis. 2020;70 :2715–2718. 10.1093/cid/ciz977 31605485\n8 Jernigan JA , Hatfield KM , Wolford H , et al . Multidrug-resistant bacterial infections in US hospitalized patients, 2012–2017. N Engl J Med. 2020;382 :1309–1319. 10.1056/NEJMoa1914433 32242356\n9 Corey GR , Kabler H , Mehra P , et al . SOLO I Investigators. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med 2014;370 :2180–90. 10.1056/NEJMoa1310422 24897083\n10 Corey GR , Good S , Jiang H , et al . SOLO II Investigators. Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study. Clin Infect Dis 2015; 60 :254–62. 10.1093/cid/ciu778 25294250\n11 Corey GR , Arhin FF , Wikler MA , et al . Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 2016; 48 :528–34. 10.1016/j.ijantimicag.2016.07.019 27665522\n12 Lodise TP , Redell M , Armstrong SO , et al . Efficacy and safety of oritavancin relative to vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSI) in the outpatient setting: results from the SOLO clinical trials. Open Forum Infect Dis. 2017;4 :ofw274. 10.1093/ofid/ofw274 28480266\n13 Talan DA , Salhi BA , Moran GJ , et al . Factors associated with decision to hospitalize emergency department patients with skin and soft tissue infection. West J Emerg Med. 2015;16 (1 ):89–97. 10.5811/westjem.2014.11.24133 25671016\n14 US Food and Drug Administration. Guidance for Industry. Acute bacterial skin and skin structure Infections: developing drugs for treatment. Silver Spring, MD: FDA; October 2013.\n15 Sulham K , LaPensee K , Fan W , Lodise TP . Severity and costs of acute bacterial skin and skin structure infections by treatment setting: an application of the Eron Classification to a real-world database. Value in Health. 2014;17 (3 ):A282.\n16 Lodise TP , Fan W , Sulham KA . Hospital admission patterns in adult patients with skin and soft tissue infections: Identification of potentially avoidable hospital admissions through a retrospective database analysis. Hosp Pract. 2015. 43 (3 ):137–43. 10.1080/21548331.2015.1076325 26224423\n17 Eron LJ , Lipsky BA , Low DE , et al . Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother. 2003;52 (Suppl 1 ):i3–17.14662806\n18 Deck DH , Jordan JM , Holland TL , et al . Single-dose oritavancin treatment of acute bacterial skin and skin structure infections: SOLO trial efficacy by Eron severity and management setting. Infect Dis Ther. 2016;5 :353–61. 10.1007/s40121-016-0119-9 27370913\n19 Lodise TP , Fan W , Sulham KA . Economic impact of oritavancin for the treatment of acute bacterial skin and skin structure infections in the emergency department or observation setting: cost savings associated with avoidable hospitalizations. Clin Ther. 2016;38 :136–48. 10.1016/j.clinthera.2015.11.014 26708118\n20 Lee GC , Hall RG , Boyd NK , et al . A prospective observational cohort study in primary care practices to identify factors associated with treatment failure in Staphylococcus aureus skin and soft tissue infections. Ann Clin Microbiol Antimicrob. 2016;15 :58. 10.1186/s12941-016-0175-8 27876059\n21 Eells SJ , Nguyen M , Jung J , et al . Relationship between adherence to oral antibiotics and postdischarge clinical outcomes among patients hospitalized with Staphylococcus aureus skin infections. Antimicrob Agents Chemother. 2016;60 (5 ):2941–8. 10.1128/AAC.02626-15 26926634\n22 Di Gennaro F , Marotta C , Amicone M , et al . Italian young doctors’ knowledge, attitudes and practices on antibiotic use and resistance: A national cross-sectional survey. Journal of Global Antimicrobial Resistance. 2020;23 :167–173. 10.1016/j.jgar.2020.08.022 32971291\n23 Ektare V , Khachatryan A , Xue M , et al . Assessing the economic value of avoiding hospital admissions by shifting the management of gramþ acute bacterial skin and skin-structure infections to an outpatient care setting. Journal of Medical Economics. 2015;1–10.\n24 Armstrong S, Liao N, Fan W, Sulham K. Admission rate and length of stay for skin infection patients in US hospitals: use of oritavancin is associated with lower rates of hospital admission and shorter length of stay. Poster 688. ASM Microbe 2018. June 7–11, 2018; Atlanta, GA.\n25 Fast Facts on U.S. Hospitals, 2019. American Hospital Association. https://www.aha.org/statistics/fast-facts-us-hospitals. Accessed June 26, 2019.\n26 FDA. Framework for FDA’s real-world evidence program. December 2018. https://www.fda.gov/media/120060/download. Accessed 31 July 2019.\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "16(3)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000038:Abscess; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002481:Cellulitis; D005260:Female; D006801:Humans; D000077427:Lipoglycopeptides; D008297:Male; D008875:Middle Aged; D010359:Patient Readmission; D012189:Retrospective Studies; D017192:Skin Diseases, Bacterial; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0248129", "pmc": null, "pmid": "33735185", "pubdate": "2021", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "32242356;29912305;24897083;25294250;25671016;26708118;26293161;14662806;27876059;27665522;26599005;26224423;30383858;30957165;31605485;26368787;26926634;28480266;32971291;27370913", "title": "Improved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital.", "title_normalized": "improved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital" }

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IMPROVED ECONOMIC AND CLINICAL OUTCOMES WITH ORITAVANCIN VERSUS A COMPARATOR GROUP FOR TREATMENT OF ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS IN A COMMUNITY HOSPITAL. PLOS ONE. 2021?1?13.", "literaturereference_normalized": "improved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210421", "receivedate": "20210421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19164069, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-MELINTA THERAPEUTICS, INC-US-MLNT-21-00030", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ORITAVANCIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "206334", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ORBACTIV" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ORITAVANCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "206334", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ABSCESS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ORBACTIV" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toe amputation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SADDLER K, ZHANG J, SUL J, PATEL P, CASTRO?LAINEZ M, STEVENS M, LOWERY E, KOSLER S, SIERRA?HOFFMAN M. IMPROVED ECONOMIC AND CLINICAL OUTCOMES WITH ORITAVANCIN VERSUS A COMPARATOR GROUP FOR TREATMENT OF ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS IN A COMMUNITY HOSPITAL. PLOS ONE. 2021?1?13.", "literaturereference_normalized": "improved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210408", "receivedate": "20210408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19108709, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-MELINTA THERAPEUTICS, INC-US-MLNT-21-00033", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ORITAVANCIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "206334", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ORBACTIV" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ORITAVANCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "206334", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ABSCESS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ORBACTIV" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wound infection staphylococcal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wound infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SADDLER K, ZHANG J, SUL J, PATEL P, CASTRO?LAINEZ M, STEVENS M, KOSLER S, LOWERY E, SIERRA?HOFFMAN M. IMPROVED ECONOMIC AND CLINICAL OUTCOMES WITH ORITAVANCIN VERSUS A COMPARATOR GROUP FOR TREATMENT OF ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS IN A COMMUNITY HOSPITAL. PLOS ONE. 2021 MAR 18?16(3):1?13.", "literaturereference_normalized": "improved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210408", "receivedate": "20210408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19110011, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "OBJECTIVE\nTo report the onset of choroidal neovascularization (CNV) following hormonal stimulation for in vitro fertilization (IVF) in a healthy young woman.\n\n\nMETHODS\nA 31-year-old woman presented with visual impairment following hormonal stimulation for IVF. Clinical history was collected and best-corrected visual acuity (BCVA), complete eye examination, optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography were -performed.\n\n\nRESULTS\nClinical history was negative with the exception of the use of medications for IVF in the previous weeks. Ocular examination revealed the presence of a CNV in the right eye, confirmed by OCT and FA, with a BCVA of 0.7 decimal units. Possible ocular and systemic diseases associated with CNV development were investigated and excluded. Treatment with 3 monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) was effective in reducing CNV size and restoring visual acuity.\n\n\nCONCLUSIONS\nThis is the first report describing the development of CNV following hormonal stimulation for IVF. The development of CNV may be associated with changes of sex hormones, cytokines, and angiogenic factor levels, including VEGF, induced by hormonal stimulation.", "affiliations": "Ophthalmology, Ospedale San Pietro Fatebenefratelli, Rome - Italy.", "authors": "Ciucci|Francesco|F|;Sacchetti|Marta|M|;Gaetano|Cristiano De|CD|;Bardocci|Antonio|A|;Lofoco|Giorgio|G|", "chemical_list": "D020533:Angiogenesis Inhibitors; D004396:Coloring Agents; D005300:Fertility Agents, Female; D043373:Follicle Stimulating Hormone, Human; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C571801:follitropin alfa; D011374:Progesterone; D007208:Indocyanine Green; D002064:Buserelin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1120-6721", "issue": "25(5)", "journal": "European journal of ophthalmology", "keywords": null, "medline_ta": "Eur J Ophthalmol", "mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D002064:Buserelin; D020256:Choroidal Neovascularization; D004396:Coloring Agents; D005260:Female; D005300:Fertility Agents, Female; D005307:Fertilization in Vitro; D005451:Fluorescein Angiography; D043373:Follicle Stimulating Hormone, Human; D006801:Humans; D007208:Indocyanine Green; D058449:Intravitreal Injections; D011374:Progesterone; D011994:Recombinant Proteins; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity", "nlm_unique_id": "9110772", "other_id": null, "pages": "e95-7", "pmc": null, "pmid": "25837641", "pubdate": "2015-07-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Choroidal neovascular membrane following hormonal stimulation for in vitro fertilization.", "title_normalized": "choroidal neovascular membrane following hormonal stimulation for in vitro fertilization" }

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{ "abstract": "Pancreatic allograft thrombosis (PAT) remains the leading cause of nonimmunologic graft failure. Here, we propose a new computed tomography (CT) grading system of PAT to identify risk factors for allograft loss and outline a management algorithm by retrospective review of consecutive pancreatic transplantations between 2009 and 2014. Triple-phase CT scans were graded independently by 2 radiologists as grade 0, no thrombosis; grade 1, peripheral thrombosis; grade 2, intermediate non-occlusive thrombosis; and grade 3, central occlusive thrombosis. Twenty-four (23.3%) of 103 recipients were diagnosed with PAT (including grade 1). Three (2.9%) grafts were lost due to portal vein thrombosis. On multivariate analysis, pancreas after simultaneous pancreas-kidney transplantation/solitary pancreatic transplantation, acute rejection, and CT findings of peripancreatic edema and/or inflammatory change were significant risk factors for PAT. Retrospective review of CT scans revealed more grade 1 and 2 thromboses than were initially reported. There was no significant difference in graft or patient survival, postoperative stay, or morbidity of recipients with grade 1 or 2 thrombosis who were or were not anticoagulated. Our data suggest that therapeutic anticoagulation is not necessary for grade 1 and 2 arterial and grade 1 venous thrombosis. The proposed grading system can assist clinicians in decision-making and provide standardized reporting for future studies.", "affiliations": "Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, UK.;Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, UK.;Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, UK.;Department of Medicine, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, UK.;Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, UK.;Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, UK.", "authors": "Hakeem|A|A|;Chen|J|J|;Iype|S|S|;Clatworthy|M R|MR|;Watson|C J E|CJE|;Godfrey|E M|EM|;Upponi|S|S|;Saeb-Parsy|K|K|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1111/ajt.14433", "fulltext": "\n==== Front\nAm J TransplantAm. J. Transplant10.1111/(ISSN)1600-6143AJTAmerican Journal of Transplantation1600-61351600-6143John Wiley and Sons Inc. Hoboken 10.1111/ajt.14433AJT14433Original ArticleOriginal ArticlesClinical SciencePancreatic allograft thrombosis: Suggestion for a CT grading system and management algorithm HAKEEM et al.Hakeem A. \n1\nChen J. \n1\nIype S. \n1\nClatworthy M. R. \n2\nWatson C. J. E. \n1\nGodfrey E. M. \n3\nUpponi S. \n3\nSaeb‐Parsy K. ks10014@cam.ac.uk \n1\n\n1 \nDepartment of Surgery\nUniversity of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation\nCambridge\nUK\n\n2 \nDepartment of Medicine\nUniversity of Cambridge and NIHR Cambridge Biomedical Research Centre, and NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation\nCambridge\nUK\n\n3 \nDepartment of Radiology\nCambridge University Hospitals NHS Foundation Trust\nCambridge\nUK\n* Correspondence\n\nKourosh Saeb‐Parsy\n\nEmail: ks10014@cam.ac.uk\n14 9 2017 1 2018 18 1 10.1111/ajt.2018.18.issue-1163 179 27 3 2017 09 7 2017 11 7 2017 © 2017 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant SurgeonsThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Pancreatic allograft thrombosis (PAT) remains the leading cause of nonimmunologic graft failure. Here, we propose a new computed tomography (CT) grading system of PAT to identify risk factors for allograft loss and outline a management algorithm by retrospective review of consecutive pancreatic transplantations between 2009 and 2014. Triple‐phase CT scans were graded independently by 2 radiologists as grade 0, no thrombosis; grade 1, peripheral thrombosis; grade 2, intermediate non‐occlusive thrombosis; and grade 3, central occlusive thrombosis. Twenty‐four (23.3%) of 103 recipients were diagnosed with PAT (including grade 1). Three (2.9%) grafts were lost due to portal vein thrombosis. On multivariate analysis, pancreas after simultaneous pancreas–kidney transplantation/solitary pancreatic transplantation, acute rejection, and CT findings of peripancreatic edema and/or inflammatory change were significant risk factors for PAT. Retrospective review of CT scans revealed more grade 1 and 2 thromboses than were initially reported. There was no significant difference in graft or patient survival, postoperative stay, or morbidity of recipients with grade 1 or 2 thrombosis who were or were not anticoagulated. Our data suggest that therapeutic anticoagulation is not necessary for grade 1 and 2 arterial and grade 1 venous thrombosis. The proposed grading system can assist clinicians in decision‐making and provide standardized reporting for future studies.\n\nThe Cambridge Pancreatic Allograft Thrombosis grading system may be used to standardize reports of thrombosis, identify patients who would benefit from therapeutic anticoagulation, provide prognostic information, and allow better comparison of reports from different centers for improved understanding and management of this common condition.\n\nclinical research/practicecoagulation and hemostasiscomplicationgraft survivalhealth services and outcomes researchpancreas/simultaneous pancreas‐kidney transplantationthrombosis and thromboembolismNational Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU)NHS Blood and Transplant (NHSBT) source-schema-version-number2.0component-idajt14433cover-dateJanuary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:11.01.2018\n\n\nHakeem \nA \n, \nChen \nJ \n, \nIype \nS \n, et al. Pancreatic allograft thrombosis: Suggestion for a CT grading system and management algorithm . Am J Transplant . 2018 ;18 :163 –179 . https://doi.org/10.1111/ajt.14433\n28719059\n==== Body\nAbbreviations\nAIHAautoimmune hemolytic anaemia\n\nBMIbody mass index\n\nCEUScontrast‐enhanced ultrasound scan\n\nCIconfidence interval\n\nCITcold ischemia time\n\nCIVcommon iliac vein\n\nCPRcardiopulmonary resuscitation\n\nCTcomputed tomography\n\nDBDdonation after brain death\n\nDCDdonation after circulatory death\n\nDVTdeep vein thrombosis\n\nEIAexternal iliac artery\n\nGIgastrointestinal\n\nINRinternational normalized ratio\n\nIPTRInternational Pancreas Transplant Registry\n\nIVCinferior vena cava\n\nLOSlength of stay\n\nMRImagnetic resonance imaging\n\nNT‐ACno thrombosis–anticoagulated\n\nNT‐NACno thrombosis–not anticoagulated\n\nORodds ratio\n\nPAKpancreas after kidney transplant\n\nPAMpancreatica arteria magna\n\nPASPKPancreas after Simultaneous Pancreas and Kidney Transplantation\n\nPEpulmonary embolism\n\nPGI2prostacyclin\n\nPIDpelvic inflammatory disease\n\nPVportal vein\n\nPVTportal vein thrombosis\n\nRBCred blood cell\n\nSAsplenic artery\n\nSBOsmall bowel obstruction\n\nSMAsuperior mesenteric artery\n\nSMVsuperior mesenteric vein\n\nSPKsimultaneous pancreas–kidney transplant\n\nSPTsolitary pancreas transplantation\n\nSVsplenic vein\n\nT‐ACthrombosis‐anticoagulated\n\nT‐NACthrombosis–not anticoagulated\n\nUSSultrasound scan\n\nVACvacuum therapy\n\nVREvancomycin‐resistant Enterococcus\n\n\nWITwarm ischemia time\n\n1 INTRODUCTION\nPancreatic allograft thrombosis (PAT) is a potentially catastrophic complication and remains one of the leading causes of nonimmunologic allograft loss.1, 2 The incidence reported in the literature ranges from 1% to 40% and accounts for 29% of grafts lost within the first 6 months after transplantation.3, 4 Reported risk factors for PAT include donor age, body mass index (BMI), atherosclerosis, donation after circulatory death (DCD), death from cerebrovascular accident, and premortem severe hypotension.5, 6 Recipient risk factors include vascular disease, thrombophilic state, history of previous thrombotic events, and hypotension in the intraoperative or postoperative period.3 Other significant risk factors include type of preservation solution (reduced risk with UW), prolonged cold ischemia time (CIT), and technical factors during procurement and implantation.2, 7 Rate of graft loss secondary to PAT has been reported as 4% to 8% after simultaneous pancreas–kidney transplantation (SPK) and 10% to 12% after solitary pancreatic transplantation (SPT).8\n\n\nImaging plays a vital role in the evaluation of the transplanted pancreas. The modalities commonly used are Doppler ultrasound (USS), contrast‐enhanced ultrasound (CEUS), computed tomography (CT), CT angiography, magnetic resonance imaging (MRI), and MR angiography.9, 10, 11, 12 Vascular evaluation on imaging after pancreas transplantation is challenging due to the multiple anastomoses (4 or more), tortuous nature of graft vessels, and parenchymal edema related to surgery or pancreatitis. Overlying bowel gas may make ultrasound imaging suboptimal.13, 14, 15\n\n\nAllograft thrombosis may affect arteries or veins, or sometimes both. Although there is no consensus on the classification or reporting of PAT, it is generally categorized as either complete or partial.16 Complete occlusion usually results in graft loss, unless thrombectomy or thrombolysis are undertaken soon after onset.17, 18, 19, 20 Conversely, there is some evidence to suggest a higher likelihood of pancreas allograft salvage with anticoagulation alone after partial thrombosis, although other interventions are occasionally required.21, 22 Outcomes after partial or complete occlusion of either splenic or superior mesenteric veins are better than complete occlusion of the main portal vein.23 Collateral arterial circulation may prevent infarction in cases of partial and occasionally complete PAT.24\n\n\nThere is currently no consensus on the optimal strategy for the prevention and management of PAT. Postoperative prophylaxis using low‐dose heparin infusion has been shown to reduce the thrombosis rate, but with a consequent increase in the number of bleeding events and need for repeat laparotomy.25, 26, 27\n\n\nThe aims of the current study were to analyze the incidence and management of PAT in a single center and to evaluate risk factors for PAT. We also propose a CT grading system of PAT and a management algorithm based on the grade of thrombosis.\n\n2 MATERIALS AND METHODS\nAfter institutional review board approval, a retrospective review was carried out of consecutive pancreas allograft transplants performed at our center between January 2009 and April 2014. Data regarding donor and recipient demographics, operative details, and outcomes were collected from a prospectively maintained electronic database. The outcomes reviewed were the incidence of PAT, graft and patient survival, postoperative complications, and length of postoperative hospital stay. Patients had workup for prothrombotic tendencies if a prior thrombotic event was identified.\n\nThe incidence, risk factors, and consequences of PAT were examined through the use of 2 methods. The first was a retrospective review of clinical data as recorded in the database during the original patient care episode, including incidence of thrombosis and graft and recipient outcomes (labeled “original diagnosis”). In the second stage, the first postoperative triple‐phase CT of the abdomen and pelvis (CTAP) of all pancreas transplant recipients were independently reviewed by 2 senior radiologists who were blinded to the initial CT report and the patient outcomes. Discrepancies were resolved by consensus. This “retrospective diagnosis” was used to definitively grade the thromboses and to formulate a management algorithm. The pancreatic allograft arteries and veins were graded as per the “new” grading system (Table 1). Representative cross‐sectional images demonstrating the different grades of thrombosis are shown in Figure 1.\n\nTable 1 Pancreatic allograft thrombosis grading system\n\nGrade 0\tNo thrombosis\t\nGrade 1\tPeripheral thrombosisa\n\t\nGrade 2\tIntermediate nonocclusive thrombosisb\n,\nc\n\t\nGrade 3\tCentral occlusive thrombosis\t\nThe allograft arteries and veins on triple‐phase CT scans were graded independently by 2 radiologists.\n\na Grade 1 thrombosis: Thrombus lies in the very distal vessel at the transected margin of the superior mesenteric vein (SMV)/splenic vein (SV) or superior mesenteric artery (SMA)/SA and lies in a single branch only, without encroachment into the main trunk of the vessel.\n\nb Grade 2 venous: Thrombus extending into parenchymal vessels/main trunk of the SMV or SV to the SMV/SV confluence but not into the portal vein.\n\nc Grade 2 arterial: Thrombus extending into the main trunk of the SMA/SA to the “Y” graft but not into the Y graft.\n\nJohn Wiley & Sons, LtdFigure 1 Representative cross‐sectional images demonstrating grades 1‐3 of venous and arterial pancreas allograft thrombosis. IMAGE 1: Grade 1 venous thrombus: axial image of a portal phase study demonstrating non‐occlusive thrombus (arrow) within an SMV tributary within fat, at the transected margin of the graft. IMAGE 2: Grade 2 venous thrombus: coronal reformatted image of a portal phase study demonstrating non‐occlusive thrombus extending along the splenic vein within the body of graft pancreas (arrow). Adjacent patent splenic artery (short arrow). IMAGE 3: Grade 3 venous thrombus: unenhanced axial image demonstrating acute hyper‐dense thrombus in an expanded SMV. IMAGE 4: Grade 3 venous thrombus: portal phase axial image demonstrating thrombus in the SMV extending into the IVC (arrow). This component is seen as hypo‐dense within otherwise opacified cava. IMAGE 5: Grade 1 arterial thrombus: axial arterial phase image demonstrating minimal thrombus in the distal splenic artery (arrow). IMAGE 6: Grade 2 arterial thrombus: axial arterial phase image demonstrating thrombus extending into the mid SMA. IMAGE 7: Grade 3 arterial thrombus: (image not from current series; obtained from a library) arterial phase coronal reformatted image demonstrating acute occlusive thrombus expanding the Y graft and SMA (arrow). Enhancement of the residual patent proximal Y graft stump (short arrow)\n\nAcute rejection was defined as rejection on kidney or pancreas biopsy. Graft pancreatitis was defined as peripancreatic edema and/or inflammatory change on CT scanning.\n\n2.1 Operative technique\nBack‐bench preparation of the pancreatic graft involved removal of spleen, ligation of all the distal mesenteric vessels, and anastomosis of a donor iliac Y‐graft to the graft superior mesenteric and splenic arteries. The pancreas was placed in the right iliac fossa intraperitoneally through a midline incision, with anastomosis of the portal vein to the inferior vena cava and the donor iliac artery Y‐graft to the recipient common iliac artery. Enteric drainage was via a Roux‐en‐Y duodenoenterostomy. Feeding jejunostomy was inserted in most cases, and prophylactic appendicectomy and cholecystectomy (the latter, if preoperative USS demonstrated sludge/gallstones) were performed. All recipients were started on intravenous epoprostenol (Flolan®) 4.0 ng/kg/min immediately after reperfusion and continued for a period of 5 days or discontinued earlier in case of hemodynamic instability or bleeding. Those patients who were not taking aspirin 75 mg once daily were started on it at discharge or earlier if platelet count was greater than 500 × 109/L. The standard immunosuppression protocol was induction with alemtuzumab (CD52 monoclonal antibody; Campath 1H®) 30 mg subcutaneously. Maintenance immunosuppression was steroid free with tacrolimus 0.05 mg/kg twice daily started on the first postoperative day (trough concentration 8‐12 ng/mL) and mycophenolate mofetil started at 500 mg twice daily on postoperative day 7.\n\n2.2 CT scanning\nTriple‐phase CTAP was performed using 64‐ or 256‐section CT systems (Siemen AG Healthcare, Camberley, Surrey, UK). Unenhanced imaging of the abdomen was performed to localize the pancreatic graft, followed by early arterial phase imaging of the pancreatic and renal grafts and portal phase imaging of the abdomen and pelvis. We administered 100 mL of iopamidol nonionic contrast (Niopam 300; Bracco, High Wycombe, Bucks, UK) at a rate of 3 mL per second. Images were reconstructed and reviewed at 2‐mm section thickness on the picture archive and communication system (PACS GE). The triple‐phase CT scans were performed for clinical/biochemical reasons, and no routine or protocol scans were performed. Intravenous fluid rehydration was considered in recipients with a raised creatinine of greater than 150 μmol/L. Routine USS is performed to evaluate the renal allograft; routine USS of the pancreatic graft is not performed in our unit.\n\n2.3 Statistical analysis\nCategorical variables are expressed as frequency (%), and continuous variables as median (range). Categorical variables were analyzed by use of Fisher's exact or χ2 test, and continuous variables were analyzed by unpaired student t test, Mann‐Whitney U test, or other nonparametric tests. Bonferroni correction was used for multiple comparisons. The variables significant on univariate analysis were subjected to multivariate logistic regression analysis. Kaplan‐Meier survival curves were studied by using log‐rank statistics (SPSS 20.0; SPSS Institute, Chicago, IL, USA).\n\n3 RESULTS\nOne hundred three consecutive pancreatic transplantations were performed during the study period. The mean follow‐up period was 53.7 months (range 21.7‐83.3 months). Twenty‐four (23.3%) recipients were diagnosed with PAT (original diagnosis), of whom 4 patients had this diagnosis confirmed on laparotomy, while 1 patient had a negative laparotomy. The thromboses were initially reported as arterial (n = 11, 10.7%), venous (n = 9, 8.7%) or both (n = 4, 3.9%). Of the arterial thromboses, 14 were grade 1 or 2 and 1 was grade 3. Of the venous thromboses, 8 were grade 1 or 2 and 5 were grade 3. Three patients required intraoperative revision of anastomosis for thrombosis during the index transplant operation, 2 of whom developed postoperative thrombosis and hence were included in the thrombosis group.\n\nThe patients who had thrombosis as their original diagnosis (n = 24, 23.3%) were compared with those who did not have thrombosis (n = 79, 76.7%) (Tables 2, 3, 4, 5).\n\nTable 2 Donor characteristics\n\n\tThrombosis group (n = 24)\tNo‐thrombosis group (n = 79)\t\nP valuea\n\t\nAge (y)\t41 (12‐59)\t37 (7‐64)\t.548\t\nGender (male)\t15 (62.5%)\t34 (43.0%)\t.107\t\nWhite ethnicity\t21 (87.5%)\t71 (90.0%)\t.715\t\nBody mass index (kg/m2)\t23 (15‐28)\t23 (17‐33)\t.947\t\nWeight (kg)\t70 (33‐90)\t70 (44‐96)\t.960\t\nDonor type (DBD)\t19 (79.2%)\t50 (63.3%)\t.215\t\nDonor cause of death\t\nTraumatic brain injury\t9 (37.5%)\t21 (26.6%)\t.315\t\nIntracranial hemorrhage\t7 (29.2%)\t26 (32.9%)\t.807\t\nAnoxic brain damage\t5 (20.8%)\t15 (18.9%)\t1.000\t\nCerebral infarct\t2 (8.3%)\t2 (2.5%)\t.231\t\nCentral nervous system infection\t1 (4.2%)\t4 (5.1%)\t1.000\t\nBrain tumor\t0 (0.0%)\t5 (6.3%)\t.588\t\nOther causes (pneumonia, sepsis)\t0 (0.0%)\t6 (7.7%)\t.332\t\nHemoglobin (g/L)\t117 (74‐160)\t117 (63‐161)\t.629\t\nPlatelets (×109/L)\t194 (69‐303)\t197 (7‐707)\t.718\t\nSerum amylase (units/L)\t58 (8‐1075)\t45 (6‐338)\t.721\t\nSmoking history (yes)\t13 (54.2%)\t42 (53.2%)\t1.000\t\nInotrope use at referral (yes)\t20 (83.3%)\t60 (75.9%)\t.580\t\nPrevious thrombotic events\t1 (4.2%) [DVT]\t0 (0.0%)\t.262\t\nAnti‐inflammatory drug use\t1 (4.2%)\t0 (0.0%)\t.262\t\nDonor demographics were similar in the thrombosis and no‐thrombosis groups. Continuous variables are expressed as median (range) and categorical variables as frequencies (percentages).\n\nDVT, deep vein thrombosis.\n\na \nP value considered to be significant if <.025 (Bonferroni corrected 0.05/2 = 0.025).\n\nJohn Wiley & Sons, LtdTable 3 Recipient characteristics\n\n\tThrombosis group (n = 24)\tNo‐thrombosis group (n = 79)\t\nP value*\t\nAge (y)\t43 (32‐51)\t44 (24‐58)\t.468\t\nGender (male)\t17 (70.8%)\t47 (59.5%)\t.348\t\nBody mass index (kg/m2)\t25 (19‐30)\t26 (18‐30)\t.691\t\nWeight (kg)\t73 (56‐94)\t70 (45‐102)\t.402\t\nDialysis type\t\nPredialysis\t9 (37.5%)\t35 (44.3%)\t.641\t\nPeritoneal dialysis\t2 (8.3%)\t15 (19.0%)\t.347\t\nHemodialysis\t12 (50.0%)\t31 (36.7%)\t.357\t\nHemodialysis/peritoneal dialysis\t1 (4.2%)\t0 (0.0%)\t.233\t\nDuration of dialysis (mo)\t10.5 (0‐154)\t5 (0‐114)\t.343\t\nTotal HLA‐A, ‐B, ‐DR mismatches\t\n0‐1\t0 (0.0%)\t2 (2.6%)\t1.000\t\n2‐4\t16 (66.7%)\t49 (62.0%)\t.810\t\n5‐6\t8 (33.3%)\t28 (35.4%)\t1.000\t\nPrevious myocardial infarction\t5 (20.8%)\t16 (20.2%)\t1.000\t\nPrevious thrombotic events\t\n3 (12.5%)\n\n[DVTs 2; pancreas graft venous thrombosis 1]\n\t\n5 (6.3%)\n\n[DVT 3; PE 2]\n\t.385\t\nHistory of hypercoagulability\t2 (8.3%)\t8 (10.1%)\t1.000\t\nAnti‐inflammatory drug use\t1 (4.2%)\t5 (6.3%)\t1.000\t\nPreoperative hemoglobin\t121 (84‐154)\t113 (79‐150)\t.065\t\nPreoperative platelets\t242 (135‐429)\t236 (110‐605)\t.823\t\nPreoperative urea\t13.5 (5.9‐31.0)\t19.0 (5.3‐42.0)\t.311\t\nPreoperative creatinine\t485 (98‐981)\t499 (175‐1142)\t.823\t\nPrevious failed transplants\t\n3 (12.5%)\n\n[all SPKs]\n\t\n4 (5.1%)\n\n[2 SPK and 2 kidney alone transplants]\n\t.349\t\nContinuous variables are expressed as median (ranges) and categorical variables as frequencies (percentages).\n\nDVT, deep vein thrombosis; PE, pulmonary embolism; SPK, simultaneous pancreas–kidney transplant.\n\nJohn Wiley & Sons, LtdTable 4 Operative characteristics\n\n\tThrombosis group (n = 24)\tNo‐thrombosis group (n = 79)\t\nP valueb\n\t\nYear of transplantation\t\n2009\t2 (8.3%)\t17 (21.5%)\t\t\n2010\t8 (33.3%)\t22 (27.8%)\t1.000\t\n2011\t1 (4.2%)\t13 (16.4%)\t.100\t\n2012\t3 (12.5%)\t9 (11.4%)\t1.000\t\n2013\t8 (33.3%)\t15 (19.0%)\t.280\t\n2014\t2 (8.3%)\t3 (3.8%)\t.602\t\nOrgan transplanted\t\nSPK\t18 (75.0%)\t78 (98.7%)\t\n<.001\n\t\nPASPK/PAK\t4 (25.0%) [3 PASPK and 1 PAK]\t1 (1.3%) [PASPK]\t–\t\nPancreas artery reconstruction\t\nDonor Y‐graft (SMA and SA)\t20 (83.3%)\t75 (95.0%)\t.083\t\nDonor Y‐graft plus PAM anastomosis\t\n2 (8.3%)\n\n[onto Y‐graft; using donor splenic artery segment]\n\t2 (2.5%)\t.231\t\nDonor Y‐graft (aberrant artery from coeliac. SMA and coeliac onto Y‐graft)\t1 (4.2%)\t0 (0.0%)\t.233\t\nNo donor Y‐graft\t\n1 (4.2%)\n\n[Splenic onto SMA]\n\t\n2 (2.5%)\n\n[donor coeliac artery from SMA, SMA and SA onto EIA and end‐side anastomosis]\n\t.553\t\nPancreas PV reconstruction (yes)\t1 (4.2%)\t0 (0.0%)\t.233\t\nArterial conduit implant site\t\nAorta\t0 (0.0%)\t1 (1.3%)\t1.000\t\nCommon iliac artery\t22 (91.7%)\t56 (70.8%)\t.055\t\nExternal iliac artery\t2 (8.3%)\t21 (26.6%)\t.091\t\nInternal iliac artery\t0 (0.0%)\t1 (1.3%)\t1.000\t\nPortal vein implant site\t\nIVC\t23 (95.8%)\t78 (98.7%)\t.413\t\nCommon iliac vein\t1 (4.2%) [right CIV]\t0 (0.0%)\t.233\t\nExternal iliac vein\t0 (0.0%)\t1 (0.0%)\t1.000\t\nIntraoperative thrombosis requiring revision of anastomosis\t\n2 (8.3%)\n\n[portal vein anastomosis]\n\t\n1 (1.3%)\n\n[arterial anastomosis]\n\t.135\t\nDonor WIT for DCD organs (min)\t12 (7‐13)\t13 (3‐134)\t.104\t\nRecipient WIT (min)\t40 (25‐79)\t37 (19‐57)\t.103\t\nCold ischemia time (CIT) (min)\t608 (423‐817)\t583 (271‐895)\t.393\t\nCIT‐DBD (min)a\n\t624 (423‐805) [19]\t599 (271‐895) [50]\t.400\t\nCIT‐DCD (min)a\n\t577 (455‐817) [5]\t537 (297‐773) [29)\t.524\t\nIntraoperative blood transfusion\t7 (29.2%)\t23 (29.1%)\t.588\t\nContinuous variables are expressed as median (range) and categorical variables as frequencies (percentages).\n\nPancreas after SPK or pancreas after kidney (PASPK/PAK) was the only significant risk factor for allograft thrombosis.\n\nCIT, cold ischemia time; CIV, common iliac vein; DCD, donation after circulatory death; EIA, external iliac artery; IVC, inferior vena cava; PAK, pancreas after kidney transplant; PAM, pancreatica arteria magna; PV, portal vein; SA, splenic artery; SMA, superior mesenteric artery; SPK, simultaneous pancreas–kidney transplant; WIT, warm ischemia time.\n\na Number of patients given in brackets.\n\nb \nP value considered to be significant if <.025 (Bonferroni corrected 0.05/2 = 0.025). P values that are significant are highlighted in bold.\n\nJohn Wiley & Sons, LtdTable 5 Recipient outcomes\n\n\tThrombosis group (n = 24)\tNo‐thrombosis group (n = 79)\t\nP value*\n\t\nNumber of RBC units transfused (intraoperative plus postoperative)\t4 (2‐7)\t3 (1‐9)\t.513\t\nPeak serum amylase (units/L) [within 3 days postoperative]\t128 (8‐832)\t134 (3‐512)\t.823\t\nTime of thrombosis diagnosis after transplantation (days)\t5 (0‐120)\tNot applicable\t–\t\nTherapeutic anticoagulation posttransplantation\t24 (100%)\tNot applicable\t–\t\nSurgical reexploration for thrombosis\t\n5 (20.8%)\n\n(1 arterial, 3 venous, and 1 arterial and venous thrombosis)\n\tNot applicable\t–\t\nSurgical reexploration for bleeding\t\n8 (33.3%)\n\n[3 preanticoagulation and 5 postanticoagulation; 1 patient had 2 explorations postanticoagulation]\n\t\n12 (15.2%)\n\n[1 patient had 2 explorations]\n\t.074\t\nLength of postoperative stay (days)\t21 (10‐57)\t15 (6‐305)\t\n.001\n\t\nAcute rejection\t8 (33.3%)\t7 (8.9%)\t\n.006\n\t\nPeripancreatic edema and/or inflammatory changes on CT\t12 (50.0%)\t11 (13.9%)\t\n<.001\n\t\nIndication for first postoperative CT\t\nHyperglycemia\t10 (41.7%)\t22 (21.0%)\t.216\t\nSuspected bleeding\t5 (20.8%)\t14 (17.7%)\t.767\t\nAbdominal pain\t3 (12.5%)\t6 (4.8%)\t.432\t\nAbdominal distention\t1 (4.1%)\t3 (4.8%)\t1.000\t\nSepsis\t3 (12.5%)\t17 (22.6%)\t.393\t\nIncreasing amylase/lipase\t0 (0.0%)\t6 (6.5%)\t.331\t\nIncreasing drain amylase\t0 (0.0%)\t1 (1.6%)\t1.000\t\nNumber of postoperative days for first CT (days)\t5 (1‐41)\t5 (0‐632)\t.862\t\nTotal number of CT scans during the study period\t4 (0‐15)\t2 (0‐18)\t\n.003\n\t\nPostoperative complications (30‐day)\t13 Patients/21 complications\t31 Patients/39 complications\t.241\t\nWound infection\t3\t3\t\t\nPerinephric collection – USS drainage\t1\t3\t\t\nAbdominal collection – USS drainage\t1\t2\t\t\nGraft pancreatitis\t1\t1\t\t\nPneumonia\t2\t6\t\t\nVRE bacteremia\t1\t0\t\t\nRelaparotomy for SBO\t1\t0\t\t\nRelaparotomy for SB ischemia\t0\t1\t\t\nRelaparotomy for internal hernia\t0\t1\t\t\nRelaparotomy for GI bleed\t0\t1\t\t\nLine‐related sepsis\t3\t2\t\t\nWound dehiscence (VAC therapy)\t1\t0\t\t\nWound dehiscence (skin graft/VAC)\t0\t1\t\t\nComplete wound dehiscence (repaired)\t0\t1\t\t\nGraft pancreatectomy\t3\t0\t\t\nGraft nephrectomy\t1\t0\t\t\n\nClostridium difficle infection\t1\t2\t\t\nLeft brachial plexus neuralgia\t1\t0\t\t\nUrinary tract infection\t0\t7\t\t\nPulmonary embolism\t0\t1\t\t\nCardiac arrest needing CPR\t0\t1\t\t\nLaparotomy for pneumatosis coli\t0\t1\t\t\nSpinal cord infarct – paraplegia\t0\t1\t\t\nProstatic abscess drained\t0\t1\t\t\nAbdominal compartment syndrome\t0\t1\t\t\nDonor duodenum bleeding embolized\t0\t1\t\t\nReactivation of PID (tubo‐ovarian abscess)\t0\t1\t\t\nRadial artery thrombosis secondary to indwelling catheter\t1\t0\t\t\nRenal allograft outcome – creatinine at the end of study follow‐up (μmol/L)\t111 (50‐353)\t99 (67‐342)\t.605\t\nGraft loss\t\n6 (25.0%)\n\n[3 venous thrombosis, 1 pancreatitis with abscess formation and 2 chronic rejection]\n\t\n3 (3.8%)\n\n[1 chronic rejection, 1 graft vasculopathy, 1 immunological recurrence of type 1diabetes mellitus]\n\t\n<.0001\n**\n\t\nPatient death\t\n2 (8.3%)\n\n[1 Unexplained sudden cardiac event, 1 unknown cause]\n\t\n4 (5.1%)\n\n[1 Ischemic small bowel, 1 gastric adenocarcinoma, 1 metastatic esophageal cancer, and 1 AIHA]\n\t.436**\n\t\nContinuous variables are expressed as median (range) and categorical variables as frequencies (percentages).\n\nAIHA, autoimmune hemolytic anaemia; CPR, cardiopulmonary resuscitation; CT, computed tomography; GI, gastrointestinal; PE, pulmonary embolism; PID, pelvic inflammatory disease; PV, portal vein; RBC, red blood cell; SBO, small bowel obstruction; USS, ultrasound scan; VAC, vacuum therapy; VRE, vancomycin‐resistant Enterococcus.\n\n*P value considered to be significant if <.025 (Bonferroni corrected 0.05/2 = 0.025). P values that are significant are highlighted in bold.\n\n**Log‐rank (Mantel‐Cox) P value from survival analysis.\n\nJohn Wiley & Sons, Ltd3.1 Donor characteristics\nThere was no difference between the 2 groups in terms of donor age, sex, ethnicity, weight, and BMI (Table 2). There were numerically more donation after brainstem death (DBD) donors in the thrombosis group (n = 19, 79.2%) compared with the no‐thrombosis group (n = 50, 63.3%), but this was not statistically significant (P = .107).\n\n3.2 Recipient characteristics\nThere was no difference between the 2 groups in terms of recipient age, sex, weight, BMI, or previous thrombotic events (Table 3). Three (12.5%) patients in the thrombosis group had previous failed transplants (all SPK pancreases: 2 failed due to the recurrence of diabetes and 1 due to venous thrombosis) in comparison to 4 patients (5.1%) in the no‐thrombosis group (2 SPKs [lost due to venous thrombosis and chronic rejection] and 2 kidney‐alone transplantations) (P = .349).\n\n3.3 Operative characteristics\nIn total, 4 (80%) of 5 pancreas after kidney or SPK (PAK/PASPK) transplants had thrombosis post‐operatively (P < .001) (Table 4). Only 1 recipient had portal vein reconstruction at the time of transplantation using an 8‐mm extension graft; he subsequently developed portal venous thrombosis. Two (8.3%) patients in the thrombosis group had intraoperative thrombosis, and the portal vein anastomoses were redone, in comparison to 1 patient (1.3%) in the no‐thrombosis group in whom the arterial anastomosis was redone (P = .135).\n\n3.4 Recipient outcomes\nRecipient outcomes for the 2 groups are shown in Table 5. The retrospective grading of CTs in patients with the original diagnosis of thrombosis were arterial thrombosis – grade 1 (n = 10), grade 2 (n = 4) and grade 3 (n = 1); and venous thrombosis – grade 1 (n = 5), grade 2 (n = 3) and grade 3 (n = 4). The median time of thrombosis diagnosis after transplantation was 5 days (range 0‐120 days). Of the 24 patients with an original diagnosis of thrombosis, 23 had a CT‐based diagnosis and 1 patient underwent surgical exploration without a CT scan. This patient, who was noted to be at high risk of venous thrombosis at the initial implant surgery and was anticoagulated in the immediate postoperative period, was reexplored on postoperative day 1 with removal of splenic vein thrombus. With continuing hyperglycemia and worsening lactate, the patient was reexplored again at 48 hours posttransplantation, and graft pancreatectomy was performed.\n\nAll patients with an original diagnosis of thrombosis were therapeutically anticoagulated with dalteparin (140 units/kg/day split into 2 doses at 12‐hour interval) in the first instance followed by warfarin for a period of 3 months (target INR 2‐2.5). Patients who underwent reexploration were anticoagulated after exploration surgery, unless graft pancreatectomy (3 patients) was performed.\n\nThere were no contrast‐induced allergic reactions in our study cohort. Eighty‐one patients had at least 1 postoperative CT during the study period. Serial creatinine results were available for 67 of these patients. Twelve patients had an acute rise in creatinine after CT scans, in keeping with contrast‐induced acute kidney injury (CI AKI), although 7 patients were receiving dialysis at the time. An alternative possible explanation for the rise in creatinine was identified in all 5 patients: 1 patient was diagnosed with rejection, 1 with hemorrhage, 1 with renal arterial flow abnormality on USS, and 2 with abdominal pain ± pyrexia. Renal function recovered in all 12 patients with rehydration.\n\n3.4.1 Arterial thrombosis\nOne patient with grade 1 arterial thrombosis and extrinsic compression of the portal vein on CT was reexplored and no thrombus was seen within the artery, but there was severe pancreatitis of the allograft. The patient subsequently had a graft pancreatectomy performed on postoperative day 46 due to abscess formation and severe pancreatitis. One other patient with grade 1 arterial thrombosis (with grade 3 PVT) was reexplored, and the PV thrombus was removed. The graft failed on postoperative day 144 due to chronic rejection (biopsy proven). All other patients with arterial thrombosis (including grade 2 [n = 4] and grade 3 [n = 1]) were anticoagulated and had functioning grafts at the end of study follow‐up. The grade 3 arterial thrombosis patient's CT scan on retrospective review was reported as no thrombosis and only short‐segment stricture of splenic artery.\n\n3.4.2 Venous thrombosis\nAll patients with grade 1 (n = 5) venous thrombosis were anticoagulated and had functioning grafts at the end of study follow‐up. The only patient who had a PV extension graft had a CT diagnosis of grade 2 venous thrombosis on postoperative day 5. Reexploration and thrombectomy did not improve graft perfusion, and pancreatectomy was performed. Another patient with grade 2 venous thrombosis was reexplored on postoperative day 1 and portal vein thrombus was removed; the graft was functioning at the end of study follow‐up. One other patient with grade 3 venous thrombosis on CT scanning on postoperative day 3 was managed with anticoagulation initially but was reexplored on day 9 due to hemorrhage and the graft was subsequently removed on day 11 due to severe hemorrhage and PVT. All other patients with grade 2 (n = 1) and 3 (n = 2) venous thrombosis were managed with anticoagulation and had a functioning graft at the end of study follow‐up.\n\n3.4.3 Postoperative complications and length of hospital stay\nEight (33.3%) patients in the thrombosis group were reexplored for bleeding (3 preanticoagulation and 5 postanticoagulation patients), whereas 12 (15.2%) were reexplored for bleeding in the control (no thrombosis) group (P = .074). There were 21 early (within 30 days) complications in 13 patients in the thrombosis group and 39 complications in 31 patients in the control group (P = .241) (Table 5). The median length of postoperative stay (21 days vs 15 days; P = .001), the number of acute rejection episodes (8 [33.3%] vs 7 [8.9%]; P = .006), and the likelihood of CT finding of pancreatitis (12 [50.0%] vs 11 [13.9%]; P < .001) were significantly higher in the thrombosis group in comparison to the no‐thrombosis group (Table 5).\n\n3.4.4 Risk factors for PAT\nOn multivariate analysis, PASPK/PAK transplant (odds ratio [OR] 1.09, confidence interval [CI] 1.01‐0.97, P = .047), acute rejection (OR 1.25, CI 1.07‐1.90, P = .034), and CT finding of pancreatitis (OR 1.23, CI 1.08‐1.72, P = .011) were risk factors for PAT (Table 6). The risk of vascular thrombosis was 9% higher with PASPK/PAK transplant in comparison to SPK transplant, 25% higher when there was acute rejection (although most cases of thrombosis were diagnoses early and before the diagnosis of rejection), and 23% higher when there were CT findings of allograft pancreatitis.\n\nTable 6 Risk factors for allograft thrombosis\n\n\tThrombosis group (n = 24)\tNo‐thrombosis group (n = 79)\tMultivariate analysisa\n\t\n95% CI\t\nP value\t\nOrgan transplanted\t\nSPK\t18 (75.0%)\t78 (98.7%)\t0.01‐0.97\t\n.047\n\t\nPASPK/PAK\t4 (25.0%)\t1 (1.3%)\t\t\t\nAcute rejection\t8 (33.3%)\t7 (8.9%)\t0.07‐0.90\t\n.034\n\t\nPeripancreatic edema and/or inflammatory changes on CT\t12 (50.0%)\t11 (13.9%)\t0.08‐0.72\t\n.011\n\t\nThe risk of vascular thrombosis was 9% higher with PASPK/PAK transplant in comparison to SPK transplant, 25% higher when there was acute rejection, and 23% higher when there were CT findings of allograft pancreatitis. P values that are significant are highlighted in bold.\n\nCI, confidence interval; CT, computed tomography; OR, odds ratio; PAK, pancreas after kidney transplant; SPK, simultaneous pancreas–kidney transplant.\n\na Logistic regression analysis.\n\nJohn Wiley & Sons, Ltd3.4.5 Graft and patient survival\nThere were 6 (25.0%) graft losses in the thrombosis group with 3 grafts lost within 30 days due to portal vein thrombosis resulting in graft pancreatectomy on days 2, 5, and 11. The other 3 graft losses were due to severe pancreatitis with abscess formation in 1 patient and biopsy‐proved chronic rejection in 2 patients. There were 3 (3.8%) graft losses in the control group, 2 due to chronic rejection and 1 due to recurrence of “autoimmune” diabetes mellitus (Table 5). The 1‐, 3‐, and 5‐year death‐censored graft survival for thrombosis and no‐thrombosis groups were 75%, 75%, and 75% vs 100%, 90%, and 90%, respectively (log‐rank P < .0001) (Figure 2). There was no difference in patient survival between the 2 groups (1‐, 3‐, and 5‐year rates were 98%, 96%, and 94% in each group) (Figure 3). None of the patient deaths in the study groups were directly related to PAT (Table 5).\n\nFigure 2 Death‐censored graft survival. Graft survival was significantly inferior in the thrombosis group compared to controls. All graft losses in this group occurred within two weeks of transplantation\n\nFigure 3 Patient survival. There was no difference in patient survival between thrombosis and no‐thrombosis groups\n\n3.4.6 Risk factors for graft loss\nOn univariate analysis, recipient anastomosis time (48 ± 11 minutes in graft loss group vs 38 ± 9 minutes in control group; P = .001) and PAT (66.7% in graft loss group vs 19.1% in control group; P = .005) were statistically significant predictors of graft loss. On multivariate analysis, PAT was the only significant risk factor for graft loss (OR 1.17, 95% CI 1.04‐1.83, P = .028).\n\n3.5 Independent retrospective review of CT scans\nDuring the study period, 81 CT examinations were reported during the index admission. In total, 16 different senior radiologists reported the CT scans over the study period. On independent review of the CTs, previously unreported thromboses (additional thromboses) were identified by both review radiologists. In consensus, the review radiologists identified a total of 28 new thromboses: 17 grade 1 arterial, 2 grade 2 arterial, 5 grade 1 venous, and 4 grade 2 venous thromboses. No new grade 3 arterial or venous thromboses were identified on review (Table 7). Four patients who were initially reported to have thrombosis were subsequently reviewed as having no thrombosis. The thrombosis grade for these 4 patients on initial reports were grade 1 arterial, grade 3 arterial, and 2 patients with grade 1 venous.\n\nTable 7 Retrospective review of CT scans for allograft thrombosis\n\n\tInitial CT report\tRadiologist 1\tRadiologist 2\tConsensus‐ Radiologists 1 and 2\tConsensus vs initial CT report (additional “new thrombosis”)\t\nNo arterial or venous thrombosis\t58/81\t37/81\t33/81\t28/81\tN/A\t\nArterial thrombosis\t\nGrade 0 (no thrombosis)\t66\t48\t44\t38\tN/A\t\nGrade 1 (peripheral)\t10\t30\t33\t23\t17\t\nGrade 2 (intermediate nonocclusive)\t4\t3\t4\t3\t2\t\nGrade 3 (central occlusive)\t1\t0\t0\t0\t0\t\nVenous thrombosis\t\nGrade 0 (no thrombosis)\t69\t61\t60\t57\tN/A\t\nGrade 1 (peripheral)\t5\t9\t11\t7\t5\t\nGrade 2 (intermediate nonocclusive)\t3\t7\t6\t6\t4\t\nGrade 3 (central occlusive)\t4\t4\t4\t4\t0\t\nA total of 28 new thromboses were identified on retrospective review of the CT scans. Four patients who were initially reported to have thrombosis were subsequently reviewed as having no thrombosis.\n\nJohn Wiley & Sons, LtdUsing the new retrospective diagnoses, we repeated the earlier analysis that is shown in Tables 1, 2, 3, 4 using the original diagnoses. Univariate analysis comparing those who had thrombosis on retrospective CT review (n = 53) with those who had no thrombosis (n = 28) demonstrated no significant predisposing factors for thrombosis (Tables S1‐S4).\n\n3.6 Outcomes based on retrospective review of CT scans\nBased on the retrospective review, patients were divided into 4 distinct groups according to the presence or absence of thrombosis (as a consensus of radiologists 1 and 2) and whether the recipients were anticoagulated. The retrospective review gave us an opportunity to compare outcomes in these groups, in a manner that would not be possible prospectively outside of a randomized controlled trial. Moreover, if we assume that the “new” thromboses diagnosed only on retrospective review were originally not reported at random, this approach reduces (but does not eliminate) bias.\n\nTwenty‐six patients were identified to have thrombosis on retrospective CT review but were previously not anticoagulated (T‐NAC). Eighteen patients with thrombosis on retrospective review were anticoagulated (T‐AC). Compared with the T‐NAC group, T‐AC group demonstrated trends toward more reexploration for bleeding (7 [38.9%] vs 3 [11.5%]; P = .064), longer median length of stay (21 days vs 15 days; P = .077), and more peripancreatic edema and/or inflammatory changes on CT (10 [55.5%] vs 4 [15.4%]; P = .008). There were 2 grafts lost in the T‐AC group due to portal vein thrombosis (Table 8 and Figure 4).\n\nTable 8 Comparison of outcomes based on retrospective CT report and initial management\n\n\tT‐AC (all grades of thrombosis) (n = 18)\tT‐NAC (n = 26)\tT‐AC (grade 1 and 2 only) (n = 11)\tNT‐AC (n = 6)\tNT‐NAC (n = 31)\t\nReexploration for bleeding\t\n7 (38.9%)\n\n[2 pre‐ and 5 post‐anticoagulation]\n\nP = .064\n\t3 (11.5%)\t\n4 (36.4%)\n\n[2 pre‐ and 2 post‐anticoagulation]\n\nP = .210\n\t\n3 (50.0%)\n\n[1 pre‐ and 2 post‐anticoagulation]\n\t5 (16.1%)\t\nLength of postoperative stay (days)\t\n21 (10‐57)\n\nP = .077\n\t15 (8‐305)\t\n17 (10‐38)\n\nP = .374\n\t19 (17‐33)\t14 (6‐35)\t\nAcute rejection\t\n5 (27.8%)\n\nP = .451\n\t4 (15.4%)\t\n3 (27.3%)\n\nP = .638\n\t3 (50.0%)\t2 (6.4%)\t\nPeripancreatic edema and/or inflammatory changes on CT\t\n10 (55.5%)\n\nP = .008\n\t4 (15.4%)\t\n7 (63.6%)\n\nP = .013\n\t2 (33.3%)\t6 (19.3%)\t\nGraft loss\t\n3 (16.7%)\n\n(PVT 2, chronic rejection)\n\nLog‐rank P = .123\n\t\n1 (3.8%)\n\n(recurrence of DM)\n\t\n1 (9.1%) (chronic rejection) Log‐rank\n\nP = .567\n\t\n2 (33.3%)\n\n(graft pancreatitis, chronic rejection)\n\t\n2 (6.4%)\n\n(chronic rejection, graft vasculopathy)\n\t\nPatient death\t\n0 (0.0%)\n\nLog‐rank P = .281\n\t\n2 (7.7%)\n\n(gastric and esophageal cancer)\n\t\n0 (0.0%)\n\nLog‐rank( )P = .353\n\t1 (16.7%)\t1 (3.2%)\t\nA total of 28 new thromboses were identified on retrospective review of the CT scans. Four patients who were initially reported to have thrombosis were subsequently reviewed as having no thrombosis.\n\n\nP values are comparison between 2 groups: Column 1: T‐AC (all grades of thrombosis) vs T‐NAC; Column 3: T‐AC (grade 1 and 2 thromboses only) vs T‐NAC. P values that are significant are highlighted in bold.\n\nAC, anticoagulated; NAC, not anticoagulated; NT, no thrombosis; T, thrombosis.\n\nJohn Wiley & Sons, LtdFigure 4 Flowchart depicting the 2 distinct stages of the retrospective study\n\nWhen comparing the T‐NAC group (n = 26) with the T‐AC group with only grade 1 and 2 thromboses (n = 11), there was no difference in reexploration for bleeding (2 postanticoagulation [18.2%] vs 3 [11.5%]; P = .210) and median length of stay (17 days vs 15 days; P = .374). There was no graft loss due to thrombosis in those with T‐NAC and T‐AC with grade 1 and 2 thromboses only (Table 8). There was also no difference in graft and patient survival on comparing those who were anticoagulated for grade 1 and 2 thrombosis and those who were not anticoagulated (Figures 5 and 6).\n\nFigure 5 Death‐censored graft survival. Graft survival was similar between thrombosis‐Anticoagulated (Grade 1 and 2) and Thrombosis‐Not anticoagulated groups\n\nFigure 6 Patient survival. There was no statistical difference in patient survival between thrombosis‐Anticoagulated (Grade 1 and 2) and Thrombosis‐Not anticoagulated groups\n\nBased on these findings, an algorithm for the management of thrombosis based on new CT grading system is presented in Figure 7.\n\nFigure 7 Management algorithm for allograft thrombosis based on the Cambridge Pancreas Allograft Thrombosis (CPAT) grading system\n\n3.7 Evolution of thrombosis on retrospective review of CT scans\nTo determine if anticoagulation influences the evolution of grade 1 and 2 thromboses, we compared late CT images in the T‐AC and TNAC groups (Table 9). Retrospective review of CT images at 3 months of those who were anticoagulated for thrombosis demonstrated a reduction in grade of thrombosis in 5 of 8 patients and an increase in thrombosis grade in 2 patients. Review of last CT scans done at a median of 530 days posttransplant showed a decrease in thrombosis grade in 5 of 7 patients and an increase in grade in 2 patients. In those patients who were not anticoagulated for thrombosis, CT scans at 3 months showed 2 of 5 patients with reduction in grade of thrombosis and 1 patient with increase in thrombosis grade. Further CT scans at median of 670 days showed 10 of 15 patients with reduction in grade of thrombosis and 2 with increase in thrombosis grade.\n\nTable 9 Evolution of thrombus at 3 months and last CT scan\n\n\tThrombosis anticoagulated (n = 18)\tThrombosis not anticoagulated (n = 26)\t\n\nFirst postoperative CT scan\n\tMedian 4 days\tMedian 4 days\t\nBaseline CT vein scores\tGrade 0 (n = 7)\tGrade 0 (n = 17)\t\nGrade 1 (n = 2)\tGrade 1 (n = 7)\t\nGrade 2 (n = 5)\tGrade 2 (n = 2)\t\nGrade 3 (n = 4)\tGrade 3 (n = 0)\t\nBaseline CT artery scores\tGrade 0 (n = 6)\tGrade 0 (n = 5)\t\nGrade 1 (n = 11)\tGrade 1 (n = 19)\t\nGrade 2 (n = 1)\tGrade 2 (n = 2)\t\nGrade 3 (n = 0)\tGrade 3 (n = 0)\t\nPeripancreatic edema and/or peripancreatic inflammatory changes at baseline CT scan\t13\t16\t\n\nCT scan 3 months\n\tMedian 117 days (8 patients)\n\tMedian 96 days (5 patients)\n\t\nCT vein at 3 monthsa\n\tPrevious thrombosis downgraded (n = 3) [3 to 2, 2 to 0, and 1 to 0]\tPrevious thrombosis downgraded (n = 1) [1 to 0]\t\nCT artery at 3 monthsa\n\tPrevious thrombosis downgraded (n = 2) [both 1 to 0]\tPrevious thrombosis downgraded (n = 1) [1 to 0]\t\nPrevious thrombosis upgraded (n = 2) [both from 1 to 2]\tPrevious thrombosis upgraded (n = 1) [0 to 2]\t\nPeripancreatic edema at 3‐month CT\t1\t2\t\n\nLast CT scan\n\tMedian 530 days (7 patients)\n\tMedian 670 days (15 patients)\n\t\nLast CT veina\n\tPrevious thrombosis downgraded (n = 2) [2 to 0 and 1 to 0]\tPrevious thrombosis downgraded (n = 4) [all 1 to 0]\t\nLast CT arterya\n\tPrevious thrombosis downgraded (n = 3) [all 1 to 0]\tPrevious thrombosis downgraded (n = 6) [1 to 0]\t\nPrevious thrombosis upgraded (n = 2) [0 to 3, 1 to 3]\tPrevious thrombosis upgraded (n = 2) [0 to 2, 1 to 2]\t\nPeripancreatic edema on last CT\t2\t0\t\nThe evolution of thrombosis was not obviously affected by anticoagulation.\n\na Comparison of 3‐month CT and last follow‐up CT was made with the first postoperative CT scan.\n\nJohn Wiley & Sons, Ltd4 DISCUSSION\nThe incidence of PAT in our center is 23.3% (n = 24). The rate is high because we have included grade 1 thrombosis (peripheral thrombus), which forms a majority of our thromboses (45.8%; n = 11). We believe many of these are not reported in previous publications. Only 5.8% of recipients in our series were diagnosed with occlusive (grade 3) thrombosis. Moreover, the incidence of graft loss secondary to thrombosis was only 2.9%.5, 28 While managements of recipients with PAT must be primarily based on individual clinical circumstances, we believe that our analysis can potentially inform and enhance evidence‐based clinical decision‐making. Based on our proposed grading system, henceforth termed the Cambridge Pancreas Allograft Thrombosis (CPAT) grading, our data suggest that grade 1 and 2 arterial thromboses and grade 1 venous thrombosis can be managed safely without formal anticoagulation. Although we report 17% higher risk of graft loss with thrombosis, all of the graft losses in our cohort were due to grade 2 or 3 thrombosis and grade 1 thrombosis had no effect on graft or patient survival. The risk factors for PAT in our cohort were pancreas transplantation into a nonuremic patient, acute rejection, and pancreatitis on CT, similar to previous published literature.29, 30\n\n\nThe important findings from our study are that arterial thrombosis presented late (median 5 days) compared with venous thrombosis (median 3 days) and most cases of arterial thrombosis could be managed with anticoagulation alone. In comparison, more than half of our cases of venous thromboses were diagnosed within the first 72 hours and prompted reexploration; there was higher risk of graft loss when a grade 3 thrombosis was present. Arterial thrombosis including both partial (grades 1 and 2) and complete (grade 3) were managed with anticoagulation alone in our cohort with no graft loss, albeit the grade 3 thrombosis on retrospective review was reported as no thrombosis. Only 1 graft was reexplored for grade 1 arterial thrombosis (thrombus distally in the graft), but there was also concern about extrinsic compression of the portal vein on this patient's CT scan, which contributed significantly to the decision to reexplore. At reexploration, there was only evidence of severe graft pancreatitis and no arterial thrombosis. This was the only negative laparotomy in our study cohort. On retrospective review of this patient's CT scan, radiologist 1 reported no arterial thrombosis and radiologist 2 reported a grade 1 arterial thrombosis. Fridell et al, in a retrospective review of 35 reexplorations for thrombosis in 345 transplantations over a 7‐year period, reported a negative laparotomy rate of 43%.18\n\n\nThe proposed CPAT grading system helps clinicians make decisions on which grafts may require reexploration and which can be managed with anticoagulation alone. The retrospective review of the CT scans allowed us to compare 2 groups – one therapeutically anticoagulated for grade 1 and 2 thromboses and one managed conservatively. Because the diagnoses of thrombosis in the nonanticoagulated group were not reported at random, this reduces potential bias arising from allocation of patients to the 2 groups. In this study, therefore, patients were in effect “inadvertently randomized” into anticoagulation and conservative groups at the time of the index admission. Importantly, we were able to compare outcomes in the 2 groups where the CPAT grades of the thrombosis were comparable (grades 1 and 2). Those who were managed without anticoagulation had similar graft and patient survivals. Of note is that the morbidities associated with anticoagulation such as reexploration for bleeding were numerically less in the nonanticoagulated group (11.5% vs 36.4%; P = .201) and, hence, the length of stay was shorter (15 days vs 17 days; P = .374). An ideal prospective study would be to randomize patients with grade 1 and 2 (partial thrombosis) into anticoagulation vs no‐anticoagulation arms. Such a study would need large number of transplants to adequately power the study and may not have clinical equipoise to justify such randomization. Although the CPAT grading system has been used to report CT studies, we believe the same grading system could be applicable for USS or CEUS or MR reporting of PAT.\n\nManagement of PAT without anticoagulation (except aspirin) has been reported previously with no deleterious effects on the graft. Ciancio et al. reported 6 patients with partial PAT of the splenic vein, who were started on aspirin 81 mg once daily and followed with serial Doppler USS. None progressed to complete thrombosis, and all had a functioning graft at the end of follow‐up.31 Delis et al. managed partial venous thrombosis (n = 10) with aspirin alone and showed no progression of thrombosis. They reported recanalization of the thrombosed veins on follow‐up imaging and, overall, there was no effect on graft survival.32 Our retrospective review of images at 3 months and subsequently showed that majority of patients who were not anticoagulated for thrombosis had a reduction in grade of thrombosis to no thrombosis or lower grade thrombosis. This is in keeping with our suggestion that formal anticoagulation with LMWH is unnecessary in grade 1 and 2 arterial and grade 1 venous thromboses. Thromboelastography‐directed anticoagulation may have a role in identifying patients who need anticoagulation in the postoperative period.33\n\n\nThe major strength of our study is the inclusion of unselected, consecutive patients from a single center. The retrospective nature of the study and the relatively small number of patients are obvious limitations. There were no changes in the preoperative assessment of the recipients, immunosuppression protocols, or postoperative management during the study period, thereby reducing the bias associated with the retrospective studies. Triple‐phase CT was requested in the post‐operative period to rule out thrombosis if there was a rise in pancreatic enzyme levels (amylase or lipase) or raised glucose (>10 mmol/L). Hence, these scans were not driven by any routine protocol. However, it is difficult to ascertain if those who did not have CT (one‐fifth of our patients) may have had subclinical thrombosis, and therefore our results may not give a true picture of the incidence of thrombosis. It is also likely that too many CT scans could have picked up peripheral thrombosis (grade 1), which would not have altered clinical outcome but resulted in therapeutic anticoagulation in our cohort. The retrospective independent and blinded review of CT examinations by 2 radiologists gave us a specific cohort, allowing comparison of those who had grade 1 and 2 thromboses and were managed with and without anticoagulation. Although retrospective combined review of CT examinations resulted in a greater number of small‐volume thromboses being identified, those except central occlusive thromboses in either the arterial or venous system can be managed without anticoagulation.\n\n5 CONCLUSION\nThis retrospective study reports findings that suggest thromboses that do not involve the central vessels (portal vein or Y‐graft) of pancreatic grafts (grade 1 or grade 2) can be managed without anticoagulation. The proposed CPAT grading system may help reporting of thrombosis, provide prognostic information for the individual patient, and allow better comparison of reports from different centers for improved understanding and management of this common condition. Future studies should focus on reporting outcomes when partial thrombosis is managed without anticoagulation. Prospective studies are needed to verify the suggested protocol, and ascertain the evolution of allograft thrombosis when the patients are anticoagulated, and to determine the optimal duration of anticoagulation.\n\nAUTHOR CONTRIBUTION\nKSP and AH planned and designed the study. JC and SI collected the clinical data needed for the study. AH performed the statistical analysis and wrote the manuscript. All coauthors reviewed and revised the study design and the manuscript, which was finalized by KSP. SU and EMG defined the grading system used and carried out the retrospective review of CT images.\n\nDISCLOSURE\nThe authors of this manuscript have no conflicts of interests to disclose as described by the American Journal of Transplantation.\n\nSupporting information\n \n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThe research was supported by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or NHSBT.\n==== Refs\nREFERENCES\n1 \n\nFarney \nAC \n, \nRogers \nJ \n, \nStratta \nRJ \n. Pancreas graft thrombosis: causes, prevention, diagnosis, and intervention . Curr Opin Organ Transplant . 2012 ;17 (1 ):87 ‐92 .22186095 \n2 \n\nRamessur Chandran \nS \n, \nKanellis \nJ \n, \nPolkinghorne \nKR \n, \nSaunder \nAC \n, \nMulley \nWR \n. Early pancreas allograft thrombosis . Clin Transplant . 2013 ;27 (3 ):410 ‐416 .23495654 \n3 \n\nMuthusamy \nAS \n, \nGiangrande \nPL \n, \nFriend \nPJ \n. Pancreas allograft thrombosis . Transplantation . 2010 ;90 (7 ):705 ‐707 .20616765 \n4 \n\nBurke \nGW \n3rd\n, \nCiancio \nG \n, \nFigueiro \nJ \n, et al. Hypercoagulable state associated with kidney‐pancreas transplantation. Thromboelastogram‐directed anti‐coagulation and implications for future therapy . Clin Transplant . 2004 ;18 (4 ):423 ‐428 .15233820 \n5 \n\nShahrestani \nS \n, \nWebster \nAC \n, \nLam \nVW \n, et al. Outcomes from pancreatic transplantation in donation after cardiac death: a systematic review and meta‐analysis . Transplantation . 2017 ;101 (1 ):122 ‐130 .26950713 \n6 \n\nSalvalaggio \nPR \n, \nDavies \nDB \n, \nFernandez \nLA \n, \nKaufman \nDB \n. Outcomes of pancreas transplantation in the United States using cardiac‐death donors . Am J Transplant . 2006 ;6 (5 Pt 1 ):1059 ‐1065 .16611344 \n7 \n\nPatel \nSR \n, \nHakim \nN \n. Prevention and management of graft thrombosis in pancreatic transplant . Exp Clin Transplant . 2012 ;10 (3 ):282 ‐289 .22631067 \n8 \n\nGruessner \nAC \n, \nGruessner \nRW \n. Pancreas Transplantation of US and Non‐US Cases from 2005 to 2014 as Reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) . Rev Diabet Stud . 2016 ;13 :35 ‐58 .26982345 \n9 \n\nBozlar \nU \n, \nBrayman \nKL \n, \nHagspiel \nKD \n. Pancreas allografts: comparison of three‐dimensional rotational angiography with standard digital subtraction angiography . J Vasc Interv Radiol . 2008 ;19 (2 Pt 1 ):239 ‐244 .18341956 \n10 \n\nO'Malley \nRB \n, \nMoshiri \nM \n, \nOsman \nS \n, \nMenias \nCO \n, \nKatz \nDS \n. Imaging of pancreas transplantation and its complications . Radiol Clin North Am . 2016 ;54 (2 ):251 ‐266 .26896223 \n11 \n\nTolat \nPP \n, \nFoley \nWD \n, \nJohnson \nC \n, \nHohenwalter \nMD \n, \nQuiroz \nFA \n. Pancreas transplant imaging: how I do it . Radiology . 2015 ;275 (1 ):14 ‐27 .25799333 \n12 \n\nYates \nA \n, \nParry \nC \n, \nStephens \nM \n, \nEynon \nA \n. Imaging pancreas transplants . Br J Radiol . 1030 ;2013 (86 ):20130428 .\n13 \n\nLiong \nSY \n, \nDixon \nRE \n, \nChalmers \nN \n, \nTavakoli \nA \n, \nAugustine \nT \n, \nO'Shea \nS \n. Complications following pancreatic transplantations: imaging features . Abdom Imaging . 2011 ;36 (2 ):206 ‐214 .20563577 \n14 \n\nVandermeer \nFQ \n, \nManning \nMA \n, \nFrazier \nAA \n, \nWong‐You‐Cheong \nJJ \n. Imaging of whole‐organ pancreas transplants . Radiographics . 2012 ;32 (2 ):411 ‐435 .22411940 \n15 \n\nKim \nYH \n, \nPark \nJB \n, \nLee \nSS \n, \nByun \nJH \n, \nKim \nSC \n, \nHan \nDJ \n. How to avoid graft thrombosis requiring graftectomy: immediate posttransplant CT angiography in pancreas transplantation . Transplantation . 2012 ;94 (9 ):925 ‐930 .23034560 \n16 \n\nSiskind \nE \n, \nMaloney \nC \n, \nAshburn \nS \n, et al. The use of venous jump grafts in pancreatic transplantation ‐ no difference in patient or allograft outcomes ‐ an update of the UNOS database . Clin Transplant . 2014 ;28 (8 ):883 ‐888 .24930804 \n17 \n\nBarrufet \nM \n, \nBurrel \nM \n, \nAngeles Garcia‐Criado \nM \n, et al. Pancreas transplants venous graft thrombosis: endovascular thrombolysis for graft rescue . Cardiovasc Intervent Radiol . 2014 ;37 (5 ):1226 ‐1234 .24305984 \n18 \n\nFridell \nJA \n, \nMangus \nRS \n, \nMull \nAB \n, et al. Early reexploration for suspected thrombosis after pancreas transplantation . Transplantation . 2011 ;91 (8 ):902 ‐907 .21301398 \n19 \n\nHan \nK \n, \nKo \nHK \n, \nTsauo \nJ \n, et al. Endovascular management for the treatment of pancreas transplant venous thrombosis: a single‐center experience . J Vasc Interv Radiol . 2016 ;27 (6 ):882 ‐888 .27107981 \n20 \n\nSaad \nWE \n, \nDarwish \nWE \n, \nTurba \nUC \n, et al. Endovascular management of vascular complications in pancreatic transplants . Vasc Endovascular Surg . 2012 ;46 (3 ):262 ‐268 .22492112 \n21 \n\nMargreiter \nC \n, \nMark \nW \n, \nWiedemann \nD \n, et al. Pancreatic graft survival despite partial vascular graft thrombosis due to splenocephalic anastomoses . Am J Transplant . 2010 ;10 (4 ):846 ‐851 .20420640 \n22 \n\nMaraschio \nMA \n, \nKayler \nLK \n, \nMerion \nRM \n, et al. Successful surgical salvage of partial pancreatic allograft thrombosis . Transpl Proc . 2003 ;35 (4 ):1491 ‐1493 .\n23 \n\nMatsumoto \nI \n, \nShinzeki \nM \n, \nAsari \nS \n, et al. Functioning pancreas graft with thromboses of splenic and superior mesenteric arteries after simultaneous pancreas‐kidney transplantation: a case report . Transpl Proc . 2014 ;46 (3 ):989 ‐991 .\n24 \n\nChoi \nBH \n, \nLee \nHY \n, \nPark \nYM \n, \nYang \nKH \n, \nRyu \nJH \n, \nChu \nCW \n. Formation of collateral veins in a graft pancreas after a simultaneous pancreas and kidney transplantation: a case report . Transpl Proc . 2015 ;47 (7 ):2270 ‐2273 .\n25 \n\nScheffert \nJL \n, \nTaber \nDJ \n, \nPilch \nNA \n, \nChavin \nKD \n, \nBaliga \nPK \n, \nBratton \nCF \n. Clinical outcomes associated with the early postoperative use of heparin in pancreas transplantation . Transplantation . 2014 ;97 (6 ):681 ‐685 .24285337 \n26 \n\nSchenker \nP \n, \nVonend \nO \n, \nErtas \nN \n, et al. Incidence of pancreas graft thrombosis using low‐molecular‐weight heparin . Clin Transplant . 2009 ;23 (3 ):407 ‐414 .19537302 \n27 \n\nAboalsamh \nG \n, \nAnderson \nP \n, \nAl‐Abbassi \nA \n, \nMcAlister \nV \n, \nLuke \nPP \n, \nSener \nA \n. Heparin infusion in simultaneous pancreas and kidney transplantation reduces graft thrombosis and improves graft survival . Clin Transplant . 2016 ;30 :1002 ‐1009 .27293140 \n28 \n\nNagai \nS \n, \nPowelson \nJA \n, \nTaber \nTE \n, \nGoble \nML \n, \nMangus \nRS \n, \nFridell \nJA \n. Allograft pancreatectomy: indications and outcomes . Am J Transplant . 2015 ;15 (9 ):2456 ‐2464 .25912792 \n29 \n\nGruessner \nAC \n. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty‐four years at the International Pancreas Transplant Registry (IPTR) . Rev Diabet Stud . 2011 ;8 (1 ):6 ‐16 .21720668 \n30 \n\nGruessner \nAC \n, \nGruessner \nRW \n. Long‐term outcome after pancreas transplantation: a registry analysis . Curr Opin Organ Transplant . 2016 ;21 :377 ‐385 .27258580 \n31 \n\nCiancio \nG \n, \nCespedes \nM \n, \nOlson \nL \n, \nMiller \nJ \n, \nBurke \nGW \n. Partial venous thrombosis of the pancreatic allografts after simultaneous pancreas‐kidney transplantation . Clin Transplant . 2000 ;14 (5 ):464 ‐471 .11048991 \n32 \n\nDelis \nS \n, \nDervenis \nC \n, \nBramis \nJ \n, \nBurke \nGW \n, \nMiller \nJ \n, \nCiancio \nG \n. Vascular complications of pancreas transplantation . Pancreas . 2004 ;28 (4 ):413 ‐420 .15097859 \n33 \n\nVaidya \nA \n, \nMuthusamy \nAS \n, \nHadjianastassiou \nVG \n, et al. Simultaneous pancreas–kidney transplantation: to anticoagulate or not? Is that a question? \nClin Transplant . 2007 ;21 (4 ):554 ‐557 .17645719\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1600-6135", "issue": "18(1)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "clinical research/practice; coagulation and hemostasis; complication; graft survival; health services and outcomes research; pancreas/simultaneous pancreas-kidney transplantation; thrombosis and thromboembolism", "medline_ta": "Am J Transplant", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000465:Algorithms; D064591:Allografts; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D013927:Thrombosis; D014057:Tomography, X-Ray Computed; D055815:Young Adult", "nlm_unique_id": "100968638", "other_id": null, "pages": "163-179", "pmc": null, "pmid": "28719059", "pubdate": "2018-01", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "24305984;21720668;26896223;24767399;24285337;11048991;20616765;18341956;22492112;15097859;28719059;27107981;22186095;15233820;25912792;27258580;23034560;24026227;20420640;26982345;26361697;20563577;17645719;22411940;12826202;22631067;16611344;21301398;23495654;19537302;27293140;26950713;25799333;24930804", "title": "Pancreatic allograft thrombosis: Suggestion for a CT grading system and management algorithm.", "title_normalized": "pancreatic allograft thrombosis suggestion for a ct grading system and management algorithm" }

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{ "abstract": "Vertebral arterial dissection is a known cause of stroke in young adults. There has been a multitude of cases of bilateral vertebral dissections, including progression from one vertebral artery to another. This case reports the curious sequential nature of the healing of a previously dissected vertebral artery with subsequent dissection of the collateral vertebral artery. Follow-up neuroimaging evaluation performed several months later showed healed bilateral vertebral artery. The potential trigger was neck cracking.", "affiliations": "Department of Neurology, Loyola University Medical Center, Maguire Center, Maywood, Illinois, USA.;Department of Neurology, Loyola University Medical Center, Maguire Center, Maywood, Illinois, USA.;Department of Neurology, Loyola University Medical Center, Maguire Center, Maywood, Illinois, USA.", "authors": "Morales Vidal|Sarkis|S|;Lara|Carlos|C|;Gordin|Ari|A|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000506766", "fulltext": "\n==== Front\nCase Rep Neurol\nCase Rep Neurol\nCRN\nCase Reports in Neurology\n1662-680X S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000506766\ncrn-0012-0189\nSingle Case − General Neurology\nSequential Bilateral Vertebral Artery Dissections with Prompt Resolution of Initial Insult\nMorales Vidal Sarkis * Lara Carlos Gordin Ari Department of Neurology, Loyola University Medical Center, Maguire Center, Maywood, Illinois, USA\n*Sarkis Morales Vidal, Department of Neurology, Loyola University Medical Center, Maguire Center, Suite 2700, 2160 South First Avenue, Maywood, IL 60153 (USA), sarkismorales@gmail.com\nMay-Aug 2020 \n11 6 2020 \n11 6 2020 \n12 2 189 198\n16 1 2020 20 2 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Vertebral arterial dissection is a known cause of stroke in young adults. There has been a multitude of cases of bilateral vertebral dissections, including progression from one vertebral artery to another. This case reports the curious sequential nature of the healing of a previously dissected vertebral artery with subsequent dissection of the collateral vertebral artery. Follow-up neuroimaging evaluation performed several months later showed healed bilateral vertebral artery. The potential trigger was neck cracking.\n\nKeywords\nIschemic strokeDissectionVasculopathyVertebral artery\n==== Body\nCase Presentation\nA 32-year-old right handed man presented to the emergency room with persistent dizziness and neck pain for the past 3 days. He was discharged home 1 month prior after being diagnosed with a cerebellar infarction secondary to a spontaneous right vertebral artery dissection (Fig. 1, 2, 3). The clinical presentation of the first event was headaches associated with dizziness and right beating nonpersistent horizontal nystagmus. He reported to occasionally cracking his neck during his initial admission but reported not cracking his neck during his second admission. His family history was pertinent for a spontaneous left cervical carotid dissection in his mother at the age of 41 years. He had no history of illicit drug use, alcohol abuse, or cigarette smoking. General examination was normal. No abnormal body habitus. No blue sclera. No skin abnormalities like cutaneous xanthomas or other abnormalities suggestive of connective tissue disease were observed. The neurologic examination during his second admission was normal and symptoms of neck pain and dizziness resolved within 24 h. Neuroimaging studies performed during his second admission included MRI of the brain and MRA of the head/neck initially and then followed by CTA of the head and neck. MRI brain during his second admission showed no evidence of recurrent cerebral or cerebellar infarction; however, MRA of the head showed an intracranial vertebral artery narrowing most consistent with arterial dissection on the left and recanalization of the previously seen right vertebral dissection during his prior admission (Fig. 4, 5). Additional investigations including lipid profile hemoglobin A1C, and other routine testing were within reference laboratory values. He had further testing, including alpha-1 antitrypsin levels, CTA of the renal arteries, genetic testing for COAL3A4 (vascular Ehlers-Danlos), and homocysteine levels that were all unremarkable. Antinuclear antibody screen test was negative (test performed using HEP 2 cells and screened at 1:40 dilution); however, anti-RNP (ribonucleoprotein) antibodies were 38 units (normal reference range: <20 units). Rheumatology revaluated the patient and their impression was that the slightly elevated anti-RNP antibodies were nondiagnostic and that the patient did not meet all criteria for the diagnosis of mixed connective tissue disease. The patient was initially started on aspirin and clopidogrel; however, he was unable to tolerate clopidogrel due to an allergic reaction, hence he was continued on aspirin monotherapy. In addition, the patient was also started on statin therapy. He was discharged home asymptomatic and with a normal neurologic examination. Follow-up neuroimaging evaluation performed several months later showed resolution of left vertebral dissection. Statin therapy was discontinued and he was maintained on low-dose aspirin therapy.\n\nDiscussion\nCervicocephalic arterial dissection is a known cause of stroke in young adults. The most commonly identifiable cause is trauma; however, the underlying etiology is frequently unclear. There are many cases diagnosed as spontaneous arterial dissections with underlying predisposing risk factors. Observational studies have recognized an association between several types of minor trauma and cervicocephalic arterial dissections [1]. Neck cracking has been associated with vertebral artery dissection; however, causality is difficult to establish [2]. Weather neck cracking played a role as the underlying cause in this patient's recurrent multivessel vertebral artery dissections is not completely clear. Anti-RNP antibodies were of questionable significance. Thus far, there are reported cases of cervicocephalic vertebral dissection associated with mixed connective tissue disease. Nonetheless, Ohki et al. [3] reported a case of an intracranial dissecting aneurysm involving the posterior cerebral artery. The decision to start him on statin therapy was based on indirect evidence of vessel remodeling [4].\n\nBilateral vertebral artery dissection has been reported in multiple scenarios including subarachnoid hemorrhage, acute disseminated encephalomyelitis (ADEM), sports related, in association with osteogenesis imperfecta, as the initial presentation of Cushing's syndrome, trampoline use, cervical spine manipulation, postpartum period, eclampsia and HELLP, labor and delivery, essential thrombocytopenia, dynamic arterial compression, blunt trauma, connective tissue aberrations, Hirschsprung's disease, syphilis, fibromuscular dysplasia, chiropractic manipulation, facial massage, neck cracking, roller coaster ride, and various gene mutations. Table 1 and Table 2 provide a summary of selected reported cases of bilateral vertebral dissections in association with particular diseases [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41].\n\nThis case should encourage new research to better understand the process of healing of a dissected vertebral artery. Our case is unique since our patient exhibited successive spontaneous intracranial vertebral dissections with evidence of prompt (within 1 month) resolution of the initially dissected vessel. The intriguing mechanism of these events could be related to an underlying connective tissue disease (positive family history) in association with minor trauma (neck cracking).\n\nStatement of Ethics\nThe authors confirm obtaining written consent from the patient for publication of the manuscript.\n\nDisclosure Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding Sources\nThe authors received no funding for the publication of the manuscript.\n\nAuthor Contributions\nS.M., A.G., and C.L. contributed to the manuscript development, rationale, manuscript images, and patient management.\n\nFig. 1 Axial diffusion-weighted image showing a punctate region of an acute right inferior cerebellar infarction.\n\nFig. 2 Reconstructed MRA showing evidence of decreased flow in the distal right vertebral artery.\n\nFig. 3 Reconstructed CRA showing evidence of decreased flow in the distal right vertebral artery.\n\nFig. 4 Reconstructed MRA during the second admission showing evidence of decreased flow in the distal left vertebral artery with resolution of the previously seen right vertebral artery.\n\nFig. 5 Intracranial view of reconstructed MRA during the second admission showing evidence of decreased flow in the distal left vertebral artery with resolution of the previously seen right vertebral artery.\n\nTable 1 Cerebrovascular diseases with reported associated bilateral dissections of vertebral arteries\n\nCerebrovascular and Related Disorders\t\nSAH\tSubarachnoid hemorrhage with bilateral intracranial vertebral artery dissecting aneurysms [5]\t\n\t\nCerebral sinus venous thrombosis\tIntracranial bilateral vertebral artery dissection during anticoagulation after cerebral venous and sinus thrombosis (CSVT) [6]\t\n\t\nCystic medial necrosis\tFatal bilateral vertebral artery dissection in a patient with cystic medial necrosis [7]\t\n\t\nIntracranial aneurysm\tBilateral spontaneous dissection of the posteroinferior cerebellar arteries [8]\t\n\t\nEssential thrombocythemia\tA rare case of bilateral vertebral artery dissection associated with essential thrombocythemia [9]\nBilateral vertebral artery dissection and essential thrombocythemia with JAK2 mutation [10]\t\n\t\nReversible cerebral vasoconstriction\tThe link between migraine, reversible cerebral vasoconstriction syndrome and cervical artery dissection [11]\t\n\t\nConnective Tissue Disease\t\t\nConnective tissue disease\tBilateral vertebral artery dissection and unilateral carotid artery dissection in case of Ehlers-Danlos syndrome type IV [12]\nBilateral vertebral artery dissection, agenesis of both ICAs, and connective tissue aberrations [13]\t\n\t\nInfectious\t\t\nSyphilis\tBilateral vertebral artery and internal carotid artery dissecting aneurysms due to syphilis [14]\t\n\t\nViral meningitis\tVertebral artery dissection associated with viral meningitis [15]\t\n\t\nAutoimmune\t\t\nADEM\tBilateral vertebral artery dissection in the setting of ADEM [16]\t\n\t\nMetabolic/Endocrine/Toxic\t\t\nCushing's syndrome\tBilateral vertebral artery dissection revealing Cushing's syndrome [17]\t\n\t\nPregnancy Related\t\t\nCesarean section\tReversible cerebral vasoconstriction syndrome and bilateral vertebral artery dissection presenting in a patient after cesarean section [18]\t\n\t\nPregnancy\tBilateral vertebral artery dissection causing a cerebrovascular accident in pregnancy [19]\t\n\t\nPostpartum period\tBilateral carotid and vertebral artery dissection: a life-threatening cause of postpartum headache [20]\t\n\t\nPreeclampsia and HEELP\tBilateral thalamic infarct caused by spontaneous vertebral artery dissection in pre-eclampsia with HELLP syndrome [21]\t\n\t\nGenetic and Congenital Disorders\t\t\nSingle-nucleotide polymorphism of PHACTR1\tSpontaneous bilateral cervical internal carotid and vertebral artery dissection in a Japanese patient without collagen vascular disease with special reference to single-nucleotide polymorphisms [22]\t\n\t\nPAI-1, MTHFR C677T, and ACE\tSpontaneous bilateral vertebral artery dissection secondary to PAI-1, MTHFR C677T, and ACE gene mutations in a young man [23]\t\n\t\nOsteogenesis imperfecta\tProgressive bilateral vertebral artery dissection in a case of osteogenesis imperfecta [24]\t\n\t\nAfibrinogenemia\tBilateral vertebral artery dissection in a patient with afibrinogenemia [25]\t\n\t\nHirschsprung's disease\tBilateral vertebral artery dissection with familial Hirschsprung's disease [26]\t\n\t\nFibromuscular dysplasia\tFollow-up of intracranial aneurysms in patients with fibromuscular dysplasia [22]\t\nTable 2 Cerebrovascular diseases with reported associated bilateral dissections of vertebral arteries (continued)\n\nTrauma/Minor Trauma\t\t\nCervical spine manipulation\tLocked-in syndrome due to bilateral vertebral artery dissection after cervical spine manipulation [27] Vertebral artery injury during cervical discectomy and fusion in a patient with bilateral anomalous arteries in the disc space [28] Postoperative bilateral vertebral artery dissection (cervical discectomy) [29]\t\n\t\nNeck cracking\tPatient with only associated trauma with recent self neck cracking [2]\t\n\t\nSports\tSpontaneous bilateral vertebral artery dissection during a basketball game [30] Combined thrombolysis in posterior circulation stroke caused by bilateral vertebral artery dissection in a squash player [31]\nBilateral spontaneous dissection of extracranial vertebral arteries (tennis) [32]\t\n\t\nInline skating\tInline skating as a possible cause of consecutive bilateral vertebral artery dissection [33]\t\n\t\nRoller coaster ride\tBilateral internal carotid artery and vertebral artery dissections with retinal artery occlusion after a roller coaster ride [34]\t\n\t\nDynamic arterial compression\tDynamic arterial compression in pediatric vertebral arterial dissection [35]\t\n\t\nBlunt trauma\tBilateral internal carotid and left vertebral artery dissection after blunt trauma [36]\t\n\t\nFacial massage\tBilateral carotid and bilateral vertebral artery dissection following facial massage [37]\nBilateral cerebellar infarction caused by intracranial dissection of the vertebral artery after long periods of Shiatsu [38]\t\n\t\nChiropractic manipulation\tBilateral vertebral artery dissection during chiropractic treatment [39]\t\n\t\nCervical traction\tVertebral artery dissection related to basilar impression: case report [40]\t\n\t\nTemperature related\tSeasonal variation in cervical artery dissection in the Hunter New England region, New South Wales, Australia: a retrospective cohort study [41]\n==== Refs\nReferences\n1 Biller J Sacco RL Albuquerque FC Demaerschalk BM Fayad P Long PH American Heart Association Stroke Council Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association Stroke 2014 10 45 (10) 3155 74 25104849 \n2 Fujii M Ohgushi M Chin T Brain infarction due to vertebral artery dissection caused by a bone protrusion from the condylar fossa in a juvenile case Br J Neurosurg 2018 2 1 3 \n3 Ohki M Nakajima M Sato K Kondo R Saito S Nakai O [A case of dissecting aneurysm associated with mixed connective tissue disease] No To Shinkei 1994 9 46 (9) 855 8 7999443 \n4 Suzuki M Saito M Nagai T Saeki H Kazatani Y Prevention of positive coronary artery remodeling with statin therapy in patients with coronary artery diseases Angiology 2006 May-Jun 57 (3) 259 65 16703185 \n5 Zhao WY Zhao KJ Huang QH Xu Y Hong B Liu JM Single-stage endovascular treatment of subarachnoid hemorrhage related to bilateral vertebral artery dissecting aneurysms Interv Neuroradiol 2016 4 22 (2) 138 42 26686384 \n6 Turowski B Hanggi D Siebler M Intracranial bilateral vertebral artery dissection during anticoagulation after cerebral venous and sinus thrombosis (CSVT) Acta Neurochir (Wien) 2007 8 149 (8) 793 7 17660937 \n7 Chang CM Ng HK Leung SY Fong KY Yu YL Fatal bilateral vertebral artery dissection in a patient with cystic medial necrosis Clin Neurol Neurosurg 1991 93 (4) 309 11 1686748 \n8 Shinoda S Murata H Waga S Kojima T Bilateral spontaneous dissection of the posteroinferior cerebellar arteries: case report Neurosurgery 1998 8 43 (2) 357 9 9696091 \n9 Raza HK Jing J Chen H Zhu J Zhang Z Chansysouphanthong T A Rare Case of Bilateral Vertebral Artery Dissection Associated with Essential Thrombocythemia J Neurol Surg A Cent Eur Neurosurg 2019 6 81 (1) 75 9 31170738 \n10 Verdure P Lefaucheur R Guegan-Massardier E Triquenot-Bagan A Gerardin E Maltête D Bilateral vertebral artery dissection and essential thrombocythemia with JAK2 mutation Rev Neurol (Paris) 2012 6 168 (6-7) 543 4 22677324 \n11 Mawet J Debette S Bousser MG Ducros A The Link Between Migraine, Reversible Cerebral Vasoconstriction Syndrome and Cervical Artery Dissection Headache 2016 4 56 (4) 645 56 27016026 \n12 Ohshima T Miyachi S Isaji T Matsuo N Kawaguchi R Takayasu M Bilateral Vertebral Artery Dissection and Unilateral Carotid Artery Dissection in Case of Ehlers-Danlos Syndrome Type IV World Neurosurg 2019 1 121 83 7 30315974 \n13 Lill CM Günther-Kunkel K Hoch H Paul F Grond-Ginsbach C Hausser I Bilateral vertebral artery dissection, agenesis of both ICAs, and connective tissue aberrations Neurology 2013 4 80 (15) 1442 3 23568999 \n14 Najem K Margolin E Krishnan P Syphilitic Perineuritis with Preserved Visual Function. In 42nd Annual Meeting 2016 22 \n15 Pan X Ma A Wang K Nie S Wu M Vertebral artery dissection associated with viral meningitis BMC Neurol 2012 8 12 (1) 79 22909191 \n16 Stirn SL Freilinger C Roeben B Tünnerhoff J Berg D Freilinger T Bilateral vertebral artery dissection in the setting of ADEM J Neurol Sci 2016 6 365 212 3 27206909 \n17 Ilie I Vouillarmet J Decaussin-Petrucci M Jeannin-Mayer S Lifante JC Thivolet C Bilateral vertebral artery dissection revealing Cushing's syndrome Ann Endocrinol (Paris) 2019 2 80 (1) 67 9 29555079 \n18 Mitchell LA Santarelli JG Singh IP Do HM Reversible cerebral vasoconstriction syndrome and bilateral vertebral artery dissection presenting in a patient after cesarean section J Neurointerv Surg 2014 1 6 (1) e5 24415454 \n19 Mass SB Cardonick E Haas S Gopalani S Leuzzi RA Bilateral vertebral artery dissection causing a cerebrovascular accident in pregnancy. A case report J Reprod Med 1999 10 44 (10) 887 90 10554752 \n20 Simon EL Griffin G Bosman E Bilateral carotid and vertebral artery dissection: a life-threatening cause of postpartum headache Am J Emerg Med 2015 4 33 (4) 600.e1 3 \n21 Borelli P Baldacci F Vergallo A Del Dotto P Lucetti C Nuti A Bilateral thalamic infarct caused by spontaneous vertebral artery dissection in pre-eclampsia with HELLP syndrome: a previously unreported association J Stroke Cerebrovasc Dis 2012 11 21 (8) 914.e9 10 \n22 Ma Y Li M Zhang H Ling F A 10-year follow-up of extracranial-intracranial bypass for the treatment of bilateral giant internal carotid artery aneurysms in a patient with fibromuscular dysplasia: case report Acta Neurochir (Wien) 2010 12 152 (12) 2191 5 20734090 \n23 Hotait M Sawaya R Spontaneous bilateral vertebral artery dissection secondary to PAI-1, MTHFR C677T and ACE gene mutations in a young man Cerebrovasc Dis 2013 35 (2) 182 3 23429214 \n24 Kato Y Nagoya H Abe T Hayashi T Yasuda M Uchino A Progressive Bilateral Vertebral Artery Dissection in a Case of Osteogenesis Imperfecta J Stroke Cerebrovasc Dis 2017 3 26 (3) e43 6 28089253 \n25 García-Moncó JC Fernández Cantón G Gómez Beldarrain M Bilateral vertebral artery dissection in a patient with afibrinogenemia Stroke 1996 12 27 (12) 2325 7 8969801 \n26 Sato K Sasaki R Ohta Y Takemoto M Hishikawa N Yamashita T A Unique Recurrent Stroke Case due to Bilateral Vertebral Artery Dissection with Familial Hirschsprung Disease J Stroke Cerebrovasc Dis 2019 8 28 (8) e113 5 31129106 \n27 Ke JQ Yin B Fu FW Shao SM Lin Y Dong QQ A Case Report of Locked-in Syndrome Due to Bilateral Vertebral Artery Dissection After Cervical Spine Manipulation Treat-ed by Arterial Embolectomy Medicine (Baltimore) 2016 2 95 (5) e2693 26844510 \n28 Gantwerker BR Baaj AA Maughan PH McDougall CG White WL Vertebral artery injury during cervical discectomy and fusion in a patient with bilateral anomalous arteries in the disc space: case report Neurosurgery 2010 9 67 (3) E874 5 20657320 \n29 Manaouil C Graser M Delcour J Le Gars D Gontier MF Loriau J Postoperative bilateral vertebral artery dissection: a case report J Clin Forensic Med 2003 6 10 (2) 81 4 15275026 \n30 Mas Rodriguez MF Berrios RA Ramos E Spontaneous Bilateral Vertebral Artery Dissection During a Basketball Game: A Case Report Sports Health 2016 Jan-Feb 8 (1) 53 6 26733592 \n31 Frankowska E Brzozowski K Staszewski J Kolmaga N Stępień A Bogusławska-Walecka R Combined thrombolysis in posterior circulation stroke caused by bilateral vertebral artery dissection in squash player Neurol Neurochir Pol 2014 48 (4) 299 304 25168332 \n32 Leys D Lesoin F Pruvo JP Gozet G Jomin M Petit H Bilateral spontaneous dissection of extracranial vertebral arteries J Neurol 1987 5 234 (4) 237 40 3612194 \n33 Karnik R Rothmund T Bonner G Valentin A Reuther G Inline skating as a possible cause of consecutive bilateral vertebral artery dissection Acta Neurol Scand 2000 1 101 (1) 70 1 10660157 \n34 Ozkan Arat Y Volpi J Arat A Klucznik R Diaz O Bilateral internal carotid artery and vertebral artery dissections with retinal artery occlusion after a roller coaster ride - case report and a review Ulus Travma Acil Cerrahi Derg 2011 1 17 (1) 75 8 21341139 \n35 Rollins N Braga B Hogge A Beavers S Dowling M Dynamic Arterial Compression in Pediatric Vertebral Arterial Dissection Stroke 2017 4 48 (4) 1070 3 28246279 \n36 Ariyada K Shibahashi K Hoda H Watanabe S Nishida M Hanakawa K Bilateral Internal Carotid and Left Vertebral Artery Dissection after Blunt Trauma: A Case Report and Literature Review Neurol Med Chir (Tokyo) 2019 4 59 (4) 154 61 30880295 \n37 Chakrapani AL Zink W Zimmerman R Riina H Benitez R Bilateral carotid and bilateral vertebral artery dissection following facial massage Angiology 2008 12 59 (6) 761 4 18388028 \n38 Iwanami H Odaka M Hirata K [Bilateral cerebellar infarction caused by intracranial dissection of the vertebral artery after long periods of “Shiatsu”] Brain Nerve 2007 2 59 (2) 169 71 \n39 Kuitwaard K Flach HZ van Kooten F [Bilateral vertebral artery dissection during chiropractic treatment] Ned Tijdschr Geneeskd 2008 11 152 (45) 2464 9 19051799 \n40 Dickinson LD Tuite GF Colon GP Papadopoulos SM Vertebral artery dissection related to basilar impression: case report Neurosurgery 1995 4 36 (4) 835 8 7596516 \n41 Thomas LC Makaroff AP Oldmeadow C Attia JR Levi CR Seasonal variation in cervical artery dissection in the Hunter New England region, New South Wales, Australia: A retrospective cohort study Musculoskelet Sci Pract 2017 2 27 106 11 27852529\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-680X", "issue": "12(2)", "journal": "Case reports in neurology", "keywords": "Dissection; Ischemic stroke; Vasculopathy; Vertebral artery", "medline_ta": "Case Rep Neurol", "mesh_terms": null, "nlm_unique_id": "101517693", "other_id": null, "pages": "189-198", "pmc": null, "pmid": "32647525", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "31170738;1686748;29405773;26733592;27852529;30880295;16703185;22341668;8969801;10660157;23568999;26844510;7596516;25104849;25168332;3612194;17660937;26686384;19051799;17315759;9696091;31129106;20734090;28246279;22677324;30315974;21341139;22909191;7999443;25440228;28089253;18388028;23429214;10554752;29555079;27206909;20657320;24415454;27016026;15275026", "title": "Sequential Bilateral Vertebral Artery Dissections with Prompt Resolution of Initial Insult.", "title_normalized": "sequential bilateral vertebral artery dissections with prompt resolution of initial insult" }

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{ "abstract": "Metformin is the first line treatment for type 2 diabetes. It is also indicated in patients with insulin-resistant type 1 diabetes. It has several benefic effects on carbohydrate metabolism, weight loss and vascular protection. However, it can also cause serious adverse reactions such as the risk of anemia associated with long term use. It has been reported that long-term metformin use might reduce serum vitamin B12 levels. Oral signs combining Hunter glossitis and stomatodynia may be revelatory and lead to early diagnosis of vitamin B12 deficiency. We here report the case of a female patient who had had these oral signs for 2 years and whose laboratory tests revealed normocytic anemia with iron and vitamin B12 deficiency. The diagnosis of vitamin B12 deficiency due to long-term metformin was suspected while excluding other potential causes. Intramuscular hydroxocobalamin injection associated with oral iron led to the normalization of serum levels and to the disappearance of clinical signs. The patient was referred to a specialized center for further etiological assessment. This clinical case highlights the essential role of dentists in early diagnosis of vitamin B12 deficiency and the prevention of its progression, which can be dramatic in the case of late discovery.", "affiliations": "Environnement et Santé, Département de Biologie, Faculté des Sciences et Techniques d'Errachidia, Université Moulay Ismaïl de Meknès, Meknès, Maroc.", "authors": "Attiya|Nourdine|N|", "chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin", "country": "Uganda", "delete": false, "doi": "10.11604/pamj.2020.37.280.19776", "fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688 The African Field Epidemiology Network \n\nPAMJ-37-280\n10.11604/pamj.2020.37.280.19776\nCase Report\nDiagnostic buccal d´une carence en vitamine B12 due à un traitement au long court avec le metformine: à propos d´un cas\nOral diagnosis of vitamin B12 deficiency due to long-term metformin treatment: a case report Attiya Nourdine 1& 1 Environnement et Santé, Département de Biologie, Faculté des Sciences et Techniques d’Errachidia, Université Moulay Ismaïl de Meknès, Meknès, Maroc\nCorresponding author: Nourdine Attiya, Environnement et Santé, Département de Biologie, Faculté des Sciences et Techniques d’Errachidia, Université Moulay Ismaïl de Meknès, Meknès, Maroc. nourdineattiya@gmail.com\n26 11 2020 \n2020 \n37 28017 7 2019 29 10 2020 Copyright: Nourdine Attiya et al.2020The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Le metformine est actuellement placé en première ligne pour le traitement du diabète de type 2. Il est également indiqué dans le diabète de type 1 en cas de résistance à l´insuline. Il présente de nombreux effets bénéfiques sur le métabolisme des carbohydrates, la perte de poids et la protection vasculaire. Cependant, il peut également engendrer d´importants effets indésirables comme le risque d´anémie en cas d´utilisation prolongée. Il est rapporté que les patients sous metformine au long court présentent une réduction de la concentration sérique de la vitamine B12. Les signes buccaux associant une glossite de Hunter et une stomatodynie peuvent être révélateurs et conduire à un diagnostic précoce d´une carence en vitamine B12. Nous rapportons ici le cas d´une patiente qui présente ces signes buccaux depuis 2 ans et dont les bilans biologiques ont révélé une anémie normocytaire ferriprive avec carence en vitamine B12. La prise prolongée du metformine a été considérée comme étiologie de l´avitaminose B12 en attendant d´écarter d´autres causes probables. La correction par injection intramusculaire d´hydroxocobalamine avec du fer par voie orale ont permis la normalisation des taux sériques et la disparition des signes cliniques. La patiente a été adressée à un centre spécialisé pour un bilan étiologique plus poussé. Ce cas clinique met en relief le rôle important que peut jouer le médecin dentiste dans le diagnostic précoce de la déficience en vitamine B12 et la prévention de son évolution qui peut être dramatique en cas de découverte tardive.\n\nMetformin is the first line treatment for type 2 diabetes. It is also indicated in patients with insulin-resistant type 1 diabetes. It has several benefic effects on carbohydrate metabolism, weight loss and vascular protection. However, it can also cause serious adverse reactions such as the risk of anemia associated with long term use. It has been reported that long-term metformin use might reduce serum vitamin B12 levels. Oral signs combining Hunter glossitis and stomatodynia may be revelatory and lead to early diagnosis of vitamin B12 deficiency. We here report the case of a female patient who had had these oral signs for 2 years and whose laboratory tests revealed normocytic anemia with iron and vitamin B12 deficiency. The diagnosis of vitamin B12 deficiency due to long-term metformin was suspected while excluding other potential causes. Intramuscular hydroxocobalamin injection associated with oral iron led to the normalization of serum levels and to the disappearance of clinical signs. The patient was referred to a specialized center for further etiological assessment. This clinical case highlights the essential role of dentists in early diagnosis of vitamin B12 deficiency and the prevention of its progression, which can be dramatic in the case of late discovery.\n\nMetforminevitamine B12glossite de Hunterstomatodyniecase reportMetforminvitamin B12Hunter's glossitisstomatodyniacase report\n==== Body\nIntroduction\nLes manifestations buccales d´une carence en vitamine B12 peuvent constituer un motif de consultation chez le dentiste. Une meilleure connaissance de la symptomatologie stomatologique liée à cette carence permet de faire un diagnostic précoce. L´installation de signes hématologiques et surtout neuropsychiatriques constitue une étape tardive de la maladie pouvant laisser des séquelles irréversibles [1]. Les patients sous biguanides constituent une population à risque de carence en vitamine B12 [2]. La surveillance des taux sériques de cette vitamine n´est pas systématique chez ces patients. Les signes buccaux peuvent constituer un signal d´alerte assez précoce permettant de pallier à cette absence de surveillance.\n\nPatient et observation\nUne femme marocaine de 65 ans a été reçue dans notre cabinet pour une algie linguale chronique évoluant depuis 2 ans. Ces douleurs sont à type de brulure empêchant une bonne alimentation et une hygiène orale correcte. Les traitements institués par d´autres médecins dentistes consistaient essentiellement en une association d´antibiotiques (spiramycine et métronidazole), d´antifongiques ainsi que d´antiseptiques locaux type chlorhexidine ou des bicarbonates en bain de bouche. Ces traitements n´ont permis aucune amélioration notable. L´examen endobuccal a révélé la présence d´une parodontite chronique à un stade avancé et une hygiène orale médiocre. Le tiers antérieur de la langue présente sur les faces dorsale et latérales jusqu´à la pointe une zone atrophique, érythémateuse et bien limitée qui semblait migratrice selon les renseignements de la patiente (Figure 1, Figure 2). L´interrogatoire a révélé que la patiente était diabétique depuis 30 ans et qu´elle utilisait, en plus de l´insuline, le metformine à la dose de 2000mg par jour fractionnée en deux prises et ce depuis 15 ans. En plus des signes buccaux, la patiente présente d´autres symptômes neuropsychiatriques: une insomnie, une irritabilité avec tendance dépressive, une perte d´appétit et une asthénie. La patiente s´expliquait la dégradation de son état psychologique par la période de deuil qu´elle traverse (décès de son conjoint depuis 18 mois). Sur le plan neurologique, la patiente présente des vertiges intermittents même en position allongée, des picotements et des décharges électriques aux extrémités supérieures et des fourmillements aux extrémités inférieures.\n\nFigure 1 vue supéro-antérieure montrant l'atteinte de la face dorsale de la langue\n\nFigure 2 vue supéro-latérale montrant l'atteinte du bord de la langue\n\nDevant ce tableau clinique, une avitaminose B12 a été suspectée et un bilan biologique a été demandé comprenant une numération formule sanguine et un dosage de la vitamine B12 et de l´acide folique sériques. Plusieurs anomalies ont été observées: hémoglobine à 10,30 g/100ml (N: 12 à 16g/100ml); hématocrite à 32,90% (N: 35 à 47%); teneur corpusculaire moyenne en hémoglobine (TCMH) à 25,80pg (N: 27 à 33pg); le volume globulaire moyen (VGM) était normal : 82,5µ3 (N: 80 à 95 µ3). La vitamine B12 sérique était très diminuée: 80ng/l (N: 180 à 914ng/l). La vitamine B9 était dans les normes. Les fourchettes de « normalité » indiquées sont celles proposées par le laboratoire ayant réalisé le bilan. D´après ces résultats et vu la normalité du VGM et la diminution de la TCMH (ainsi que de l´hémoglobine et de l´hématocrite), une carence martiale a été suspectée. Un dosage de la ferritine sérique a confirmé ce doute: 5,62ng/ml (N: 25 à 280ng/ml) En concertation avec le diabétologue traitant ainsi qu´avec un gastro-entérologue, le traitement antidiabétique est maintenu inchangé et la prise en charge de l´anémie a été instituée par un apport de vitamine B12 en intramusculaire (hydroxocobalmine 5000µg avec une injection tous les 5 jours) et du fer per os (fer protéinsuccinylate 40mg à raison de 2 prises journalières). L´utilisation prolongée à grande dose du metformine a été retenue comme étiologie provisoire et plausible de la déficience en vitamine B12 en attendant que la patiente se décide à faire d´autres explorations pour éliminer d´autres causes probables. La patiente a été revue en consultation après deux semaines où l´on a noté une disparition complète de la glossite de Hunter ainsi que de la stomatodynie. Les autres symptômes se sont aussi estompés de façon significative.\n\nDiscussion\nLe diagnostic et la prise en charge de cette patiente dont le signe évocateur était stomatologique ont permis de résoudre aussi bien ses problèmes buccaux ainsi qu´une amélioration de ses problèmes neuropsychiatriques. Cette prise en charge a permis de juguler l´évolution de la maladie. La vitamine B12 est un élément essentiel à la synthèse de l´ADN et son déficit retentit sur le turn-over cellulaire ce qui se traduit par des lésions au niveau des tissus à renouvellement rapide comme la muqueuse digestive et en particulier la muqueuse buccale [1,3]. Elle participe également à la synthèse de la myéline ce qui explique les signes neurologiques associés [1]. Il s´agit d´un élément hydrosoluble de structure chimique proche de l´hème avec un atome central de cobalt d´où le nom de cobalamine [4]. Il est fourni exclusivement par l´alimentation d´origine animale. Les besoins quotidiens estimés sont entre 2 et 5µg par jour. L´excédent est stocké au niveau du foie. La réserve hépatique varie entre 2 et 5mg ce qui représente 1000 jours d´apport [4]. D´après les données épidémiologiques disponibles, plusieurs travaux ont montré un lien entre une baisse de la vitamine B12 sérique et la prise prolongée du metformine [2,5,6]. Cette baisse est d´autant plus significative que la dose est grande [2,6]. Sur le plan physiopathologique, le principal mécanisme impliqué semble être une maldigestion des cobalamines alimentaires [5].\n\nL´installation de l´anémie avec un syndrome neurologique (paresthésie des extrémités, ataxie, aréflexie tendineuse, sclérose amyotrophique de la moelle) parfois irréversible constitue probablement le signe cardinal du diagnostic de la carence en vitamine B12 [1,5]. Or ce tableau met plusieurs années pour s´installer et il est souvent précédé par des signes cliniques en rapport avec l´atteinte épithéliale. Les lésions buccales sont fréquemment observées avant l´apparition de l´anémie [1], il s´agit classiquement de la glossite de Hunter qui se présente sous deux aspects cliniques: i) une phase inflammatoire ou pré-atrophique caractérisée par la perte de l´aspect velouté de la langue et l´apparition de zones vernissées et de plaques érythémateuses brillantes et sèches, intéressant la pointe et les bords de la langue. Ces zones peuvent parfois s´ulcérer; ii) une phase atrophique d´emblée ou faisant suite à la première avec une langue dépapillée, lisse et de couleur allant du rose pâle au rouge carminé. A la protraction, la langue parait parfois amincie et pointue [4]. L´atteinte linguale complète est rarement rencontrée car elle correspond à des lésions évoluées. Les atteintes partielles de la langue sont les plus fréquemment décrites dans la littérature [1,4]. D´autres lésions de la sphère oro-faciale sont possibles comme les faces internes des joues, la lèvre inférieure, le palais mou ou même le pharynx. Un diagnostic différentiel doit se faire surtout avec une candidose (présence d´un érythème lingual chez les personnes âgées) ou une glossite exfoliatrice migratrice s´il y a migration des lésions comme dans notre cas [1].\n\nLes biguanides dont le metformine peuvent être associés à des déficits et à des carences en vitamine B12 - voire les générer- chez les patients diabétiques [5]. Sur le plan épidémiologique, la fréquence de cette association est de 5,8% à 52% [2]. Le dosage de vitamine B12 n´étant pas systématique chez les diabétiques sous biguanides au long court, l´examen de la cavité buccale peut être un élément de surveillance clinique direct et facile à explorer. La présence d´une glossite (même partielle) et une stomatodynie doivent alerter le clinicien à suspecter une avitaminose B12 [1]. Ces signes précoces - même non spécifiques- vont permettre de juguler une évolution dramatique avec des séquelles neurologiques. Un traitement substitutif avant ce stade permet la disparition totale des symptômes [1,5,7]. Une telle surveillance est facilement réalisable par les médecins dentistes omnipraticiens même en exercice libéral en ville, il suffit juste d´une sensibilisation puisque les lésions sont facilement identifiables [8]. Ceci est vrai pour toutes les carences en vitamine B12 et non seulement celles associées aux biguanides. La présence de signes buccaux évocateurs d´une carence en vitamine B12 doit inciter le praticien à réaliser un bilan biologique comprenant un hémogramme et un dosage de la vitamine B12 sérique [9]. La carence en vitamine B12 est définie en général par une valeur inférieure à 200pg/ml avec une zone grise entre 200 et 300pg/ml [7]. Or, cette définition ne fait pas l´unanimité. En cas de doute, la présence de signes cliniques en faveur de cette carence ainsi que le dosage sérique de l´homocystéine totale ainsi que de l´acide méthyl-malonique permettent de conforter le diagnostic en cas de doute [4].\n\nConclusion\nLe cas clinique présenté montre le rôle important que peut jouer le médecin dentiste dans le diagnostic des anémies par carence en vitamine B12 ainsi que dans la surveillance de ces carences comme effet indésirable des biguanides (pharmacovigilance). La reconnaissance des lésions buccales associées à ces avitaminoses, bien que facilement identifiables, doit cependant faire l´objet de formation ciblée des médecins dentistes pour éviter l´errance médicale des patients qui en sont atteints et rendre efficace la surveillance de ce risque chez les diabétiques sous metformine.\n\nCite this article: Nourdine Attiya et al. Diagnostic buccal d´une carence en vitamine B12 due à un traitement au long court avec le metformine: à propos d´un cas. Pan African Medical Journal. 2020;37(280). 10.11604/pamj.2020.37.280.19776\n\nConflits d'intérêts\nL’auteur ne déclare aucun conflit d´intérêts.\n\nContributions des auteurs\nL’auteur a lu et approuvé la version finale du manuscrit.\n==== Refs\n1 Campana F Sibaud V Taieb A Fricain JC Manifestations buccales révélatrices d´un déficit en vitamine B12: à propos d´un cas Med Buccale Chir Buccale 2007 13 4 213 217 \n2 Khan A Shafiq I Hassan Shah M Prevalence of vitamin B12 deficiency in patients with type 2 diabetes mellitus on metformin: A study from Khyber Pakhtun Khwa Cereus 2017 9 8 e1577 \n3 Serraj K Mecili M Andrès E Signes et symptômes de la carence en vitamine B12: revue critique de la littérature Med Thérap 2010 16 1 13 20 \n4 Loup-Leuciuc A Loup PJ Lombardi T Samson J Carence en vitamine B12 (1re partie): mise au point Médecine Buccale Chir Buccale 2011 17 3 211 24 \n5 Andrès E Metformine et déficit ou carence en vitamine B12: quel impact pour le clinicien Med Therap 2016 22 5 280 83 \n6 Liu Q Li S Quan H Li S Vitamin B12 status in metformin treated patients: Systematic review PLOS ONE 2014 9 6 e100379 24959880 \n7 Bosco C Favrat B Cheseaux M Carences en vitamine B12 et fer: du diagnostic au suivi Rev Med Suisse 2012 8 1348 51 22792601 \n8 Loup-Leuciuc A Loup PJ Lombardi T Samson J Carence en vitamine B12 (2ème partie): présentation de 13 cas découverts sur des manifestations buccales Med Buccale Chir Buccale 2011 17 4 297 313 \n9 Langan RC Goodbred AJ Vitamin B12 Deficiency: Recognition and Management Am Fam Physician 2017 96 6 384 389 28925645\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "37()", "journal": "The Pan African medical journal", "keywords": "Hunter's glossitis; Metformin; case report; stomatodynia; vitamin B12", "medline_ta": "Pan Afr Med J", "mesh_terms": "D000368:Aged; D000740:Anemia; D003920:Diabetes Mellitus; D003945:Diagnosis, Oral; D005260:Female; D005928:Glossitis; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D014806:Vitamin B 12 Deficiency", "nlm_unique_id": "101517926", "other_id": null, "pages": "280", "pmc": null, "pmid": "33598094", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "22792601;24959880;28925645;29057189", "title": "Oral diagnosis of vitamin B12 deficiency due to long-term metformin treatment: a case report.", "title_normalized": "oral diagnosis of vitamin b12 deficiency due to long term metformin treatment a case report" }

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{ "abstract": "BACKGROUND\nVisual impairment occurred as an infrequent form of chemotherapeutic toxicity and was often underestimated despite of several reports. We described a case of acute unilateral visual impairment after one cycle of intravenous chemotherapy of a normal dose, aiming at raising attention to chemotherapy-induced ocular toxicity.\n\n\nMETHODS\nThe patient developed a progressive vision loss in the right eye during the chemotherapy. After one cycle of intravenous chemotherapy, her visual acuity decreased by 0.6 in the right eye (VOD = 0.4) compared to the previous value of 1.0 (VOD = 1.0). No evidence of ocular infiltration was observed from the cerebral magnetic resonance imaging (MRI). During her follow-up period, we documented the ophthalmologic examinations including visual acuity, visual field (VF), visual evoked potential (VEP), electroretinogram (ERG), fundus photograph (FP), fundus fluorescein angiography (FFA) and optical coherence tomography (OCT). Ophthalmoscope examination and fundus photograph showed optic disc edema, fuzzy boundary and linear hemorrhages in her right eye. Fundus fluorescein angiography (FFA) revealed capillary underdevelopment at the nasal and superior temporal area of the optic disc in the early phase and capillary fluorescein leakage in the late phase. The result of VEP test suggested the impaired function of the optic nerve. Thus, a diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION) was made by the ophthalmologist according to these results. The patient was prescribed prednisone combined with neuroprotective drugs, which did not work. After the cessation of chemotherapy, her impaired vision gradually recovered.\n\n\nCONCLUSIONS\nThis is the first reported case of acute visual impairment in a patient who underwent chemotherapy of a normal dose. It is indicated that while receiving benefits from chemotherapy, cancer patients simultaneously suffer from the risk of vision loss.", "affiliations": "Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, People's Republic of China.;Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China.;Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.;Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, People's Republic of China. limeiscu78@163.com.", "authors": "Yuan|Xia|X|;Feng|Yuliang|Y|;Li|Dan|D|;Li|Mei|M|", "chemical_list": "D000970:Antineoplastic Agents; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil", "country": "England", "delete": false, "doi": "10.1186/s12886-019-1246-3", "fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 124610.1186/s12886-019-1246-3Case ReportUnilateral visual impairment in a patient undergoing chemotherapy: a case report and clinical findings Yuan Xia 18382288349@163.com 1Feng Yuliang 28522584@qq.com 2Li Dan 1161329872@qq.com 3Li Mei limeiscu78@163.com 11 0000 0001 0807 1581grid.13291.38Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041 People’s Republic of China 2 0000 0001 0807 1581grid.13291.38Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041 China 3 0000 0001 0807 1581grid.13291.38Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041 China 21 11 2019 21 11 2019 2019 19 23624 2 2019 7 11 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nVisual impairment occurred as an infrequent form of chemotherapeutic toxicity and was often underestimated despite of several reports. We described a case of acute unilateral visual impairment after one cycle of intravenous chemotherapy of a normal dose, aiming at raising attention to chemotherapy-induced ocular toxicity.\n\nCase presentation\nThe patient developed a progressive vision loss in the right eye during the chemotherapy. After one cycle of intravenous chemotherapy, her visual acuity decreased by 0.6 in the right eye (VOD = 0.4) compared to the previous value of 1.0 (VOD = 1.0). No evidence of ocular infiltration was observed from the cerebral magnetic resonance imaging (MRI). During her follow-up period, we documented the ophthalmologic examinations including visual acuity, visual field (VF), visual evoked potential (VEP), electroretinogram (ERG), fundus photograph (FP), fundus fluorescein angiography (FFA) and optical coherence tomography (OCT). Ophthalmoscope examination and fundus photograph showed optic disc edema, fuzzy boundary and linear hemorrhages in her right eye. Fundus fluorescein angiography (FFA) revealed capillary underdevelopment at the nasal and superior temporal area of the optic disc in the early phase and capillary fluorescein leakage in the late phase. The result of VEP test suggested the impaired function of the optic nerve. Thus, a diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION) was made by the ophthalmologist according to these results. The patient was prescribed prednisone combined with neuroprotective drugs, which did not work. After the cessation of chemotherapy, her impaired vision gradually recovered.\n\nConclusions\nThis is the first reported case of acute visual impairment in a patient who underwent chemotherapy of a normal dose. It is indicated that while receiving benefits from chemotherapy, cancer patients simultaneously suffer from the risk of vision loss.\n\nKeywords\nVision lossChemotherapyNonarteritic anterior ischemic optic neuropathyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nPatients with malignancies benefit from the advancement in chemotherapeutic treatments, but chemotherapeutic agents also present a wide spectrum of toxic effects in parallel. In recent years, it has been reported that chemotherapy could induce irreversible or reversible visual loss due to an infrequent form of chemotherapeutic toxicity. For instance, a case that a male patient who had lung cancer suffered from acute unilateral blindness after 5 cycles of cisplatin/gemcitabine (cisplatin 80 mg/m2, gemcitabine 1250 mg/m2) was reported in a study [1]. Visual complications including visual loss are very likely to emerge after patients receive chemotherapy, which are imperative to consult at the ophthalmology department.\n\nCase presentation\nA 48-year-old woman developed tinnitus and enlarged cervical lymph nodes. Nasopharyngoscopy examination and biopsy confirmed the diagnosis of nasopharyngeal squamous cell carcinoma, thus, she received the anti-tumor therapy of a combination of docetaxel, cisplatin and fluorouracil (TPF: docetaxel used on the first day at 75 mg/m2, cisplatin used on the first and second day at 75 mg/m2 and fluorouracil used from the first day to fifth day at 500 mg/m2) which was repeated every four weeks. The patient complained of visual loss in the right eye two weeks after the first cycle of chemotherapy, and she received the second cycle of chemotherapy as planned.\n\nOne week later, she visited an ophthalmologist for the first time because of progressing vision loss, and visual acuity was tested (VOD: visio oculus dexter, for the right eye; VOS: visio oculus sinistra, for the left eye). Her visual acuity had a decrease of 0.6 in the right eye (VOD = 0.4) compared to the original value (VOD = 1.0), and the relative afferent pupillary defect (RAPD) was tested for the right eye. She had a history of high myopia and amblyopia in her left eye evidenced by the low visual acuity (VOS=CF/25 cm, meaning that she could only count fingers at the distance of 25 cm ahead). The current vision impairment in her right eye therefore seriously affected her quality of life. Ophthalmoscope examination and fundus photograph showed optic disc edema, fuzzy boundary and linear hemorrhages in the right eye (Fig. 1a). Typical fundus changes of high myopia were observed in the left eye, such as atrophic arc around optic disc, fuchs spot and tigroid fundus (Fig. 1b). The cerebral magnetic resonance imaging (MRI) provided evidence of no tumor involvement in orbits and central visual pathways (Fig. 1c and d). The long optic axis of the left eye is a typical feature of high myopia eyeball (Fig. 1d). The patient received neurotrophic drug treatments including mecobalamine and citicoline. Three weeks later, the visual acuity in the right eye decreased to 0.3 and the signs of optic disc mentioned above also existed.\nFig. 1 Ophthalmoscope examination and MRI images of orbits during chemotherapy. a: fundus photo of the right eye, b: fundus photo of the left eye (December 6th, 2017), c: MRI images of skull base invasion in nasopharyngeal carcinoma, d: MRI images of orbits (December 26th, 2017)\n\n\n\nAbout one week after the third cycle of chemotherapy, she visited the ophthalmologist for the third time. The VOD was determined to be 0.3. The optic disc edema subsided, the upper part of the optic disc became gray and residual retinal hemorrhage was located on the inferior rim. Macular pucker, depigmented macules and hard exudate were observed in the macular area (Fig. 2a). The optic disc optical coherence tomography (OCT) of the right eye showed that the thickness from the internal limiting membrane to the retinal pigment epithelium (ILM-RPE) at the superior side and nasal side was thinner than that in normal eyes (Fig. 2b). Visual field (VF) examination of the right eye indicated severe visual field defects (Fig. 2c). Fundus fluorescein angiography (FFA) as the most important assistant examination revealed an early phase capillary underdevelopment at the nasal and superior temporal area of the optic disc and a late phase capillary fluorescein leakage (Fig. 2d-f). Thus, a diagnosis of NAION was made for the right eye, and gradually reduced high-dose oral prednisone along with neuroprotective drugs were used for treatment. Meanwhile, retrobulbar injection of compound betamethasone (1 ml) combined with eye drops of ocular hypotensive agents were given to the right eye.\nFig. 2 Ophthalmologic examinations of the right eye one week after chemotherapy ends. a: ophthalmoscope examination, b: optic disc OCT, c: visual field examination, d-f: fundus fluorescein angiography (January 5th, 2018)\n\n\n\nOne month after finishing three cycles of induction chemotherapy, concomitant intravenous antitumor therapy with radiotherapy was started. Due to the suspicious ocular toxicities of cisplatin, Nimotuzumab, a targeted agent, was recommended as an alternative treatment. The patient made the fourth visit to the ophthalmologist, and the VOD of the right eye was determined to be 0.4. The optic disc edema subsided with clear boundary, but the color of the optic disc was still gray (Fig. 3a). OCT showed the secondary macular epiretinal membrane (Fig. 3b). The VF improved obviously compared with the image three weeks ago, which means the function of the optic nerve had been partially repaired (Fig. 3c). The ERG results of the right eye showed that the amplitudes of a-type and b-type wave, as well as P1-type wave were almost normal, suggesting the normal function of the retina (Fig. 3d). The incubation period of P100-type wave in P-VEP test was lengthened, indicating that the function of optic nerve was partially impaired (Fig. 3e).\nFig. 3 Ophthalmologic examinations of the right eye one month after chemotherapy ends. a: ophthalmoscope examination, b: macula OCT, c: visual field examination, d: ERG test, e: P-VEP test (January 25th, 2018)\n\n\n\nAfter finishing radiotherapy, the patient had not been treated with chemotherapy for 3 months. She made her follow-up visit at the ophthalmic clinic and the VOD improved to be 0.5. Moreover, the color of the optic disc was not as gray as before while the macular epiretinal membrane still existed (Fig. 4a and b). The amplitude and incubation periods of P2-type wave from the right eye were almost normal in F-VEP-1HZ test, which signified that the function of the optic nerve had been mostly repaired (Fig. 4c). About 7.5 months after chemotherapy, the patient’s visual acuity remained at VOD 0.5. The VF of her right eye improved dramatically (Fig. 4d). The results of ophthalmologic examinations during her follow-up period are presented in Table 1.\nFig. 4 Ophthalmologic examinations of the right eye at follow-up visits to ophthalmology. a: ophthalmoscope examination, b: macula OCT, c: F-VEP (March 28th,2018), d: visual field examination (August 13th, 2018)\n\n\nTable 1 The results of ophthalmologic examinations in the right eye during the follow-up period\n\nTime points\tEye symptoms\tVisual field\tERG\tVEP\tOCT\tOphthalmoscope examination\tFundus fluorescein angiography\tVisual acuity\t\nDecember 6th, 2017 (during chemotherapy)\tProgressive visual loss\t–\t–\t–\t–\tOptic disc edema, fuzzy boundary and linear hemorrhages.\t–\t0.4\t\nDecember 29th, 2017 (during chemotherapy)\tProgressive visual loss\t–\t–\t–\t–\tOptic disc edema, fuzzy boundary and linear hemorrhages.\t–\t0.3\t\nJanuary 5th, 2018 (1 week after chemotherapy)\tProgressive visual loss\tSevere visual field defects\t–\t–\tThinner ILM-RPE at superior side and nasal side\tThe upper part of the optic disc becoming gray, optic disc edema subsiding and residual retinal hemorrhage on the inferior rim; creases, depigmented macules and hard exudate in the macular area.\tCapillary underdevelopment at the nasal and superior temporal area of optic disc in the early phase and capillary fluorescein leakage in the late phase\t0.3\t\nJanuary 25th, 2018 (1 month after chemotherapy)\tImproved vision\tObviously improved visual field.\tNormal amplitudes of a-type wave, b-type wave and P1-type wave.\tLengthened incubation period of P100-type wave in P-VEP test.\tSecondary macular epiretinal membrane\tGray optic disc without edema and with clear boundary.\t–\t0.4\t\nMarch 28th, 2018 (3 months after chemotherapy)\tImproved vision\t–\t–\tNormal incubation period of P2-type wave.\tSecondary macular epiretinal membrane.\tThe optic disc becoming not so gray as before.\t–\t0.5\t\nAugust 13th, 2018 (7.5 months after chemotherapy)\tImproved vision\tDramatically improved visual field.\t–\t–\t–\t–\t–\t0.5\t\nNote: On October 31st, 2017 the patient received the first cycle of chemotherapy. On November 30th, 2017, she received the second cycle of chemotherapy. On December 29th, 2017, she received the third cycle of chemotherapy. From January 26th, 2018 to March 22th, 2018, she received radiotherapy combined with targeted therapy. VEP visual evoked potential, ERG electroretinogram, OCT optical coherence tomography\n\n\n\nDiscussion and conclusions\nThe neck mass constitutes the most common presenting symptom of nasopharyngeal carcinoma (NPC) [2]. Impaired vision as the initial presentation of NPC caused by the involvement of the optic nerve was rarely reported. As a treatment of NPC, neoadjuvant chemotherapy was currently reported to effectively reduce local-regional recurrences and distant metastases [3]. Fluorouracil and cisplatin are commonly used with major toxicities including myelo-suppression and vomiting. Ocular complications as rare toxicities have not been widely recognized yet and are difficult to be detected. Owing to the improvement in anti-cancer therapies, NPC manifests a favorable prognosis, which helps patients to live a longer life. In addition, healthy eyes and good vision represent an important part of life quality. Therefore, we reported a case aiming at raising the attention to chemotherapy-induced ocular toxicity in the treatment of NPC.\n\nDue to a sharp decrease of visual acuity, the patient was suggested to consult in an ophthalmology clinic for etiological diagnosis and potential therapy. The diagnoses of glaucoma, cataracts, macular degeneration and other eye diseases were excluded; the right optic disk edema was observed by funduscopic examination; and a diagnosis of NAION was made with etiology unknown. NAION is the most common cause of acute visual loss in people aged over 50, resulting from non-inflammatory small vessel ischemic damage to the anterior portion of the optic nerve. However, the cause and pathogenesis of this disorder remain unclear [4, 5]. Neuroprotective drugs or agents acting on the disc edema are often included in the treatment of NAION, but currently none of the therapy has yet been proved to be effective [6]. Given the temporal relationship between chemotherapy and vision loss of the patient, we suspected that the onset of NAION might be attributed to the intravenous chemotherapy. Because of a combination of drugs, it is difficult to identify a specific agent accounting for the followed vision loss. Since the toxic effect on the retinal or optic nerve might cause irreversible vision loss, the early detection of ocular toxicity and the opportune cessation of anti-cancer therapy are necessary. However, sometimes a trade-off between the risk of permanent visual damage and the effectiveness of anti-cancer therapy may emerge.\n\nVision loss attributed to cisplatin, docetaxel and fluorine has been reported in several previous studies. Cisplatin-associated retinal toxicity including blurred vision, color vision defects, and electroretinographic (ERG) changes was dose-dependent or unique to high doses. There was a case that a patient with lung cancer who received five cycles of cisplatin/gemcitabine treatment for lung cancer was admitted to the emergency room unfortunately and complained of acute blindness in his left eye. His fundus examination was normal in both eyes, and the MRI of the left optic nerve and orbit did not reveal any relevant findings. A diagnosis of left retrobulbar optic neuritis was made eventually [1]. There was another case that a 55-year-old man planned to receive a 4-day continuous infusion of cisplatin at a dose of 25 mg/m2 daily as part of a chemotherapeutic salvage regimen for non-Hodgkin lymphoma, but received actual dose of 100 mg/m2 daily for 4 days inadvertently. Except for anorexia, nausea and tinnitus, he developed bilateral decreased vision immediately after the treatment. The ERG showed diminished a-wave and missed b-wave [7]. A clinical study of 52 patients determined the prevalence rates of 5-FU-associated ocular abnormalities [8]. The results showed that the most common presentation was tearing (26.9%), followed by blurred vision (11.5%). After receiving 12 courses of intravenous 5-FU for metastatic breast cancer, a 72-year-old woman complained of a sudden visual loss, and her vision started to recover after the discontinuation of anti-cancer agent. A deficiency of dihydropyrimidine dehydrogenase (DPD) was detected and 5-FU was considered to be responsible for the visual loss associated with DPD deficiency [9]. Another female who received monthly intravenous infusion of docetaxel for metastastic breast cancer also complained of blurred vision in both eyes two months later after the treatment. Then docetaxel was replaced by Xeloda, and her vision started to recover [10].\n\nWhen patients suddenly develop vision loss while receiving chemotherapy, the possibility of chemotherapy-induced NAION should be considered. Most ophthalmic complications are reversible if recognized in an early phase. Besides, dosage reduction or agent cessation could rescue patients from vision loss. However, if the optic nerve or the retinal was involved, patients might develop irreversible vision loss. Induction chemotherapy plays a crucial role in the treatment of local advanced nasopharyngeal carcinoma, and presented here was one case of severe visual impairment induced by chemotherapy. Therefore, it is indicated that cancer patients take the risk of vision loss while benefiting from chemotherapy.\n\nAlthough it has been reported that intravenous chemotherapy of cisplatin and docetaxel could cause retinal toxicity, this is the first case demonstrating that intravenous administration of chemotherapy (TPF) for NPC could induce NAION and cause irreversible vision loss. This reported case suggests that when patients suddenly develop visual impairment after receiving chemotherapy, the possibility of ophthalmic complications should be considered. In addition, as soon as symptoms are recognized, the patient should be scheduled for further examinations in the ophthalmology clinic, and a cooperation between oncologists and ophthalmologists is necessary for subsequent treatment.\n\nAbbreviations\nERGElectroretinogram\n\nFFAFundus fluorescein angiography\n\nFPFundus photograph\n\nILMInternal limiting membrane\n\nMRIMagnetic resonance imaging\n\nNAIONNonarteritic anterior ischemic optic neuropathy\n\nNPCNasopharyngeal carcinoma\n\nOCTOptical coherence tomography\n\nRAPDRelative afferent pupillary defect\n\nVEPVisual evoked potential\n\nVFVisual field\n\nVODVisio oculus dexter, for the right eye\n\nVOSVisio oculus sinistra\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nXia Yuan and Yuliang Feng contributed equally to this work.\n\nAcknowledgements\nWe thank the patient for consenting and for assenting to the publication of this article.\n\nAuthors’ contributions\nM.L. conceived the idea, participated in information gathering, literature search and data analysis. X.Y. participated in information gathering, literature search, data analysis and drafting the final manuscript. Y.F. performed the ophthalmologic examination and composed this manuscript. D. L participated in drafting the final manuscript and editing the figures. All authors read and approved the final manuscript.\n\nFunding\nThis research did not receive any funding.\n\nAvailability of data and materials\nThe data supporting the conclusions of this article are included within the article.\n\nEthics approval and consent to participate\nThe report of patient data was approved by the Institutional Animal Care and Use Committee and Ethics Committee.\n\nConsent for publication\nWritten consent was obtained from the patient for the publication of the patient’s details.\n\nCompeting interests\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1. Gonzalez F Menendez D Gomez-Ulla F Monocular visual loss in a patient undergoing cisplatin chemotherapy Int Ophthalmol 2001 24 6 301 304 10.1023/B:INTE.0000006763.61637.7e 14750566 \n2. Chu EA Wu JM Tunkel DE Ishman SL Nasopharyngeal carcinoma: the role of the Epstein-Barr virus Medscape J Med 2008 10 7 165 18769688 \n3. Langendijk JA Leemans CR Buter J Berkhof J Slotman BJ The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology 2004 22 22 4604 10.1200/JCO.2004.10.074 15542811 \n4. Atkins EJ Bruce BB Newman NJ Biousse V Treatment of Nonarteritic anterior ischemic optic neuropathy Surv Ophthalmol 2010 55 1 47 63 10.1016/j.survophthal.2009.06.008 20006051 \n5. Listed N Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the ischemic optic neuropathy decompression trial Arch Ophthalmol 1996 114 11 1366 1374 10.1001/archopht.1996.01100140566007 8906027 \n6. Hattenhauer MG Leavitt JA Hodge DO Grill R Gray DT Incidence of nonarteritic anterior ischemic optic neuropathy Am J Ophthalmol 1997 123 1 103 10.1016/S0002-9394(14)70999-7 9186104 \n7. Katz BJ Ward JH Digre KB Creel DJ Mamalis N Persistent severe visual and electroretinographic abnormalities after intravenous Cisplatin therapy J Neuroophthalmol 2003 23 2 132 135 10.1097/00041327-200306000-00005 12782925 \n8. Eiseman AS Flanagan JC Brooks AB Mitchell EP Pemberton CH Ocular surface, ocular adnexal, and lacrimal complications associated with the use of systemic 5-fluorouracil Ophthalmic Plast Reconstr Surg 2003 19 3 216 224 10.1097/01.IOP.0000066648.33513.3D 12918558 \n9. Delval L Klastersky J Optic neuropathy in cancer patients. Report of a case possibly related to 5 fluorouracil toxicity and review of the literature J Neurooncol 2002 60 2 165 10.1023/A:1020613600826 12635664 \n10. Teitelbaum BA Tresley DJ Cystic maculopathy with normal capillary permeability secondary to docetaxel Optometry & Vision Science Official Publication of the American Academy of Optometry 2003 80 4 277 10.1097/00006324-200304000-00004 12692483\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2415", "issue": "19(1)", "journal": "BMC ophthalmology", "keywords": "Chemotherapy; Nonarteritic anterior ischemic optic neuropathy; Vision loss", "medline_ta": "BMC Ophthalmol", "mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D014786:Vision Disorders", "nlm_unique_id": "100967802", "other_id": null, "pages": "236", "pmc": null, "pmid": "31752765", "pubdate": "2019-11-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15542811;8906027;20006051;18769688;14750566;12782925;12635664;12918558;9186104;12692483", "title": "Unilateral visual impairment in a patient undergoing chemotherapy: a case report and clinical findings.", "title_normalized": "unilateral visual impairment in a patient undergoing chemotherapy a case report and clinical findings" }

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"drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "018057", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "75 MG/M2, 1ST AND 2ND DAY, FIRST CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "KERATINISING SQUAMOUS CELL CARCINOMA OF NASOPHARYNX", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20171031", "drugstartdateformat": "102", "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG/M2, 1ST TO 5TH DAY, FIRST CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "KERATINISING SQUAMOUS CELL CARCINOMA OF NASOPHARYNX", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20171031", "drugstartdateformat": "102", "drugstructuredosagenumb": "500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic ischaemic neuropathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201711" } }, "primarysource": { "literaturereference": "YUAN X., FENG Y., LI D., LI M.. UNILATERAL VISUAL IMPAIRMENT IN A PATIENT UNDERGOING CHEMOTHERAPY: A CASE REPORT AND CLINICAL FINDINGS. BMC OPHTHALMOLOGY. 2019?19(1):236", "literaturereference_normalized": "unilateral visual impairment in a patient undergoing chemotherapy a case report and clinical findings", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20200803", "receivedate": "20200803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18105905, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "OBJECTIVE\nTo present a case of new-onset, bilateral, rapidly progressive keratoconus induced by secondary hypothyroidism after radioactive iodine therapy during the sixth decade of life that was successfully treated with corneal cross-linking.\n\n\nMETHODS\nCase report and literature review.\n\n\nRESULTS\nA 53-year-old woman with no ocular complaints but with a history of Graves' disease and thyrotoxicosis was treated with radioactive iodine therapy and oral levothyroxine for secondary acquired hypothyroidism 3 years prior. Initially, uncorrected distance visual acuity (UDVA) was 20/40 and corrected distance visual acuity (CDVA) was 20/25 in both eyes. Over the following 3 years, the patient developed worsening UDVA and CDVA, with increasing manifest astigmatism of greater than 7.00 diopters (D) in the right eye and 4.75 D in the left eye, with corneal thinning and focal steepening and was diagnosed as having bilateral progressive keratoconus. The patient underwent sequential corneal cross-linking with resultant postoperative CDVA of 20/20 and reduced maximum keratometry and manifest astigmatism in both eyes. The patient's thyroid levels were within normal limits throughout the clinical course.\n\n\nCONCLUSIONS\nThis case provides evidence of the relationship between keratoconus development and thyroid gland dysfunction. The pathophysiology of this relationship has yet to be completely elucidated, but elevated levels of thyroxine in the aqueous humor and tear film and thyroxine receptors in the cornea likely play a role. Screening topographies for patients with thyroid gland dysfunction may be of value for these higher risk patients. [J Refract Surg. 2018;34(5):351-353.].", "affiliations": null, "authors": "Lee|Ramon|R|;Hafezi|Farhad|F|;Randleman|J Bradley|JB|", "chemical_list": "D003432:Cross-Linking Reagents; D007457:Iodine Radioisotopes; D017319:Photosensitizing Agents; D011988:Receptors, Thyroid Hormone; D003094:Collagen", "country": "United States", "delete": false, "doi": "10.3928/1081597X-20171031-02", "fulltext": null, "fulltext_license": null, "issn_linking": "1081-597X", "issue": "34(5)", "journal": "Journal of refractive surgery (Thorofare, N.J. : 1995)", "keywords": null, "medline_ta": "J Refract Surg", "mesh_terms": "D003094:Collagen; D063171:Corneal Pachymetry; D003319:Corneal Stroma; D003432:Cross-Linking Reagents; D005260:Female; D006111:Graves Disease; D006801:Humans; D007037:Hypothyroidism; D007457:Iodine Radioisotopes; D007640:Keratoconus; D008875:Middle Aged; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D011832:Radiation Injuries; D011988:Receptors, Thyroid Hormone; D013961:Thyroid Gland; D013971:Thyrotoxicosis; D041623:Tomography, Optical Coherence; D014466:Ultraviolet Rays; D014792:Visual Acuity", "nlm_unique_id": "9505927", "other_id": null, "pages": "351-353", "pmc": null, "pmid": "29738593", "pubdate": "2018-05-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Bilateral Keratoconus Induced by Secondary Hypothyroidism After Radioactive Iodine Therapy.", "title_normalized": "bilateral keratoconus induced by secondary hypothyroidism after radioactive iodine therapy" }

[ { "companynumb": "US-BRACCO-2018US03313", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "010929", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2012", "drugenddateformat": "602", "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Keratoconus", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "LEE R. BILATERAL KERATOCONUS INDUCED BY SECONDARY HYPOTHYROIDISM AFTER RADIOACTIVE IODINE THERAPY. JOURNAL OF REFRACTIVE SURGERY 2018 MAY? 34: (5):351-353.", "literaturereference_normalized": "bilateral keratoconus induced by secondary hypothyroidism after radioactive iodine therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180629", "receivedate": "20180629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15089654, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-MIST-TIR-2018-0639", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "NOT PROVIDED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOACTIVE IODINE THERAPY" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021924", "drugbatchnumb": "NOT PROVIDED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125MCG AND 112MCG ON ALTERNATING DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SECONDARY HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Keratoconus", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Blepharitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Blood thyroid stimulating hormone increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "RANDLEMAN, MD J, LEE, MD R, HAFEZI, MD, PHD F. BILATERAL KERATOCONUS INDUCED BY SECONDARY HYPOTHYROIDISM AFTER RADIOACTIVE IODINE THERAPY. JOURNAL OF REFRACTIVE SURGERY. 2018?34(5):351?353.", "literaturereference_normalized": "bilateral keratoconus induced by secondary hypothyroidism after radioactive iodine therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180725", "receivedate": "20180705", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15110587, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "We present a rare case of intimal sarcoma arising from the common iliac artery in an 82-year-old man who presented with intermittent claudication. He had undergone endovascular therapy with self-expanding stents to both iliac arteries that had occluded soon after placement. After salvage bypass grafting, a diagnosis of intimal sarcoma with angiosarcoma phenotype from the iliac artery was made. Further bypass graft surgery relieved symptoms temporarily. However, the tumor progressed and the left limb became ischemic. The chemotherapy of eribulin did not prevent tumor progression. The patient died of the disease 20 months after the first surgery. J. Med. Invest. 66 : 205-208, February, 2019.", "affiliations": "Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Cardiovascular Surgery, Tokushima Prefectural Central Hospital, Tokushima, Japan.;Department of Pathology, Tokushima Prefectural Central Hospital, Tokushima, Japan.;Department of Radiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Radiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.", "authors": "Kano|Masashi|M|;Nishisho|Toshihiko|T|;Miyagi|Ryo|R|;Chikugo|Fumio|F|;Kudo|Eiji|E|;Takao|Shoichiro|S|;Iwamoto|Seiji|S|;Toki|Shunichi|S|;Sairyo|Koichi|K|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.2152/jmi.66.205", "fulltext": null, "fulltext_license": null, "issn_linking": "1343-1420", "issue": "66(1.2)", "journal": "The journal of medical investigation : JMI", "keywords": "eribulin; great vessels; intimal sarcoma; salvage bypass grafting", "medline_ta": "J Med Invest", "mesh_terms": "D000369:Aged, 80 and over; D001157:Arterial Occlusive Diseases; D006801:Humans; D007083:Iliac Artery; D008297:Male; D012509:Sarcoma", "nlm_unique_id": "9716841", "other_id": null, "pages": "205-208", "pmc": null, "pmid": "31064943", "pubdate": "2019", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Intimal sarcoma arising from the common iliac artery presenting with artery occlusion : a case report and literature review.", "title_normalized": "intimal sarcoma arising from the common iliac artery presenting with artery occlusion a case report and literature review" }

[ { "companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2019-056329", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERIBULIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "201532", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": "20161207", "drugenddateformat": "102", "drugindication": "SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161130", "drugstartdateformat": "102", "drugstructuredosagenumb": "2.11", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERIBULIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERIBULIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "201532", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": "20161227", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161220", "drugstartdateformat": "102", "drugstructuredosagenumb": "2.33", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERIBULIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypoaesthesia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysgeusia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20161202" } }, "primarysource": { "literaturereference": "KANO M, NISHISYO T, MIYAGI R, CHIKUGO F, KUDO E, TAKAO S, IWAMOTO S, TOKI S, SAIRYO K. INTIMAL SARCOMA ARISING FROM THE COMMON ILIAC ARTERY PRESENTING WITH ARTERY OCCLUSION : A CASE REPORT AND LITERATURE REVIEW. J. MED. INVEST. 2019 FEB?66:205-208.", "literaturereference_normalized": "intimal sarcoma arising from the common iliac artery presenting with artery occlusion a case report and literature review", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20191017", "receivedate": "20190515", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16314584, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "JP-AMGEN-JPNSP2019134160", "fulfillexpeditecriteria": "2", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO BONE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANMARK" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ERIBULIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERIBULIN" } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeding disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoaesthesia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MASASHI K., TOSHIHIKO N., RYO M., ET. AL.. INTIMAL SARCOMA ARISING FROM THE COMMON ILIAC ARTERY PRESENTING WITH ARTERY OCCLUSION : A CASE REPORT AND LITERATURE REVIEW. THE JOURNAL OF MEDICAL INVESTIGATION. 2019?205-208:66", "literaturereference_normalized": "intimal sarcoma arising from the common iliac artery presenting with artery occlusion a case report and literature review", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190822", "receivedate": "20190822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16730225, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice.\n\n\n\nConsecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up.\n\n\n\nOne hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5-21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal.\n\n\n\nSubcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.", "affiliations": "*Servicio de Aparato Digestivo, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain; †Servicio de Aparato Digestivo, Hospital Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; ‡Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; §Servicio de Aparato Digestivo, Complejo Hospitalario de León, León, Spain; ‖Servicio de Aparato Digestivo, Hospital Universitario y Politécnico La Fe, CIBERehd, Valencia, Spain; ¶Servicio de Aparato Digestivo, Complejo Asistencial Universitario de Burgos, Burgos, Spain; **Servicio de Aparato Digestivo, Hospital Universitario Reina Sofía, IMIBIC, Córdoba, Spain; ††Servicio de Aparato Digestivo, Hospital Universitario Puerta de Hierro, Madrid, Spain; ‡‡Servicio de Aparato Digestivo, Corporació Sanitària Universitària Parc Taulí, CIBERehd, Instituto de Salud Carlos III, Sabadell, Spain; §§Servicio de Aparato Digestivo, Hospital Clínico San Carlos, Instituto de Investigación del Hospital Clínico San Carlos (IdISSC), Madrid, Spain; ‖‖Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, Spain; and ¶¶Servicio de Aparato Digestivo, Hospital Universitario Ramón y Cajal, Madrid, Spain.", "authors": "Khorrami|Sam|S|;Ginard|Daniel|D|;Marín-Jiménez|Ignacio|I|;Chaparro|María|M|;Sierra|Mónica|M|;Aguas|Mariam|M|;Sicilia|Beatriz|B|;García-Sánchez|Valle|V|;Suarez|Cristina|C|;Villoria|Albert|A|;Taxonera|Carlos|C|;Velasco-Guardado|Antonio|A|;Martínez-González|Javier|J|;Gisbert|Javier P|JP|", "chemical_list": "D000893:Anti-Inflammatory Agents; D000069549:Ustekinumab", "country": "England", "delete": false, "doi": "10.1097/MIB.0000000000000842", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0998", "issue": "22(7)", "journal": "Inflammatory bowel diseases", "keywords": null, "medline_ta": "Inflamm Bowel Dis", "mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D003424:Crohn Disease; D017577:Cutaneous Fistula; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D012003:Rectal Fistula; D019233:Retreatment; D012189:Retrospective Studies; D013030:Spain; D000069549:Ustekinumab", "nlm_unique_id": "9508162", "other_id": null, "pages": "1662-9", "pmc": null, "pmid": "27306072", "pubdate": "2016-07", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Ustekinumab for the Treatment of Refractory Crohn's Disease: The Spanish Experience in a Large Multicentre Open-label Cohort.", "title_normalized": "ustekinumab for the treatment of refractory crohn s disease the spanish experience in a large multicentre open label cohort" }

[ { "companynumb": "ES-JNJFOC-20160704298", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "USTEKINUMAB" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "125261", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "USTEKINUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pharyngitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ear infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anal abscess", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orchitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHORRAMI S, GINARD D, MARIN I, CHAPARRO M, SIERRA M, AGUAS M, ET AL. USTEKINUMAB FOR THE TREATMENT OF REFRACTORY CROHN^S DISEASE: THE SPANISH EXPERIENCE IN A LARGE MULTICENTRE OPEN-LABEL COHORT. INFLAMM BOWEL DIS JUL-2016;22 (7):1662-9.", "literaturereference_normalized": "ustekinumab for the treatment of refractory crohn s disease the spanish experience in a large multicentre open label cohort", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20160725", "receivedate": "20160725", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12586998, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "Nivolumab is an immune checkpoint inhibitor that is used in the treatment of a variety of cancers in the adjuvant or metastatic setting. Adverse effects include non-specific activation of T cells, leading to immune-related adverse events in downstream organs. We present a case of a 36-year-old man with unresectable oropharyngeal squamous cell carcinoma who developed nivolumab-induced rheumatoid arthritis. As immune checkpoint inhibitor use is becoming widespread in the medical oncology domain, the purpose of this case report is to increase awareness of an increasingly common cause of rheumatic disease and to alert clinicians to consider immunotherapy in their differential diagnosis of polyarthritis. This case also highlights the importance of working in an interdisciplinary manner to enhance cancer care for the patient as well as to increase awareness of the potential adverse effects of immunotherapy in patients with cancer.", "affiliations": "Department of Medicine, University of Toronto, Toronto, Ontario, Canada.;Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.", "authors": "Kwok|Timothy Shun Him|TSH|;Bell|Mary Jane|MJ|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab", "country": "England", "delete": false, "doi": "10.1136/bcr-2018-227995", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(2)", "journal": "BMJ case reports", "keywords": "cancer intervention; drugs: musculoskeletal and joint diseases; medical management; rheumatology; unwanted effects/adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D018771:Arthralgia; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D006801:Humans; D007167:Immunotherapy; D007596:Joints; D008297:Male; D000077594:Nivolumab; D011859:Radiography; D014463:Ultrasonography", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "30819683", "pubdate": "2019-02-27", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28830882;24357284;28600350;27752360;27890174;12431386;29567705;24916606;17992258;27539666;24613573", "title": "Immune checkpoint inhibitor-induced rheumatoid arthritis: insights into an increasingly common aetiology of polyarthritis.", "title_normalized": "immune checkpoint inhibitor induced rheumatoid arthritis insights into an increasingly common aetiology of polyarthritis" }

[ { "companynumb": "CA-ACCORD-116657", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OROPHARYNGEAL SQUAMOUS CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VITAMIN SUPPLEMENTATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206775", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR CUTANEOUS SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OROPHARYNGEAL SQUAMOUS CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Streptococcal sepsis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KWOK TSH, BELL MJ. IMMUNE CHECKPOINT INHIBITOR-INDUCED RHEUMATOID ARTHRITIS: INSIGHTS INTO AN INCREASINGLY COMMON AETIOLOGY OF POLYARTHRITIS. BMJ CASE REPORTS. 2019:12(2):ARTICLE NUMBER E227995.", "literaturereference_normalized": "immune checkpoint inhibitor induced rheumatoid arthritis insights into an increasingly common aetiology of polyarthritis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190402", "receivedate": "20190402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16145464, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "CA-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-031570", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125554", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM/KILOGRAM, Q2WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OROPHARYNGEAL SQUAMOUS CELL CARCINOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rheumatoid arthritis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KWOK T, BELL M, ET AL. IMMUNE CHECKPOINT INHIBITOR?INDUCED RHEUMATOID ARTHRITIS INSIGHTS INTO AN INCREASINGLY COMMON AETIOLOGY OF POLYARTHRITIS. BMJ CASE REPORT. 2019?12(2):22799", "literaturereference_normalized": "immune checkpoint inhibitor induced rheumatoid arthritis insights into an increasingly common aetiology of polyarthritis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20210419", "receivedate": "20190402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16146650, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210716" } ]

{ "abstract": "Patients receiving treatment for tuberculosis may experience an unexpected deterioration of their disease; this is known as a paradoxical reaction. We present the case of a 59-year-old man with lupus vulgaris who experienced a paradoxical deterioration of cutaneous lesions after starting antituberculosis therapy. The reaction was self-limiting; the lesions gradually improved, and the final outcome was very good. Paradoxical reactions are well-known in patients with human immunodeficiency virus (HIV) infection who start antiretroviral therapy, but they can also occur in non-HIV-infected patients with tuberculosis who start antituberculosis therapy. In the literature reviewed, paradoxical reactions involving skin lesions were described in patients with miliary tuberculosis. The case we report is the first of a paradoxical reaction in lupus vulgaris. The increasing frequency of tuberculosis in Spain could lead to a rise in the number of paradoxical reactions.", "affiliations": "Servicio de Dermatología, Complejo Hospitalario de Navarra, Pamplona, España. Electronic address: raquel.santesteban@hotmail.com.;Servicio de Dermatología, Complejo Hospitalario de Navarra, Pamplona, España.;Servicio de Anatomía Patológica, Complejo Hospitalario de Navarra, Pamplona, España.;Servicio de Dermatología, Complejo Hospitalario de Navarra, Pamplona, España.", "authors": "Santesteban|R|R|;Bonaut|B|B|;Córdoba|A|A|;Yanguas|I|I|", "chemical_list": "D000995:Antitubercular Agents", "country": "Spain", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0001-7310", "issue": "106(2)", "journal": "Actas dermo-sifiliograficas", "keywords": "Cutaneous tuberculosis; Immune reconstitution syndrome; Lupus vulgar; Lupus vulgaris; Mycobacterium tuberculosis; Síndrome de reconstitución inmune; Tuberculosis cutánea", "medline_ta": "Actas Dermosifiliogr", "mesh_terms": "D000995:Antitubercular Agents; D003875:Drug Eruptions; D006801:Humans; D008177:Lupus Vulgaris; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "0373062", "other_id": null, "pages": "e7-e12", "pmc": null, "pmid": "25089032", "pubdate": "2015-03", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Paradoxical reaction to antituberculosis therapy in a patient with lupus vulgaris.", "title_normalized": "paradoxical reaction to antituberculosis therapy in a patient with lupus vulgaris" }

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PARADOXICAL REACTION TO ANTITUBERCULOSIS THERAPY IN A PATIENT WITH LUPUS VULGARIS. 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{ "abstract": "Scedosporium apiospermum, an ubiquitous filamentous fungus, a known cause of mycetoma, is emerging as an opportunistic pathogen in immunocompromised individuals. We report a case of painful foot abscess in a renal allograft recipient on immunosuppressive therapy, which was clinically diagnosed as a suppurative bacterial abscess. Pus was aspirated, which showed septate, branching hyphal elements and culture on Sabouraud's dextrose agar yielded S. apiospermum, which was identified based on its macroscopic and microscopic features. There are very few reports of scedosporiasis from India. High index of suspicion for unusual fungal infection helps in prompt etiological diagnosis in a transplant recipient and rapid management prevents further dissemination.", "affiliations": "Department of Microbiology, ESI-Post Graduate Institute of Medical Sciences and Research and ESIC Medical College, Kolkata, West Bengal, India.;Department of Dermatology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.;Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.;Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.", "authors": "Ghosh|R|R|;Mishra|P|P|;Maiti|P K|PK|;Debnandi|A|A|", "chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole", "country": "India", "delete": false, "doi": "10.4103/0022-3859.201415", "fulltext": "\n==== Front\nJ Postgrad MedJ Postgrad MedJPGMJournal of Postgraduate Medicine0022-38590972-2823Medknow Publications & Media Pvt Ltd India 28272067JPGM-63-20010.4103/0022-3859.201415Case ReportPrompt diagnosis of Scedosporium apiospermum soft tissue infection: Life-saving in a renal transplant recipient Ghosh R Mishra P 1Maiti PK 2Debnandi A 2Department of Microbiology, ESI-Post Graduate Institute of Medical Sciences and Research and ESIC Medical College, Kolkata, West Bengal, India1 Department of Dermatology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India2 Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, IndiaAddress for correspondence: Dr. Roumi Ghosh, E-mail: roumighosh@gmail.comJul-Sep 2017 63 3 200 202 21 8 2016 23 11 2016 01 12 2016 Copyright: © 2017 Journal of Postgraduate Medicine2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Scedosporium apiospermum, an ubiquitous filamentous fungus, a known cause of mycetoma, is emerging as an opportunistic pathogen in immunocompromised individuals. We report a case of painful foot abscess in a renal allograft recipient on immunosuppressive therapy, which was clinically diagnosed as a suppurative bacterial abscess. Pus was aspirated, which showed septate, branching hyphal elements and culture on Sabouraud's dextrose agar yielded S. apiospermum, which was identified based on its macroscopic and microscopic features. There are very few reports of scedosporiasis from India. High index of suspicion for unusual fungal infection helps in prompt etiological diagnosis in a transplant recipient and rapid management prevents further dissemination.\n\nKEY WORDS\nHyalohyphomycosesrenal transplantationScedosporium apiospermumvoriconazole\n==== Body\nIntroduction\nThe incidence of severe systemic fungal infections has been increased significantly, mainly because of the marked increase in the number of patients with compromised immune system. Invasive fungal infections (IFIs) are among the most important causes of morbidity and mortality among solid organ transplant recipients who are on long-term graft-preserving immunosuppressive therapy. Immunosuppressive treatment with calcineurin inhibitors, such as cyclosporine, pimecrolimus and tacrolimus impairs interleukin-2 (IL-2) expression, resulting in increased susceptibility to various invasive fungal diseases. Indiscriminate use of antibiotics also contributes to the worsening of this picture, leading to the installation of fungal infections. High mortality rate (25%–80%) due to IFIs within the first 6 months after organ transplantation has been documented.[1] Commonly reported IFIs among transplant recipients are invasive candidiasis, cryptococcosis, and invasive mold infections, such as aspergillosis and zygomycosis.[1] Among nonAspergillus molds, Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections after transplantation and can present with broad spectrum clinical diseases.\n\nCase Report\nA 27-year-old girl presented with a very painful, gradually increasing swelling in the left sole which appeared following a trauma sustained 3 months ago. She underwent renal allograft transplantation 18 months back due to chronic kidney disease Stage 5D. The patient was on tacrolimus (1 mg BD), azathioprine (50 mg OD), and prednisolone (10 mg OD) when she presented. She was also suffering from diabetes with a fasting sugar 92 mg/dl and was on glipizide and pioglitazone. Her history sheet revealed that induction immunosuppressive therapy was carried out before transplantation with 20 mg single dose basiliximab on the day of transplant. There was no episode of graft rejection during posttransplant period. On clinical examination, it was tender, soft, fluctuant abscess over the left sole measuring about 4 cm × 3 cm, there was local increase of temperature and pus oozing from small breach of overlying skin [Figure 1].\n\nFigure 1 Soft, fluctuant abscess over left sole (4 cm × 3 cm in size) with oozing pus\n\nAbscess was surgically drained and a pus swab and biopsy was taken from abscess bed. Histopathological examination revealed irregular epidermal acanthosis, dermal fibrosis, vascular proliferation, and dense infiltration of inflammatory cells. Pus swab was cultured on routine media and showed the growth of coagulase negative Staphylococcus. With the view of immunosupressed condition of the patient, she was treated with amoxicillin-clavulanic acid and levofloxacin but pus filled swelling reappeared within 7 days. Then, the aspirated pus sample was collected in the Microbiology Laboratory which was examined by Gram-staining, Ziehl–Neelsen staining, and potassium hydroxide (KOH) preparation. KOH mount showed the plenty of branching, septate hyaline hyphae. The sample was inoculated on blood agar, Sabouraud's dextrose chloramphenicol agar and incubated at 25°C and 37°C. Growth of white mycelial fungus was seen after the 3rd day of incubation. Fast growing, grayish-white colony, with suede like surface and grayish-black reverse was examined with lactophenol-cotton blue preparation on the 5th day and it showed hyaline, branching, septate hyphae with single, oval conidia present on the tip of erect conidiophores [Figure 2]. Slide culture was done on distilled water agar and potato dextrose agar showed the presence of cleistothecia after 3 weeks of incubation. With the help of suggestive microscopic features isolate was phenotypically identified as Scedosporium spp.[2] The isolate was deposited (Deposition no.: ILK997) in the reference laboratory at Postgraduate Institute of Medical Education and Research, Chandigarh, India for and it was confirmed as Scedosporium apiospermum.\n\nFigure 2 (a) Sabouraud dextrose agar with growth of greyish-white colony and greyish-black reverse. (b) Lactophenol-cotton blue preparation showing hyaline branching septate hyphae with single conidia present on the tip of erect conidiophores (×400)\n\nThe patient was promptly started on oral voriconazole 250 mg BD and continued for 6 weeks. Dose of tacrolimus was reduced from 2 to 1 mg/day. Her infection started to improve. However, 6 weeks later, she reported nausea, difficulty in concentration and visual hallucinations. The complaints were consistent with known voriconazole side effects. Hence, the dose of voriconazole was reduced to 200 mg twice/day. In this regimen, her adverse symptoms improved in 2 weeks. The patient ultimately completed a total of 3 months of oral voriconazole and remained free of any signs of recurrence 8 months after the completion of therapy.\n\nDiscussion\nS. apiospermum complex, the asexual form or anamorph state of Pseudallescheria boydii, has been recognized to encompass several distinct, medically important species[3]. It is a hyaline, filamentous, ascomycetous fungus, ubiquitously present in soil, sewage, and polluted waters. The asexual form produces brown colored, round, or elliptical single celled conidia borne singly from the tips of long or short erect, slender conidiophores. The sexual form (teleomorph) exhibits cleistothecia, which are sac like structures that contain asci and ascospores. Unlike S. apiospermum, Scedosporium prolificans produces conidiophores with distinctly swollen bases, and the conidial mass forms apical aggregates of conidia. The teleomorph state is also not produced by S. prolificans.[2]\n\nIt was described more than a century ago as a cause of Madura foot and subsequently white grain mycetoma, otitis externa and disseminated mycosis in lungs with cystic fibrosis. Four types of infection caused by either Pseudallescheria or Scedosporium spp. have been described in literature: (i) Mycetoma, (ii) opportunistic infections among transplantation recipients and those receiving antineoplasic or immunosuppressive therapy, (iii) nonopportunistic infections commonly following penetrating trauma, (iv) sino-pulmonary and central nervous system infections in immunocompetent individuals following near drowning in polluted waters.[3] Although, previously the organism with low inherent virulence was considered exceedingly rare, an increasing number of invasive infections are being reported in recent times mainly in patients with hematological malignancies or in those who have undergone solid organ transplantation.[3] High rate of dissemination following deep seated Scedosporium infections commonly seen in transplant recipients due to their immune-suppressed status. There are very few subcutaneous and invasive Scedosporium infections have been reported from India except mycetoma.[456]\n\nIn histopathological examination, Scedosporium could not be distinguished from other septate, hyaline molds, such as Aspergillus, Fusarium, Paecilomyces, which are relatively common but have different resistance profile. Fungal culture is the gold standard in establishing accurate and prompt diagnosis of S. apiospermum. It is essential, because this organism can often be misidentified as other filamentous fungus with different resistance profiles.[7] Scedosporium species are generally resistant to amphotericin B and. S. prolificans, in particular, is also resistant to most of the currently available antifungal agents.[8] Hence, empirical use of antifungals against Candida and Aspergillus in immunocompromised patients might create a selective pressure and contribute to the increased incidence of Scedosporium infections.\n\nIn our case, the early detection of fungal elements in the direct microscopy, culture isolation and speciation were all necessary to make a timely and accurate diagnosis. Treatment of Scedosporium spp. is often difficult, particularly when abscess sites are not amenable to surgical intervention, as inadequate debridement impedes the penetration of systemic antifungals. Although voriconazole, with broadened antifungal spectrum, showed promising result in S. apiospermum infections, significant side effect of vision disturbance and its pharmacokinetic interaction with IL-2 inhibitors, makes the dose titration difficult.[3] Combination therapy of voriconazole and terbinafine/micafungin, antifungal with granulocyte-macrophage colony-stimulating factor also showed efficacy in disseminated cases.[8] Fortunately, our case responded with oral voriconazole therapy without further spread.\n\nConclusion\nThis case enlightens us to consider fungal infections in the differential diagnosis, especially in immunocompromised patients and to be aware of unusual hyalohyphomycosis. It also highlights the importance of sending aspirated pus sample instead of a swab for diagnosing fungal etiology; which plays a vital role in prompt treatment and favorable outcome for the patient.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Khan A El-Charabaty E El-Sayegh S Fungal infections in renal transplant patients J Clin Med Res 2015 7 371 8 25883698 \n2 Chander J A Text Book of Medical Mycology 2002 2nd ed New Delhi Mehta Publishers 324 5 \n3 Cortez KJ Roilides E Quiroz-Telles F Meletiadis J Antachopoulos C Knudsen T Infections caused by Scedosporium spp Clin Microbiol Rev 2008 21 157 97 18202441 \n4 Vijaya D Nagaratnama T Satihish JV Diabetic foot ulcer due to Scedosporium apiospermum J Clin Diagn Res 2013 7 2579 80 24392407 \n5 Rathi M Gundlapalli S Ramachandran R Mohindra S Kaur H Kumar V A rare case of Cytomegalovirus , Scedosporium apiospermum and Mycobacterium tuberculosis in a renal transplant recipient BMC Infect Dis 2014 14 259 24885965 \n6 Verma S Minhas S Verma GK Shanker V Tegta GR Sharma S Disseminated Scedosporium apiospermum infection with leprosy responsive to voriconazole JMM Case Rep 2014 1 1 5 \n7 Shinohara MM George E Scedosporium apiospermum : An emerging opportunistic pathogen that must be distinguished from Aspergillus and other hyalohyphomycetes J Cutan Pathol 2009 36 Suppl 1 39 41 \n8 Goldman C Akiyama MJ Torres J Louie E Meehan SA Scedosporium apiospermum infections and the role of combination antifungal therapy and GM-CSF: A case report and review of the literature Med Mycol Case Rep 2016 11 40 3 27182483\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0022-3859", "issue": "63(3)", "journal": "Journal of postgraduate medicine", "keywords": null, "medline_ta": "J Postgrad Med", "mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008271:Mycetoma; D009181:Mycoses; D021681:Scedosporium; D013211:Staphylococcus aureus; D066027:Transplant Recipients; D016896:Treatment Outcome; D065819:Voriconazole", "nlm_unique_id": "2985196R", "other_id": null, "pages": "200-202", "pmc": null, "pmid": "28272067", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "19775393;24392407;18202441;24885965;25883698;27182483", "title": "Prompt diagnosis of Scedosporium apiospermum soft tissue infection: Life-saving in a renal transplant recipient.", "title_normalized": "prompt diagnosis of scedosporium apiospermum soft tissue infection life saving in a renal transplant recipient" }

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{ "abstract": "Delayed hypoxic leukoencephalopathy is an underrecognized syndrome of delayed demyelination, which is important to consider when delayed onset of neuropsychiatric symptoms follows a hypoxic event. The authors describe clinical and diagnostic features of three such cases, review the pathophysiology of delayed hypoxic leukoencephalopathy, and discuss features which may help distinguish it from toxic leukoencephalopathy.", "affiliations": "University of Rochester, Department of Neurology, 1351 Mt. Hope Ave, Suite 100, Rochester, NY 14620-3917, USA. David_Shprecher@urmc.rochester.edu", "authors": "Shprecher|David R|DR|;Flanigan|Kevin M|KM|;Smith|A Gordon|AG|;Smith|Shawn M|SM|;Schenkenberg|Thomas|T|;Steffens|John|J|", "chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D001569:Benzodiazepines; D003042:Cocaine; D008691:Methadone; D005283:Fentanyl", "country": "United States", "delete": false, "doi": "10.1176/appi.neuropsych.20.4.473", "fulltext": null, "fulltext_license": null, "issn_linking": "0895-0172", "issue": "20(4)", "journal": "The Journal of neuropsychiatry and clinical neurosciences", "keywords": null, "medline_ta": "J Neuropsychiatry Clin Neurosci", "mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D001569:Benzodiazepines; D001921:Brain; D003042:Cocaine; D003072:Cognition Disorders; D003865:Depressive Disorder, Major; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D005356:Fibromyalgia; D020233:Gait Disorders, Neurologic; D006801:Humans; D002534:Hypoxia, Brain; D008279:Magnetic Resonance Imaging; D008691:Methadone; D008875:Middle Aged; D009046:Motor Neurons; D009292:Narcotic Antagonists; D009483:Neuropsychological Tests; D011605:Psychoses, Substance-Induced; D013406:Suicide, Attempted", "nlm_unique_id": "8911344", "other_id": null, "pages": "473-7", "pmc": null, "pmid": "19196933", "pubdate": "2008", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Clinical and diagnostic features of delayed hypoxic leukoencephalopathy.", "title_normalized": "clinical and diagnostic features of delayed hypoxic leukoencephalopathy" }

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CLINICAL AND DIAGNOSTIC FEATURES OF DELAYED HYPOXIC LEUKOENCEPHALOPATHY. J NEUROPSYCHIATRY CLIN NEUROSCI. 2008?20(4):473-7.", "literaturereference_normalized": "clinical and diagnostic features of delayed hypoxic leukoencephalopathy", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20200629", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "4", "safetyreportid": 17422767, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-VISTAPHARM, INC.-VER202002-000307", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE" } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxic-ischaemic encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHPRECHER D, FLANIGAN K, SMITH A, SMITH S, SCHENKENBERG T, STEFFENS J. CLINICAL AND DIAGNOSTIC FEATURES OF DELAYED HYPOXIC LEUKOENCEPHALOPATHY. J NEUROPSYCHIATRY CLIN NEUROSCI. 2008?20(4):473-7.", "literaturereference_normalized": "clinical and diagnostic features of delayed hypoxic leukoencephalopathy", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20200630", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17422768, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-VISTAPHARM, INC.-VER202002-000308", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxic-ischaemic encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHPRECHER D, FLANIGAN K, SMITH A, SMITH S, SCHENKENBERG T, STEFFENS J. CLINICAL AND DIAGNOSTIC FEATURES OF DELAYED HYPOXIC LEUKOENCEPHALOPATHY. J NEUROPSYCHIATRY CLIN NEUROSCI. 2008?20(4):473-7. DOI:10.1176/APPI.NEUROPSYCH.20.4.473", "literaturereference_normalized": "clinical and diagnostic features of delayed hypoxic leukoencephalopathy", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20200629", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "4", "safetyreportid": 17422769, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]

{ "abstract": "Both hepatitis C virus infection (HCV) and chronic kidney disease (CKD) have been comorbid illnesses with increasing morbidity and mortality. The present study was conducted to present real-life experiences about treatment of HCV and CKD with a fixed-dose combination of paritaprevir 150 mg/day, ritonavir 100 mg/day as a booster, ombitasvir 25 mg/day, and dasabuvir 250 mg twice/day, the PROD regimen.\n\n\n\nThis was a multicenter, retrospective cohort study. Seventy-five patients with both HCV and CKD were treated with a PROD-based regimen with or without ribavirin. Fifty-three of 75 patients were on maintenance hemodialysis program. Seven patients had compensated liver cirrhosis. The patients with genotype 1a or compensated liver cirrhosis were treated with the PROD regimen and ribavirin in a dose of 200 mg every other day for 12 weeks. The patients with genotype 1b were treated with PROD for 12 weeks. The patients with genotype 4 were treated with a combination of paritaprevir, ritonavir, ombitasvir, and ribavirin 200 mg every other day.\n\n\n\nAll patients except one were HCV-RNA negative (98.6%) at the end of treatment. One patient had decompensated after the fourth day of therapy. She stopped the treatment, and she was exitus after 2 months. Two patients died of reasons not related to the drugs 2 months after negativity of HCV-RNA. Sustained viral rate 12 weeks after treatment was found in 96% of the patients.\n\n\n\nThe PROD regimen was very effective and safe for treatment in patients with HCV and CKD who were in stages 4 and 5.", "affiliations": "Departments of Gastroenterology.;Department of Gastroenterology, Mersin University Medical School, Mersin.;Department of Infectious Diseases, Namik Kemal University Medical School, Research and Education Hospital, Tekirdağ.;Department of Infectious Diseases, Erciyes University Medical School, Kayseri, Turkey.;Departments of Gastroenterology.;Department of Gastroenterology, Mersin University Medical School, Mersin.;Department of Infectious Diseases, Namik Kemal University Medical School, Research and Education Hospital, Tekirdağ.;Department of Infectious Diseases, Erciyes University Medical School, Kayseri, Turkey.;Departments of Gastroenterology.;Nephrology, Ankara University Medical School, Ankara.;Departments of Gastroenterology.", "authors": "Örmeci|Necati|N|;Sezgin|Orhan|O|;Karaali|Ridvan|R|;Aygen|Bilgehan|B|;Turan|Dilara|D|;Yaras|Serkan|S|;Erdem|İlknur|İ|;Yildiz|Orhan|O|;Karakaya|Fatih|F|;Ateş|Kenan|K|;Asiller|Özgün Ö|ÖÖ|", "chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir", "country": "England", "delete": false, "doi": "10.1097/MEG.0000000000001334", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-691X", "issue": "31(4)", "journal": "European journal of gastroenterology & hepatology", "keywords": null, "medline_ta": "Eur J Gastroenterol Hepatol", "mesh_terms": "D015081:2-Naphthylamine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D019438:Ritonavir; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine", "nlm_unique_id": "9000874", "other_id": null, "pages": "534-539", "pmc": null, "pmid": "30672829", "pubdate": "2019-04", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Effectiveness of fixed-dose combination of paritaprevir, ritonavir, ombitasvir, and dasabuvir in patients with chronic hepatitis C virus infection and chronic kidney diseases: real-life experiences.", "title_normalized": "effectiveness of fixed dose combination of paritaprevir ritonavir ombitasvir and dasabuvir in patients with chronic hepatitis c virus infection and chronic kidney diseases real life experiences" }

[ { "companynumb": "TR-KADMON PHARMACEUTICALS, LLC-KAD201904-000230", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076203", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OMBITASVIR\\PARITAPREVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25/150/100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMBITASVIR/PARITAPREVIR/RITONAVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DASABUVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DASABUVIR" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ORMECI N, SEZGIN O, KARAALI R, AYGEN B, TURAN D, YARAS S. EFFECTIVENESS OF FIXED-DOSE COMBINATION OF PARITAPREVIR, RITONAVIR, OMBITASVIR, AND DASABUVIR IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION AND CHRONIC KIDNEY DISEASES: REAL-LIFE EXPERIENCES. EUR J GASTROENTEROL HEPATOL. 2019 APR 01?31(4):534-9.", "literaturereference_normalized": "effectiveness of fixed dose combination of paritaprevir ritonavir ombitasvir and dasabuvir in patients with chronic hepatitis c virus infection and chronic kidney diseases real life experiences", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "TR", "receiptdate": "20190413", "receivedate": "20190413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16193141, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "A 51-year-old man with head and neck skin lesions was diagnosed with Kaposi's sarcoma (KS) as his initial presentation of acquired immunodeficiency syndrome. Following initiation of antiretroviral therapy and subsequent full virologic suppression, his facial lesions worsened, consistent with immune reconstitution inflammatory syndrome (IRIS). He was started on glucocorticoids in an attempt to ameliorate the KS-IRIS but experienced paradoxical worsening of the KS lesions. Steroids were subsequently discontinued and he required chemotherapy for severe and cosmetically disfiguring skin lesions. This article describes the potential for worsening of KS lesions in individuals started on glucocorticoids for KS-IRIS as this has been reported rarely in published literature. The mechanisms underlying this phenomenon remain poorly understood but potential explanations are offered in the case discussion. This article aims to raise clinician awareness on the harms of steroid use in patients with KS-IRIS.", "affiliations": "Department of Medicine, Waterbury Hospital, Waterbury, CT, USA.;Yale AIDS Program, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.;Yale AIDS Program, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA onyema.ogbuagu@yale.edu.", "authors": "Chabria|Shiven|S|;Barakat|Lydia|L|;Ogbuagu|Onyema|O|", "chemical_list": "D013256:Steroids", "country": "England", "delete": false, "doi": "10.1177/0956462415627735", "fulltext": null, "fulltext_license": null, "issn_linking": "0956-4624", "issue": "27(11)", "journal": "International journal of STD & AIDS", "keywords": "AIDS; HIV; IRIS; Kaposi’s sarcoma; opportunistic infection; steroids", "medline_ta": "Int J STD AIDS", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000163:Acquired Immunodeficiency Syndrome; D023241:Antiretroviral Therapy, Highly Active; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D012867:Skin; D013256:Steroids; D016896:Treatment Outcome", "nlm_unique_id": "9007917", "other_id": null, "pages": "1026-9", "pmc": null, "pmid": "26769754", "pubdate": "2016-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Steroid-exacerbated HIV-associated cutaneous Kaposi's sarcoma immune reconstitution inflammatory syndrome: 'Where a good intention turns bad'.", "title_normalized": "steroid exacerbated hiv associated cutaneous kaposi s sarcoma immune reconstitution inflammatory syndrome where a good intention turns bad" }

[ { "companynumb": "US-HORIZON-PRE-0358-2016", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EMTRICITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202020", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME ASSOCIATED KAPOSI^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome associated Kaposi^s sarcoma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CHABRIA S, BARAKAT L, OGBUAGU O. STEROID-EXACERBATED HIV-ASSOCIATED CUTANEOUS KAPOSI^S SARCOMA IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME: ^WHERE A GOOD INTENTION TURNS BAD^. INT J STD AIDS. 2016;27(11):1026-9.?", "literaturereference_normalized": "steroid exacerbated hiv associated cutaneous kaposi s sarcoma immune reconstitution inflammatory syndrome where a good intention turns bad", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161213", "receivedate": "20161213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13021922, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2016JUB00396", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "040362", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "KAPOSI^S SARCOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040362", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHABRIA S, BARAKAT L, OGBUAGU O. STEROID-EXACERBATED HIV-ASSOCIATED CUTANEOUS KAPOSI?S SARCOMA IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME: ?WHERE A GOOD INTENTION TURNS BAD^. INT J STD AIDS (DOI: 10.1177/0956462415627735). 2016;27(11):1026-1029", "literaturereference_normalized": "steroid exacerbated hiv associated cutaneous kaposi s sarcoma immune reconstitution inflammatory syndrome where a good intention turns bad", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161128", "receivedate": "20161128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12980093, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]

{ "abstract": "Whipple disease (WD) is a rare bacterial infectious disease that is classically characterized by years of arthralgia, followed by malabsorption, diarrhea, and weight loss. However, WD may manifest in virtually any organ system, and patients with WD rarely develop subcutaneous erythema nodosum-like lesions. We report a case of a 51-year-old man diagnosed with WD who subsequently developed widely distributed erythematous subcutaneous nodules after 5 months of antibiotic therapy.", "affiliations": "Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Canada.;Division of Rheumatology, Department of Medicine, Nova Scotia Health Authority (Central Zone) and Dalhousie University, Halifax, Canada.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Canada.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Canada.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Canada.", "authors": "Borretta|Lisa|L|;Walsh|Noreen M|NM|;Bakowsky|Volodko|V|;Arnason|Thomas|T|;Croul|Sidney|S|;Pasternak|Sylvia|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/DAD.0000000000001925", "fulltext": null, "fulltext_license": null, "issn_linking": "0193-1091", "issue": "43(9)", "journal": "The American Journal of dermatopathology", "keywords": null, "medline_ta": "Am J Dermatopathol", "mesh_terms": null, "nlm_unique_id": "7911005", "other_id": null, "pages": "e104-e106", "pmc": null, "pmid": "33606378", "pubdate": "2021-09-01", "publication_types": "D016428:Journal Article", "references": null, "title": "A Case of Whipple Disease With Cutaneous Manifestations.", "title_normalized": "a case of whipple disease with cutaneous manifestations" }

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A Case of Whipple Disease With Cutaneous Manifestations. Am-J-Dermatopathol 2021;43(9):e104-e106.", "literaturereference_normalized": "a case of whipple disease with cutaneous manifestations", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20220218", "receivedate": "20220203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20423610, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20220423" } ]

{ "abstract": "A case of delayed eruption of the primary dentition secondary to phenytoin therapy in a 4-year-old child is reported. The patient had been on phenytoin therapy since the first months of life. Radiographs revealed that alveolar but not gingival emergence had occurred. Surgical excision of the excess gingival tissue was accomplished under general anesthesia. Oral hygiene procedures were stressed and parental cooperation solicited. Three- and nine-month postoperative visits revealed no regrowth of gingival tissue and continued eruption of the primary dentition.", "affiliations": null, "authors": "Church|L F|LF|;Brandt|S K|SK|", "chemical_list": "D010672:Phenytoin", "country": "United States", "delete": false, "doi": "10.1902/jop.1984.55.1.19", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-3492", "issue": "55(1)", "journal": "Journal of periodontology", "keywords": null, "medline_ta": "J Periodontol", "mesh_terms": "D002675:Child, Preschool; D005885:Gingival Hyperplasia; D006801:Humans; D008297:Male; D010672:Phenytoin; D014078:Tooth Eruption; D014094:Tooth, Deciduous", "nlm_unique_id": "8000345", "other_id": null, "pages": "19-21", "pmc": null, "pmid": "6582260", "pubdate": "1984-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Phenytoin-induced gingival overgrowth resulting in delayed eruption of the primary dentition. A case report.", "title_normalized": "phenytoin induced gingival overgrowth resulting in delayed eruption of the primary dentition a case report" }

[ { "companynumb": "US-PFIZER INC-2021392252", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, 1X/DAY (AT BEDTIME)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 1X/DAY (AT NOON)", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "84427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILANTIN" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gingival hypertrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tooth development disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHURCH, L.. PHENYTOIN?INDUCED GINGIVAL OVERGROWTH RESULTING IN DELAYED ERUPTION OF THE PRIMARY DENTITION. A CASE REPORT.. JOURNAL OF PERIODONTOLOGY. 1984?55 (1):19?21", "literaturereference_normalized": "phenytoin induced gingival overgrowth resulting in delayed eruption of the primary dentition a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210420", "receivedate": "20210420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19157835, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (AS). This underlines the critical need to explore novel treatment strategies, which could postpone or prevent the need for aortic valve replacement in patients with asymptomatic AS. The objectives of this study were to investigate whether metoprolol reduce the hemodynamic and metabolic burden imposed by AS.\n\n\n\nIn a double-blinded design, 40 patients with moderate-severe asymptomatic AS (aortic valve area, 0.5±0.1 cm2/m2; peak gradient, 53±19 mm Hg) were randomized to placebo or metoprolol treatment for 22 weeks. Patients were evaluated by echocardiography, cardiovascular magnetic resonance, and 11C-acetate positron emission tomography. Compared with placebo, metoprolol (100±53 mg/d) decreased heart rate; mean difference (95% confidence interval) -8 minute-1 (-13, -3; P=0.003) and increased ejection time 26 ms (2, 50; P=0.03). Furthermore, metoprolol reduced aortic valve peak -7 mm Hg (-13, 0; P=0.05) and mean -4 mm Hg (-7, -1; P=0.03) gradients, without affecting stroke volume 3 mL/m2 (-2, 8; P=0.16). Valvuloarterial impedance (ie, global afterload) and myocardial oxygen consumption were reduced by -11% and -12% (P=0.03 and 0.01), respectively; and decreased heart rate correlated with lower valvuloarterial impedance, myocardial oxygen consumption, and improved myocardial efficiency defined as stroke work/myocardial oxygen consumption (r=0.63-0.65; all P<0.01). There were 2 adverse cardiovascular events in the metoprolol group and none in the placebo group.\n\n\n\nIn patients with asymptomatic AS, metoprolol increases systolic ejection time and reduces aortic valve gradients, global afterload, and myocardial oxygen requirements. Thus, metoprolol displays favorable hemodynamic and metabolic effects and could improve outcome in patients with asymptomatic AS.\n\n\n\nURL: http://www.clinicaltrials.gov. Unique identifier: NCT02076711.", "affiliations": "From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.). nilhan@rm.dk.;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).;From the Department of Cardiology (N.H.H., W.Y.K., R.N., S.H.P., H.W.) and Department of Nuclear Medicine and PET-Center (J.S., H.J.H., L.P.T., J.F., K.B.), Aarhus University Hospital, Denmark; Department of Cardiology, Horsens Regional Hospital, Denmark (K.K.D.); and Aarhus Hjerteklinik, Denmark (I.S.).", "authors": "Hansson|Nils Henrik|NH|;Sörensen|Jens|J|;Harms|Hendrik Johannes|HJ|;Kim|Won Yong|WY|;Nielsen|Roni|R|;Tolbod|Lars Poulsen|LP|;Frøkiær|Jørgen|J|;Bouchelouche|Kirsten|K|;Dodt|Karen Kaae|KK|;Sihm|Inger|I|;Poulsen|Steen Hvitfeldt|SH|;Wiggers|Henrik|H|", "chemical_list": "D058671:Adrenergic beta-1 Receptor Antagonists; D008790:Metoprolol", "country": "United States", "delete": false, "doi": "10.1161/CIRCIMAGING.117.006557", "fulltext": null, "fulltext_license": null, "issn_linking": "1941-9651", "issue": "10(10)", "journal": "Circulation. Cardiovascular imaging", "keywords": "aortic valve stenosis; magnetic resonance imaging; metoprolol; oxygen consumption; positron-emission tomography", "medline_ta": "Circ Cardiovasc Imaging", "mesh_terms": "D058671:Adrenergic beta-1 Receptor Antagonists; D000368:Aged; D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D058070:Asymptomatic Diseases; D003718:Denmark; D004311:Double-Blind Method; D015150:Echocardiography, Doppler; D004734:Energy Metabolism; D005260:Female; D006439:Hemodynamics; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008790:Metoprolol; D008875:Middle Aged; D010101:Oxygen Consumption; D049268:Positron-Emission Tomography; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "101479935", "other_id": null, "pages": null, "pmc": null, "pmid": "28956773", "pubdate": "2017-10", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Metoprolol Reduces Hemodynamic and Metabolic Overload in Asymptomatic Aortic Valve Stenosis Patients: A Randomized Trial.", "title_normalized": "metoprolol reduces hemodynamic and metabolic overload in asymptomatic aortic valve stenosis patients a randomized trial" }

[ { "companynumb": "DK-IPCA LABORATORIES LIMITED-IPC-2018-DK-000609", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78459", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTIC VALVE STENOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary congestion", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NILS HENRIK HANSSON, JENS SORENSEN, HENDRIK JOHANNES HARMS ET AL. METOPROLOL REDUCES HEMODYNAMIC AND METABOLIC OVERLOAD IN ASYMPTOMATIC AORTIC VALVE STENOSIS PATIENTS A RANDOMIZED TRIAL. CIRC CARDIOVASC IMAGING. 2017?1-10", "literaturereference_normalized": "metoprolol reduces hemodynamic and metabolic overload in asymptomatic aortic valve stenosis patients a randomized trial", "qualification": "1", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20180404", "receivedate": "20180404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14713381, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "BACKGROUND\nThis study aimed to evaluate the feasibility and clinical effect of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for the treatment of pediatric patients with chronic active Epstein-Barr virus infection (CAEBV).\n\n\nMETHODS\nChildren with CAEBV who did not have matched donors and underwent haplo-HSCT in Beijing Children's Hospital, Capital Medical University, from October 2016 to June 2020 were analyzed retrospectively. Data relating to the clinical manifestations, engraftment, and prognosis of the children were extracted from medical records.\n\n\nRESULTS\nTwenty-five patients, including 16 males and 9 females, with an onset age of 5.0 ± 2.6 years and a transplantation age of 6.9 ± 2.9 years, were enrolled in this study. The mean time from diagnosis to transplantation was 3.8 (2.0-40.2) months. The mean observation time was 19.0 ± 12.0 months. Three patients received the reduced intensity conditioning regimen, and the remaining patients all received the modified myeloablative conditioning regimen. By the end of the follow-up, 23 patients were characterized by disease-free survival (DFS), 22 were characterized by event-free survival (EFS), and two died. One of the patients died of thrombotic microangiopathy (TMA), and another died of graft versus host disease (GVHD); this patient discontinued the treatment for economic reasons. The 3-year overall survival (OS) rate was estimated to be 92.0% ± 5.4%, and the 3-year EFS rate was estimated to be 87.4% ± 6.8%. All active patients survived after HSCT event-free. Acute GVHD degrees 1-3 were observed in ten patients (40.0%), and degree IV was observed in six (24.0%), who were all cured except for one patient. Chronic GVHD was observed in nine (36.0%), and most of these cases were mild. The incidence of TMA and veno-occlusive disease (VOD) was 28.0% and 4.0%.\n\n\nCONCLUSIONS\nHaploidentical hematopoietic stem cell transplantation is safe and effective in the treatment of pediatric CAEBV and can be used as an alternative therapy without matched donors or emergency transplantation. Patients with active disease before HSCT also benefited from haplo-HSCT. Haplo-HSCT requires careful monitoring for complications, such as GVHD and TMA. Early detection of TMA and timely treatment can reduce mortality and can improve the survival rate.", "affiliations": "Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Nanlishi Road No. 56, Beijing 100045, China. wangtianyou@bch.com.cn.", "authors": "Luo|Yan-Hui|YH|;Yang|Jun|J|;Wei|Ang|A|http://orcid.org/0000-0002-7046-2417;Zhu|Guang-Hua|GH|;Wang|Bin|B|;Zhang|Rui|R|;Jia|Chen-Guang|CG|;Yan|Yan|Y|;Wang|Kai|K|;Li|Sidan|S|;Zhou|Xuan|X|;Qin|Mao-Quan|MQ|;Wang|Tian-You|TY|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1007/s12519-021-00470-9", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "17(6)", "journal": "World journal of pediatrics : WJP", "keywords": "Chronic active Epstein–Barr virus infection; Graft versus host diseases; Haploidentical hematopoietic stem cell transplantation; Prognosis; Thrombotic microangiopathy", "medline_ta": "World J Pediatr", "mesh_terms": null, "nlm_unique_id": "101278599", "other_id": null, "pages": "626-636", "pmc": null, "pmid": "34739695", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": "10745621", "title": "Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center.", "title_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center" }

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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "0.25", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM/SQ. METER PER DAY FOR 5 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM/KILOGRAM PER DAY FOR 4 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM/KILOGRAM FOR 4 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THYMOCYTE IMMUNE GLOBULIN NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.8-1.2 MG/KG FOR 4 DAYS AND THE N 3 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSULFAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM/SQ. METER, BID, 8 TIMES BEGIN AT NIGHT ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6000 U/M2 ONCE EVERY OTHER DAY FOR 5 TIMES BEGIN ON DAY 5", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World-J-Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220406", "receivedate": "20220406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20681607, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220720" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332852", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20707907, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332862", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic graft versus host disease", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):62-36", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20710388, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332853", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. 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METER, BID (8 TIMES BEGIN AT NIGHT ON DAY 1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, PER DAY (6000 U/M2 ONCE EVERY OTHER DAY FOR 5 TIMES BEGIN ON DAY 5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al.. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center.. 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, REDUCED INTENSITY CONDITIONING REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM/KILOGRAM, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "THYMOCYTE IMMUNE GLOBULIN NOS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, REDUCED INTENSITY CONDITIONING REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THYMOCYTE IMMUNE GLOBULIN NOS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.1 MILLIGRAM/KILOGRAM, THEN 2 DAYS, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.1", "drugstructuredosageunit": "007", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "BUSULFAN" } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al.. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center.. World-J-Pediatr.. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220406", "receivedate": "20220406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20681660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332859", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20710390, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332850", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic graft versus host disease", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20708610, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332858", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al.. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20709450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CN-STRIDES ARCOLAB LIMITED-2022SP003553", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM/SQ. 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METER (ON DAY 1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM/KILOGRAM PER DAY (ON DAYS 1-3)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM/KILOGRAM PER DAY (ON DAYS 4-7)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM/KILOGRAM PER DAY (ON DAYS 8-14 FOLLOWED BY GRADUAL TAPERING THE FOLLOWING WEEK)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM/SQ. METER PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM/KILOGRAM PER DAY (CONDITIONING REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM/KILOGRAM (CONDITIONING REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "THYMOCYTE IMMUNE GLOBULIN NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.8-1.2 MG/KG (CONDITIONING REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic active Epstein-Barr virus infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "7", "drugtreatmentdurationunit": "804", "medicinalproduct": "BUSULFAN" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al.. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center.. World-J-Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220406", "receivedate": "20220406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20681655, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332860", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20708795, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332864", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombotic microangiopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein?Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20708801, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332851", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Chronic graft versus host disease", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Luo Y-H, Yang J, Wei A, Zhu G-H, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17(6):626-636", "literaturereference_normalized": "haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active epstein barr virus infection a retrospective analysis of a single center", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220414", "receivedate": "20220414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20708603, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" } ]

{ "abstract": "BACKGROUND\nAntiretroviral (ARV)-associated mitochondrial toxicity in HIV/ARV-exposed healthy infants is a concern. Clinically relevant toxicity is rare. Hyperlactatemia is common but nonspecific, both increased and decreased mitochondrial DNA (mtDNA) level has been reported. Mitochondrial function has scarcely been investigated.\n\n\nMETHODS\nIn a prospective observational study of 133 HIV/ARV-exposed infants, mtDNA content was measured with quantitative real-time polymerase chain reaction, and mitochondrial respiratory chain enzymatic activity of complex IV (CIV) and mitochondrial mass (MM) were assessed spectrophotometrically from cryopreserved peripheral blood mononuclear cells obtained at 6 weeks and 3, 6 and 12 months of age and compared with a control group.\n\n\nRESULTS\nMost mothers (88%) received combined ARV therapy during pregnancy, and 92% of infants received zidovudine monotherapy. No infant had clinical evidence of mitochondrial disease during follow-up. Nonsignificant higher MM and lower mtDNA levels (normalized by MM) were observed over time in HIV/ARV-exposed infants. MM-normalized CIV activity was consistently lower in HIV/ARV-exposed children than in controls over time (0.09 vs. 0.35, 0.12 vs. 0.38, 0.13 vs. 0.24 and 0.14 vs. 0.24 nmol/min/mg at 6 weeks and 3, 6 and 12 months; P = 0.014, P < 0.0001, P = 0.065 and P = 0.011, respectively) and showed a linear trend toward normalization with age (P < 0.01). In HIV/ARV-exposed infants, an inverse correlation between CIV activity and mtDNA levels was observed until 6 months of age (r = -0.327, P = 0.016; r = -0.311, P = 0.040 and r = -0.275, P = 0.046).\n\n\nCONCLUSIONS\nMitochondrial-encoded CIV activity was consistently lower among HIV/ARV-exposed healthy infants and inversely correlated with mtDNA levels, suggesting upregulation of the latter.", "affiliations": "From the *Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain; †Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; ‡Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain; §Fondo Europeo de Desarrollo Regional (FEDER), Spain; and ¶Blanquerna School of Health Science, Universitat Ramon Llull, Barcelona, Spain.", "authors": "Noguera-Julian|Antoni|A|;Morén|Constanza|C|;Rovira|Núria|N|;Garrabou|Glòria|G|;Catalán|Marc|M|;Sánchez|Emília|E|;Cardellach|Francesc|F|;Miró|Óscar|Ó|;Fortuny|Clàudia|C|", "chemical_list": "D044966:Anti-Retroviral Agents; D004272:DNA, Mitochondrial", "country": "United States", "delete": false, "doi": "10.1097/INF.0000000000000894", "fulltext": null, "fulltext_license": null, "issn_linking": "0891-3668", "issue": "34(12)", "journal": "The Pediatric infectious disease journal", "keywords": null, "medline_ta": "Pediatr Infect Dis J", "mesh_terms": "D044966:Anti-Retroviral Agents; D004272:DNA, Mitochondrial; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008928:Mitochondria; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011446:Prospective Studies", "nlm_unique_id": "8701858", "other_id": null, "pages": "1349-54", "pmc": null, "pmid": "26372453", "pubdate": "2015-12", "publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Decreased Mitochondrial Function Among Healthy Infants Exposed to Antiretrovirals During Gestation, Delivery and the Neonatal Period.", "title_normalized": "decreased mitochondrial function among healthy infants exposed to antiretrovirals during gestation delivery and the neonatal period" }

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DECREASED MITOCHONDRIAL FUNCTION AMONG HEALTHY INFANTS EXPOSED TO ANTIRETROVIRALS DURING GESTATION, DELIVERY AND THE NEONATAL PERIOD. 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DECREASED MITOCHONDRIAL FUNCTION AMONG HEALTHY INFANTS EXPOSED TO ANTIRETROVIRALS DURING GESTATION, DELIVERY AND THE NEONATAL PERIOD. 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DECREASED MITOCHONDRIAL FUNCTION AMONG HEALTHY INFANTS EXPOSED TO ANTIRETROVIRALS DURING GESTATION, DELIVERY AND THE NEONATAL PERIOD. 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DECREASED MITOCHONDRIAL FUNCTION AMONG HEALTHY INFANTS EXPOSED TO ANTIRETROVIRALS DURING GESTATION, DELIVERY AND THE NEONATAL PERIOD. 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DECREASED MITOCHONDRIAL FUNCTION AMONG HEALTHY INFANTS EXPOSED TO ANTIRETROVIRALS DURING GESTATION, DELIVERY AND THE NEONATAL PERIOD. THE PEDIATRIC INFECTIOUS DISEASE. 2015?1-27", "literaturereference_normalized": "decreased mitochondrial function among healthy infants exposed to antiretrovirals during gestation delivery and the neonatal period", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20151005", "receivedate": "20151005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11593295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "ES-CIPLA LTD.-2015ES07717", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMIVUDINE" 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DECREASED MITOCHONDRIAL FUNCTION AMONG HEALTHY INFANTS EXPOSED TO ANTIRETROVIRALS DURING GESTATION, DELIVERY AND THE NEONATAL PERIOD. THE PEDIATRIC INFECTIOUS DISEASE. 2015?1-27", "literaturereference_normalized": "decreased mitochondrial function among healthy infants exposed to antiretrovirals during gestation delivery and the neonatal period", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20151005", "receivedate": "20151005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11593193, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "Listeria monocytogenes is a rare cause of potentially lethal infection and sepsis in transplant recipients. Listeriosis is usually described after kidney or bone marrow transplant, and has been less frequently reported after liver transplantation. Here, the authors present two cases of severe Listeria infection occurring within 4 months after complicated liver transplantation in patients still recovering on the ward. The patients were successfully treated by intravenous ampicillin. These cases should remind transplant physicians that listeriosis may develop in liver transplant recipients, that food safety advice should be provided, and that intravenous ampicillin might be an effective treatment for systemic listeriosis in solid organ recipients. It is likely that trimethoprim-sulfamethoxazole prophylaxis might help prevent early listeriosis after solid organ transplantation.", "affiliations": "Department of Abdominal and Transplant Surgery, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.;Department of Abdominal and Transplant Surgery, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.;Department of Abdominal and Transplant Surgery, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.;Department of Abdominal and Transplant Surgery, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.;Department of Internal Medicine and Infectious Diseases, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.;Department of Abdominal and Transplant Surgery, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.;Department of Abdominal and Transplant Surgery, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium.", "authors": "Piette|Estelle|E|;Vandermeulen|Morgan|M|https://orcid.org/0000-0001-6157-2510;Meurisse|Nicolas|N|https://orcid.org/0000-0002-1641-5986;Schielke|Astrid|A|;Meuris|Christelle|C|https://orcid.org/0000-0002-0084-9755;Honoré|Pierre|P|;Detry|Olivier|O|https://orcid.org/0000-0002-9436-6673", "chemical_list": "D000900:Anti-Bacterial Agents; D000667:Ampicillin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination", "country": "Denmark", "delete": false, "doi": "10.1111/tid.13122", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "21(4)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "ascites; complications; infection; listeria monocytogenes; liver transplantation; meningitis; peritonitis; sepsis", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000667:Ampicillin; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008089:Listeria monocytogenes; D008088:Listeriosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D018805:Sepsis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13122", "pmc": null, "pmid": "31141258", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Early listeriosis after liver transplantation: Report of two cases.", "title_normalized": "early listeriosis after liver transplantation report of two cases" }

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EARLY LISTERIOSIS AFTER LIVER TRANSPLANTATION: REPORT OF TWO CASES. 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EARLY LISTERIOSIS AFTER LIVER TRANSPLANTATION: REPORT OF TWO CASES. 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EARLY LISTERIOSIS AFTER LIVER TRANSPLANTATION: REPORT OF TWO CASES. 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{ "abstract": "Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between β-adrenergic receptors (protein targets of propranolol) and δ-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the β-blocker-driven inhibition of glycolysis and resulting lactate production. The opioid-facilitated β-adrenergic blockade would be essentially additivity or even synergism putatively existing between antagonism of β-adrenergic receptors and agonism of δ-opioid receptor in lowering cellular cAMP and dependent functions.", "affiliations": "Inserm, Laboratory of Molecular Biology and Biochemistry, Hormonology Metabolism Nutrition and Oncology, Center of Biology and Pathology, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University of Lille 2, Lille 59037, France. joseph.vamecq@inserm.fr.;Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille 59037, France. karine.mention@chru-lille.fr.;Pediatric Critical Care Unit, Hôpital Jeanne de Flandre, CHRU Lille, Lille 59037, France. francis.leclerc@chru-lille.fr.;Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille 59037, France. dries.dobbelaere@chru-lille.fr.", "authors": "Vamecq|Joseph|J|;Mention-Mulliez|Karine|K|;Leclerc|Francis|F|;Dobbelaere|Dries|D|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/ph8040664", "fulltext": "\n==== Front\nPharmaceuticals (Basel)Pharmaceuticals (Basel)pharmaceuticalsPharmaceuticals1424-8247MDPI 2642602510.3390/ph8040664pharmaceuticals-08-00664Concept PaperOpioid Facilitation of β-Adrenergic Blockade: A New Pharmacological Condition? Vamecq Joseph 1*Mention-Mulliez Karine 2Leclerc Francis 3Dobbelaere Dries 2Vanden Eynde Jean Jacques Academic Editor1 Inserm, Laboratory of Molecular Biology and Biochemistry, Hormonology Metabolism Nutrition and Oncology, Center of Biology and Pathology, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University of Lille 2, Lille 59037, France2 Centre de Référence Maladies Héréditaires du Métabolisme de l’Enfant et de l’Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille 59037, France; E-Mails: karine.mention@chru-lille.fr (K.M.-M.); dries.dobbelaere@chru-lille.fr (D.D.)3 Pediatric Critical Care Unit, Hôpital Jeanne de Flandre, CHRU Lille, Lille 59037, France; E-Mail: francis.leclerc@chru-lille.fr* Author to whom correspondence should be addressed; E-Mail: joseph.vamecq@inserm.fr; Tel.: +33-320-445694; Fax: +33-320-445693.25 9 2015 12 2015 8 4 664 674 16 8 2015 17 9 2015 © 2015 by the authors; licensee MDPI, Basel, Switzerland.2015This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between β-adrenergic receptors (protein targets of propranolol) and δ-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the β-blocker-driven inhibition of glycolysis and resulting lactate production. The opioid-facilitated β-adrenergic blockade would be essentially additivity or even synergism putatively existing between antagonism of β-adrenergic receptors and agonism of δ-opioid receptor in lowering cellular cAMP and dependent functions.\n\nlactateglycolysis disruptionNa+/K+ ATPaseβ-adrenergic receptorG proteincAMPprotein kinase Ashockδ-opioid receptor\n==== Body\n1. Introduction\nIn a previous report, the prevention of hyperlactatemia development in a nine-month-old child undergoing a shock directly caused by dehydration was put in relation with exposure to propranolol, a drug not usually indicated in shock, but here given as a chronic therapy to treat hemangioma [1]. Main clinical features of this patient under shock are summarized in Table 1. Anti-hyperlactatemia mechanisms proposed in this circumstance were propranolol-driven β-adrenergic blockade in skeletal muscle, a key organ in regulation of lactate overproduction [1].\n\npharmaceuticals-08-00664-t001_Table 1Table 1 Main clinical features and therapeutic measures in a child undergoing a hypovolemic shock caused by dehydration a.\n\nClinical Period\tClinical Signs\t\nBefore shock\t\nThe girl child has a Cyrano hemangioma and is treated since 4 months of age with propranolol (3 × 15 mg/day)\n\n\t\nOnset and outcome of shock\t\nAt 9 months, she develops an acute episode of rotavirus gastroenteritis complicated by profuse diarrheas and drowsiness and treated with oral rehydration solution and racecadotril (10 mg/day).\n\nThe child becomes shocked and dehydrated, presenting with mottled skin, cold extremities, capillary-refill time of 5 s, weight of 7.5 kg, heart rate at 100 beats/min, arterial pressure at 62/21 mmHg, and respiratory frequency of 40 cycles/min.\n\nBiology (normal range values between rounded brackets) indicates severe hypernatremia 163 mmol/L (137–145 mmol/L), hypokaliemia 2.2 mmol/L (3.5–4.5 mmol/L), elevated blood chloride 138 mmol/L (102–108 mmol/L), acidic blood pH at 6.80 (7.35–7.45) low CO2 partial pressure at 20 mmHg (35.7–44.8), a negative base excess at −25 mEq/L (−2 to +2 mEq/L) and hypocalcemia at 69 mg/L [total calcium 92–106 mg/L].\n\nBlood protein level is normal at 70 g/L) as well as glycemia at1.31 g/L, uremia at 0.45 g/L or 7.5 mmol/L, creatininemia at 6 mg/L or 53 µmol/L and blood lactate at 0.8 mmol/L [0.66–2.4 mmol/L]. Hemoglobin at 9.5 g/100 mL [12.5–21.5 g/100 mL] indicates anemia.\n\nFluid resuscitation initiated by intraosseous route followed by intravenous rehydration resolves hypovolemic shock while blood ionogram and pH partially improved, lactatemia staying normal (0.7 mmol/L).\n\nIntravenous rehydration is continued and bicarbonate administered. Dehydration signs, hypernatremia and acidosis gradually resolve, patient recovering without sequelae.\n\n\t\na The patient was subject to a previous case report [1].\n\nEven though previously proposed mechanisms were coherent, a facilitation of the β-blocker effects is here considered for three main reasons:\nThough it is a known inhibitor of glycolysis, propranolol, outside this previous observation, has never been reported to fully protect against lactate overproduction.\n\nDuring shock, the patient was treated by the anti-diarrheic racecadotril [1], a pro-drug of the enkephalinase inhibitor thiorphan [2,3] acting via a rise in enkephalins and hence a stimulation of opioid receptor signaling, conferring a reduced intestinal secretory activity [4,5,6,7,8,9,10,11,12,13].\n\nImportantly, previous experimental support has been given in favor of a cross-talk between β-adrenergic receptors and δ-opioid receptor signaling [14,15,16] (Figure 1).\n\n\n\nFigure 1 Cross-talk between β-adrenergic and δ-opioid signaling pathways in cardiomyocytes as an experimental basis for regulation of myocardial cell calcium and contraction.\n\nExperimental evidence for the depicted events has been previously given [15,16] and reviewed [14] through works from which the figure is also adapted. In brief, β-adrenergic and δ-opioid receptors modulate Protein kinase A (PKA) and non-PKA mechanisms involved in cell calcium and excitation-contraction coupling. Whereas, as a whole, β-adrenergic receptors positively impact adenylate cyclase and then stimulate PKA and resulting activation of PKA target proteins, δ-opioid receptor acts in an inverse way, blunting recruitment of PKA and target proteins. Not only adenylate cyclase is inhibited but also concomitant activation of phosphodiesterase activity (PDE) by δ-opioid receptor further strengthens the negative signaling operated on PKA activation through removal of cAMP in the form of AMP. In parallel with PKA-dependent pathways, non-PKA mechanisms are mediated by β-adrenergic and δ-opioid receptors in the control of myocardial cell calcium and contraction. These mechanisms may either amplify or reduce PKA-dependent signaling, in the same time as mediating other effects. More especially and not illustrated, the β2-adrenergic receptor, like the δ-opioid receptor, is coupled to a Gi protein and in both cases the βγ subunits of the Gi proteins may activate RAS/MAPK signaling and PI3K [14].\n\nAbbreviations are: β1-AR, β1-adrenergic receptor; β2-AR, β2-adrenergic recptor; δ-OR, δ-opioid receptor; Gs, Gs-protein; Gi, Gi-protein; ATP, adenosine triphosphate; AMP, adenosine monophoshate; cAMP, cyclic AMP; PPi, inorganic pyrophosphate; PKA, proteine kinase A; PDE, phosphodiesterase; + and −, stimulation and inhibition, respectively.\n\nKeeping in mind these aspects, opioid-facilitated β-adrenergic blockade, more especially facilitation of the metabolic effects of propranolol by racecadotril, is presented thereafter as a new pharmacological condition mainly based on the known cross-talk between β-adrenergic and δ-opioid signaling pathways, being aware of other cross-talks between adrenergic and opioid (α-adrenergic and δ-opioid [17], β-adrenergic and κ-opioid [18]) signaling pathways. The facilitation of β-adrenergic blockade by opioid signaling essentially lies in the fact that notably δ-opioid activation decreases levels of the second messenger (cAMP), the depression of which mediates the cellular effects of β-adrenergic blockade. Preliminary brief introductions are meanwhile given to fast glycolysis, β-adrenergic control of lactate production and effects of propranolol on glycolysis.\n\n2. Fast Glycolysis and Lactate Production\nSubstantial lactate production by cells is the result of a glycolysis not relayed by mitochondrial oxidations. In these conditions, as a result of limited amounts of ATP produced per molecule of glucose, glycolysis proceeds at fast rates to yield sufficient ATP to cover cell energetic needs. Anaerobic glycolysis includes physiological glucose oxidations taking place when either mitochondrion are absent (erythrocytes) or when oxygen supply to mitochondrion is swamped (e.g., sustained and intense muscle contractions). Anaerobic glycolysis may also develop in pathophysiological hypoxic/anoxic conditions. When taking place in normoxic conditions, glycolysis may be relayed by mitochondrial oxidations and due to an overall improvement of ATP production per molecule of glucose, this glycolysis occurs at a slow pace with little or no lactate production. Nevertheless, even in such normoxic conditions, glycolysis may be not relayed by mitochondrial oxidations, and for this reason may also proceed at fast rates with substantial lactate production. This occurs when mitochondrial oxidations are deficient or when they are regulated negatively under biased signaling such as observed in the Warburg’s effect [19]. Because like anaerobic glycolysis, it exhibits intensive glucose utilization, this biased normoxic glycolysis is called aerobic glycolysis. [19].\n\n3. Adrenergic Signaling and Lactate Production\nLactic acid, in the ionized lactate form at physiological pH, is a glycolysis byproduct that increases in blood under tissue hypoxia and other conditions reviewed elsewhere [20]. Lactate formation attests for the activity of the anaerobic glycolysis, and therefore occurs when anaerobic glycolysis physiologically (e.g., rapid and sustained muscle contraction) or pathophysiologically (e.g., tissue hypoperfusion) develops. Under tissue hypoperfusion, the reliability of lactate as a blood marker of shock severity, however, still remains debated; lactate production having been supported to depend on adrenergic response rather than on shock severity itself [21] and, in sepsis, to be the result of increased pyruvate formation rather than decreased oxygen availability [22]. The link between adrenergic cell signaling and blood lactate has been experimentally shown in an animal model of hemorrhagic shock [20], before being proposed in the humans [23]. In shock, catecholamines are increased, and taking into account that epinephrine potently stimulates lactate formation under well-oxygenated conditions, adrenergic signaling has been proposed to contribute, besides tissue hypoperfusion, to the rise of lactate which may be observed during shock [21,24,25]. In rat muscle, epinephrine and other agonists of β-adrenergic receptors stimulate glycolysis but also membrane polarization, cell sodium efflux and potassium influx, this decreased intracellular Na+ to K+ ratio attesting for stimulation of the Na+/K+ ATPase pump [26,27]. Interestingly, propranolol, which inhibits β-adrenergic receptors, and ouabain, which inhibits the Na+/K+ ATPase pump, are capable of blunting epinephrine-stimulated glycolysis [26,28,29,30]. On the basis of this experimental background, additional support has been given to link increased muscle glycolysis (the main producer of circulating lactate) to epinephrine-stimulated Na+/K+ ATPase pump activity [21]. The fact that β-adrenergic blockers such as propranolol may aggravate increased circulating glucose and insulin resistance in diabetic patients may be consistent with a link between β-adrenergic blockade and disrupted glycolysis [31]. Finally, the best support to link lactate formation and adrenergic signaling might perhaps lie in compelling evidence stressing the ability of the β-adrenergic agonist therapy to rise lactatemia in asthmatic and healthy subjects [32,33,34,35,36,37,38,39,40,41,42].\n\n4. β-Adrenergic Blockade by Propranolol Decreases Lactate Production in a Non-Septic Shock\nThough sometimes described in septic shock [43], the lack of hyperlactatemia during decompensated hypovolemic shock caused by dehydration represents, in contrast, a rather unique event [1]. In this respect, we have recently described a child developing shock caused by dehydration during the course of a viral gastroenteritis and without hyperlactatemia [1]. In this case, prevention of hyperlactatemia was attributed to adrenergic blockade by propranolol [1].\n\n5. Facilitation of Propranolol-Driven β-Adrenergic Blockade by Racecadotril\nThough proposed underlying mechanisms (reduction of cAMP and hence drop in both PKA-mediated phosphorylation of phospholemman and subsequent stimulation of Na+/K+ ATPase) [1] were coherent, prevention of lactate over production by propranolol still remains a unique observation. This led us to review all other factors that might have helped the drug to prevent hyperlactatemia in our previous observation. Though no link with glycolysis disruption was previously suggested in the literature for the anti-diarrheic racecadotril (a prodrug of thiorphan, an enkephalinase inhibitor [2,3]), a detailed analysis of its signaling effects suggests some putative cross-talk with signaling triggered by propranolol. In fact, δ-opioid receptor activation by enkephalins accumulating under racecadotril might facilitate β-blocker effects as regards to lactate production. The notion of “opioid-facilitated β-adrenergic blockade” is here proposed to underline the particular pharmacological context induced by the concurrent administration of the two drugs. The mechanisms by which this situation may negatively impact glycolysis rates are presented thereafter essentially through the abilities of the two drugs, racecadotril and propranolol, to act in concert in lowering cell cAMP levels.\n\n6. Opioid-Facilitated β-Adrenergic Blockade as a Mean to Prevent Hyperlactatemia\nPrevious support for propranolol-driven inhibition of lactate production [1] is explained thereafter. β-adrenergic blockade may be achieved by propranolol, a non-selective blocker of β1 and β2 adrenergic receptors. Though β2-adrenergic receptor may also activate Gi proteins-driven signaling, these β-adrenergic receptors are coupled to Gs proteins that activate adenylate cyclase [44]. Subsequent rises in intracellular cAMP level and protein kinase A activity (PKA) induce enhanced phosphorylation of phospholemman (FXYD1, a member of FXYD protein family) and stimulation of plasma membrane Na+/K+ ATPase in organs including heart, liver and skeletal muscle [45]. This ATPase by hydrolyzing ATP to ADP maintains a high cytosolic ADP/ATP ratio stimulating glycolysis, pyruvate and hence lactate production. By blocking β-adrenergic receptors, propranolol prevents cytosolic rise in cAMP and activation of PKA induced by catecholamines. Phospholemman phosphorylation and its stimulatory effect on Na+/K+ ATPase activity are consequently prevented, reducing ATP hydrolysis, ADP/ATP ratio and glycolytic rate (Figure 2), a scenario in agreement with experimental inhibition by adrenergic blockade of lactate production [23]. As mentioned above, racecadotril (acetorphan) is a pro-drug of thiorphan. This enkephalinase inhibitor increases steady-state concentrations of enkephalins in gut and signaling via δ-opioid receptor, lowering intracellular cAMP and hence ion and water secretory activity of enterocytes [4,5,6,7,8,9,10,11,12,13]. These changes reverse enterocyte high cAMP levels causative of diarrhea [11]. Racecadotril produces significant inhibition of plasma enkephalinases after oral administration [7], likely stimulating opioid signaling in δ-opioid receptors-containing organs. These organs involving heart also include skeletal muscle [46,47], which therefore also represents a bona fide target for endogenous enkephalins accumulating secondarily to inhibition of enkephalinases. Resulting drop in intracellular cAMP would mimic β-adrenergic blockade making δ-opioid receptor stimulation a potentiator of adrenergic blockade in skeletal muscle (Figure 2).\n\nFigure 2 Cross-talk between β-adrenergic and δ-opioid signaling pathways in skeletal myocytes as a theoretical basis for reinforced inhibition of glycolysis and prevention of hyperlactatemia.\n\nThis particular pharmacological context is attributed to the combined administration of propranolol and racecadotril in a patient in severe hypovolemic shock caused by dehydration [1]. For abbreviations, see Figure 1 or below in this legend. β1- and β2-adrenergic receptors (β1-AR and β2-AR, respectively) are coupled to Gs proteins (“s” for stimulation of adenylate cyclase) and δ-opioid receptor (δ-OR) to a Gi protein (“i” for inhibition of adenylate cyclase). Propranolol β-adrenergic blockade prevents the increase of plasma membrane adenylate cyclase activity and intracellular cAMP levels induced by catecholamines. Racecadotril induces the inhibition of adenylate cyclase via activation of δ-OR. The resulting cumulated drop in cAMP prevents the activation of protein kinase A (PKA) and phosphorylation of phospholemman (PPL), alleviating the stimulatory effect of this membrane protein on the activity of Na+/K+ ATPase. Decreasing the contribution of ATPase to recycle cytosolic ADP from ATP explains why cytosolic ADP/ATP ratio lowers and why glycolysis rate is slowed by the drugs. One glucose gives rise to 2 pyruvate, and the 2 ATP consumed during the first steps of glycolysis (glucokinase/hexokinase(s) and phosphofructose kinase 1) are recovered at the end of the phosphoglycerate kinase-catalyzed reaction. Only the ATP molecules generated by pyruvate kinase (PK) are considered to provide cells with a net gain in ATP formation during glycolysis. As illustrated by the figure, this is this pool of ATP that needs to be converted back to ADP in order to allow continuation of glycolysis. Note that NAD+ (cofactor oxidized form) needs also to be recycled (from NADH + H+ (cofactor reduced form)) to maintain glycolysis. In the figure, the recycling is illustrated to be ensured essentially by lactate dehydrogenase (LDH). This occurs when alternative ways to consume cytosolic NADH are substantially switched off, i.e., when mitochondrial oxidation of pyruvate is deficient, notably under hypoxia/anoxia (by lack of oxygen), inflammatory and truncated HIF signaling conditions. Shock is a condition that may combine inflammatory and hypoxic conditions, and then which favors increased cellular production of lactate and hyperlactatemia. Auxiliary systems that need to be recruited to optimize the underlying stimulation of glycolysis include those that maintain the cytosolic ADP/ATP ratio at high levels. In this exercise, exacerbated membrane Na+/K+ ATPase activity is essential. In fact, propranolol and racecadotril acting synergistically to alleviate recruitment of the Na+/K+ ATPase activity defeat the whole sketch, which in shock leads to exacerbated glycolysis, lactate production and hyperlactatemia.\n\n7. Additivity or Synergism of Drug Actions?\nA last but not least aspect of the proposed new concept holds in the nature of how each of the drug actions on glycolysis may act in concert. Additivity refers to drug mechanisms just adding, so as a net result, the intensity of the action of the combined drugs corresponds to the expected sum of each individual drug activity. Synergism refers to a net result which differs from that expected from simply the sum of each of the individual drug activity. Analysis of data on the cross-talks between β-adrenergic and δ-opioid receptors might suggest synergism in heart since the effects of local stimulation of β-adrenergic receptor are attenuated by positive opioid signaling at ineffective concentrations [48]. In the scope of impacting skeletal muscle metabolism involved in the control of body lactate production, one might suggest that some synergism also takes place in the pharmacological concept illustrated in Figure 2. Indeed, in addition to the sum of the expected decreases in productions of cAMP induced by blockade of β-adrenergic receptors and activation of δ-opioid receptor through the drop in adenylate cyclase activity, the δ-opioid receptor may further influence PKA activation by a stimulation of phosphodiesterase action and resulting enhancement in cAMP degradation, then potentiating the direct decrease in cAMP production. Modulation of PKA effects through the signaling triggered in parallel by δ-opioid receptor activation in non-PKA dependent mechanisms (Figure 1 and Figure 2) is not ruled out. These non-PKA mechanisms have been mentioned above in the case of the cross-talk between β-adrenergic and δ-opioid signaling pathways taking place in the heart. Regarding other cross-talks also mentioned above for heart function, between α-adrenergic and δ-opioid [17] and between β-adrenergic and κ-opioid [18] signaling pathways, they might be, on the opposite, a priori considered of a limited importance in our proposed concept because propranolol is a β-adrenergic blocker [49,50] and skeletal muscle does not exhibit κ-opioid receptors [51], respectively.\n\nAuthor Contributions\nJ.V. prepared the manuscript. F.L. ensured the medical and therapeutic follow-up of the patient, D.D. and K.M.M. contributed to metabolic studies and interpretation. All the authors contributed to the discussion about racecadotril effects on lactate production.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1. Dobbelaere D. Leclerc F. Mention-Mulliez K. Vamecq J. Propranolol and lactatemia during hypovolemic shock: A case report Arch. Pediatr. 2015 22 292 295 10.1016/j.arcped.2014.11.010 25524288 \n2. De la Baume S. 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Statnick M.A. κ-Opioid receptors control the metabolic response to a high-energy diet in mice FASEB J. 2010 24 1151 1159 10.1096/fj.09-143610 19917675\n\n", "fulltext_license": "CC BY", "issn_linking": "1424-8247", "issue": "8(4)", "journal": "Pharmaceuticals (Basel, Switzerland)", "keywords": "G protein; Na+/K+ ATPase; cAMP; glycolysis disruption; lactate; protein kinase A; shock; β-adrenergic receptor; δ-opioid receptor", "medline_ta": "Pharmaceuticals (Basel)", "mesh_terms": null, "nlm_unique_id": "101238453", "other_id": null, "pages": "664-74", "pmc": null, "pmid": "26426025", "pubdate": "2015-09-25", "publication_types": "D016428:Journal Article", "references": "23331938;12370063;8678625;22654896;6995479;17767464;9187208;10646047;10646046;12068341;20067434;19917675;9603080;10465191;10409142;15288447;22147818;18462465;3183961;11469892;3519939;23949578;9133523;10646045;6739311;10198190;6782584;9124441;192771;10717506;25524288;12439640;10646049;10338406;6247002;4965821;10646048;17906597;10646044;14132613;24599614;24378041;15922254;15566403;15459835;21802882;15276466;11455191;198530;21440203;19818946", "title": "Opioid Facilitation of β-Adrenergic Blockade: A New Pharmacological Condition?", "title_normalized": "opioid facilitation of adrenergic blockade a new pharmacological condition" }

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{ "abstract": "This report discusses a case of nonconvulsive status epilepticus, caused by cerebral amyloid angiopathy-related inflammation. Brain biopsy demonstrated cerebral amyloid angiopathy, with clinical and radiographic features indicative of a fluctuating inflammatory process. Immunomodulatory treatment with pulse steroids resulted in rapid and dramatic clinical and radiographic improvement. Cerebral amyloid angiopathy-related inflammation should be considered in the differential diagnosis of new-onset seizures after the age of 40, when associated with fluctuating multifocal T2 hyperintensities and petechial hemorrhages on gradient echo (GRE) or susceptibility-weighted (SWI) MRI sequences.", "affiliations": "Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.;Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.;Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.", "authors": "Tolchin|Benjamin|B|;Fantaneanu|Tadeau|T|;Miller|Michael|M|;Helgager|Jeffrey|J|;Lee|Jong Woo|JW|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ebcr.2016.05.003", "fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(16)30026-310.1016/j.ebcr.2016.05.003Case ReportStatus epilepticus caused by cerebral amyloid angiopathy-related inflammation Tolchin Benjamin btolchin@partners.orga⁎Fantaneanu Tadeau aMiller Michael bHelgager Jeffrey bLee Jong Woo aa Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United Statesb Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States⁎ Corresponding author. Tel.: + 1 347 721 8491; fax: + 1 617 730 2885. btolchin@partners.org04 6 2016 2016 04 6 2016 6 19 22 17 5 2016 21 5 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).This report discusses a case of nonconvulsive status epilepticus, caused by cerebral amyloid angiopathy-related inflammation. Brain biopsy demonstrated cerebral amyloid angiopathy, with clinical and radiographic features indicative of a fluctuating inflammatory process. Immunomodulatory treatment with pulse steroids resulted in rapid and dramatic clinical and radiographic improvement. Cerebral amyloid angiopathy-related inflammation should be considered in the differential diagnosis of new-onset seizures after the age of 40, when associated with fluctuating multifocal T2 hyperintensities and petechial hemorrhages on gradient echo (GRE) or susceptibility-weighted (SWI) MRI sequences.\n\nKeywords\nCerebral amyloid angiopathyInflammationStatus epilepticusMRIEEGPathology\n==== Body\n1 Case report\nWe present a case of status epilepticus due to cerebral amyloid angiopathy-related inflammation, successfully treated with immunomodulation. A 52-year-old man with a history of hypertension and alcohol abuse, presented in January of 2015 with new-onset seizures. The patient's family first noted new-onset irritability, paranoia, and confusion that were thought to be atypical for him. Two days later, the patient noted a 45-minute episode of elementary visual hallucinations consisting of bright colors and stars in his right visual field with an associated expressive aphasia. He reported that he could understand questions and formulate responses in his head but not actually speak.\n\nHe was brought to an outside hospital where he had a witnessed seizure during which he had deviation of his head to the left, evolving to a generalized tonic-convulsion seizure lasting 40 seconds, with associated tongue biting and postictal confusion but no incontinence. His exam was notable only for a right inferior quadrant visual field defect, which was homonymous but more profound in the right eye. A lumbar puncture was performed, and cerebrospinal fluid was acellular with normal protein and glucose, with no oligoclonal bands, and with negative cytology and flow cytometry. Routine electroencephalograms (EEGs) showed spike–wave discharges with several electrographic seizures in the left occipital region. Magnetic resonance imaging (MRI) revealed left occipital white matter and cortical T2 hyperintensity with mild focal mass effect, without enhancement but with petechial hemorrhages on gradient echo (GRE) imaging and with a second smaller focus of T2 hyperintensity in the left anterior insula (Fig. 1). Magnetic resonance angiography of the head and neck was unremarkable. He was loaded with levetiracetam and was discharged from the hospital.\n\nUpon initial formulation, the patient's history, exam, and studies were thought to be most consistent with a multifocal glioma, less likely an infectious or inflammatory process, and even less likely an old stroke. His levetiracetam dose was increased because of a recurrent episode of visual symptoms and aphasia, and he was scheduled for a biopsy of the left occipital lesion. However, a repeat MRI performed in March 2015 in preparation for the biopsy showed significant improvement of the left occipital and left anterior insular lesions (Fig. 2B). These shifting lesions were thought to be more consistent with a demyelinating process such as acute disseminated encephalomyelitis (ADEM).\n\nThe brain biopsy was aborted, and the patient was instead admitted for an expedited inflammatory workup. A repeat lumbar puncture was again unrevealing (including negative oligoclonal bands, cytology, flow cytometry, and IgH gene rearrangement). A computed tomography (CT) scan of the chest, abdomen, and pelvis revealed multiple 1- to 2-cm hepatic lesions with peripheral nodular enhancements, which were then confirmed as hepatic hemangiomas on abdominal MRI. Magnetic resonance imaging of the cervical and thoracic spine showed only mild degenerative disc disease, and CT angiogram of the head and neck was unremarkable.\n\nThe patient was again discharged home, but follow-up MRI in June 2015 showed worsening of the left occipital T2 hyperintensity (Fig. 2C) and new left frontal T2 hyperintensities, as well as new enhancement of the lesion in the right anterior temporal lobe (not shown). Biopsy of the left occipital lesion was performed. The biopsy showed reactive changes and thickened blood vessels with beta-amyloid deposition in vessel walls (Fig. 3). These findings were thought to be consistent with cerebral amyloid angiopathy.\n\nHe was then brought to the emergency department for a sudden clinical deterioration with global aphasia and confusion. He was unable to name objects, repeat phrases, or follow commands; made frequent paraphasic errors; and was noted to have decreased blink to threat on the right. An EEG was obtained, revealing continuous lateralized periodic discharges with overlying fast activity over the left posterior quadrant (Fig. 4A), evolving into 3–4 electrographic seizures per hour (Fig. 4B), consisting of 9-Hz rhythmic sharp waves, without clinical return to baseline between seizures. He was therefore determined to be in nonconvulsive status epilepticus (NCSE) and was admitted. Over the course of approximately 24 h, he was started on lacosamide, phenytoin, and valproic acid in addition to levetiracetam, and NCSE was aborted. Notably, Mr. G's clinical status improved only slightly with the arrest of seizures, and he continued to demonstrate significant global aphasia and confusion.\n\nPositron emission tomography (PET) scan of the brain and whole body revealed increased fluorodeoxyglucose (FDG) uptake in the left occipital and left temporal regions, consistent with the known lesions on MRI. These areas of increased FDG uptake were thought to be most likely due to an inflammatory process and less likely due to recent seizure activity. At this point, the diagnosis of cerebral amyloid angiopathy-related inflammation was advanced, and he was started on a 5-day course of methylprednisolone, 1000 mg daily as a diagnostic and therapeutic maneuver. Clinically, his speech difficulties and confusion resolved almost entirely, and he was able to name, repeat, and follow commands normally. He was able to discontinue phenytoin and valproic acid without recurrence of seizures (either clinically or on EEG). Following pulse-dose steroids, he was discharged on a slow taper of oral prednisone. Repeat imaging in September of 2015 showed marked improvement of all T2 hyperintense lesions and complete resolution of all enhancement (Fig. 2D).\n\n2 Discussion\nCerebral amyloid angiopathy (CAA) consists of β-amyloid deposition in small and medium arteries of the brain and leptomeninges [1]. It is found in 23–57% of the asymptomatic elderly population and at increased rates in those with dementia and intracerebral hemorrhage [2]. Cerebral amyloid angiopathy can more rarely cause an inflammatory reaction, known as CAA-related inflammation (CAA-I). This has historically been described as primary angiitis of the central nervous system associated with CAA, cerebral amyloid angiitis, and cerebral amyloid inflammatory vasculopathy [3], [4], [5]. Cerebral amyloid angiopathy-related inflammation presents with subacute cognitive decline, headaches, and seizures rather than the chronic dementia or hemorrhagic strokes classically associated with cerebral amyloid angiopathy. The mean age at onset is approximately 68 years, significantly younger than for hemorrhagic CAA. Magnetic resonance imaging findings in CAA-I include shifting multifocal white matter T2 hyperintensities abnormalities colocalized with petechial hemorrhages on SWI [6]. Cerebrospinal fluid is typically bland, though protein may be elevated, and more rarely, pleiocytosis has been observed [3]. The APOE ε4/ε4 genotype is present at increased rates — 71% of patients in one case series [6]. Histopathologic findings include amyloid deposition within vessel walls and perivascular, transmural, or intramural inflammation, including perivascular multinucleated giant cells.\n\nSeveral published cases and case series describe treatment with immunosuppressive therapy, including corticosteroids with or without additional immunosuppressive therapy such as methotrexate, mycophenolate mofetil, or most commonly cyclophosphamide. Thirty-eight of 53 published cases showed improvement with immunosuppressive treatment, as did Mr. G [3].\n\nOur patient's case was notable for a typically subacute fluctuating clinical course and multifocal fluctuating radiographic findings, classically bland CSF, and a biopsy demonstrating amyloid deposition within artery walls. Inflammatory infiltrate was not seen on biopsy, and this was attributed to the biopsied lesion being an older, “burned out” lesion already undergoing gliosis. Clinically and radiographically, our patient showed the commonly dramatic response to immunomodulatory treatment.\n\nCerebral amyloid angiopathy-related inflammation is an unusual but highly treatable cause of new-onset seizures in the middle-aged and elderly population and should be considered in the differential diagnosis of new-onset seizures after the age of 40, associated with fluctuating multifocal T2 hyperintensities and petechial hemorrhages on MRI.\n\nFig. 1 Axial T2 MRI FLAIR sequences with multifocal hyperintensities in the right temporal lobe (A), left anterior insula (B), and left occipital lobe (B, C). Blooming artifact over the left occipital region showing micro hemorrhages on the gradient echo sequences (D).\n\nFig. 1Fig. 2 Relapsing appearance of the left posterior quadrant lesion at 1 month, 3 months, 6 months, and 9 months of symptom onset (A, B, C, D, respectively).\n\nFig. 2Fig. 3 Hematoxylin and eosin (H&E) staining showed reactive changes including vacuolization suggestive of edema and astrocytosis/gliosis (A). Glial fibrillary acidic protein (GFAP) staining highlighted reactive astrocytes (B). H&E staining also demonstrated thickened blood vessels with perivascular hemosiderin deposition (C), and beta-amyloid immunohistochemistry revealed beta-amyloid deposition in blood vessel walls (D). These findings were consistent with cerebral amyloid angiopathy.\n\nFig. 3Fig. 4 Continuous lateralized periodic discharges with overlying fast activity (LPD + F) over the left posterior quadrant (maximal at O1 > P3/T5) (A), evolving into 3–4 electrographic seizures per hour, consisting of 9-Hz rhythmic sharp activity (B), without clinical return to baseline between seizures.\n\nFig. 4\n==== Refs\nReferences\n1 Vinters H.V. Cerebral amyloid angiopathy. A critical review Stroke 18 1987 311 324 3551211 \n2 Coria F. Rubio I. Cerebral amyloid angiopathies Neuropathol Appl Neurobiol 22 1996 216 2227 8804023 \n3 Chung K.K. Anderson N.E. Hutchinson D. Synek B. Barber P.A. Cerebral amyloid angiopathy related inflammation: three case reports and a review J Neurol Neurosurg Psychiatry 82 2011 20 26 20935328 \n4 Fountain N.B. Eberhard D.A. Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy: report of two cases and review of the literature Neurology 46 1996 190 197 8559373 \n5 Harkness K.A. Coles A. Pohl U. Xuereb J.H. Baron J.C. Lennox G.G. Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy Eur J Neurol 11 2004 59 62 14692890 \n6 Eng J.A. Frosch M.P. Choi K. Rebeck G.W. Greenberg S.M. Clinical manifestations of cerebral amyloid angiopathy-related inflammation Ann Neurol 55 2004 250 256 14755729\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-3232", "issue": "6()", "journal": "Epilepsy & behavior case reports", "keywords": "Cerebral amyloid angiopathy; EEG; Inflammation; MRI; Pathology; Status epilepticus", "medline_ta": "Epilepsy Behav Case Rep", "mesh_terms": null, "nlm_unique_id": "101614202", "other_id": null, "pages": "19-22", "pmc": null, "pmid": "27408804", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "8804023;14755729;3551211;14692890;20935328;8559373", "title": "Status epilepticus caused by cerebral amyloid angiopathy-related inflammation.", "title_normalized": "status epilepticus caused by cerebral amyloid angiopathy related inflammation" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOLCHIN B, FANTANEANU T, MILLER M, HELGAGER J, LEE JW. STATUS EPILEPTICUS CAUSED BY CEREBRAL AMYLOID ANGIOPATHY-RELATED INFLAMMATION. EPILEPSY + BEHAVIOR. 2016?6:19-22", "literaturereference_normalized": "status epilepticus caused by cerebral amyloid angiopathy related inflammation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17208126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "BACKGROUND\nIn recent decades, ritualistic use of ayahuasca has spread throughout the world. Retrospective studies have suggested a good psychological safety profile, but prospective studies involving ceremony ayahuasca-naive participants are lacking.\n\n\nMETHODS\nWe conducted the study using a subsample from a previous study, for which first-time ceremony ayahuasca participants were recruited. The subsample consisted of 7 subjects who experienced acute and challenging psychological reactions. The semistructured Mini-International Neuropsychiatric Interview and psychometric questionnaires were administered before participants attended the ayahuasca ceremony and at 1 and 6 months after exposure. Subjective experiences were also recorded.\n\n\nRESULTS\nSeven subjects from a sample of 40 reported having experienced intense challenging psychological effects during the ayahuasca ceremony. Four of those 7 subjects met the diagnostic criteria for 1 or more psychiatric disorder before the ayahuasca ceremony. One month after the ceremony, 2 of those subjects no longer showed psychiatric symptoms, whereas the symptoms of the other 2 were reduced considerably. Those results persisted at the 6-month follow-up. Inappropriate setting/context (poor guiding skills and screening) contributed to some of the challenging reactions. Most of the participants (6 of 7) did not take ayahuasca again during the study period.\n\n\nCONCLUSIONS\nBased on the cases reported here, we suggest that although it is possible that participating in ayahuasca ceremonies may entail acute psychological negative reactions, those challenging experiences can also have positive long-term effects. Prospective research on the safety profile of ayahuasca and how it is affected by the context of different practices and safety strategies is therefore necessary.", "affiliations": "From the International Center for Ethnobotanical Education, Research, and Services, Barcelona.;From the International Center for Ethnobotanical Education, Research, and Services, Barcelona.;Department of Biological & Health Psychology, School of Psychology, Madrid Autonomous University, Madrid, Spain.", "authors": "Gómez-Sousa|María|M|;Jiménez-Garrido|Daniel F|DF|;Ona|Genís|G|;Dos Santos|Rafael Guimaraes|RG|;Hallak|Jaime E C|JEC|;Alcázar-Córcoles|Miguel Ángel|MÁ|;Bouso|José Carlos|JC|", "chemical_list": "D006213:Hallucinogens; D028321:Plant Preparations", "country": "United States", "delete": false, "doi": "10.1097/JCP.0000000000001343", "fulltext": null, "fulltext_license": null, "issn_linking": "0271-0749", "issue": "41(2)", "journal": "Journal of clinical psychopharmacology", "keywords": null, "medline_ta": "J Clin Psychopharmacol", "mesh_terms": "D000328:Adult; D031581:Banisteriopsis; D002562:Ceremonial Behavior; D005260:Female; D005500:Follow-Up Studies; D006213:Hallucinogens; D006801:Humans; D008297:Male; D001523:Mental Disorders; D028321:Plant Preparations; D011446:Prospective Studies; D011594:Psychometrics; D011795:Surveys and Questionnaires; D013997:Time Factors", "nlm_unique_id": "8109496", "other_id": null, "pages": "163-171", "pmc": null, "pmid": "33606432", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": null, "title": "Acute Psychological Adverse Reactions in First-Time Ritual Ayahuasca Users: A Prospective Case Series.", "title_normalized": "acute psychological adverse reactions in first time ritual ayahuasca users a prospective case series" }

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{ "abstract": "OBJECTIVE\nPatients affected with Stage IV colorectal cancer and unresectable metastases represent a heterogeneous group. Resection of the primary tumor or stent positioning followed by chemotherapy and/or targeted therapies still represent a difficult choice for surgeons.\n\n\nMETHODS\nFrom February 2013 to September 2019, 46 patients were enrolled into a prospective randomized open label parallel trial presenting with Stage IVA and IVB rectal cancer, unresectable metastases and symptoms of subacute large bowel obstruction. Our population was divided into two groups: Group 1 included 20 patients who underwent placement of a self-expandable metal stent and Group 2 included 26 patients in whom primary tumor resection was performed.\n\n\nRESULTS\nOne-year actuarial survival rate of Group 1 was significantly lower compared to Group 2. Overall 17 patients had survival longer than 1-year (3 in Group 1 and 14 in Group 2). Cox regression analysis showed that endoscopic stent positioning and the suspension of the chemotherapy because of deterioration of liver function tests were the two most important factors negatively influencing survival.\n\n\nCONCLUSIONS\nPatients affected with stage IVA and IVB rectal cancer and symptoms of bowel obstruction had a significant longer survival rate when submitted to surgical rectal resection followed by chemotherapy.", "affiliations": "Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy danielecrocetti@hotmail.it.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.;Department of Radiology, Radiotherapy, Oncology and Anatomopathology, \"Sapienza\" University of Rome, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Rome, Italy.", "authors": "Fiori|Enrico|E|;Crocetti|Daniele|D|;Lamazza|Antonietta|A|;DE Felice|Francesca|F|;Tarallo|Mariarita|M|;Sterpetti|Antonio V|AV|;Mingoli|Andrea|A|;Sapienza|Paolo|P|;DE Toma|Giorgio|G|", "chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin", "country": "Greece", "delete": false, "doi": "10.21873/anticanres.13893", "fulltext": null, "fulltext_license": null, "issn_linking": "0250-7005", "issue": "39(12)", "journal": "Anticancer research", "keywords": "Rectal cancer; stent positioning; targeted therapy", "medline_ta": "Anticancer Res", "mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007415:Intestinal Obstruction; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds; D011446:Prospective Studies; D012004:Rectal Neoplasms; D000069322:Self Expandable Metallic Stents; D015996:Survival Rate", "nlm_unique_id": "8102988", "other_id": null, "pages": "6781-6786", "pmc": null, "pmid": "31810943", "pubdate": "2019-12", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial", "references": null, "title": "Resection or Stenting in the Treatment of Symptomatic Advanced Metastatic Rectal Cancer: A Dilemma.", "title_normalized": "resection or stenting in the treatment of symptomatic advanced metastatic rectal cancer a dilemma" }

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{ "abstract": "The retinoic acid derivatives are used for disorders of keratinization such as psoriasis. Retinoic acid syndrome is a cytokine release syndrome, commonly encountered in patients with acute promyelocytic leukaemia (APL). It is very rarely described in psoriasis seconday to use of retoind derivatives. Here we report a case of elderly male with psoriasis presenting with acitretin induced retinoic acid syndrome.", "affiliations": "Dept. of Pulmonary Medicine, Gauhati Medical College and Hospital, Srimanta Sakaradeva University of Health Sciences, Guwahati, 781032, Assam, India.;Dept. of Pulmonary Medicine, Gauhati Medical College and Hospital, Srimanta Sakaradeva University of Health Sciences, Guwahati, 781032, Assam, India.;Dept. of Pulmonary Medicine, Gauhati Medical College and Hospital, Srimanta Sakaradeva University of Health Sciences, Guwahati, 781032, Assam, India.;Dept. of Pulmonary Medicine, Gauhati Medical College and Hospital, Srimanta Sakaradeva University of Health Sciences, Guwahati, 781032, Assam, India.", "authors": "Metage|Chandan|C|;Hazarika|Basanta|B|;Sarma|Jogesh|J|;Karwa|Rahul|R|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2018.04.007", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30412-410.1016/j.rmcr.2018.04.007Case ReportRetinoic acid syndrome in a elderly male with psoriasis- A case report Metage Chandan chandanmetage13@gmail.com∗Hazarika Basanta Sarma Jogesh Karwa Rahul Dept. of Pulmonary Medicine, Gauhati Medical College and Hospital, Srimanta Sakaradeva University of Health Sciences, Guwahati, 781032, Assam, India∗ Corresponding author. chandanmetage13@gmail.com23 4 2018 2018 23 4 2018 24 81 83 25 12 2017 13 4 2018 © 2018 Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The retinoic acid derivatives are used for disorders of keratinization such as psoriasis. Retinoic acid syndrome is a cytokine release syndrome, commonly encountered in patients with acute promyelocytic leukaemia (APL). It is very rarely described in psoriasis seconday to use of retoind derivatives. Here we report a case of elderly male with psoriasis presenting with acitretin induced retinoic acid syndrome.\n==== Body\n1 Introduction\nRetinoic acid syndrome is multisystem disorder presenting with a constellation of symptoms. It is commonly encountered in patients with acute promyelocytic leukaemia (APL) as an adverse effect after administration of all-trans retinoic acid (ATRA) with incidence range from 2 to 27% [1]. This syndrome is very rarely described in psoriasis seconday to use of retoind derivatives [2]. Acitretin, a synthetic retinoid, is the pharmacologically active metabolite of etretinate, used in treating psoriasis and other keratinizing disorders [3]. Here we report a case of elderly male with psoriasis presenting with acitretin induced retinoic acid syndrome.\n\n2 Case report\nA 67year old man with 8years history of psoriasis presented to Emergency Department (ED) with acute onset dyspnea, cough, hemoptysis and fever. The symptoms progressed rapidly over past 4days. Physical examination revealed tachypnea (RR- 40cycles/min), tachycardia (PR-108bps), blood pressure of 120/80 mmHg, temperature 101F and SpO2 was 60% in room air. Chest auscultation revealed bilateral coarse crepetations and scattered ronchi. His laboratory investigations showed Leucocytosis(TC- 13000 cells/cumm) with 81% neutrophils, serum creatinine of 1.3mg/dl and normal liver enzymes (Table 1). His arterial blood gases revealed hypoxia (pH- 7.36, pO2-64 with Fio2 80%, pCo2-36.9 and HCO3- 21.1). After a provisional diagnosis of CAP he was started on broad spectrum antibiotics. A chest radiograph at the time of admission revealed dense consolidation involving both the lungs (Fig. 1). The patient deteriorated over next 24hrs with new onset hypotension, hematuria, worsening of symptoms, saturation and laboratory values (Table 1). His sputum and blood culture reports were negative, non-reactive HIV status, CRP was normal and 2D-Echo revealed normal LV function with LVEF of 60%. The patient tested negative for CTD and vasculitis screening (negative ANA and ANCA reflux tests). HRCT thorax revealed bilateral interstitial and alveolar infiltrates with consolidation and ground glass opacities (Fig. 2). After reviewing his treatment history it was revealed that he was on ACETRETIN 35mg orally for past 6months as a part of his psoriasis treatment.Fig. 1 Chest xray of the patient on the day of admission showing diffuse inhomogenous opacity involving both the lung fields.\n\nFig. 1Fig. 2 HRCT showing diffuse alveolar and interstitial infiltrates with dense consolidation and ground glassing.\n\nFig. 2Table 1 Showing the laboratory investigations, oxygen saturation on various days of admission and serial improvement in oxygen saturation values after administration of i.v. steroids.\n\nTable 1\tDay1 (Admission Day)\tDay3\tDay7\tDay12\t\nHb\t8.4 gm%\t6.8 gm%\t8.4 gm%\t9.3 gm%\t\nTC(cells/cumm)\t13,184\t16,800\t10,100\t10,184\t\nNeutrophils\t81%\t88%\t76%\t81%\t\nEosinophils\t0.6%\t0.1%\t1%\t0.8%\t\nMonocytes\t10%\t5%\t3.8%\t4.1%\t\nLymphocytes\t7%\t6%\t19%\t13.8%\t\nPlatelets (cells/cumm)\t1.6 lakh\t1.4 lakh\t–\t1.9 lakh\t\nProthrombin time\t14s\t16.8s\t–\t–\t\naPTT\t39.6s\t38.2s\t–\t–\t\nS. Creatinine\t1.3mg/dl\t1.8mg/dl\t1.1mg/dl\t0.9mg/dl\t\nCRP\t15.6mg/dl\t25.2mg/dl\t–\t–\t\nO2 Saturation\t60% (RA)\t55% (RA)\t80%(RA)\t94%(RA)\t\nSteroid dose (Day of steroid)\t–\tMethyprednisolone 1 gm i.v.OD* 3days (Day 1 of steroid)\tMethyprednisolone 40mg i.v. TID (Day 4 of steroid)\tMethyprednisolone 40mg i.v. BID (Day 9 of steroid)\t\nCXR\tBilateral diffuse infiltrates (Fig. 1)\t–\tLess dense opacities compared to previous film. (Fig. 3)\tComplete resolution of opacities. (Fig. 4)\t\n\n\nWith a background of clinical picture, laboratory investigations, negative culture reports, normal CRP levels and recent use of acetretin a diagnosis of Retionoic Acid Syndrome (RAS) was made, acetretin was withdrawn and he was started on i.v. methylprednisolone 1 gm daily. The patient showed dramatic improvement after 48hours of steroid administration. Oxygen requirement was reduced with decreased respiratory rate, resolution of crepetations and normalisation of blood pressure. Follow-up lab reports showed improvement in leukocyte count, serum creatinine and other parameters (Table 1) and resolution of opacities on chest xray (Fig. 3). The methylprednisolone was tapered to 120 mg daily in three divided doses which was further tapered gradually over a period of 2weeks. Follow-up chest xray after 9days of steroid therapy showed complete resolution of opacities (Fig. 4).Fig. 3 Chest xray after 3days of steroid administration (Day 7 of hospitalisation) showing less dense opacities compared to previous film.\n\nFig. 3Fig. 4 Chest xray after 9days of steroid administration (Day 12 of hospitalisation) showing complete resolution of opacities compared to previous film.\n\nFig. 4\n\n3 Discussion\nAll trans retinoic acid (ATRA) syndrome also known as differentiation syndrome is a condition that was first described as a life-threatening complication in patients with acute promyelocytic leukemia after therapy with all-trans-retinoic acid (ATRA) [4]. The pathogenesis of RAS is poorly understood and proposed mechanism is that ATRA treated APL cells release inflammatory cytokines, such as interleukin (IL)-1b, IL-6, IL-8 and tumor necrosis factor alpha (TNF-a) interacting with the haemostatic system. These inflammatory cytokines may play a role in the development of RAS [1]. The final common pathway is an insult to the endothelium followed by a predictable series of events, including, oedema, haemorrhage, fibrinous exudates, leukocyte infiltration and respiratory failure [5].\n\nRetinoic Acid Syndrome is a diagnosis of exclusion and the diagnosis is made based on various clinical features in the absence of other causes. It has been suggested that the diagnosis be based on the presence of at least three of the following signs and/or symptoms in the absence of alternative explanations: fever, weight gain, respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, hypotension and renal failure [6].\n\nRAS less frequently described with other retinoids. Previous literature review showed only 4 case reports of acetretin induced RAS [2,[7], [8], [9]], no case has been reported from India. Here we report a case of elderly male who was a diagnosed case of psoriasis and was started of acetretin, later presented with dyspnea, fever, hemoptysis, hypoxic respiratory failure, diffuse pulmonary infiltrates and acute renal failure with negative sepsis screening, features consistent with RAS. He was started on corticosteroid therapy and showed a rapid response with resolution of symptoms and radiological opacities. This rapid response to glucocorticoids is also supportive of the diagnosis of RAS.\n\n4 Conclusion\nAcitretin has been widely used in treatment of psoriasis and a number of difficult-to-treat hyperkeratotic and inflammatory dermatoses. Though rare, acetretin induced respiratory adverse effects should be looked for and diagnostic possibility of life threatening complication RAS should be considered in such patients. High clinical suspicion and early administration of steroids to prevent mortality is of utmost importance\n==== Refs\nReferences\n1 Patatanian E. Thompson D.F. Retinoic acid syndrome: a review J. Clin. Pharm. Therapeut. 33 2008 331 338 \n2 Contreras Jose Jr. Nangrani Pooja Khokar Abid Upadhyay Hinesh Hashemi Zary Nangrani Kunal A. Arjomand Farhad Vasudevan Viswanath Vitamin derivative induced acute lung injury Am. J. Respir. Crit. Care Med. 193 2016 A189 \n3 Sarkar R. Chugh S. Garg V.K. Acitretin in dermatology Indian J. Dermatol. Venereol. Leprol. 79 2013 759-7 \n4 Frankel S.R. Weiss M. Warrell P. A “retinoic acid syndrome” in acute promyelocytic leukemia: reversal by corticosteroids (abstract) Blood 78 1991 380A \n5 Tallman M.S. Andersen J.W. Schiffer C.A. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome Blood 95 2000 90 95 10607690 \n6 Retinoic acid syndrome: manifestations, pathogenesis, and treatment Larson, Richard S.Tallman, Martin S. et al. Best Pract. Res. Clin. Haematol. , Volume 16 , Issue 3 , 453 – 461.\n7 Weijie Gu Acetretin-induced retinoic acid syndrome J. Am. Acad. Dermatol. 65 5 2011 e148 e149 22000885 \n8 Cuhadaroglu C. Respiratory distress with acitretin, reversal by corticosteroid Dermatol. Online J. 7 2 2001 5 \n9 Liu D. Cao F. Yan X. Chen X. Chen Y. Tu Y. Furue M. Retinoic acid syndrome in a patient with psoriasis Eur. J. Dermatol. 19 6 2009 Nov-Dec 632 634 19605343\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "24()", "journal": "Respiratory medicine case reports", "keywords": null, "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "81-83", "pmc": null, "pmid": "29977766", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "10607690;19605343;22000885;24177607;18613850;12165221;12935962", "title": "Retinoic acid syndrome in a elderly male with psoriasis- A case report.", "title_normalized": "retinoic acid syndrome in a elderly male with psoriasis a case report" }

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{ "abstract": "While elimination of the hepatitis C virus (HCV) following acute infection is not uncommon, spontaneous clearance once the infection becomes chronic is extremely rare. The mechanisms involved in the clearance of chronic HCV infection without intervening antiviral therapy are not well known. Herein we describe a case of a renal transplant recipient who acquired HCV infection while immunosuppressed, experienced a rapid histological progression, and thereafter cleared the virus spontaneously long after withdrawal of immunosuppression following kidney graft rejection and failure. We review the literature and summarize the reports of spontaneous clearance of chronic HCV infection in various settings.", "affiliations": "Section on Infectious Diseases, Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina.;Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina.;Section on Infectious Diseases, Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina.", "authors": "Mori Ubaldini|Francesca|F|https://orcid.org/0000-0002-1746-902X;Stratta|Robert J|RJ|;Nunez|Marina|M|", "chemical_list": "D007166:Immunosuppressive Agents; D012367:RNA, Viral", "country": "Denmark", "delete": false, "doi": "10.1111/tid.13079", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "21(3)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "chronic HCV; immune restoration; kidney transplantation; spontaneous viral clearance", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D012367:RNA, Viral; D012075:Remission, Spontaneous; D019562:Viral Load", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13079", "pmc": null, "pmid": "30882950", "pubdate": "2019-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Delayed spontaneous hepatitis C virus elimination in a renal transplant patient following graft rejection.", "title_normalized": "delayed spontaneous hepatitis c virus elimination in a renal transplant patient following graft rejection" }

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"reactionoutcome": "1" }, { "reactionmeddrapt": "Device related infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatic fibrosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2006" } }, "primarysource": { "literaturereference": "MORI UBALDINI F, STRATTA RJ, NUNEZ M. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200304", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THYMOGLOBULIN" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2003" } }, "primarysource": { "literaturereference": "MORI UBALDINI, F.. DELAYED SPONTANEOUS HEPATITIS C VIRUS ELIMINATION IN A RENAL TRANSPLANT PATIENT FOLLOWING GRAFT REJECTION. TRANSPLANT INFECTIOUS DISEASE. 2019?21 (3):10.1111/TID.13079", "literaturereference_normalized": "delayed spontaneous hepatitis c virus elimination in a renal transplant patient following graft rejection", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190704", "receivedate": "20190702", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16519593, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.", "affiliations": "Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Klinik für Strahlentherapie und Radioonkologie, Mannheim, Germany.;Radiologische Allianz, Strahlentherapie, Hamburg, Germany.;Universitätsklinikum Freiburg, Strahlenheilkunde, Freiburg, Germany.;Universitätsklinikum Heidelberg, Klinik für Radioonkologie und Strahlentherapie, Heidelberg, Germany.;Universitätsklinikum Jena, Klinik für Strahlentherapie und Radioonkologie, Jena, Germany.;Radioonkologie LMU München, Strahlentherapie und Radioonkologie, Munich, Germany.;Universitätsspital Zürich, Universität Zürich, Klinik für Radio-Onkologie, Zürich, Switzerland.;Medizinische Hochschule Hannover, Klinik für Strahlentherapie und Spezielle Onkologie, Hannover, Germany.;Technische Universität München (TUM), Department of Radiation Oncology, Munich, Germany.;Universitätsklinikum Halle (Saale), Klinik für Strahlentherapie, Halle (Saale), Germany.;Zentrum für Strahlentherapie und Radioonkologie, Belegklinik am St. Agnes-Hospital, Bocholt, Germany.;Gemeinschaftspraxis für Strahlentherapie, Bogenhausen - Harlaching - Neuperlach, Munich, Germany.;MediClin Robert Janker Klinik, Klinik für Strahlentherapie und Radioonkologie, Bonn, Germany.;Universitätsklinikum Schleswig-Holstein, Klinik für Strahlentherapie, Kiel, Germany.;Universitätsklinikum Jena, Klinik für Strahlentherapie und Radioonkologie, Jena, Germany.;Cyberknife Centrum Mitteldeutschland GmbH, Institut für Radiochirurgie und Präzisionsbestrahlung, Erfurt, Germany.;Universitätsklinikum Magdeburg, Klinik für Strahlentherapie, Magdeburg, Germany.;Universitätsspital Zürich, Universität Zürich, Klinik für Radio-Onkologie, Zürich, Switzerland.;Universitätsklinikum Augsburg, Klinik für Strahlentherapie und Radioonkologie, Augsburg, Germany.;Städtisches Klinikum Dessau, Klinik für Strahlentherapie und Radioonkologie, Dessau, Germany.;Klinikum Darmstadt GmbH, Institut für Radioonkologie und Strahlentherapie, Darmstadt, Germany.;Universitätsklinikum Halle (Saale), Klinik für Strahlentherapie, Halle (Saale), Germany.;Universitätsklinikum Erlangen, Strahlenklinik, Erlangen, Germany.;Universitätsklinikum Heidelberg, Klinik für Radioonkologie und Strahlentherapie, Heidelberg, Germany.;Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Klinikum der Universität München, LMU, Munich, Germany.;Technische Universität München (TUM), Department of Radiation Oncology, Munich, Germany.;Universitätsspital Zürich, Universität Zürich, Klinik für Radio-Onkologie, Zürich, Switzerland.;Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Klinik für Strahlentherapie und Radioonkologie, Mannheim, Germany.", "authors": "Buergy|Daniel|D|0000-0001-5913-3332;Würschmidt|Florian|F|;Gkika|Eleni|E|;Hörner-Rieber|Juliane|J|;Knippen|Stefan|S|;Gerum|Sabine|S|;Balermpas|Panagiotis|P|;Henkenberens|Christoph|C|;Voglhuber|Theresa|T|;Kornhuber|Christine|C|;Barczyk|Steffen|S|;Röper|Barbara|B|;Rashid|Ali|A|;Blanck|Oliver|O|;Wittig|Andrea|A|;Herold|Hans-Ulrich|HU|;Brunner|Thomas B|TB|;Klement|Rainer J|RJ|0000-0003-1401-4270;Kahl|Klaus Henning|KH|;Ciernik|Ilja F|IF|;Ottinger|Annette|A|;Izaguirre|Victor|V|;Putz|Florian|F|;König|Laila|L|;Hoffmann|Michael|M|;Combs|Stephanie E|SE|;Guckenberger|Matthias|M|;Boda-Heggemann|Judit|J|0000-0002-5831-0197", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/ijc.33546", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-7136", "issue": "149(2)", "journal": "International journal of cancer", "keywords": "SBRT; adrenal; oligometastases; outcome; patterns of care", "medline_ta": "Int J Cancer", "mesh_terms": "D000310:Adrenal Gland Neoplasms; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D016634:Radiosurgery; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "0042124", "other_id": null, "pages": "358-370", "pmc": null, "pmid": "33682927", "pubdate": "2021-07-15", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.", "title_normalized": "stereotactic or conformal radiotherapy for adrenal metastases patient characteristics and outcomes in a multicenter analysis" }

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{ "abstract": "Continuous quadratus lumborum (QL) analgesia is a new option for proximal femur surgery considered safe and effective. The purpose of this report was to show that we may not be aware of all the possible complications of this technique, and urinary retention may occur even when the block is performed unilaterally.\nTo an obese, intubated, mechanically ventilated, female patient, operated in prone position for removal of a femur tumour, we performed a trans-muscular quadratus lumborum block (TQL). We mounted a catheter and administered continuous infusion of local anaesthetic in the postoperative period. The patient experienced urinary retention. A urinary catheter was placed and it was maintained for the entire period of local anaesthetic infusion. When the catheter was removed, 72 hours after the surgery, the patient resumed normal bladder functions.\nUrinary retention is a possible complication when continuous quadratus lumborum analgesia is used, even when performed unilaterally.", "affiliations": "Department of Anaesthesiology and Intensive Care, University of Medicine and Pharmacy \"Iuliu Haţieganu\" Cluj-Napoca, Romania.;Department of Orthopedy, Emergency County Hospital Cluj-Napoca, Romania.;Research Center for Advanced Medicine Medfuture, University of Medicine and Pharmacy \"Iuliu Haţieganu\" Cluj-Napoca, Romania.", "authors": "Dîrzu|Dan Sebastian|DS|;Dicu|Cosmin|C|;Dîrzu|Noémi|N|", "chemical_list": null, "country": "Romania", "delete": false, "doi": "10.2478/rjaic-2019-0011", "fulltext": null, "fulltext_license": null, "issn_linking": "2392-7518", "issue": "26(1)", "journal": "Romanian journal of anaesthesia and intensive care", "keywords": "quadratus lumborum block; regional anaesthesia complications; toracolumbar plane block; ultrasound guided regional anaesthesia; urinary retention", "medline_ta": "Rom J Anaesth Intensive Care", "mesh_terms": null, "nlm_unique_id": "101681752", "other_id": null, "pages": "75-78", "pmc": null, "pmid": "31111099", "pubdate": "2019-04", "publication_types": "D002363:Case Reports", "references": "25978765;27185672;27543534;27730633;27871532;27997495;27997498;28036319;28154824;28277325;28549524;28731927;29122123;29290856;29536008", "title": "Urinary retention: a possible complication of unilateral continuous quadratus lumborum analgesia - a case report.", "title_normalized": "urinary retention a possible complication of unilateral continuous quadratus lumborum analgesia a case report" }

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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATRACURIUM" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "88", "reaction": [ { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DIRZU D, DICU C, DIRZU N. URINARY RETENTION: A POSSIBLE COMPLICATION OF UNILATERAL CONTINUOUS QUADRATUS LUMBORUM ANALGESIA-A CASE REPORT. ROM J ANAESTH INTENSIVE CARE. 2019?26:75-78.", "literaturereference_normalized": "urinary retention a possible complication of unilateral continuous quadratus lumborum analgesia a case report", "qualification": "1", "reportercountry": "RO" }, "primarysourcecountry": "RO", "receiptdate": "20190517", "receivedate": "20190517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16326942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "OBJECTIVE\nTo describe the 6-month clinical outcome and the long-term safety profile of B cell depletion therapy (BCDT) in 50 patients with active systemic lupus erythematosus (SLE), who were nonresponsive or poorly responsive to conventional immunosuppression.\n\n\nMETHODS\nAll except 4 of 50 patients with active SLE received 1 gm of rituximab, 750 mg of cyclophosphamide, and 100-250 mg of methylprednisolone, administered on 2 occasions 2 weeks apart, to achieve B cell depletion. Clinical outcome was assessed using the British Isles Lupus Assessment Group (BILAG) activity index and serial serologic measurements of disease activity. Remission was defined as a change from a BILAG A or B score to a C or D score in every organ system. Partial remission was a change from a BILAG A or B score to a C or D score in at least 1 system, but with the persistence of 1 score of A or B in another system. No improvement was defined as a BILAG A or B score that remained unchanged after treatment.\n\n\nRESULTS\nOf the 45 patients available for followup at 6 months, 19 patients (42%) achieved remission, and 21 patients (47%) reached partial remission after 1 cycle of BCDT (mean followup 39.6 months). BCDT resulted in a decrease in median global BILAG scores from 12 to 5 (P < 0.0001) and median anti-double-stranded DNA antibody titers from 106 to 42 IU/ml (P < 0.0001), and an increase in the median C3 level from 0.81 to 0.95 mg/liter (P < 0.02) at 6 months. Five serious adverse events were observed.\n\n\nCONCLUSIONS\nBCDT is an effective treatment for patients with active SLE whose disease has failed to respond to standard immunosuppressive therapy. Although the safety profile of BCDT is favorable, ongoing monitoring is required.", "affiliations": "University College of London, London, UK.", "authors": "Lu|Tim Y-T|TY|;Ng|Kristine P|KP|;Cambridge|Geraldine|G|;Leandro|Maria J|MJ|;Edwards|Jonathan C W|JC|;Ehrenstein|Michael|M|;Isenberg|David A|DA|", "chemical_list": "D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D004247:DNA; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.1002/art.24341", "fulltext": null, "fulltext_license": null, "issn_linking": "0004-3591", "issue": "61(4)", "journal": "Arthritis and rheumatism", "keywords": null, "medline_ta": "Arthritis Rheum", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes; D003520:Cyclophosphamide; D004247:DNA; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008137:Longitudinal Studies; D008180:Lupus Erythematosus, Systemic; D008212:Lymphocyte Depletion; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab; D012720:Severity of Illness Index; D055815:Young Adult", "nlm_unique_id": "0370605", "other_id": null, "pages": "482-7", "pmc": null, "pmid": "19333973", "pubdate": "2009-04-15", "publication_types": "D016428:Journal Article", "references": null, "title": "A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients.", "title_normalized": "a retrospective seven year analysis of the use of b cell depletion therapy in systemic lupus erythematosus at university college london hospital the first fifty patients" }

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A RETROSPECTIVE SEVEN-YEAR ANALYSIS OF THE USE OF B CELL DEPLETION THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS AT UNIVERSITY COLLEGE LONDON HOSPITAL: THE FIRST FIFTY PATIENTS. 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A RETROSPECTIVE SEVEN-YEAR ANALYSIS OF THE USE OF B CELL DEPLETION THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS AT UNIVERSITY COLLEGE LONDON HOSPITAL: THE FIRST FIFTY PATIENTS.. ARTHRITIS-CARE-RES-(HOBOKEN). 2009;61(4):482-7", "literaturereference_normalized": "a retrospective seven year analysis of the use of b cell depletion therapy in systemic lupus erythematosus at university college london hospital the first fifty patients", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150407", "receivedate": "20150407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10993039, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "PHHY2015GB039710", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ISENBERG DA, LU TY-T, NG KP, CAMBRIDGE G, LEANDRO MJ, EDWARDS JCW, ET AL.. A RETROSPECTIVE SEVEN-YEAR ANALYSIS OF THE USE OF B CELL DEPLETION THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS AT UNIVERSITY COLLEGE LONDON HOSPITAL: THE FIRST FIFTY PATIENTS.. ARTHRITIS-CARE-RES-(HOBOKEN). 2009;61(4):482-7", "literaturereference_normalized": "a retrospective seven year analysis of the use of b cell depletion therapy in systemic lupus erythematosus at university college london hospital the first fifty patients", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150407", "receivedate": "20150407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10993041, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "Anterior choroidal artery (AChoA) aneurysms are rare intracranial aneurysms, which are treated with endovascular techniques or surgical clipping procedures. AChoA aneurysm may have variable symptomatologies, clinical courses, and outcomes due to the eloquent territory of the artery. We have presented 3 cases of AChoA aneurysms, which differ from each other and literature by rare oculomotor nerve palsy, antiplatelet treatment complication and near-complete late resolution of the oculomotor nerve palsy. We have tried to share our AChoA case experiences to emphasize the importance of being flexible and adaptable in the diagnosis, treatment and follow up of this rare intracranial aneurysm type.", "affiliations": "Namik Kemal University, Medical Faculty, Radiology Department, Namik Kemal Mahallesi, Kampus Caddesi 1/14, 59100 Suleymanpasa, Tekirdag, Turkey. Electronic address: yturk@nku.edu.tr.;Kirklareli State Hospital, Radiology Department, Yayla Mahallesi, 39000 Merkez, Kirklareli, Turkey.", "authors": "Turk|Yasar|Y|;Kuskun|Atakan|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clinimag.2020.01.006", "fulltext": null, "fulltext_license": null, "issn_linking": "0899-7071", "issue": "61()", "journal": "Clinical imaging", "keywords": "Aneurysm; Anterior choroidal artery; Anterior choroidal artery aneurysm; Oculomotor nerve palsy", "medline_ta": "Clin Imaging", "mesh_terms": "D002343:Carotid Artery, Internal; D002536:Cerebral Arteries; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D015840:Oculomotor Nerve Diseases; D016896:Treatment Outcome", "nlm_unique_id": "8911831", "other_id": null, "pages": "11-14", "pmc": null, "pmid": "31954345", "pubdate": "2020-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Anterior choroidal artery aneurysms could have different symptoms, and outcomes: a report of 3 cases treated endovascularly.", "title_normalized": "anterior choroidal artery aneurysms could have different symptoms and outcomes a report of 3 cases treated endovascularly" }

[ { "companynumb": "TR-SA-2020SA033518", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020839", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLAVIX" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" } ], "patientagegroup": "5", "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Red blood cell count abnormal", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Subarachnoid haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aneurysm", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TURK Y, KUSKUN A.. ANTERIOR CHOROIDAL ARTERY ANEURYSMS COULD HAVE DIFFERENT SYMPTOMS, AND OUTCOMES: A REPORT OF 3 CASES TREATED ENDOVASCULARLY. CLINICAL IMAGING. 2020?61:11-14", "literaturereference_normalized": "anterior choroidal artery aneurysms could have different symptoms and outcomes a report of 3 cases treated endovascularly", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200305", "receivedate": "20200220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17442500, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "BACKGROUND\nInfantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD).\n\n\nMETHODS\nTreatment and outcome of 95 children with IM registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2016) were evaluated.\n\n\nRESULTS\nLD was diagnosed in 71 patients at a median age of 0.4 years (range 0.0-17.7). MFD was present in 24 patients. The mainstay of treatment was watch-and-wait strategy (w&w) after initial biopsy or resection. Low-dose chemotherapy (CHT) was administered to 16/71 (23%) patients with LD and eight of 24 (33%) patients with MFD, imatinib was added in two. A delayed resection was possible in eight of 71 (11%) and five of 24 (21%) patients with LD and MFD, respectively. Overall, patients were alive in complete remission (n = 77) and partial remission (n = 10) at a median follow-up time of 3.4 years after diagnosis (range 0.01-19.4); no data available (n = 5). Three patients died of progressive disease (PD) despite CHT. Gender, tumor size, and location correlated with a favorable event-free survival (EFS) in patients with LD. The 5-year EFS and overall survival of patients with LD were 73% (±12, confidence interval [CI] 95%) and 95% (±6, CI 95%), respectively; for MFD 51% (±22, CI 95%) and 95% (±10, CI 95%).\n\n\nCONCLUSIONS\nPrognosis is excellent in patients with LD and MFD. Targeted treatment needs to be evaluated for rare fatal PD.", "affiliations": "Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Klinikum der Landeshauptstadt Stuttgart gKAöR, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.;Department of Pathology, Section of Pediatric Pathology, Bonn, Germany.;Department of Pediatric Surgery, University Children´s Hospital Marburg, Marburg, Germany.;Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Klinikum der Landeshauptstadt Stuttgart gKAöR, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.;Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Olgahospital, Institute of Radiology, Stuttgart, Germany.;Klinikum Stuttgart, Institute of Radiotherapy, Stuttgart, Germany.;Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Klinikum der Landeshauptstadt Stuttgart gKAöR, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.;Pediatric Oncology, St. Anna Kinderspital, Wien, Austria.;Department of Women`s and Children`s Health, University of Uppsala, Children`s University Hospital, Uppsala, Sweden.;Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland.;Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Augsburg, Augsburg, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Olgahospital, Institute of Pediatric Surgery, Stuttgart, Germany.;Department for Children and Adolescents, Universityhospital Frankfurt, Frankfurt, Germany.;Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Klinikum der Landeshauptstadt Stuttgart gKAöR, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.", "authors": "Sparber-Sauer|Monika|M|https://orcid.org/0000-0001-9551-2399;Vokuhl|Christian|C|https://orcid.org/0000-0002-4138-4536;Seitz|Guido|G|https://orcid.org/0000-0001-9280-1451;Sorg|Benjamin|B|;Tobias|Möllers|M|;von Kalle|Thekla|T|;Münter|Marc|M|;Bielack|Stefan S|SS|;Ladenstein|Ruth|R|;Ljungman|Gustaf|G|;Niggli|Felix|F|;Frühwald|Michael|M|;Loff|Stefan|S|;Klingebiel|Thomas|T|;Koscielniak|Ewa|E|https://orcid.org/0000-0002-1519-7569", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.29403", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": null, "journal": "Pediatric blood & cancer", "keywords": "CWS Group; infantile myofibromatosis; infants and children; localized and multifocal disease", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": null, "nlm_unique_id": "101186624", "other_id": null, "pages": "e29403", "pmc": null, "pmid": "34636137", "pubdate": "2021-10-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.", "title_normalized": "infantile myofibromatosis excellent prognosis but also rare fatal progressive disease treatment results of five cooperative weichteilsarkom studiengruppe cws trials and one registry" }

[ { "companynumb": "DE-AUROBINDO-AUR-APL-2022-016814", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "212773", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Leiomyoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "212773", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile fibromatosis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Leiomyoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile fibromatosis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Leiomyoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile fibromatosis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Leiomyoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile fibromatosis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Sparber-Sauer M, Vokuhl C, Seitz G, Sorg B, Tobias M, von Kalle T, et al.. Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease.Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.. Pediatric Blood Cancer. 2022;69(3):1-10", "literaturereference_normalized": "infantile myofibromatosis excellent prognosis but also rare fatal progressive disease treatment results of five cooperative weichteilsarkom studiengruppe cws trials and one registry", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220531", "receivedate": "20220531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20892883, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" } ]

{ "abstract": "Chromoblastomycosis and phaeohyphomycosis are melanized fungal infections, which affect skin and subcutaneous tissues in immunocompetent and immunosuppressed patients, as solid-organ transplant recipients, respectively. In this present study, we report six cases of melanized fungal infection in kidney transplant recipients. In five cases, culture of tissue specimens identified two cases of Exophiala spp. and three cases of Fonsecaea spp. Molecular identification was performed in three cases based on sequencing of rDNA (ITS region) that revealed the following agents: Exophiala xenobiotica, Exophiala bergeri and Fonsecaea monophora. Clinically, they presented verrucous lesion, erythematous-squamous plaque, nodules and lymphangitic distribution. Histopathological aspect was tuberculous granuloma, with concomitant presence of muriform bodies and hyphae. Some patients presented fungal transepithelial elimination. One patient received only terbinafine. Three patients underwent surgery, and two of them received itraconazole. In these four cases, the infection did not relapse. The other two patients were treated only with itraconazole, one of them is still under treatment and the other one was lost to follow-up. These patients presented clinical and histopathological characteristics ranging from resistant to nonresistant forms.", "affiliations": "Department of Dermatology, Federal University of São Paulo (UNIFESP), Rua Borges Lagoa, 508, São Paulo, SP, CEP 04038-001, Brazil. mariliaogawa@gmail.com.;Department of Dermatology, Federal University of São Paulo (UNIFESP), Rua Borges Lagoa, 508, São Paulo, SP, CEP 04038-001, Brazil.;Department of Pathology, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.;Special Laboratory of Mycology, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.;Department of Pathology, Federal University of Espírito Santo (UFES), Vitória, Brazil.;Department of Dermatology, Federal University of São Paulo (UNIFESP), Rua Borges Lagoa, 508, São Paulo, SP, CEP 04038-001, Brazil.", "authors": "Ogawa|Marilia M|MM|;Peternelli|Marcella P|MP|;Enokihara|Milvia M S S|MM|;Nishikaku|Angela S|AS|;Gonçalves|Sarah Santos|SS|;Tomimori|Jane|J|", "chemical_list": "D000935:Antifungal Agents; D004271:DNA, Fungal; D021903:DNA, Ribosomal Spacer", "country": "Netherlands", "delete": false, "doi": "10.1007/s11046-016-0005-8", "fulltext": null, "fulltext_license": null, "issn_linking": "0301-486X", "issue": "181(5-6)", "journal": "Mycopathologia", "keywords": "Chromoblastomycosis; Dematiaceous; Kidney transplantation; Mycosis; Pathology; Phaeohyphomycosis", "medline_ta": "Mycopathologia", "mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D001203:Ascomycota; D004271:DNA, Fungal; D021903:DNA, Ribosomal Spacer; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D017422:Sequence Analysis, DNA; D066027:Transplant Recipients; D016896:Treatment Outcome", "nlm_unique_id": "7505689", "other_id": null, "pages": "379-85", "pmc": null, "pmid": "27025729", "pubdate": "2016-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "8821168;19107636;9870861;17645522;19488919;17596364;6032507;12497547;21128710;1308064;16850396;24048727;16396338;21392438;10353215;18096404;11797173;19815309;22217212;18404547;18324495;20930077;4601425;16951740;18951291;23471535;14708965;16897561", "title": "Spectral Manifestation of Melanized Fungal Infections in Kidney Transplant Recipients: Report of Six Cases.", "title_normalized": "spectral manifestation of melanized fungal infections in kidney transplant recipients report of six cases" }

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SPECTRAL MANIFESTATION OF MELANIZED FUNGAL INFECTIONS IN KIDNEY TRANSPLANT RECIPIENTS: REPORT OF SIX CASES. 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SPECTRAL MANIFESTATION OF MELANIZED FUNGAL INFECTIONS IN KIDNEY TRANSPLANT RECIPIENTS: REPORT OF SIX CASES. MYCOPATHOL. 2016;181(56):379-85", "literaturereference_normalized": "spectral manifestation of melanized fungal infections in kidney transplant recipients report of six cases", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20170927", "receivedate": "20170927", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14014353, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" } ]

{ "abstract": "Lamivudine has demonstrated efficacy in the treatment and prevention of hepatitis B virus (HBV) reactivation after hematopoietic stem cell transplantation (HSCT). However, most of these studies involved short durations of prophylaxis, so there is significant concern regarding lamivudine resistance in these patients. Between March 1984 and November 2002, 71 HBV surface antigen-positive HSCT recipients, including a subgroup of 16 who received pretransplantation lamivudine therapy, which was continued into the posttransplantation period to prevent reactivation hepatitis, were enrolled onto our study. The efficacy of lamivudine therapy was first evaluated for the subgroup of 16 patients in terms of treatment response, lamivudine resistance, and viral recurrence after discontinuation by using virologic assays. Efficacy was then evaluated for all patients in terms of the hazards of lamivudine therapy for reactivation hepatitis after transplantation. During a median lamivudine therapy period of 73 weeks (range, 19-153 weeks), the initial response showed a median reduction of 2.54 log10 in serum HBV DNA (-0.28 to 6.72 range). Lamivudine-resistant mutations were detected in 10 (63%) of 16 patients during therapy, and 1 (12%) of 16 patients finally developed a viral breakthrough. At a median follow-up of 30 months after discontinuation, 3 (27%) of 11 cases had recurrence of HBV infection. Despite the emergence of the mutations, no deaths were due to HBV reactivation or severe cases of hepatitis. In the Cox proportion regression model regarding reactivation hepatitis after transplantation of all enrolled patients, lamivudine therapy was found to be the only favorable factor for the event, with a hazard ratio of 0.122 (95% confidence interval, 0.016-0.908; P = .040). In conclusion, extended lamivudine therapy is safe and effective for the prevention of HBV reactivation in an HSCT setting and significantly decreases reactivation hepatitis after transplantation.", "affiliations": "Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.", "authors": "Hsiao|Liang-Tsai|LT|;Chiou|Tzeon-Jye|TJ|;Liu|Jin-Hwang|JH|;Chu|Chiau-Jun|CJ|;Lin|Yu-Chen|YC|;Chao|Ta-Chung|TC|;Wang|Wei-Shu|WS|;Yen|Chueh-Chuan|CC|;Yang|Muh-Hwa|MH|;Tzeng|Cheng-Hwai|CH|;Chen|Po-Min|PM|", "chemical_list": "D000998:Antiviral Agents; D019259:Lamivudine", "country": "United States", "delete": false, "doi": "10.1016/j.bbmt.2005.09.001", "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "12(1)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": null, "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D004351:Drug Resistance; D005260:Female; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011292:Premedication; D019562:Viral Load; D014775:Virus Activation", "nlm_unique_id": "9600628", "other_id": null, "pages": "84-94", "pmc": null, "pmid": "16399572", "pubdate": "2006-01", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients.", "title_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients" }

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EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124744, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03905", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B VIRUS TEST POSITIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral mutation identified", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "LIANG-TSAI HSIAO, TZEON-JYE CHIOU, JIN-HWANG LIU, CHIAU-JUN CHU,YU-CHEN LIN,TA-CHUNG CHAO ET AL. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124718, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03904", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B SURFACE ANTIGEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Virologic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral mutation identified", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIANG-TSAI HSIAO, TZEON-JYE CHIOU, JIN-HWANG LIU, CHIAU-JUN CHU,YU-CHEN LIN,TA-CHUNG CHAO ET AL. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124709, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03943", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HSIAO L, CHIOU.T, LIU.F, CHU.C, LIN.Y, CHAO.T, WANG.W, YEN.C, YANG.M, TZENG.C, CHEN.P.. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION.. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150522", "receivedate": "20150522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11130239, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03938", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B SURFACE ANTIGEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HSIAO L, CHIOU.T, LIU.F, CHU.C, LIN.Y, CHAO.T, WANG.W, YEN.C, YANG.M, TZENG.C, CHEN.P.. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124762, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03908", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B VIRUS TEST POSITIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Viral mutation identified", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "LIANG-TSAI HSIAO, TZEON-JYE CHIOU, JIN-HWANG LIU, CHIAU-JUN CHU,YU-CHEN LIN,TA-CHUNG CHAO ET AL. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124772, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03944", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B SURFACE ANTIGEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HSIAO L, CHIOU.T, LIU.F, CHU.C, LIN.Y, CHAO.T, WANG.W, YEN.C, YANG.M, TZENG.C, CHEN.P.. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION.. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150522", "receivedate": "20150522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11130251, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03939", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B SURFACE ANTIGEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Viral mutation identified", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HSIAO L, CHIOU.T, LIU.F, CHU.C, LIN.Y, CHAO.T, WANG.W, YEN.C, YANG.M, TZENG.C, CHEN.P.. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124761, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03941", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B SURFACE ANTIGEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Virologic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HSIAO L, CHIOU.T, LIU.F, CHU.C, LIN.Y, CHAO.T, WANG.W, YEN.C, YANG.M, TZENG.C, CHEN.P.. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION.. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124763, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "TW-CIPLA LTD.-2015TW03907", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B VIRUS TEST POSITIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Virologic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIANG-TSAI HSIAO, TZEON-JYE CHIOU, JIN-HWANG LIU, CHIAU-JUN CHU,YU-CHEN LIN,TA-CHUNG CHAO ET AL. EXTENDED LAMIVUDINE THERAPY AGAINST HEPATITIS B VIRUS INFECTION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006;12:84-94", "literaturereference_normalized": "extended lamivudine therapy against hepatitis b virus infection in hematopoietic stem cell transplant recipients", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11124743, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months' follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26-86). Median follow-up was 34 months (range 6-149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0-312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6-18.4) and 66.8 months (95% CI 52.1-79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.", "affiliations": "Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Via P. Maroncelli 40, 47014, Meldola, Italy. flavia.foca@irst.emr.it.;Oncology Unit, Infermi Hospital, Rimini, Italy.;Oncological Unit, Vito Fazzi Hospital, Lecce, Italy.;Division of Medical Oncology, Ramazzini Hospital, Carpi, Italy.;Ospedali Riuniti di Ancona, Ancona, Italy.;Oncology Unit, Degli Infermi Hospital, Faenza, Italy.;IRCCS National Cancer Institute (INT), Milan, Italy.;Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;IT Service, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.", "authors": "Bongiovanni|Alberto|A|;Foca|Flavia|F|;Fantini|Manuela|M|;Forcignanò|Maria Rosachiara|MR|;Artioli|Fabrizio|F|;Berardi|Rossana|R|;Campadelli|Enrico|E|;Procopio|Giuseppe|G|;Silvestris|Francesco|F|;Riva|Nada|N|;Gurrieri|Lorena|L|;Debonis|Silvia Angela|SA|;Di Menna|Giandomenico|G|;Fausti|Valentina|V|;Recine|Federica|F|;Vespignani|Roberto|R|;Ibrahim|Toni|T|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1038/s41598-021-83749-1", "fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322 Nature Publishing Group UK London \n\n83749\n10.1038/s41598-021-83749-1\nArticle\nFirst prospective data on breast cancer patients from the multicentre italian bone metastasis database\nBongiovanni Alberto 1 Foca Flavia flavia.foca@irst.emr.it 2 Fantini Manuela 3 Forcignanò Maria Rosachiara 4 Artioli Fabrizio 5 Berardi Rossana 6 Campadelli Enrico 7 Procopio Giuseppe 8 Silvestris Francesco 9 Riva Nada 1 Gurrieri Lorena 1 Debonis Silvia Angela 1 Di Menna Giandomenico 1 Fausti Valentina 1 Recine Federica 1 Vespignani Roberto 10 Ibrahim Toni 1 1 Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy \n2 Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Via P. Maroncelli 40, 47014 Meldola, Italy \n3 grid.414614.2Oncology Unit, Infermi Hospital, Rimini, Italy \n4 grid.417011.20000 0004 1769 6825Oncological Unit, Vito Fazzi Hospital, Lecce, Italy \n5 Division of Medical Oncology, Ramazzini Hospital, Carpi, Italy \n6 grid.415845.9Ospedali Riuniti di Ancona, Ancona, Italy \n7 Oncology Unit, Degli Infermi Hospital, Faenza, Italy \n8 grid.417893.00000 0001 0807 2568IRCCS National Cancer Institute (INT), Milan, Italy \n9 grid.7644.10000 0001 0120 3326Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy \n10 IT Service, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy \n22 2 2021 \n22 2 2021 \n2021 \n11 432914 5 2020 5 2 2021 © The Author(s) 2021Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months’ follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26–86). Median follow-up was 34 months (range 6–149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0–312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6–18.4) and 66.8 months (95% CI 52.1–79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.\n\nSubject terms\nCancerBreast cancerMetastasisissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nBreast cancer (BC) is the most common malignancy and a major cause of morbidity and mortality among women. The mortality rate has decreased thanks to improved diagnostic procedures, screening and more advanced treatments. However, the rate of recurrence in distant organs is still fairly high, ranging from 20 to 30%1,2.\n\nBone is the most common site of metastasis in BC and significantly impacts patient survival3–5.\n\nBone metastases (BMs) represent an important clinical-epidemiological issue in oncology because their diagnosis and treatment are often necessarily handled by several specialists, resulting in fragmented patient information6. For these reasons, great efforts have been made to develop a new scientific and clinical branch of medicine, i.e. Osteoncology7.\n\nThe major problem faced by BM patients is the risk of skeletal complications defined as skeletal-related events (SREs) all of which are highly detrimental to quality of life and survival2,8,9.\n\nThere is still limited information available on BM clinical presentation, the difference in disease response between bone and visceral sites, and the difference in prognosis between solitary, oligometastatic and multiple sites or axial and trunk bone metastases10. A clearer understanding of their natural evolution would thus help us to identify new strategies capable of reducing both BM incidence and morbidity.\n\nThe risk of SREs in BC patients with BM has been the focus of numerous studies11–13. However, their findings are of limited value because of their poor generalizability with respect to current clinical practice. In the retrospective studies, authors usually considered a lengthy time period during which available therapies and clinical practice may have changed substantially. In the prospective studies, patients were followed for a short period (24 months) and data were extrapolated from a BC database rather than from a database dedicated to BM. Furthermore, in recent years, new therapeutic options have become available. There has also been growing interest in BM since dedicated multidisciplinary groups began to emerge14.\n\nThe main aims of this prospective multicenter study were to evaluate the evolution of skeletal disease in BC patients, assess the impact of BM on disease outcome, examine the role of a number of clinical-pathological parameters in predicting survival, and further our understanding of the natural history of patients with BM from BC.\n\nMaterials and methods\nThis was a multicentre prospective observational study of patients with BM from BC with at least 6 months follow-up, enrolled into the prospective Italian Bone Metastases Data Base (BMDB). The study was approved by the Local Ethics Committee of each participating centre and carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. List of participating centers was provided in Supplementary Table 1. Written informed consent was obtained from all patients. Information on data source is provided in Appendix 1.\n\nData extraction and measure definition\nThe evolution of skeletal disease in BC patients was evaluated by extracting data from the BMDB for patients who had a first diagnosis of BC with a synchronous (within 2 months) or metachronous diagnosis of bone metastasis and were followed up for at least 6 months after the BM diagnosis.\n\nTime to event outcomes were defined as follows: disease-free interval (DFI) was the time from primary BC disease to the appearance of the first metastasis (bone or visceral), and bone disease-free interval (bDFI) was the time between diagnosis of primary BC and first diagnosis of BM. Overall survival (OS) was calculated as the time from the date of the diagnosis of primary BC to the date of death. OS from metastatic disease (metOS) was calculated as the time from the diagnosis of metastasis (either bone or visceral) to death. Progression-free survival (PFS) was the time between the date of the first diagnosis of bone metastasis and date of the first documented evidence of disease progression (bone or visceral) and death. Bone PFS (bPFS) was the time between the date of the first diagnosis of BM and first progression to bone and death. Time-to-first SRE was the time between the first diagnosis of BM and the first SRE event. Patients without events of interest were censored at the date of the last follow-up visit.\n\nStatistical analysis\nDescriptive statistics are used to summarize baseline patient characteristics, BM characteristics and treatment patterns. Continuous variables are presented using median and range or interquartile range. The Wilcoxon rank-sum test was used for continuous variables, together with the chi-squared test or Fisher’s exact test, as appropriate. McNemar’s test was used in cases of paired data. Time-to-event measures were analysed using the Kaplan–Meier method, and the nonparametric log-rank test was used to evaluate the role of stratification factor. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and relative 95% confidence intervals (CI) of potential clinical prognostic factors for time-to-event outcomes.\n\nAll statistical analyses were performed using STATA/MP 15.0 for Windows (StataCorp LLP, College Station, TX, USA).\n\nResults\nPatient characteristics\nFrom October 1st 2014 to June 30th 2018, 618 patients with BM from any solid tumor were registered in the Italian BMDB. Three hundred and nine had BC as the primary site of disease and 220/309 with at least 6 months’ follow up were included in the present analysis (Fig. 1). Median age was 62 (range 26–85) years.Figure 1 Study flow diagram.\n\n\n\nAt the time of the first diagnosis of BM, 152 (92.1%) patients showed a good ECOG PS (0–1). Forty-nine (22.3%) patients were diagnosed with BM synchronous to the primary tumor, while metachronous BM were found in 171 patients.\n\nBone-only metastases (BOM) were found in 109 (50.0%) patients, while the remaining 109 had concomitant visceral and BM (BVM). Histological and biological characteristics of the primary BC are shown in Tables 1 and 2. Luminal A and B tumors were more frequently associated with BOM, whereas basal-like or HER2-enriched BC subtypes more often showed BVM (p = 0.012). A higher, albeit not significant, Ki-67 value was observed for patients with BVM (p = 0.074). The majority of patients had T0-T2 (n = 159, 85%) and node-positive tumors (n = 138, 74.6%) at diagnosis (Table 3), the former associated with a higher rate of metachronous BM than synchronous BM (83.2% and 16.8%, respectively) (p < 0.001) (Table 4). Patients with N0 primary tumors had a higher incidence of metachronous BM than synchronous (95.8% and 4.2%, respectively) (p = 0.001). No difference between BOM or BVM according to node status (node negative vs. node positive tumors) was observed. Both node-negative and node-positive patients showed a high rate of metachronous BM (95.8% and 75.5%, respectively), even if in node-negative patients there is a significantly higher proportion of patients with metachronous BM.Table 1 Patient characteristics at baseline and at onset of BM.\n\n\tPatients (n = 220)\t\nMedian age, years (range)\t62 (26–85)\t\n\tNo. (%)\t\nAge at diagnosis of primary BM, years\t\t\n< 65\t133 (60.5)\t\n  65\t87 (69.5)\t\nECOG PS at diagnosis of primary BM\t\t\n0–1\t152 (92.1)\t\n ≥ 2\t13 (7.9)\t\nUnknown\t55\t\nHistology\t\t\nDuctal carcinoma\t166 (75.5)\t\nLobular carcinoma\t29 (13.0)\t\nMixed ductal and lobular carcinoma\t11 (5.0)\t\nAdenocarcinoma, NOS\t9 (4.0)\t\nSignet ring cell carcinoma\t1 (0.5)\t\nOther\t4 (2.0)\t\npT at primary diagnosis of BC\t\t\nT0–T2\t159 (85.0)\t\nT3–T4\t28 (15.0)\t\nTx\t31\t\npN at primary diagnosis of BC\t\t\nN0\t47 (25.4)\t\nN+\t138 (74.6)\t\nNx\t33\t\nStage at diagnosis of primary disease\t\t\nI\t28 (14.1)\t\nII\t68 (34.3)\t\nIII\t42 (21.2)\t\nIV\t60 (30.3)\t\nUnknown\t22\t\nBC molecular subtype\t\t\nLuminal A\t35 (18.8)\t\nLuminal B\t118 (63.4)\t\nBasal-like\t8 (4.3)\t\nHER+\t25 (13.4)\t\nUnknown\t34\t\nGrading\t\t\nG1\t6 (3.7)\t\nG2\t85 (52.5)\t\nG3\t71 (43.8)\t\nUnknown\t58\t\nBone metastasis\t\t\nSynchronous\t49 (22.3)\t\nMetachronous\t171 (77.7)\t\nBOM\t109 (50.0)\t\nBVM\t109 (50.0)\t\nBM bone metastasis, ECOG PS Eastern Cooperative Oncology Group Performance Status, NOS not otherwise specified, BC breast cancer, pT primary tumour, pN pathological lymph node, Nx unknown lymph node stage, G grade, BOM bone-only metastasis, BVM visceral and bone metastasis.\n\nTable 2 Biomarker characteristics at diagnosis of primary BC and at onset of BM.\n\nBC characteristics\tAt diagnosis\tAt the onset of bone metastasis\t\nPositive* (%)\tNegative* (%)\tNA\tPositive* (%)\tNegative* (%)\tNA\t\nER\t183 (89.7)\t21 (10.3)\t16\t48 (88.9)\t6 (11.1)\t166\t\nPgR\t144 (70.6)\t60 (29.4)\t16\t24 (45.3)\t29 (54.7)\t167\t\n\t< 15%\t≥ 15%\tNA\t< 15%\t≥ 15%\tNA\t\nKi-67\t145 (79.7)\t37 (20.3)\t38\t29 (65.9)\t15 (34.1)\t176\t\n\tPositive/(+ + +)\tNegative/0–2 + \tNA\tPositive/(+ + +)\tNegative/0–2 + \tNA\t\nHER2 (IHC or FISH)\t24 (12.9)\t162 (87.1)\t34\t7 (13.7)\t44 (86.3)\t169\t\nBC breast cancer, BM bone metastasis, ER oestrogen receptor, PgR progesterone receptor, NA not available, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.\n\n*For ER and PgR, positive if ≥ 10%, negative if < 10%.\n\nTable 3 Baseline patient characteristics in relation to presence of visceral metastases.\n\nBaseline BC characteristics\tNo. patients\n(n = 218)\tBOM (n = 109)\nNo. (%)\tBVM (n = 109)\nNo. (%)\tp-value\t\nAge at diagnosis of bone metastasis, years\t\n< 65\t108 (49.1)\t70 (53.0)\t62 (47.0)\t0.268\t\n≥ 65\t112 (50.9)\t39 (45.3)\t47 (54.7)\t\npT at primary diagnosis of breast cancer\t\t\nT0–T2\t159 (85.0)\t84 (52.8)\t75 (47.2)\t0.531\t\nT3–T4\t28 (15.0)\t13 (46.4)\t15 (53.6)\t\npN at primary diagnosis of breast cancer\t\nN0\t47 (25.4)\t26 (55.3)\t21 (44.7)\t0.330\t\nN+\t138 (74.6)\t65 (47.1)\t73 (52.9)\t\nStage at diagnosis of primary disease\t\nI\t27 (13.8)\t16 (59.3)\t11 (40.7)\t0.621\t\nII\t67 (34.2)\t31 (46.3)\t36 (53.7)\t\nIII\t42 (21.4)\t23 (54.8)\t19 (45.2)\t\nIV\t60 (30.6)\t33 (55.0)\t27 (45.0)\t\nUnknown\t22\t6\t16\t\t\nBreast cancer molecular subtype\t\nLuminal A\t35 (19.0)\t26 (74.3)\t9 (25.7)\t0.012\t\nLuminal B\t118 (64.1)\t60 (50.8)\t58 (49.2)\t\nBasal-like\t7 (3.8)\t2 (28.6)\t5 (71.4)\t\nHER+\t24 (13.1)\t9 (37.5)\t15 (62.5)\t\nUnknown\t34\t12\t22\t\t\nMedian Ki67% (interquartile range)\t20 (10–31)\t16 (8–30)\t20 (10–35)\t0.074\t\nER\t\nNegative\t19 (9.4)\t6 (31.6)\t13 (68.4)\t0.075\t\nPositive\t183 (90.6)\t97 (53.1)\t86 (46.9)\t\nUnknown or not performed\t16\t6\t10\t\t\nPgR\t\nNegative\t58 (28.7)\t29 (50.0)\t29 (50.0)\t0.858\t\nPositive\t144 (71.3)\t74 (51.4)\t70 (48.6)\t\nUnknown or not performed\t16\t6\t10\t\t\nHER2 (IHC or FISH)\t\nNegative\t161 (87.5)\t89 (55.3)\t72 (44.7)\t0.066\t\nPositive\t23 (12.5)\t8 (34.8)\t15 (65.2)\t\nUnknown or not performed\t34\t12\t22\t\t\nAdjuvant therapy\t\nNo\t73 (33.4)\t35 (47.9)\t38 (52.1)\t0.632\t\nYes\t144 (66.1)\t74 (51.4)\t70 (48.6)\t\nNeoadjuvant therapy\t\nNo\t196 (91.2)\t97 (49.5)\t99 (50.5)\t0.484\t\nYes\t19 (8.8)\t11 (57.9)\t8 (42.1)\t\nBC breast cancer, BOM bone-only metastasis, BVM visceral and bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.\n\nTable 4 Baseline patient characteristics in relation to synchronous or metachronous metastases.\n\nBaseline BC characteristics\tNo. patients\n(n = 220)\tSynchronous BM\n(n = 49)\nNo. (%)\tMetachronous BM\n(n = 171)\nNo. (%)\tp-value\t\nAge at diagnosis of bone metastasis, years\t\n< 65\t133 (49.1)\t32 (24.1)\t101 (75.9)\t0.431\t\n≥ 65\t87 (50.9)\t17 (19.5)\t70 (80.5)\t\npT at primary diagnosis of breast cancer\t\nT0–T2\t161 (85.0)\t27 (16.8)\t134 (83.2)\t< 0.001\t\nT3–T4\t28 (15.0)\t15 (53.6)\t13 (46.4)\t\npN at primary diagnosis of breast cancer\t\nN0\t48 (25.6)\t2 (4.2)\t46 (95.8)\t0.001\t\nN+\t137 (74.3)\t34 (24.5)\t105 (75.5)\t\nStage at diagnosis of primary disease\t\nI\t28 (14.1)\t0 (0.0)\t28 (100.0)\t–\t\nII\t68 (34.4)\t0 (0.0)\t68 (100.0)\t\nIII\t42 (21.2)\t0 (0.0)\t42 (100.0)\t\nIV\t60 (30.3)\t49 (81.7)\t11 (18.3)\t\nUnknown\t22\t–\t22\t\t\nBreast cancer molecular subtype\t\nLuminal A\t35 (18.8)\t7 (20.0)\t28 (80.0)\t0.315\t\nLuminal B\t118 (63.4)\t31 (26.3)\t87 (73.7)\t\nBasal-like\t8 (4.3)\t1 (12.5)\t7 (87.5)\t\nHER+\t25 (13.4)\t10 (40.0)\t15 (60.0)\t\nUnknown\t34\t–\t34\t\t\nMedian Ki67% (interquartile range)\t20 (10–31)\t23 (15–35)\t16 (10–30)\t0.087\t\nER\t\nNegative\t21 (9.9)\t2 (9.5)\t19 (90.5)\t0.114\t\nPositive\t183 (90.1)\t47 (25.7)\t136 (74.3)\t\nUnknown or not performed\t16\t–\t16\t\t\nPgR\t\nNegative\t60 (29.4)\t11 (18.3)\t49 (81.7)\t0.220\t\nPositive\t144 (70.6)\t38 (26.4)\t106 (73.6)\t\nUnknown or not performed\t16\t–\t16\t\t\nHER2 (IHC or FISH)\t\nNegative\t162 (87.1)\t38 (23.5)\t124 (76.5)\t0.057\t\nPositive\t24 (12.9)\t10 (41.7)\t14 (58.3)\t\nUnknown or not performed\t34\t1\t33\t\t\nBM bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.\n\n\n\nBone biopsy was performed in 58 (26.4%) cases. The median time from primary disease diagnosis to the appearance of BM in this subgroup was 79 months (95%CI: 65.0–118.1).\n\nTime to event outcomes\nDisease-free interval\nDisease free-interval was calculated excluding patients with synchronous disease at bone (n = 49) and visceral (n = 2). The disease-free interval (DFI) differed slightly according to molecular subtype. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.66, 95% confidence interval [CI] 1.1–2.5) (p = 0.023), basal-like tumors (3.92, 95% CI 1.6–9.7) (p = 0.003), and HER2-enriched tumors (1.28, 95% CI 0.7–2.4) (p = 0.442).\n\nDFI for patients with stage I disease at diagnosis of primary BC was longer than that for stage III patients (median 67.2 months, 95% CI 53.1–96.1, vs. 58.1 months, 95% CI 41.9–73.4), with a univariate HR of 1.84 (95% CI 1.1–3.0) (p = 0.015) for the stage III group, and 0.98 (95% CI 0.6–1.5) (p = 0.931) for the stage II group. Older patients had a higher risk of metastasis (HR 1.91, 95% CI 1.4–2.7), as did those with larger tumors at diagnosis (HR: 3.7, 95% CI 1.9–7.1). Multivariate analysis confirmed these data for patients with basal-like and larger tumors (Table 5).Table 5 Median DFI and independent risk factors for metastasis.\n\n\tOverall DFI\tbDFI\t\n\tMedian\n(95%CI)\tHR from univariate Cox regression model (95%CI)\tHR from multivariate Cox regression model (95%CI)\tMedian\n(95%CI)\tHR from univariate Cox regression model (95%CI)\tHR from multivariate Cox regression model (95%CI)\t\nAll cases\t75.7 (63.5–87.3)\t–\t–\t78.2 (63.6–87.9)\t–\t–\t\nAge at diagnosis of primary BC, years\t\n < 55\t82.1 (65.4–112.9)\t1.00\t1.00\t89.6 (65.4–114.8)\t1.00\t1.00\t\n ≥ 55\t65.0 (48.1–81.5)\t1.91 (1.4–2.7)\t1.48 (0.9–2.2)\t65.0 (51.1–86.0)\t1.89 (1.4–2.6)\t1.27 (0.9–1.9)\t\nBC molecular subtypes\t\nLuminal A\t101.9 (57.0–125.7)\t1.00\t1.00\t101.9 (57.0–125.7)\t1.00\t1.00\t\nLuminal B\t63.5 (48.6–75.7)\t1.66 (1.1–2.5)\t1.46 (0.9–2.4)\t63.6 (52.7–78.5)\t1.54 (0.9–2.4)\t1.27 (0.8–2.0)\t\nBasal-like\t30.0 (13.4–NE)\t3.92 (1.6–9.7)\t3.94 (1.4–11.0)\t30.0 (2.1–66.1)\t4.29 (1.8–10.1)\t3.82 (1.4–10.6)\t\nHER2+\t53.1 (30.9–100.1)\t1.28 (0.7–2.4)\t1.44 (0.7–2.9)\t53.1 (47.9–100.2)\t1.17 (0.6–2.2)\t1.22 (0.6–2.5)\t\nStage at diagnosis\t\nI\t67.2 (53.1–96.1)\t1.00\t1.00\t82.2 (53.6–125.7)\t1.00\t1.00\t\nII\t83.3 (66.5–99.2)\t0.98 (0.6–1.5)\t1.09 (0.5–2.3)\t83.2 (66.5–101.9)\t1.07 (0.7–1.7)\t1.16 (0.6–2.4)\t\nIII\t58.1 (41.9–73.4)\t1.84 (1.1–3.0)\t1.35 (0.5–3.2)\t60.9 (41.9–75.6)\t2.1 (1.3–3.5)\t1.55 (0.7–3.7)\t\nIV\t–\t–\t–\t–\t–\t–\t\npT at primary diagnosis of BC\t\nT0–T2\t76.7 (61.0–87.3)\t1.00\t1.00\t78.5 (63.6–87.9)\t1.00\t1.00\t\nT3–T4\t20.6 (3.3–65.4)\t3.7 (1.9–7.1)\t3.24 (1.5–7.1)\t18.6 (3.3–57.0)\t4.5 (2.4–8.2)\t3.02 (1.4–6.6)\t\npN at primary diagnosis of BC\t\nN0\t83.3 (56.1–101.9)\t1.00\t1.00\t89.6 (61.1–118.2)\t1.00\t1.00\t\nN+\t66.5 (56.3–80.0)\t1.36 (0.9–1.9)\t0.91 (0.5–1.7)\t66.5 (57.0–79.0)\t1.47 (1.0–2.1)\t0.97 (0.5–1.8)\t\nDFI disease-free interval, bDFI bone disease-free interval, HR hazard ratio, BC breast cancer, NE not evaluable from statistical software, pT primary tumour, pN pathological lymph node.\n\n\n\nBone disease-free interval\nFor this analysis, were excluded all patients with synchronous bone metastasis (n = 49). Median time to BM appearance was 78.2 months (95% confidence interval [CI] 63.6–87.9) for all patients.\n\nMedian bone disease-free interval (bDFI) was 63.5 months (95% CI 47.9–83.3) for the BM-only group at diagnosis and 86.6 months (95% CI 66.5–99.6) for those with visceral metastases. Median bDFI was 78.5 months (95% CI 63.6–87.9) in T0–T2 patients and 18.6 months (95% CI 3.3–57.0) in the T3–T4 group (p ≤ 0.001). The group with node-negative BC had a median bDFI of 8.6 months (95% CI 61.1–118.2) compared to 66.5 months (95% CI 57.0–79.0) for the node-positive subgroup (log rank test p = 0.032) (Fig. 2a,b). bDFI was significantly higher (p < 0.001) in patients aged < 55 years at diagnosis than in those ≥ 55 years, (median 89.6 [95% CI 65.4–114.8] vs. 65.0 [95% CI 51.1–86.0] months) (Supplementary Fig. 1). Multivariate analyses confirmed a higher risk for patients with basal-like and larger tumors (Table 5).Figure 2 Disease-free interval by (a) T and (b) N of primary disease.\n\n\n\nOverall survival\nMedian follow-up was 46 months (range: 6–117) on 220 evaluable patients.\n\nSeventy-four deaths were observed during follow-up. Median OS was 217.5 months (95% CI 172.5–340.1).\n\nMolecular profile subtypes were an independent prognostic factor. Median OS (mOS) in patients with luminal A tumors was not-reached and 128.1 months (95% CI 108.0–182.6) for those with luminal B tumors, 101.2 months (95% CI 17.1–not estimable) for patients with basal-like BC, and 274.5 months (95% CI 70.3-–not estimable) for those HER2-enriched BC (p = 0.010). Patients aged ≥ 55 years and those with stage IV disease at diagnosis had a shorter mOS (128.1 months [95% CI 101.2–182.6] and 65.3 months [95% CI 41.0–80.9], respectively) than the groups diagnosed at a younger age (< 55 years) and with lower-stage disease (Supplementary Fig. 2a,b). Patients with pain at the first diagnosis of bone metastases had an mOS of 143.8 months (95% CI 98.0–247.5) with respect to 257.4 months (95% CI 135.1–not estimable) for those with no pain. mOS of the group with axial BM was 252.5 months (95% CI 182.5–343.0), 157.6 months (95% CI41.0–Not estimable) for those with appendicular BM, and 217.5 months (95% CI 100.9–Not estimable) for patients with both types of metastases (p = 0.009).\n\nmOS of patients undergoing first-line treatment was 135.1 months (95% CI 102.9–257.4) for the chemotherapy (CH) ± biological therapy (BIO) group and 252.5 months (95%CI:202.1-not estimable) for those receiving endocrine therapy (ENDO) ± BIO, but was not-reached in patients undergoing CH + ENDO (p = 0.0305). Patients aged ≥ 55 years (HR 2.92, 95% CI 1.4–6.0), those with luminal B (HR 4.10, 95% CI 1.5–11.1), stage IV disease (HR 8.69, 95% CI 2.6–28.9) or axial + appendicular or other site of BM (HR:2.20, 95% CI 1.1–4.6) had a higher risk of death, while those with no pain at BM diagnosis (HR 0.49, 95% CI 0.2–0.9) and patients receiving ENDO ± BIO (HR:0.40, 95% CI 0.2–0.8) had a better prognosis considering multivariate Cox regression model (Supplementary Table 2).\n\nOS from diagnosis of metastatic disease\nThe median OS for patients with metastatic disease (metOS) was 66.8 months (95% CI 52.1–79.2). The molecular profile of subtypes was an independent prognostic factors according to metOS. A multivariate Cox regression model confirmed a poorer prognosis for patients with luminal B subtype (HR 3.67, 95% CI 1.5–8.7) (Supplementary Table 2).\n\nProgression-free survival\nDisease progression occurred in 167 patients. Median progression-free survival (PFS) was 15.1 months (95% CI 12.6–18.4). With respect to first-line treatment, median PFS was 13.4 months (95% CI 10.0–16.6) in the CH ±BIO arm, 17.3 months (95% CI 12.0–23.6) in the ENDO ± BIO group and 32.0 months (95% CI 12.7-Not estimable) in CH + ENDO patients. None of analyzed prognostic factors were found as statistically significant in univariate analysis, even if a HR of 0.51 (95% CI 0.27–0.95) was observed for patients treated with CH + ENDO with respect to those given CH alone after the first diagnosis of metastasis (p = 0.0849) (Supplementary Fig. 3) in univariate analysis. No differences in terms of time to disease progression were seen between synchronous and metachronous BM, BOM vs. BVM, first-line treatment, number and type of BM, and presence of pain at diagnosis. The presence of SREs at diagnosis did not have an impact on disease progression (Supplementary Table 3).\n\nBone metastasis progression-free survival\nMedian BM PFS was 45.9 months (95% CI 30.8–63.0). Older patients had a higher risk for progression to bone (HR: 1.51, 95% CI 1.1–2.1) in univariate analysis (Supplementary Table 3).\n\nTime to first SRE\nNinety-eight (44.5%) patients had at least one SRE during the course of their metastatic disease. Patients treated with zoledronic acid or pamidronate had a similar HR for SREs with respect to untreated patients (HR 1.32, 95% CI 0.74–2.38), while those taking denosumab had a HR of 0.20 (95% CI 0.04–0.87), indicating a reduced risk of SRE (Supplementary Fig. 4). Supplementary data are reported in Appendix 2.\n\nDiscussion\nBone metastases represent a common complication of cancer, their incidence reaching around 65% in BC2. There are still aspects of bone metastatic disease that need to be further investigated15,16.\n\nAs reported in previous studies, our case series showed a majority of lytic bone metastases17,18. The nature (lytic or not) of BM would not appear to impact patient outcome. Small BC tumors (T0–T2) were associated with metachronous BM, with a time to bone involvement of 65.1 months after the primary diagnosis of BC, indicating that the information collected also regarded patients with latent BM. This subgroup possesses the clinical phenotype of bone metastatic cells characterized by dormancy in which adjuvant BTT could prove useful to prevent BM formation19. The mOS from the diagnosis of distant disease (5.5 years) was similar to that reported in other studies, whereas mOS from the primary BC diagnosis differed20–22. Such findings reflect the good prognosis of the primary BC patients included in our study, representing a real-world population.\n\nRecent studies on a population-based cancer registry and a National Cancer Database observed that patients aged < 60 years now show better survival than those reported in previous studies in which younger age and premenopausal status were associated with poorer survival22–24. Our study had similar findings, with improved mOS from the time of diagnosis of metastastic disease and primary BC in patients < 55 years and < 65 years, respectively.\n\nOur data are also consistent with previous literature reporting that luminal BC subtype confers an independent survival benefit regardless of tumor receptor status25,26.\n\nThe initial stage of disease at BC diagnosis represented an important prognostic factor for survival and is consistent with the literature on this topic27,28. Some preclinical and clinical studies have reported promising results for concurrent ENDO + CH in postmenopausal patients with metastatic hormone-positive BC29,30. In line with these findings, our patients undergoing the ENDO + CH combination showed a slight benefit in terms of mPFS with respect to those treated with ENDO + CH ± BIO. These fascinating suggestions warrant further exploration and validation prospective clinical trials.\n\nPrevious studies have shown a better prognosis for BOM patients than for those with BVM. However, in our study BOM and BVM groups had a similar mOS which may be attributable to a conditioning effect of the molecular BC subtype and also to new treatments available.\n\nA recently published study on BOM reported no correlation between bone pain and survival. Our results are in line with these findings in both BOM and BVM groups. BM localization proved to have a prognostic value in our case series, an appendicular site negatively impacting mOS more than axial or mixed localizations. In a retrospective study conducted by Parkes et al., BOM patients with axial localisation had a mOS from the diagnosis of distant disease of 5.62 years compared to 6.78 years for those with appendicular BM and 4.58 years the appendicular + axial BM group31. A possible explanation for this could be the higher incidence of axial bone metastases in luminal BC.\n\nAnother interesting finding of our study was that patients with single or oligo- metastases had a better prognosis than those with multiple bone lesions. Although there is already evidence of this for the former32, interest in oligo-metastatic disease has recently come to the fore because of its challenging management33,34.\n\nIt has been seen that changes in BC cell biology occur between primary tumors and metastases35,36. In our study a significant difference in PgR expression was observed between primary BC and metastatic bone lesions. Clinicians should take this into account in cases of disease recurrence more than 5 years after the primary diagnosis.\n\nAge was found to have a significant impact on OS. This is in line with retrospective works published on BC and BM patients in which age was found to be an independent prognostic factor30.\n\nFinally, our data confirm the protective effect of denosumab in preventing SREs, which leveled off over time. Albeit with an incidence reducing over time.\n\nOne of the limitations of our study is the patient sample even though it’s consistent with other studies in which patients were followed prospectively in a dedicated database on BM and not extrapolated from large registries28,32. Another limit is the lack of information available on specific treatments, a result of opting not to enter a large amount of data into the database. To overcome this we grouped treatments into specific categories.\n\nIn contrast, the strengths of our study are its collection of prospective data on BM and their clinical evolution and the fact that it constitutes a national representative study population for this disease setting.\n\nIn conclusion, the Italian BMDB represents an invaluable tool to better understand the natural history of bone metastases from breast cancer and improve their management. The Italian BMDB continues to enroll patients also in other solid tumors to increase the case series and give more answer to clinician questions.\n\nSupplementary Information\n\nSupplementary Information.\n\n \n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1038/s41598-021-83749-1.\n\nAcknowledgements\nThe authors thanks all the other members of Banca Dati Metastasi Ossee Study Team: Luigi Cavanna (A.O. Piacenza, Piacenza, Italy), Antonio Maestri (S. Maria della Scaletta Hospital, Imola, Bologna), Francesco Ferraù (Medical Oncology Division, San Vincenzo Hospital, Taormina, Italy), Maria Banzi (Medical Oncology Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy), Bruno Daniele (Gaetano Rummo Hospital, Benevento, Italy), Sergio Fava (Ospedale Civile di Legnano, Legnano, Italy), Gaetano Lanzetta (Medical Oncology Unit, Istituto Neurotramutologico Italiano, Grottaferrata, Italy). The authors thanks Gráinne Tierney and Cristiano Verna for editorial assistance.\n\nAuthor contributions\nConception and design: A.B., T.I. and F.F. IT support: R.V. Provision of study materials or patients: A.B., T.I., F.F., M.F., M.R.F., F.A., R.B., E.C., G.P., F.S., N.R., L.G., S.D.B., G.D.M., V.F. and F.R. Data analysis and interpretation: A.B., T.I., F.F., M.R.F., F.A., M.F., R.B., G.P., F.S. and E.C. Manuscript writing and final approval of manuscript: All authors.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nData availability\nThe datasets gathered and analyzed during the current study are available from the corresponding author on reasonable request.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Kennecke H Yerushalmi R Woods R Metastatic behavior of breast cancer subtypes J. Clin. Oncol. 2010 28 20 3271 3277 10.1200/JCO.2009.25.9820 20498394 \n2. Coleman R Rubens R The clinical course of bone metastases from breast cancer Br. J. Cancer 1987 55 1 61 66 10.1038/bjc.1987.13 3814476 \n3. Mundy GR Metastasis to bone: Causes, consequences and therapeutic opportunities Nat. Rev. Cancer 2002 2 8 284 293 10.1038/nrc867 \n4. Coleman RE Metastatic bone disease: Clinical features, pathophysiology and treatment strategies Cancer Treat Rev. 2001 27 3 165 176 10.1053/ctrv.2000.0210 11417967 \n5. Macedo F Ladeira K Pinho F Bone metastases: An overview Oncol. Rev. 2017 11 1 321 28584570 \n6. Ibrahim T Mercatali L Amadori D A new emergency in oncology: Bone metastases in breast cancer patients (Review) Oncol. Lett. 2013 2 306 310 10.3892/ol.2013.1372 \n7. Ibrahim T Mercatali L Amadori D Bone and cancer: the osteoncology Clin. Cases Miner. Bone Metab. 2013 10 2 121 123 24133529 \n8. Weinfurt KP Castel LD Li Y Health related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions Med. Care 2004 42 2 164 175 10.1097/01.mlr.0000108746.69256.45 14734954 \n9. Coleman RE Clinical features of metastatic bone disease and risk of skeletal morbidity Clin. Cancer Res. 2006 12 20 Pt 2 6243s s6249 10.1158/1078-0432.CCR-06-0931 17062708 \n10. Cetin K Christiansen CF Sværke C Survival in patients with breast cancer with bone metastasis: A Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval BMJ Open 2015 5 4 e007702 10.1136/bmjopen-2015-007702 25926150 \n11. Oster G Lamerato L Glass AG Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: A 15-year study in two large US health systems Support Care Cancer 2013 21 12 3279 3286 10.1007/s00520-013-1887-3 23884473 \n12. Cazzaniga ME Dogliotti L Cascinu S Diagnosis, management and clinical outcome of bone metastases in breast cancer patients: Results from a prospective, multicenter study Oncology 2006 71 5–6 374 381 10.1159/000107772 17785994 \n13. Schröder J Fietz T Köhler A Treatment and pattern of bone metastases in 1094 patients with advanced breast cancer: Results from the prospective German Tumour Registry Breast Cancer cohort study Eur. J. Cancer 2017 79 139 148 10.1016/j.ejca.2017.03.031 28494404 \n14. Bongiovanni A Recine F Fausti V Ten-year experience of the multidisciplinary osteoncology center Support Care Cancer 2019 27 9 3395 3402 10.1007/s00520-019-4635-5 30649614 \n15. Solomayer EF Diel IJ Meyberg GC Metastatic breast cancer: Clinical course, prognosis and therapy related to the first site of metastasis Breast Cancer Res. Treat 2000 59 3 271 278 10.1023/A:1006308619659 10832597 \n16. Schneeweiss S Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics Pharmacoepidemiol. Drug Saf. 2006 15 5 291 303 10.1002/pds.1200 16447304 \n17. Colonna S Werner TL Randall RL Breast cancer bone metastases Metastatic Bone Disease: An Integrated Approach to Patient Care 2016 New York Springer 45 55 \n18. Zhang H Zhu W Biskup E Incidence, risk factors and prognostic characteristics of bone metastases and skeletal-related events (SREs) in breast cancer patients: A systematic review of the real world data J. Bone Oncol. 2018 11 38 50 10.1016/j.jbo.2018.01.004 29511626 \n19. Niikura N Liu J Hayashi N Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: A single-institution retrospective analysis Oncologist 2011 16 2 155 164 10.1634/theoncologist.2010-0350 21266401 \n20. Ahn SG Lee HM Cho SH Prognostic factors for patients with bone-only metastasis in breast cancer Yonsei Med. J. 2013 54 5 1168 1177 10.3349/ymj.2013.54.5.1168 23918566 \n21. Foukakis T Fornander T Lekberg T Age-specific trends of survival in metastatic breast cancer: 26 years of longitudinal data from a population-based cancer registry in Stockholm, Sweden Breast Cancer Res. Treat 2011 130 2 553 560 10.1007/s10549-011-1594-z 21617918 \n22. Li S Zhao J Zhu L Development and validation of a nomogram predicting the overall survival of stage IV breast cancer patients Cancer Med. 2017 6 11 2586 2594 10.1002/cam4.1224 28980424 \n23. Falkson G Gelman RS Leone L Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Leukemia Group B studies Cancer 1990 66 7 1621 9 10.1002/1097-0142(19901001)66:7<1621::AID-CNCR2820660729>3.0.CO;2-G 2208013 \n24. Kontani K Hashimoto S Murazawa C Factors responsible for long-term survival in metastatic breast cancer World J. Surg. Oncol. 2014 12 344 10.1186/1477-7819-12-344 25395387 \n25. Rhomberg W Rhomberg T Long-term survival in patients with incurable breast cancer Anticancer Res. 2014 34 10 5637 5642 25275067 \n26. Coleman RE Smith P Rubens RD Clinical course and prognostic factors following bone recurrence from breast cancer Br. J. Cancer 1998 77 2 336 340 10.1038/bjc.1998.52 9461007 \n27. Kuru B Camlibel M Dinc S Prognostic factors for survival in breast cancer patients who developed distant metastasis subsequent to definitive surgery Singapore Med. J. 2008 49 11 904 911 19037557 \n28. Jensen AØ Nørgaard M Yong M Validity of the recorded International Classification of Diseases, 10th edition diagnoses codes of bone metastases and skeletal-related events in breast and prostate cancer patients in the Danish National Registry of Patients Clin. Epidemiol. 2009 1 101 108 10.2147/CLEP.S5446 20865091 \n29. Schwartzberg LS Wang G Somer BG Phase II trial of fulvestrant with metronomic capecitabine for postmenopausal women with hormone receptor-positive, HER2−negative metastatic breast cancer Clin. Breast Cancer 2014 14 1 13 19 10.1016/j.clbc.2013.09.003 24268206 \n30. Jiang D Huang Y Han N Xu M Xu L Zhou L Fulvestrant, a selective estrogen receptor down-regulator, sensitises estrogen receptor negative breast tumours to chemotherapy Cancer Lett. 2014 346 2 292 299 10.1016/j.canlet.2014.01.008 24462822 \n31. Parkes A Warneke CL Clifton K Prognostic factors in patients with metastatic breast cancer with bone-only metastases Oncologist 2018 23 11 1282 1288 10.1634/theoncologist.2018-0085 30120166 \n32. Cronin-Fenton D Kjærsgaard A Nørgaard M Breast cancer recurrence, bone metastases, and visceral metastases in women with stage II and III breast cancer in Denmark Breast Cancer Res. Treat 2018 167 2 517 528 10.1007/s10549-017-4510-3 28948396 \n33. deSouza NM Liu Y Chiti A Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group Eur. J. Cancer 2018 91 153 163 10.1016/j.ejca.2017.12.012 29331524 \n34. Milano MT Katz AW Zhang H Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade Radiother. Oncol. 2019 131 45 51 10.1016/j.radonc.2018.11.022 30773186 \n35. Ibrahim T Farolfi A Scarpi E Mercatali L Medri L Ricci M Hormonal receptor, human epidermal growth factor receptor-2, and Ki67 discordance between primary breast cancer and paired metastases: clinical impact Oncology 2013 84 3 150 157 10.1159/000345795 23257904 \n36. Ongaro E Gerratana L Cinausero M Comparison of primary breast cancer and paired metastases: Biomarkers discordance influence on outcome and therapy Future Oncol. 2018 14 9 849 859 10.2217/fon-2017-0384 29527957\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-2322", "issue": "11(1)", "journal": "Scientific reports", "keywords": null, "medline_ta": "Sci Rep", "mesh_terms": null, "nlm_unique_id": "101563288", "other_id": null, "pages": "4329", "pmc": null, "pmid": "33619285", "pubdate": "2021-02-22", "publication_types": "D016428:Journal Article", "references": "28948396;30120166;24268206;20865091;9461007;14734954;24137321;11417967;17062708;2208013;12154351;25275067;30773186;29331524;29527957;29511626;21266401;17785994;16447304;28494404;25926150;28584570;24462822;19037557;23918566;23257904;20498394;23884473;25395387;3814476;21617918;24133529;28980424;10832597;30649614", "title": "First prospective data on breast cancer patients from the multicentre italian bone metastasis database.", "title_normalized": "first prospective data on breast cancer patients from the multicentre italian bone metastasis database" }

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{ "abstract": "In an effort to expedite the publication of articles , AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.\n\n\nOBJECTIVE\nThrombocytopenia can occur when using an Impella percutaneous ventricular assist device (pVAD), and heparin-induced thrombocytopenia (HIT) is often suspected. Data on heparin- and anticoagulant-free purge solutions in these devices are limited. Previous case reports have described argatroban-based purge solutions, both with and without systemic argatroban, at varying concentrations in patients with known or suspected HIT.\n\n\nCONCLUSIONS\nA 33-year-old male was transferred to our institution and emergently initiated on life support with venoarterial extracorporeal membrane oxygenation (ECMO), an Impella pVAD, and continuous venovenous hemofiltration to receive an urgent aortic valve replacement. Over the next several days, the patient's platelet count declined with a nadir of 17 × 10 3/µL on hospital day 13. The patient's 4T score for probability of HIT was calculated as 4. All heparin products were discontinued on hospital day 15, and the patient was initiated on systemic infusion with argatroban 1,000 µg/mL at a rate of 0.2 µg/kg/min with a purge solution of argatroban 0.05 mg/mL. The systemic infusion remained at a rate of 0.2 µg/kg/min, and the total argatroban dose was, on average, less than 0.25 µg/kg/min. On hospital day 21, the patient was transferred to another institution.\n\n\nCONCLUSIONS\nSystemic infusion and a purge solution with argatroban were used in a patient with an Impella pVAD with multisystem organ dysfunction and suspected HIT. The patient achieved therapeutic activated partial thromboplastin times without adjustment of the systemic argatroban infusion and did not experience bleeding or thrombosis. Further studies concerning the safety and effectiveness of argatroban-based purge solutions in patients with pVADs are needed.", "affiliations": "Department of Pharmacy, Upstate University Hospital, Syracuse, NY, USA.;Department of Pharmacy, Upstate University Hospital, Syracuse, NY, and Upstate Pharmacy Services Translational Research Team (UPSTART), Syracuse, NY, USA.;Department of Pharmacy, Upstate University Hospital, Syracuse, NY, and Upstate Pharmacy Services Translational Research Team (UPSTART), Syracuse, NY, USA.;Department of Pharmacy, Upstate University Hospital, Syracuse, NY, Upstate Pharmacy Services Translational Research Team (UPSTART), Syracuse, NY, and Department of Medicine, Upstate Medical University, Syracuse, NY, USA.;Department of Surgery, Upstate Medical University, Syracuse, NY, USA.;Department of Pharmacy, Upstate University Hospital, Syracuse, NY, Upstate Pharmacy Services Translational Research Team (UPSTART), Syracuse, NY, and Department of Medicine, Upstate Medical University, Syracuse, NY, USA.", "authors": "Shtoyko|Ashley N|AN|;Feldman|Elizabeth A|EA|;Cwikla|Gregory M|GM|;Darko|William|W|;Green|G Randall|GR|;Seabury|Robert W|RW|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ajhp/zxab331", "fulltext": null, "fulltext_license": null, "issn_linking": "1079-2082", "issue": null, "journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists", "keywords": null, "medline_ta": "Am J Health Syst Pharm", "mesh_terms": null, "nlm_unique_id": "9503023", "other_id": null, "pages": null, "pmc": null, "pmid": "34390237", "pubdate": "2021-08-14", "publication_types": "D016428:Journal Article", "references": null, "title": "Use of an argatroban systemic infusion and purge solution in a patient with a percutaneous ventricular assist device with suspected heparin-induced thrombocytopenia.", "title_normalized": "use of an argatroban systemic infusion and purge solution in a patient with a percutaneous ventricular assist device with suspected heparin induced thrombocytopenia" }

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Darko W, Green GR, Seabury RW. Use of an argatroban systemic infusion and purge solution in a patient with a percutaneous ventricular assist device with suspected heparin-induced thrombocytopenia. 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"drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." } ], "patientagegroup": "5", "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "107", "reaction": [ { "reactionmeddrapt": "Heparin-induced thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHTOYKO A, FELDMAN E, CWIKLA G, DARKO W, GREEN G, SEABURY R. USE OF AN ARGATROBAN SYSTEMIC INFUSION AND PURGE SOLUTION IN A PATIENT WITH A PERCUTANEOUS VENTRICULAR ASSIST DEVICE WITH SUSPECTED HEPARIN?INDUCED THROMBOCYTOPENIA. AM J HEALTH SYST PHARM. 2021?UNKNOWN:UNKNOWN?UNKNOWN. DOI:10.1093/AJHP/ZXAB331", "literaturereference_normalized": "use of an argatroban systemic infusion and purge solution in a patient with a percutaneous ventricular assist device with suspected heparin induced thrombocytopenia", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210930", "receivedate": "20210924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19875699, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "US-TEVA-2021-US-1963824", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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{ "abstract": "Tuberculosis (TB) infection is a major concern in patients with chronic autoimmune conditions under immunosuppressive therapy. Gastrointestinal tuberculosis can be misdiagnosed as Crohn's disease with detrimental consequences for the patient. We report on a 40-year old ethnic Turkish patient with HLA-B27 positive spondyloarthritis who developed gastrointestinal symptoms under immunosuppressive treatment with infliximab. Crohn's disease was diagnosed at a primary care hospital and immunosuppressive treatment was escalated. Initial diagnostic tests for tuberculosis were negative. When the clinical condition deteriorated, the patient was transferred to our intensive care unit for further diagnosis and treatment. Tuberculosis was suspected due to clinical presentation and radiological signs and anti-tuberculous treatment was initiated. After the onset of treatment, first microbiological results confirmed the diagnosis of miliary TB with Mycobacterium bovis. As an infection route we assume primary gastrointestinal infection with M. bovis during the patient's annual holidays in Turkey with a rapid development of miliary TB under infliximab and escalated immunosuppressive therapy. This case report demonstrates the difficulties in differentiating intestinal TB from other granulomatous conditions such as Crohn's disease. The diagnostic tools for gastrointestinal tuberculosis are discussed in detail regarding their sensitivity, specificity as well as positive and negative predictive values.", "affiliations": "Dept. of Gastroenterology, Heidelberg University Hospital, Heidelberg.", "authors": "Koschny|R|R|;Junghanss|T|T|;Mischnik|A|A|;Karner|M|M|;Kreuter|M|M|;Roth|W|W|;Stremmel|W|W|;Merle|U|U|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D000069285:Infliximab", "country": "Germany", "delete": false, "doi": "10.1055/s-0033-1350372", "fulltext": null, "fulltext_license": null, "issn_linking": "0044-2771", "issue": "51(10)", "journal": "Zeitschrift fur Gastroenterologie", "keywords": null, "medline_ta": "Z Gastroenterol", "mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D003937:Diagnosis, Differential; D005189:False Positive Reactions; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D013167:Spondylitis, Ankylosing; D016896:Treatment Outcome; D014391:Tuberculosis, Miliary", "nlm_unique_id": "0033370", "other_id": null, "pages": "1177-83", "pmc": null, "pmid": "24122379", "pubdate": "2013-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Development of miliary tuberculosis under infliximab in a patient with spondyloarthritis and suspected Crohn's disease.", "title_normalized": "development of miliary tuberculosis under infliximab in a patient with spondyloarthritis and suspected crohn s disease" }

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null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tuberculosis gastrointestinal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disseminated tuberculosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201211" } }, "primarysource": { "literaturereference": "KOSCHNY R, JUNGHANSS T, MISCHNIK A, KARNER M, KREUTER M, ROTH W, ET AL. DEVELOPMENT OF MILIARY TUBERCULOSIS UNDER INFLIXIMAB IN A PATIENT WITH SPONDYLOARTHRITIS AND SUSPECTED CROHN^S DISEASE. Z GASTROENTEROL OCT-2013?51(10):1177-1183.", "literaturereference_normalized": "development of miliary tuberculosis under infliximab in a patient with spondyloarthritis and suspected crohn s disease", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181009", "receivedate": "20131022", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9637331, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "We report the case of a 30-year-old woman with glioblastoma multiforme (GBM) treated with surgery followed by concomitant Temozolomide (TMZ) and external beam radiation, which she tolerated well without any interruptions. However, when she was being evaluated for adjuvant Temozolomide, she developed progressive decline in leukocyte counts and platelet counts and subsequently, febrile neutropenia with bleeding manifestations. A bone marrow aspiration and biopsy done showed a gross hypocellular bone marrow with very few erythriod and myeloid cells and no suggestion of progenitor cells, consistent with aplastic anemia.", "affiliations": "Department of Radiation Oncology, 116 Tata Memorial Hospital, Parel, Mumbai 400 012, India. rjalali@medscape.com", "authors": "Jalali|Rakesh|R|;Singh|Pritanjali|P|;Menon|Hari|H|;Gujral|Sumeet|S|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide", "country": "United States", "delete": false, "doi": "10.1007/s11060-007-9398-z", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-594X", "issue": "85(1)", "journal": "Journal of neuro-oncology", "keywords": null, "medline_ta": "J Neurooncol", "mesh_terms": "D000328:Adult; D000741:Anemia, Aplastic; D018906:Antineoplastic Agents, Alkylating; D001772:Blood Cell Count; D001853:Bone Marrow; D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D003606:Dacarbazine; D017809:Fatal Outcome; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D010198:Pancytopenia; D018805:Sepsis; D000077204:Temozolomide", "nlm_unique_id": "8309335", "other_id": null, "pages": "105-7", "pmc": null, "pmid": "17505778", "pubdate": "2007-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12670349;15885298;16648049;7577657;11905710;16728498;15758009", "title": "Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide.", "title_normalized": "unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with temozolomide" }

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{ "abstract": "BACKGROUND\nGestational trophoblastic neoplasia is a group of rare tumors that can be cured using chemotherapy. The use of artificial contraception for at least 1 year is recommended not only due to the high recurrence rate in the first year after treatment, but also because of the unclear genetic toxic effects of multidrug regimen chemotherapy on reproductive cells. There is no consensus about the contraception duration, but most patients want to have children.\nThis case involved a 33-year-old female suffering from gestational trophoblastic neoplasia and 5-fluorouracil + actinomycin-D chemotherapy. She became pregnant 1 month after finishing the chemotherapy.\n\n\nMETHODS\nGestational trophoblastic neoplasia.\n\n\nMETHODS\nNo treatment during pregnancy.\n\n\nRESULTS\nThe patient had a full-term normal delivery, and the baby showed normal development and growth after a follow-up of 48 months.\n\n\nCONCLUSIONS\nPregnancy soon after chemotherapy can be viable with rigorous prenatal care.", "affiliations": "Department of Gynecology and Obstetrics Department of Anesthesiology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, People's Republic of China.", "authors": "Niu|Gang|G|;Yuan|Lin-Jing|LJ|;Gong|Feng-Qiu|FQ|;Yang|Juan|J|;Zhu|Cai-Xia|CX|;Shen|Hong-Wei|HW|", "chemical_list": "D006063:Chorionic Gonadotropin; D003609:Dactinomycin; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000009221", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-17-0543210.1097/MD.0000000000009221092215600Research ArticleClinical Case ReportEarly pregnancy following multidrug regimen chemotherapy in a gestational trophoblastic neoplasia patient A case reportNiu Gang MDaYuan Lin-Jing MDaGong Feng-Qiu MSNbYang Juan MDaZhu Cai-Xia MDaShen Hong-Wei MDa∗NA. a Department of Gynecology and Obstetricsb Department of Anesthesiology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, People's Republic of China.∗ Correspondence: Hong-Wei Shen, Sun Yat-sen University First Affiliated Hospital, No. 58, Zhong Shan II Road, Guangzhou 510080, People's Republic of China (e-mail: 13312825970@163.com).12 2017 22 12 2017 96 51 e922130 9 2017 19 11 2017 21 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nGestational trophoblastic neoplasia is a group of rare tumors that can be cured using chemotherapy. The use of artificial contraception for at least 1 year is recommended not only due to the high recurrence rate in the first year after treatment, but also because of the unclear genetic toxic effects of multidrug regimen chemotherapy on reproductive cells. There is no consensus about the contraception duration, but most patients want to have children.\n\nPatient concerns:\nThis case involved a 33-year-old female suffering from gestational trophoblastic neoplasia and 5-fluorouracil + actinomycin-D chemotherapy. She became pregnant 1 month after finishing the chemotherapy.\n\nDiagnosis:\nGestational trophoblastic neoplasia.\n\nInterventions:\nNo treatment during pregnancy.\n\nOutcomes:\nThe patient had a full-term normal delivery, and the baby showed normal development and growth after a follow-up of 48 months.\n\nLessons:\nPregnancy soon after chemotherapy can be viable with rigorous prenatal care.\n\nKeywords\n5-fluorouracilactinomycin-Dchemotherapygestationgestational trophoblastic neoplasiaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nGestational trophoblastic neoplasia (GTN) is a group of rare tumors mainly generated from disorder proliferation of the trophoblast cells resulting from pregnancy. Women of childbearing age are at a high risk of GTN. Chemotherapy is the most effective treatment, but its teratogenic effects and reproductive toxicity are major concerns for oncologists.[1]\n\nAlthough a series of observational studies found no significant differences in fetal congenital abnormality rates between GTN patients treated with chemotherapy and the general population, most GTN patients used contraceptives for more than one year after treatment.[2,3] Methotrexate (MTX), actinomycin-D (Act-D), and 5-fluorouracil (5-Fu) are the most commonly used chemotherapy drugs in GTN,[4,5] and their teratogenic or genetic toxic mechanisms are not clear.\n\nWe presented here a case of a 33-year-old female diagnosed with GTN who received 5-Fu + Act-D chemotherapy, became pregnant the month after the last course of treatment, and delivered a full-term baby without deformities or abnormal growth and development. Informed consent for the release of patient information was obtained for the publication of this case report.\n\n2 Case presentation\nThe patient was a 33-year-old female who had received suction evacuation of the uterus for an artificial abortion 10 years prior. Unscheduled vaginal bleeding had been ongoing since January 10, 2011, without lower abdominal pain, and the last menstrual period (LMP) was unclear. Ultrasound examination on February 27, 2011, indicated hydatidiform mole, and the blood human chorionic gonadotropin (hCG) level was 924415 mIU/mL. Suction evacuation was performed on March 1, 2011, with a pathological diagnosis of partial hydatidiform mole. Because ultrasound indicated residual trophoblastic tissue with blood hCG 14672 mIU/mL, suction evacuation was performed again on March 10, 2011, but no villus tissue was found. After the operation, the minimum blood hCG level was 5869 mIU/mL and it rose again. On April 7, 2011, the blood hCG level was 12285 mIU/mL. Ultrasound showed abnormal echogenicity in uterine intracavitary, and computed tomography (CT) screening indicated multiple lung metastases. Diagnosis therefore favored invasive moles (FIGO Stage III: FIGO Score 5). Considering the high blood hCG level, 2 courses of 5-Fu 26 mg/kg QD and Act-D 6 μg/kg QD combination chemotherapy were administered for 8 days per treatment course. Because of severe myelosuppression, we reduced the dosage in the following 3 courses, with 6 days per treatment course. The blood hCG level returned to normal with no abnormality on ultrasound or chest CT screening after 3 courses of chemotherapy. The treatment was completed on August 5, 2011.\n\nThe patient's LMP was September 13, 2011, and her blood hCG level rose to 63629 mIU/mL on October 13, 2011. Ultrasound examination on November 6, 2011, indicated intrauterine singleton pregnancy of 7+ gestational weeks. It was difficult for the patient to get pregnant so she insisted on continuing the pregnancy. Ultrasound on December 15, 2011, indicated 13 weeks of gestation and the fetal nuchal translucency (NT) thickness was 1.53 mm; there were no significant abnormalities on ultrasonographic soft markers. Further fetal abnormal karyotypes in the first trimester of pregnancy showed low risk of trisomy 21, 18, and 13. Prenatal ultrasound screening on February 24, 2012 (23+1 gestational weeks) indicated 22+4 weeks of gestation and no significant fetal anomalies. The patient underwent regular obstetrical examinations throughout pregnancy and had a normal full-term delivery. Her male infant showed no deformities or abnormal growth and development after a follow-up of 48 months.\n\n3 Discussion\nThe fertility of GTN patients is always a major concern for gynecological oncologists, as most patients want children. The use of artificial contraception for at least 1 year is recommended because of the high recurrence rate in the first year after finishing treatment. However, germ cell chromosomal abnormality, which is the short-term effect most likely to occur due to the toxicity of chemotherapy, has not been studied extensively. Two results correlate to germ cell chromosomal abnormality: fetal abnormality and gene mutation-related long-term diseases. Little is known about the former.\n\nIn this case, 5-Fu and Act-D were administered. 5-Fu can be synthesized to FdUMP, which principally acts as a thymidylate synthase inhibitor. It causes cells to become dTMP deficient during deoxyribonucleic acid (DNA) replication or incorporates into ribonucleic acid (RNA) during RNA transcription.[6] Act-D binds to DNA transcription initiation complex, which also inhibits RNA transcription.[7] Both drugs are able to inhibit protein synthesis, which means that they have little influence on dormant cells such as the primary oocyte. However, when the primary oocyte is recruited 60 to 70 days before forming the secondary follicle, oogenesis and meiosis could be disturbed by 5-Fu or Act-D.\n\nUntil recently, research on the reproductive toxicity of chemotherapeutics in GTN treatment was focused on patients’ ovarian function after chemotherapy. Approximately 95% of GTN patients resumed normal menstruation, but menopause occurred earlier than in the general population.[2] Even multiagent EMA-CO chemotherapy had little effect on menstruation, but it took longer for patients to return to their normal menstrual cycle after multidrug regiments than after a single drug.[8]\n\nSecond, research also focused on the pregnancy outcomes of GTN patients who finished chemotherapy at least 3 months before becoming pregnant. More than 90% of these patients were able to conceive and more than 70% had full-term healthy births, no matter which regiments were chosen. The main complications were second hydatidiform moles and miscarriages, but reports showed no significant differences between GTN patients and the general population.[2,9,10] Few retrospective studies have reported on fetal malformations resulting from conception after the completion of chemotherapy,[2,9–11] and the sample sizes were small. Moreover, no data showed the relationship between the duration of artificial contraception and the rate of fetal malformation. As a result, more data are necessary to guide the clinical work.\n\nFurther recommendations about the duration of contraception after chemotherapy remain uncertain, which may result in inappropriate induced abortions due to fears of fetal anomaly or genetic abnormality. Based on the follicular development cycle, the effects of the oocytes’ exposure to the chemotherapeutic will last at least 3 months. In this case, the patient became pregnant just 1 month after finishing treatment, which indicated that the oocytes had been directly exposed to the chemotherapeutics, with great potential for genetic damage. The patient's pregnancy resulted in a full-term healthy birth, and the baby showed normal development and growth after a follow-up of 48 months. The study of genetic toxicity in humans is difficult due to ethical reasons. According to the results of limited observational studies, fetal anomalies and birth defects after chemotherapy were rare. But the pregnancies mostly occurred more than 3 months after the last course of chemotherapy. This case is the first report on the effects of direct exposure of chemotherapy on genotoxicity, which may provide references for clinical work.\n\nAs a result of this case, it is necessary to understand how soon a patient can safely conceive after finishing chemotherapy and the recommendations for prenatal testing.\n\nAbbreviations: 5-Fu = 5-fluorouracil, Act-D = actinomycin-D, CT = computed tomography, DNA = deoxyribonucleic acid, FIGO = International Federation of Gynecology and Obstetrics, GTN = gestational trophoblastic neoplasia, hCG = human chorionic gonadotropin, LMP = last menstrual period, MTX = methotrexate, NT = nuchal translucency, QD = quaque die, RNA = ribonucleic acid.\n\nGN and L-JY contributed equally to this work.\n\nThis work was supported by grants to L-JY from the Natural Science Foundation of Guangdong Province (no. 2016A030310171).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Tse KY Ngan HY \nGestational trophoblastic disease . Best Pract Res Clin Obstet Gynaecol \n2012 ;26 :357 –70 .22285526 \n[2] Gadducci A Lanfredini N Cosio S \nReproductive outcomes after hydatiform mole and gestational trophoblastic neoplasia . Gynecol Endocrinol \n2015 ;31 :673 –8 .26288335 \n[3] Vargas R Barroilhet LM Esselen K \nSubsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center . J Reprod Med \n2014 ;59 :188 –94 .24937955 \n[4] Even C Pautier P Duvillard P \nActinomycin D, cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia . Eur J Cancer \n2014 ;50 :2082 –9 .24910417 \n[5] Wang Y Miao JW Wang T \nComparison of MACT and 5Fu+ACT-D chemotherapy regimens in the treatment of low-risk gestational trophoblastic neoplasia, . J Chemother (Florence, Italy) \n2016 ;28 :135 –9 .\n[6] Longley DB Harkin DP Johnston PG \n5-fluorouracil: mechanisms of action and clinical strategies . Nat Rev Cancer \n2003 ;3 :330 –8 .12724731 \n[7] Sobell HM \nActinomycin and DNA transcription . Proc Natl Acad Sci USA \n1985 ;82 :5328 –31 .2410919 \n[8] Wong JM Liu D Lurain JR \nReproductive outcomes after multiagent chemotherapy for high-risk gestational trophoblastic neoplasia . J Reprod Med \n2014 ;59 :204 –8 .24937958 \n[9] Gadducci A Cosio S Fanucchi A \nPrognosis of patients with gestational trophoblastic neoplasia and obstetric outcomes of those conceiving after chemotherapy . Anticancer Res \n2016 ;36 :3477 –82 .27354611 \n[10] Williams J Short D Dayal L \nEffect of early pregnancy following chemotherapy on disease relapse and fetal outcome in women treated for gestational trophoblastic neoplasia . J Reprod Med \n2014 ;59 :248 –54 .24937965 \n[11] Lok CA van der Houwen C ten Kate-Booij MJ \nPregnancy after EMA/CO for gestational trophoblastic disease: a report from The Netherlands . BJOG \n2003 ;110 :560 –6 .12798472\n\n", "fulltext_license": "CC BY-ND", "issn_linking": "0025-7974", "issue": "96(51)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D006063:Chorionic Gonadotropin; D003609:Dactinomycin; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D047109:Fetal Development; D005472:Fluorouracil; D005865:Gestational Age; D031901:Gestational Trophoblastic Disease; D006801:Humans; D000068104:Infant Health; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D011295:Prenatal Care; D047929:Term Birth", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e9221", "pmc": null, "pmid": "29390471", "pubdate": "2017-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Early pregnancy following multidrug regimen chemotherapy in a gestational trophoblastic neoplasia patient: A case report.", "title_normalized": "early pregnancy following multidrug regimen chemotherapy in a gestational trophoblastic neoplasia patient a case report" }

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{ "abstract": "Immunotherapy with immune checkpoint inhibitor (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC). However, whether ICIs would have the risk of hepatitis B virus (HBV) reactivation and the necessary of nucleos(t)ide analogs (NUCs) prophylaxis are still unclear. We aimed to investigate the role of NUCs prophylaxis in HBV-infected patients who underwent ICIs treatment.\n\n\n\nThe study was a retrospective prospective design to review and follow-up consecutive 62 patients with chronic hepatitis B or resolved HBV infection who had received ICIs treatment for the unresectable HCC. Of them, 60 patients with documented baseline serum HBV DNA value were classified into three categories according to the baseline HBV viral load and the status of antiviral therapy before ICI treatment. The clinical status, including tumor response, viral kinetics and liver function, was recorded and investigated.\n\n\n\nNo HBV reactivation occurred in the 35 patients with HBV DNA ≤100 IU/mL on NUCs therapy. Of the 19 patients with HBV DNA >100 IU/mL who started NUCs simultaneously with ICI treatment, none encountered HBV reactivation during the immunotherapy. Of the six HBV patients without NUCs treatment, three had a greater than 1 log decrease in HBV viral load, and one maintained his serum HBV DNA in undetectable status during ICI treatment. Eventually, one out of six experienced HBV reactivation after 9 weeks of ICI treatment.\n\n\n\nNo patients on antiviral therapy developed HBV reactivation, and one out of six not receiving antiviral therapy had HBV reactivation. HBV viral load higher than 100 IU/mL is safe and not a contraindication for ICI treatment for HCC, if NUCs can be coadministrated.", "affiliations": "Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan yhhuang@vghtpe.gov.tw.", "authors": "Lee|Pei-Chang|PC|0000-0002-7492-2484;Chao|Yee|Y|;Chen|Ming-Huang|MH|0000-0003-3187-7393;Lan|Keng-Hsin|KH|;Lee|I-Cheng|IC|;Hou|Ming-Chih|MC|0000-0002-4886-0718;Huang|Yi-Hsiang|YH|0000-0001-5241-5425", "chemical_list": "D000082082:Immune Checkpoint Inhibitors", "country": "England", "delete": false, "doi": "10.1136/jitc-2020-001072", "fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32863270\njitc-2020-001072\n10.1136/jitc-2020-001072\nClinical/Translational Cancer Immunotherapy\n1506\n2435\nOriginal researchRisk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma\nhttp://orcid.org/0000-0002-7492-2484Lee Pei-Chang 123 Chao Yee 4 http://orcid.org/0000-0003-3187-7393Chen Ming-Huang 4 Lan Keng-Hsin 13 Lee I-Cheng 12 http://orcid.org/0000-0002-4886-0718Hou Ming-Chih 12 http://orcid.org/0000-0001-5241-5425Huang Yi-Hsiang 125 1 Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan\n2 Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan\n3 Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan\n4 Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan\n5 Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan\nCorrespondence to Professor Yi-Hsiang Huang; yhhuang@vghtpe.gov.tw\n2020 \n30 8 2020 \n8 2 e00107201 8 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.2020https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.Background\nImmunotherapy with immune checkpoint inhibitor (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC). However, whether ICIs would have the risk of hepatitis B virus (HBV) reactivation and the necessary of nucleos(t)ide analogs (NUCs) prophylaxis are still unclear. We aimed to investigate the role of NUCs prophylaxis in HBV-infected patients who underwent ICIs treatment.\n\nMethods\nThe study was a retrospective prospective design to review and follow-up consecutive 62 patients with chronic hepatitis B or resolved HBV infection who had received ICIs treatment for the unresectable HCC. Of them, 60 patients with documented baseline serum HBV DNA value were classified into three categories according to the baseline HBV viral load and the status of antiviral therapy before ICI treatment. The clinical status, including tumor response, viral kinetics and liver function, was recorded and investigated.\n\nResults\nNo HBV reactivation occurred in the 35 patients with HBV DNA ≤100 IU/mL on NUCs therapy. Of the 19 patients with HBV DNA >100 IU/mL who started NUCs simultaneously with ICI treatment, none encountered HBV reactivation during the immunotherapy. Of the six HBV patients without NUCs treatment, three had a greater than 1 log decrease in HBV viral load, and one maintained his serum HBV DNA in undetectable status during ICI treatment. Eventually, one out of six experienced HBV reactivation after 9 weeks of ICI treatment.\n\nConclusion\nNo patients on antiviral therapy developed HBV reactivation, and one out of six not receiving antiviral therapy had HBV reactivation. HBV viral load higher than 100 IU/mL is safe and not a contraindication for ICI treatment for HCC, if NUCs can be coadministrated.\n\nliver neoplasmsimmunotherapyhttp://dx.doi.org/10.13039/501100011912Taipei Veterans General HospitalV109C-048http://dx.doi.org/10.13039/501100004663Ministry of Science and Technology, TaiwanMOST108-2628-B-075-006special-featureunlocked\n==== Body\nIntroduction\nHepatocellular carcinoma (HCC) is the fifth most common cancer and the second-leading cause of cancer-related death worldwide that constitutes 854 000 new cases and 810 000 deaths per year.1 Hepatitis B virus (HBV) infection is common across the world, and globally approximate 54% of HCCs are attributed to chronic HBV infection.2 In Asian-Pacific region, chronic hepatitis B is endemic and plays much more important role in the development of HCC and its complications.3 4 Despite the improvement in surveillance and treatment of viral hepatitis, many patients still present with or progress to unresectable or advanced disease and require systemic therapy.2 Immunotherapies with immune checkpoint inhibitors (ICIs), such as nivolumab and pembrolizumab, the antiprogrammed cell death-1 (PD-1) antibodies, are recently emerged, effective immunotherapeutic agents for HCC.5–7\n\nHBV reactivation is defined as the abrupt reappearance or rise of HBV DNA in the serum of a patient with resolved or inactive chronic HBV infection.8 This event can be triggered by the administration of either anticancer agents, immunosuppressive or biological therapies.8–11 CD8 T cell exhaustion due to PD-1 upregulation is characterized in chronic viral infection, including chronic hepatitis B (CHB).12 13 Previous studies suggested that blockade of the axis of PD-1 and its ligand (PD-L1) could restore anti-HBV T cell responses, which could enhance the control of HBV.14–16 In CheckMate-040 trial, 3 of 51 HBV-HCC patients (6%) presented a 1 log decline of HBV surface antigen (HBsAg) level during nivolumab therapy.5 However, two case reports described HBV reactivation in patients received ICI treatment for lung cancer.17 18 Currently, most of the clinical trials, including CheckMate-040 and Keynote-224, request CHB patients should be on nucleos(t)ide analogs (NUCs) treatment and had a HBV viral load <100 IU/mL before receiving their first dose of ICI treatment.5 6 So far, whether immunotherapy with ICIs would have the risk of HBV reactivation and the necessary of NUCs prophylaxis are still unclear.2 11 19 In this study, we aimed to investigate the risk of HBV reactivation and the role of NUCs treatment in HCC patients with CHB or resolved HBV infection undergoing ICIs treatment.\n\nMaterials and methods\nPatients\nThe study was a retrospective prospective design to review and follow-up consecutive 62 patients with CHB or resolved HBV infection who had received nivolumab or pembrolizumab treatment for the unresectable HCC in Taipei Veterans General Hospital from May 2017 to September 2019. Of them, 60 patients with documented baseline serum HBV DNA level and evaluable image studies following the immunotherapy were finally enrolled in this study. Thirty-three patients who underwent immunotherapy before the end of June 2019 were retrospective reviewed of medical records. Since July 2019, the rest of the patients were recruited in an immunotherapy biomarker study and had prospectively observational monitoring.\n\nThe diagnosis of HCC was according to the AASLD treatment guidelines.20 ICI treatment was administered for HCC patients with intermediate stage after locoregional treatment failure by transarterial chemoembolization (TACE), or advanced stage with intolerable adverse events or treatment failure to sorafenib, or deteriorated liver reserves beyond Child-Pugh class A so that target therapy was not approved based on the reimbursement criteria of National Health Insurance (NHI) in Taiwan.21 22 All the enrolled patients did not receive other locoregional therapies, including TACE, during the ICI treatment. According to their baseline HBV viral load and the status of antiviral therapy before ICI treatment, the enrolled patients were classified into three categories, including (1) patients with HBV DNA ≤100 IU/mL on NUCs therapy (fulfilled CheckMate-040 and Keynote-224 HBV criteria),5 6 (2) patients with HBV DNA >100 IU/mL on NUCs therapy and (3) patients with HBV but without receiving NUCs therapy throughout the ICI treatment because of not fulfilling the NUCs reimbursement criteria for CHB in NHI, Taiwan.\n\nTreatment and outcome assessment\nICIs were prescribed according to the recommended dosage and safety information (2–3 mg/kg, every 2 weeks for nivolumab and every 3 weeks for pembrolizumab).5 6 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; V.5.0) was applied for the assessment of therapeutic safety. Clinical evaluation with Child-Pugh class, albumin-bilirubin (ALBI) grade, hemogram, serum chemistry and alpha-fetoprotein (AFP) level were performed every 2–3 weeks during the treatment. Clinical tumor response was assessed by RECIST V.1.1 based on contrast-enhanced abdominal CT scan or MRI.23 The image examinations were carried out every 6–8 weeks during ICIs treatment.22 The study complied with Taiwan NHI regulation; HBV viral load monitoring was done every 6 months while on NUCs treatment. For patients on ICI treatment without NUCs, HBV viral loads were monitored every 2–3 months in this study. Additional HBV DNA test was performed if a serum alanine aminotransferase (ALT) level exceeded 100 U/L with suspicion of HBV reactivation.24 25 According to this guidance, 45 had follow-up HBV DNA values.\n\nDefinitions\nHBV reactivation was defined as a 10-fold increase in HBV DNA from baseline, or reappearance of HBsAg in HBsAg-negative case, or HBV DNA from undetectable to higher than 1000 IU/mL.11 26 Hepatitis related to HBV reactivation was defined as a threefold or greater increase in serum ALT that exceeds 100 U/L.24 25 The upper normal limit of ALT was 40 U/L. The ALT flare was defined as a rise in ALT>5 fold upper limit of normal (ULN), which is classified as grade III hepatic toxicity by CTCAE 5.0 grading system. The ALBI score was calculated using the formula: (log10 bilirubin x 0.66) + (albumin x 0.085), where bilirubin is in umol/L and albumin in g/L; and the cut points of the ALBI grade were based on previous report.27\n\nVirological and biochemical tests\nSerum HBV DNA level was measured by quantitative PCR method (Roche COBAS 6800 HBV test) with the lower detection limit of 10 IU/mL. Serum biochemistry tests were measured by systemic multiauto-analyzer (Technicon SMAC, Technicon Instruments, Tarrytown, New York, USA). Serum AFP level was measured by chemiluminescent microparticle immunoassay (Elecsys AFP Assay, Roche Diagnostics, Mannheim, Germany) with clinically reportable range from 0.908 to 1 998 000 ng/mL.\n\nStatistical analysis\nContinuous variables were expressed as median (range), while categorical variables were analyzed as frequency and percentages. The Pearson X2 analysis or Fisher’s exact test was used to compare categorical variables, while the Student t-test or Mann-Whitney U test was applied for continuous variables. For all analyzes, p<0.05 was considered statistically significant. All statistical analyzes were performed using the Statistical Package for Social Sciences (SPSS V.17.0 for Windows, SPSS).\n\nResults\nDemographic characteristics of the study cohort\nThe patients were classified into three categories, including HBV DNA ≤100 IU/mL on NUCs therapy, HBV DNA >100 IU/mL on NUCs therapy and HBV without NUCs therapy. For the six patients without NUCs treatment, four had HBV viral load less than 2000 IU/mL; the other two had elevated HBV viral loads, but their ALT levels were less than 2 folds of ULN; which were not fulfilled the regulation of Taiwan NHI for NUCs treatment. No significant differences of liver reserves could be identified between these three groups. The patients with HBV DNA ≤100 IU/mL on antiviral therapy were significantly older (median age: 63.4 vs 58.0 and 56.5 years old, p=0.019) compared with the others. Besides, these patients had smaller tumor size (4.0 vs 8.7 and 8.8 cm, p<0.001), lower serum level of AFP (373.2 vs 1992.6 and 3082.2 ng/mL, p=0.028); and more of them had experienced surgical resection for HCC before ICI treatment (62.9% vs 21.1% and 50.0%, p=0.013). Generally, most of the patients (80%) were at BCLC stage C. The majority (73.3%) of them was within Child-Pugh class A; but 65.0% was classified beyond ALBI grade 1. Two patients presented with positive anti-HCV antibody. Both their HCV viral loads were undetectable throughout the ICI treatment. The median cycles and duration of ICI treatment were five cycles (1–35) and 2.1 months (0.5–24.5) for patients with HBV DNA ≤100 IU/mL on NUCs; five cycles (1 – 23) and 2.3 months (0.2–15.0) for HBV DNA >100 IU/mL on NUCs; nine cycles (4 – 19) and 5.1 months (1.6–13.6) for patients not on NUCs, respectively. In addition, the follow-up period of the three patient groups was 5.4 months (0.5–25.7), 3.9 months (0.2–17.9) and 10.4 months (4.0–24.8), respectively. The detailed baseline characteristics were presented in table 1.\n\nTable 1 Characteristics of 60 HBV-HCC patients treated with ICIs\n\nCharacteristics\tHBV DNA ≤100 IU/mL on NUCs\tHBV DNA >100 IU/mL on NUCs\tPatient with HBV without\nNUCs\tP value\t\n(n=35)\t(n=19)\t(n=6)\t\nAge, year\t63.4 (45.6–78.8)\t58.0 (40.8–77.7)\t56.5 (40.1–66.5)\t0.019\t\nSex (male), n (%)\t31 (88.6)\t15 (78.9)\t4 (66.7)\t0.341\t\nNUCs, ETV/TDF/TAF, n (%)\t24/8/3 (68.6/22.9/8.6)\t15/1/3 (78.9/5.3/15.8)\t–\t–\t\nAnti-HCV positive, n (%)\t1 (2.9)\t0 (0)\t1 (16.7)\t0.136\t\nMax. tumor size, cm\t4.0 (1.0–12.1)\t8.7 (3.3–17.0)\t8.8 (1.6–14.4)\t<0.001\t\nTumor >50% liver volume, n (%)\t6 (17.1)\t10 (52.6)\t4 (66.7)\t0.006\t\nMultiple tumors, n (%)\t32 (91.4)\t19 (100.0)\t6 (100.0)\t0.324\t\nExtrahepatic metastasis, n (%)\t19 (54.3)\t8 (42.1)\t2 (33.3)\t0.514\t\nPortal vein invasion, n (%)\t16 (45.7)\t4 (73.7)\t5 (83.3)\t0.058\t\nAFP, ng/mL\t373.2 (1.8–272 689.4)\t1992.6 (13.7–785 992.2)\t3082.2 (1076.2–1 148 415.7)\t0.028\t\nBCLC stage B/C, n (%)\t8/27 (22.9/77.1)\t4/15 (21.1/78.9)\t0/6 (0/100.0)\t0.429\t\nProthrombin time, INR\t1.16 (0.90–1.47)\t1.10 (1.00–3.12)\t1.09 (0.97–1.42)\t0.600\t\nPlatelet count, K/cumm\t122 (43–360)\t182 (71–553)\t148 (128–367)\t0.057\t\nALT, U/L\t35 (11–254)\t47 (17–213)\t39 (22–64)\t0.448\t\nAST, U/L\t42 (16–366)\t90 (27–480)\t61 (29–140)\t0.106\t\nTotal bilirubin, mg/dL\t0.69 (0.22–2.41)\t1.10 (0.25–10.08)\t0.97 (0.29–1.44)\t0.854\t\nAlbumin, g/dL\t3.8 (2.7–4.9)\t3.6 (2.3–4.4)\t3.5 (3.2–4.0)\t0.106\t\nNeutrophil, /cumm\t4800 (2300–11900)\t5550 (2500–12300)\t5500 (3900–11600)\t0.258\t\nNeutrophil-lymphocyte ratio\t3.89 (1.46–11.01)\t3.90 (2.52–15.13)\t4.45 (2.03–10.68)\t0.684\t\nPresence of ascites, n (%)\t11 (31.4)\t9 (47.4)\t4 (66.7)\t0.194\t\nChild-Pugh score\t6 (5–9)\t6 (5–12)\t6 (5–7)\t0.368\t\nChild-Pugh class A/B/C, n (%)\t28/7/0 (80.0/20.0/0)\t12/6/1 (63.2/31.6/5.3)\t4/2/0 (66.7/33.3/0)\t0.475\t\nALBI grade 1/2/3, n (%)\t15/18/2 (42.9/51.4/5.7)\t4/12/3 (21.1/63.2/15.8)\t2/4/0 (33.3/66.7/14.3)\t0.386\t\nICI treatment cycle\t5 (1–35)\t5 (1–23)\t9 (4–19)\t0.232\t\nICI treatment duration, months\t2.1 (0.5–24.5)\t2.3 (0.2–15.0)\t5.1 (1.6–13.6)\t0.257\t\nPrior therapy to ICI, n (%)\t\t\t\t\t\n Surgical resection\t22 (62.9)\t4 (21.1)\t3 (50.0)\t0.013\t\n RFA\t16 (45.7)\t3 (15.8)\t2 (33.3)\t0.088\t\n TACE\t22 (62.9)\t8 (42.1)\t5 (83.3)\t0.143\t\n Sorafenib\t19 (54.3)\t10 (52.6)\t5 (83.3)\t0.378\t\nCombined ICI with TKI, n (%)\t9 (25.7)\t2 (10.5)\t2 (33.3)\t0.605\t\nImmune-related AEs, n (%)\t6 (17.2)\t3 (15.8)\t0 (0)\t0.550\t\nFollow-up period, months\t5.4 (0.5–25.7)\t3.9 (0.2–17.9)\t10.4 (4.0–24.8)\t0.199\t\nContinuous variables are expressed as median (range).\n\nAEs, adverse events; AFP, alpha-fetoprotein; AL(S)T, alanine (aspartate) aminotransferase; ETV, entecavir; ALBI grade, albumin-bilirubin grade; HBV, hepatitis B virus; HCV, hepatitis C virus; ICI, immune checkpoint inhibitor; INR, international normalized ratio; NUCs, nucleos(t)ide analogs; RFA, radiofrequency ablation; BCLC stage, Barcelona Clinic Liver Cancer stage; TACE, transarterial chemoembolization; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TKI, tyrosine kinase inhibitor.\n\nViral kinetics of HBV during ICI treatment\nIn patients with HBV DNA ≤100 IU/mL on NUCs therapy, no case experienced HBV reactivation during the ICIs treatment. Of the 19 patients with HBV DNA >100 IU/mL who started antiviral therapy simultaneously with ICI treatment, seven cases had longer survival to monitor their HBV DNA after NUCs treatment (figure 1A). Only one experienced suboptimal suppression by tenofovir with low HBV viremia but without ALT elevation or adverse events (details were presented in figure 2A); the others had a substantial decrease in HBV viral load during the follow-up period (table 2).\n\nFigure 1 Kinetics of HBV DNA during ICI treatment. Kinetics of HBV DNA during ICI treatment in (A) patients with HBV DNA >100 IU/mL on NUCs, and (B) patients with HBV not on NUCs. Of 19 patients with HBV DNA >100 IU/mL on antiviral therapy, nine developed early tumor progression and short survival (<3 months), and three did not have significant ALT elevation during ICI treatment so that their followed data of HBV viral load were unavailable. ALT, alanine aminotransferase; HBV, hepatitis B virus; ICI, immune checkpoint inhibitor; NUCs, nucleos(t)ide analogs.\n\nFigure 2 Kinetics of serum alanine aminotransferase (ALT) of two patients with hepatitis B virus (HBV) DNA elevation Kinetics of serum ALT of patients with HBV DNA elevation during ICI treatment who was classified in patients with HBV DNA >100 IU/mL on NUCs (A), and patients with HBV not on NUCs (B), respectively. ICI, immune checkpoint inhibitor; NUCs, nucleos(t)ide analogs; TDF, tenofovir disoproxil fumarate.\n\nTable 2 HBV status during immune checkpoint inhibitors therapy\n\nN (%)\tHBV DNA ≤100 IU/mL on NUCs (n=35)\tHBV DNA >100 IU/mL on NUCs (n=19)\tPatients with HBV without NUCs (n=6)\t\nBaseline HBV DNA\t\t\t\t\n Undetectable\t31 (88.6)\t0\t1 (16.7)\t\n Median (range) for detectable cases, IU/mL\t41 (12–82)\t187 000 (109 –27 500 000)\t777 (252–35 900)\t\nHBV reactivation\t0\t0\t1\t\nHBV DNA during ICI treatment\t\t\t\t\n ≥1 log10 elevation\t0\t0\t1 (16.7)\t\n ≥2 log10 elevation\t0\t0\t0\t\n Undetectable to detectable\t3 (8.6)\t0\t0\t\n Undetectable to >1000 IU/mL\t0\t0\t0\t\n Peak HBV DNA during ICI, IU/mL. median (range)\t<10 (<10–1130)\t381 (<10–2700)\t70 (<10–1 68 000)\t\nHepatitis flare\t\t\t\t\n ALT >100 U/L\t10 (28.6)\t11 (57.9)\t2 (33.3)\t\n ALT >5X ULN\t5 (14.3)\t4 (21.1)\t1 (16.7)\t\n ALT >10X ULN\t2 (5.7)\t2 (10.5)\t0 (0)\t\n Icteric flare*\t5 (14.3)\t6 (31.6)\t2 (33.3)\t\n HBV DNA elevation and ALT >100 U/L\t0\t0\t1 (16.7)\t\niRAE hepatitis\t1 (2.9)\t1 (5.3)\t0 (0)\t\n*Icteric flare is defined as serum ALT raised >3X ULN together with serum total bilirubin >2X ULN.\n\nALT, alanine aminotransferase; HBV, hepatitis B virus; ICI, immune checkpoint inhibitor; iRAE, immunotherapy related adverse event; NUCs, nucleos(t)ide analogs; ULN, upper limit of normal.\n\nOf the six patients without antiviral treatment, five had detectable HBV viral load at baseline. Interestingly, three patients developed a notable decrease in HBV viral load during ICI treatment; and one maintained his serum HBV DNA in undetectable level during ICI treatment. Eventually, one patient experienced HBV reactivation with a >10 fold increase in HBV DNA level and ALT flare after 9 weeks of ICI treatment (figure 1B). After HBV reactivation, his HBV was controlled by tenofovir treatment and did not lead to HBV-related liver failure (table 3 and figure 2B). On the other hand, case N6 died of rapid tumor progression, and we could not get the followed data of HBV viral load.\n\nTable 3 Clinical characteristics of the six patients without pre-emptive nucleot(s)ide treatment\n\nPatient no\tAge\n(years)\tSex\tBaseline HBsAg (IU/mL)\tBaseline HBV\nDNA (IU/mL)\tBaseline\nAFP (ng/mL)\tICI\n±TKI therapy\tFU HBsAg (IU/mL)\tFU\nHBV DNA (IU/mL)\tFU\nAFP at BR (ng/mL)\tPeak ALT\n(U/L)\tPeak t.bili\n(mg/dL)\tRescue NUCs\tDeath caused by HBV\tBest\nTumor response to ICI\t\nN1\t40.9\tM\t26.4\t35 900\t2719.2\tNivolumab\t2.01\t1280\t2799.9\t85\t0.63\t–\tNone\tPD\t\nN2\t66.5\tF\t27.8\t252\t1859.3\tNivolumab\t58.2\t26\t4974.5\t202\t5.23\t–\tNone\tPD\t\nN3\t49.2\tM\t559.8\t8960\t1148415.8\tNivolumab\tMissing\t168 000\t544 176.1\t174\t19.75\tTDF\tNone\tPD\t\nN4\t40.1\tF\t1856.77\t777\t1076.2\tNivolumab\nLenvatinib\tMissing\t70\t179.2\t46\t0.52\t–\tNone\tCR\t\nN5\t63.9\tM\t557.88\t<20\t3445.2\tNivolumab\nRegorafenib\tMissing\t<20\t8905.3\t37\t2.77\t–\tNone\tPD\t\nN6\t64.1\tM\t0\t392\t129 258.1\tNivolumab\tMissing\tMissing\t76 472.3\t26\t9.49\t–\tNone\tPD\t\nAFP, alpha-fetoprotein; ALT, alanine aminotransferase; BR, best response; F, female; HBsAg, HBV surface antigen; HBV, hepatitis B virus; ICI, immune checkpoint inhibitor; M, male; NUCs, nucleos(t)ide analogs; T.bili, total bilirubin; TDF, tenofovir disoproxil fumarate; TKI, tyrosine kinase inhibitor.\n\nStatus of hepatitis during ICI treatment\nTwenty-three patients (38.3%) experienced ALT>100 U/L during the follow-up period. Of them, 10 patients had ALT flare (>5 fold ULN), but only four had more than 10-fold ULN ALT increase (5.7% and 10.5% in HBV DNA ≤100 IU/mL and HBV DNA >100 IU/mL on NUCs patients) (table 2). As presented in table 4, tumor progression is the main cause of ALT elevation in each group of patients. Two patients on NUCs therapy (one with baseline HBV DNA ≤100 IU/mL and the other one>100 IU/mL) had developed immune-related adverse event (iRAE) hepatitis. The incidence of iRAE hepatitis was not significantly different among the three groups. Of the six HBV patients without NUCs treatment, two developed ALT elevation >100 U/L during ICI therapy. One was resulted from HBV reactivation, and the other one was attributed to tumor progression.\n\nTable 4 Causes of ALT >100 U/L in HBV-HCC patients on ICI treatment\n\nN (%)\tHBV DNA ≤100 IU/mL on NUCs (n=10)\tHBV DNA >100 IU/mL on NUCs (n=11)\tPatients with HBV without NUCs (n=2)\t\nTumor progression\t9 (90.0)\t10 (90.9)\t1 (50.0)\t\nHBV reactivation\t0\t0\t1 (50.0)\t\niRAE hepatitis\t1 (10.0)\t1 (9.1)\t0 (0)\t\nALT, alanine aminotransferase; HBV, hepatitis B virus; ICI, immune checkpoint inhibitor; iRAE, immunotherapy related adverse event; NUCs, nucleos(t)ide analogs.\n\nDiscussion\nThis is the largest real-world cohort from Asian patients with HBV-related HCC treated by ICIs till now. In our cohort, HBV reactivation developed in only one patient who did not receive antiviral agent during ICI therapy; and was controlled by tenofovir treatment that did not lead to HBV-related liver failure. Otherwise, no patients with ongoing NUCs suffered from noteworthy HBV reactivation during ICI treatment; even their baseline HBV DNA levels were higher than 100 IU/mL.\n\nFor patients with HBV-related HCC, HBV reactivation and its subsequent morbidity were identified as poor prognostic factors of the overall survival.28 According to previous studies, the incidence of HBV reactivation ranges from 4% to 67% in patients with HBV-related HCC undergoing chemotherapy; and the contributed mortality rate was up to 18%.29 30 Apart from the direct cause of death, the scheduled treatment to HCC would be delayed or premature terminated due to deteriorated liver function by HBV reactivation that would also have impacts on the prognosis.31 32 For patients who received hepatectomy or loco-regional therapies for HCC, HBV reactivation was also reported and identified in relation to the prognosis.33–35 However, the data regarding to the kinetics of HBV viral loads during ICI therapy for HCC were still limited.\n\nIn patients with chronic hepatitis B, the upregulated inhibitory receptors on the CD8 T cells limit their defensive function and lead to the exhausted phenotype.13 PD-1 is the most expressed inhibitory receptor, especially on the intrahepatic HBV-specific T cells.36 37 Blockage of PD-1/PD-L1 pathway could restore not only antitumor but also antiviral T cell function then help to suppress HBV viral load.12 37 According to the recent phase 1b study, a single dose of nivolumab at 0.3 mg/kg could lead to HBsAg decline in HBeAg-negative chronic hepatitis B.38 Despite the lack of data to support HBsAg decline in our study, we still demonstrated three out of six cases had substantial decline in HBV DNA and additional one case maintained his HBV viral load in undetectable status during ICI therapy among patients who did not receive NUCs treatment. These findings may imply the potential role of ICI in the treatment of chronic hepatitis B. However, even under NUCs treatment, a more than 1 log increase in HBV DNA during nivolumab treatment was reported in 11% (5/47) of HBV-related HCC patients in the Asian cohort of checkmate 040.39 In spite of that, their peak HBV viral load were all less than 2000 IU/mL and no HBV-related adverse events were reported. In our cohort, presence of low HBV viremia was observed in one patient during tenofovir treatment which did not lead to ALT elevation or adverse events. According to AASLD (American Association for the Study of Liver Diseases) guideline, change NUCs is not required as it did not meet the definition of antiviral drug resistance (1 log increase in HBV DNA).11 In addition to the previous case reports,17 18 40 a recent Chinese study demonstrated that 6 of 114 (5.3%) HBsAg-positive patients with various cancers developed HBV reactivation during anti-PD-1/PD-L1 treatment, but no HBV-related fatal events occurred.41 Our real-world data also demonstrated that HBV reactivation would occur in one out of six patients who did not receive pre-emptive anti-viral treatment. Accordingly, we still have to keep awareness of HBV reactivation during ICI treatment for HBV-HCC.42\n\nIn checkmate-040 and Keynote-224 trials, patients were required to receive effective anti‐viral therapy and had a viral load <100 IU/mL before initiating ICI treatment.5 6 In the real life, however, ICIs would be delivered to more complex populations of patients than those of clinical trials that raise a question to the necessity of keeping low viral load before ICI therapy. Our data suggested that HBV viral load higher than 100 IU/mL is safe and not a contraindication for ICI treatment for HCC, if NUCs can be coadministrated. By this way, none developed HBV viral load increase during the treatment course.\n\nAlthough our data supported the feasibility of administering anti-PD-1 therapy in patients with HCC and HBV, the optimal use of NUCs remains uncertain. Whether patients at low risk of HBV reactivation may be monitored rather than receive prophylaxis in this setting, and an optimal threshold of HBV viral load that ICIs can be safely initiated without NUCs required further studies to determine.\n\nThere are several limitations in this study. First, this study only enrolled patients from a single hospital. However, our hospital is the main leading tertiary medical center in Taiwan. The information bias would be ameliorated by regular clinical assessment. Besides, it is so far the largest real-world HBV-HCC cohort that investigated the viral kinetics of HBV during ICI treatment. Second, the serum level of HBsAg was not frequently rechecked in our patients during ICI treatment according to the reimbursement criteria of NHI in Taiwan. Third, no ideal control arm could be designed in this study. For sorafenib-failed HCC patients, sorafenib on treatment group could not serve as control. For patients who received ICIs as first-line therapy, sorafenib on treatment patients were also not suitable as a control group because the pharmacologic difference between sorafenib and ICIs. The ideal control group should be HCC patients with serum HBV DNA >100 IU/mL who received ICI treatment after sorafenib failure or intolerance but was prohibited to use NUCs throughout the treatment. However, it is not ethical for this design. Forth, the risk of HBV reactivation might be underestimated because some patients only received very few cycles of ICIs and experienced early tumor progression and mortality. In our study, 15 did not have follow-up HBV DNA values; including nine patients did not experience ALT elevation during ICIs treatment; and the other six patients met early tumor progression. The risk of HBV reactivation might be underestimated in these cases. Finally, the antiviral agents prescribed to our patients were not consistent. Most of the patients (72.2%) on antiviral therapy were prescribed with entecavir; and the others used tenofovir disoproxil fumarate or tenofovir alafenamide. However, all these NUCs belong to high potency antiviral agents that could suppress high HBV viral loads.43 44\n\nIn conclusion, no patients on antiviral therapy (regardless of HBV viral load at baseline) developed HBV reactivation, and one out of six not receiving NUCs had HBV reactivation. Patients with HBV viral load higher than 100 IU/mL could safely receive ICI treatment under the protection of NUCs treatment.\n\nContributors: Study concept and design: Y-HH; Acquisition of data: P-CL, YC, M-HC and K-HL; Analysis and interpretation of data: P-CL and M-CH; Drafting of manuscript: P-CL and Y-HH; Critical revision: M-CH and YC; Study supervision: YC and Y-HH.\n\nFunding: The work was partly supported by the Taipei Veterans General Hospital, Taipei, Taiwan (grant numbers V109C-048); and Ministry of Science and Technology, Taiwan (grant numbers MOST108-2628-B-075-006).\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nEthics approval: This study was approved by the Institutional Review Board of the Taipei Veterans General Hospital (IRB numbers: 2017-09-007CC, 2019-07-007AC and 2019-08-006B).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. 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J Clin Oncol \n2020 :JCO.20.01757 . 10.1200/JCO.20.01757 \n43 Wu I-T , Hu T-H , Hung C-H , et al \nComparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-naive chronic hepatitis B patients with high viraemia: a retrospective cohort study\n. Clin Microbiol Infect \n2017 ;23 :464 –9\n. 10.1016/j.cmi.2017.02.001 28189857 \n44 Kim SU , Seo YS , Lee HA , et al \nA multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea\n. J Hepatol \n2019 ;71 :456 –64\n. 10.1016/j.jhep.2019.03.028 30959156\n\n", "fulltext_license": "CC BY", "issn_linking": "2051-1426", "issue": "8(2)", "journal": "Journal for immunotherapy of cancer", "keywords": "immunotherapy; liver neoplasms", "medline_ta": "J Immunother Cancer", "mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D005260:Female; D006515:Hepatitis B virus; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors", "nlm_unique_id": "101620585", "other_id": null, "pages": null, "pmc": null, "pmid": "32863270", "pubdate": "2020-08", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "18302293;21871026;31790344;28620797;23775967;23402625;31176752;29405329;24976705;16440366;30959156;26563120;28983565;16382236;19097774;25964247;31940757;28736952;16440357;28434648;15520068;31753012;28945827;29875066;22022563;17312113;31306680;25447850;32716741;25512453;30416833;17287266;27084039;22868358;12774010;19800335;22929808;29628281;19399803;11055239;28906278;28189857;28011918;28130846", "title": "Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.", "title_normalized": "risk of hbv reactivation in patients with immune checkpoint inhibitor treated unresectable hepatocellular carcinoma" }

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{ "abstract": "The clinical benefits of HER2 inhibitors in patients with non-small cell lung cancer (NSCLC) have been limited. There is a paucity of effective therapies in NSCLC after developing resistance to initial anti-HER2 therapy. Herein, we presented the clinical benefit of pyrotinib in a 53-year-old patient with advanced lung adenocarcinoma whose circulating tumor DNA (ctDNA) analysis of pleural effusion revealed the coexistence of HER2 exon 20 p.Y772_A775dup (mutation ratio: 38.86%) and HER2 amplification (copy number: 4.5) following failures of multiple therapies including afatinib and ado-trastuzumab emtansine (T-DM1). Notably, pyrotinib treatment induced rapid and marked improvement of clinical symptoms, and partial response was observed after 8 weeks. CtDNA monitoring during the treatment showed that the mutation ratio of HER2 decreased to 7.99%, and the amplification disappeared. The patient achieved a progression-free survival of 7.5 months after treatment with pyrotinib. Thus, pyrotinib may be a new treatment strategy for the subgroup of lung adenocarcinoma patients, with coexistence of HER2 exon 20 p.Y772_A775dup and HER2 amplification even after failures of multiple anti-HER2 therapies. It also indicated the value of capture-based next-generation sequencing to monitor and guide therapy.", "affiliations": "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.;Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.;Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.;Department of Medicine, Burning Rock Biotech, Guangzhou, People's Republic of China.;Department of Medicine, Burning Rock Biotech, Guangzhou, People's Republic of China.;Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.;Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.", "authors": "Shan|Jianzhen|J|;Ruan|Jian|J|;Tan|Yanbin|Y|;Yan|Li|L|;Chen|Songan|S|;Du|Miaoyan|M|;Wang|Lingjie|L|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/OTT.S271999", "fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930 Dove \n\n271999\n10.2147/OTT.S271999\nCase Report\nEfficacy of Pyrotinib in a Heavily Pretreated Patient with Lung Adenocarcinoma Harboring HER2 Amplification and Exon 20 Insertions: A Case Report\nShan et alShan et alShan Jianzhen 1* Ruan Jian 1* Tan Yanbin 2 Yan Li 3 Chen Songan 3 Du Miaoyan 1 Wang Lingjie 1 1 Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China\n2 Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China\n3 Department of Medicine, Burning Rock Biotech, Guangzhou, People’s Republic of China\nCorrespondence: Jianzhen Shan The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, People’s Republic of ChinaTel +86 571-87235409 Email Shanjz@zju.edu.cn* These authors contributed equally to this work\n\n\n02 10 2020 \n2020 \n13 9849 9856\n14 7 2020 05 9 2020 © 2020 Shan et al.2020Shan et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nThe clinical benefits of HER2 inhibitors in patients with non-small cell lung cancer (NSCLC) have been limited. There is a paucity of effective therapies in NSCLC after developing resistance to initial anti-HER2 therapy. Herein, we presented the clinical benefit of pyrotinib in a 53-year-old patient with advanced lung adenocarcinoma whose circulating tumor DNA (ctDNA) analysis of pleural effusion revealed the coexistence of HER2 exon 20 p.Y772_A775dup (mutation ratio: 38.86%) and HER2 amplification (copy number: 4.5) following failures of multiple therapies including afatinib and ado-trastuzumab emtansine (T-DM1). Notably, pyrotinib treatment induced rapid and marked improvement of clinical symptoms, and partial response was observed after 8 weeks. CtDNA monitoring during the treatment showed that the mutation ratio of HER2 decreased to 7.99%, and the amplification disappeared. The patient achieved a progression-free survival of 7.5 months after treatment with pyrotinib. Thus, pyrotinib may be a new treatment strategy for the subgroup of lung adenocarcinoma patients, with coexistence of HER2 exon 20 p.Y772_A775dup and HER2 amplification even after failures of multiple anti-HER2 therapies. It also indicated the value of capture-based next-generation sequencing to monitor and guide therapy.\n\nKeywords\npyrotinibHER2 mutationHER2 amplificationnon-small cell lung cancernext-generation sequencing\n==== Body\nIntroduction\nHuman epidermal growth factor receptor 2 (HER2) has been identified as a key oncogenic driver gene in non-small cell lung cancer (NSCLC).1 The incidence of HER2 mutation and amplification in NSCLC is approximately 2–3% and 2–5%, respectively.2 As shown in previous studies, typically, these modifications are not associated with each other and act as distinct molecular targets.3,4 For over a decade, many clinical trials have investigated HER2-targeted drugs for the treatment of NSCLC with HER2 variations. Trastuzumab and afatinib were previously recommended (category 2B) by National Comprehensive Cancer Network Guidelines for NSCLC with HER2 mutations, however, due to the merge of ado-trastuzumab emtansine (T-DM1), which showed superior response rates and efficacy in this patient group, the recommendation was then switched to T-DM1 (category 2A).5,6 In a Phase II basket trial, T-DM1 produced a 44% confirmed partial response rate and a median progression-free survival (PFS) of 5 months in HER2 mutated NSCLC.7 However, thus far, there is no targeted therapy specifically approved for this patient population. In China, pyrotinib (an oral irreversible tyrosine kinase inhibitor targeting HER1, HER2, and HER4 receptors) has been approved for the treatment of HER2-positive advanced breast cancer. A preclinical study of pyrotinib displayed excellent in vitro potency and selectivity, as well as robust in vivo efficacy in HER2-dependent mouse xenograft models. Metabolic pathway data indicated that pyrotinib was primarily metabolized by CYP3A4. In addition, the study also demonstrated the desirable pharmacokinetic properties and safety profile of this agent.8 A Phase I study of pyrotinib assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers in patients with HER2-positive metastatic breast cancer.9 Preliminary data showed its promising antitumor activity and acceptable tolerability, with an overall objective response rate of 50.0% (18 of 36 patients) and median PFS of 35.4 weeks. The only grade 3 adverse event reported was diarrhea. Moreover, circulating tumor DNA (ctDNA) dynamics was discovered as a novel indicator of resistance in patients with metastatic breast cancer receiving anti-HER2 therapy.10 A randomized phase II study assessed the efficacy and tolerability of pyrotinib versus lapatinib, both in combination with capecitabine, in women with HER2-positive metastatic breast cancer who received taxanes, anthracyclines, and/or trastuzumab. The results showed that pyrotinib plus capecitabine yielded statistically significant better overall response rate (78.5% vs 57.1%, respectively) and median PFS (18.1 vs 7.0 months, respectively) than lapatinib plus capecitabine.11 In addition, pyrotinib showed a superior antitumor effect than afatinib and T-DM1 in the patient-derived xenograft model and mice model. In a phase II clinical trial designed to evaluate the efficacy and safety of pyrotinib in the treatment of advanced NSCLC with HER2 exon 20 insertions showed promising results.12 In another published phase II study, pyrotinib also showed a favorable objective response rate and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.13\n\nIn this study, we report a case with HER2-mutant advanced NSCLC, who had previously been treated with multiple lines of therapy, including anti-HER2 therapies (ie, afatinib and T-DM1), benefiting from pyrotinib as salvage therapy with coexistence of HER2 mutation and amplification. During the treatment, we also detected ctDNA at various milestones by capture-based next-generation sequencing (NGS) to monitor and guide therapy.\n\nCase Report\nA 53-year-old male detected a space-occupying lesion in the left lung through physical examination 1 month prior to admission. He was admitted to our hospital on October 18, 2015. Imaging examinations showed a nodule measuring 17 × 15 × 15 mm in the upper lobe of the left lung inferior lingular segment. Moreover, the left supraclavicular lymph node was swollen (1.1 × 0.5 mm), with no evidence of brain or bone metastasis. The levels of tumor biomarker carcinoembryonic antigen were 12.2 ng/mL. Computed tomography (CT)-guided biopsy of the left lung and left supraclavicular lymph node revealed the presence of adenocarcinoma. The pathological stage of the disease was T1bN3M0 (stage IIIB). NGS analysis of blood ctDNA and tumor tissue using a targeted panel (Burning Rock Biotech, Guangzhou, China) revealed no known mutations. We summarized the therapeutic regimens received and major mutations detected in Figure 1.Figure 1 Therapeutic course timeline followed in the patient. (A) pemetrexed + carboplatin + radiotherapy + maintenance therapy of pemetrexed; (B) afatinib + radiotherapy; (C) pembrolizumab; (D) paclitaxel + carboplatin + bevacizumab; (E) T-DM1; (F) afatinib; (G) gemcitabine + intracavitary administration of Recombinant Human Endostatin Injection (ENDOSTAR); (H) pyrotinib.\n\nAbbreviations: PR, partial response; PD, progressive disease; SD, stable disease; AF, allelic frequency; CN, copy number.\n\nIn brief, our patient received multiple lines of therapy. On November 8, 2015, the patient was administered 4 cycles of chemotherapy with pemetrexed plus carboplatin. Then, combined with radiotherapy after the first cycle. After that, pemetrexed maintenance treatment for a total of 10 cycles. There was a progressive increase in blood carcinoembryonic antigen (CEA) (42.6ng/mL), the chest CT showed that the left lung lesion had increased in size. Results of a positron emission tomography-computed tomography (PET-CT) scan demonstrated mediastinal lymph nodes, right supraclavicular lymph nodes, the right scapula and vertebra bone metastasis. Capture-based targeted sequencing of plasma ctDNA revealed a HER2 exon 20 p.Y772_A775dup (mutation ratio: 5.52%). The patient was treated with afatinib (40 mg once a day) for 3 months. The levels of CEA were declined. On May 18, 2017, the PET-CT showed a slight reduction in mediastinal lymph nodes, and it was considered to be a stable disease (SD). However, due to 3-degree adverse events (diarrhea and rash), the patient stopped taking afatinib, the levels of CEA were elevated again 2 months after stopping taking afatinib. On May 10, 2017, NGS of plasma ctDNA revealed lower HER2 mutation abundance than before (0.25%). On May 18, the PET-CT scan revealed multiple lymphadenopathies in the right clavicle area and mediastinum, increasing in size and number compared with the previous PET-CT scan, as well as metastasis of the right scapula and chest bone. On June 8, the patient received radiotherapy: 4500 cGy/15 F of the right scapula, 5600 cGy/28 F of the mediastinal metastasis tumor area and chest tumor area. After radiotherapy, a reexamination of CT showed that mediastinal lymph nodes were smaller than before, the peripheral blood NGS test was negative. The Eastern Cooperative Oncology Group (ECOG) score was 1 point. No significant progress was found in head magnetic resonance imaging (MRI), chest and abdomen CT. On June 19, 2018, an MRI of thoracic vertebrae revealed thoracic appendages, thoracic vertebrae and bone metastasis. From July 4, 2018, to August 21, 2018, the patient was administered with pembrolizumab (keytruda) at a dose of 200 mg once every three weeks for 3 cycles. The patient experienced progressive disease (PD) shortly after pembrolizumab treatment, with a progressive increase of blood CEA. Results of a PET-CT scan showed an enlarged lesion in the left upper lobe, new metastasis in hepatogastric space, retroperitoneal lymph nodes and vertebral bone. The ECOG score was 1 point. Back pain and other symptoms were the same as before. On October 10, the patient was treated with chemotherapy (paclitaxel plus carboplatin) combined with an anti-vascular drug (bevacizumab) for 2 cycles. The enhanced chest CT on November 24, 2018 (after 2 cycles) showed a larger lesion in the left upper lobe than before with left pleural effusion. NGS of plasma ctDNA revealed a HER2 exon 20 p.Y772_A775dup (0.18%). Based on the NGS results, the patient started T-DM1 (320mg, once every four weeks) for 2cycles. The blood CEA level increased to 192 ng/mL, the ECOG score was 2 points. The patient showed fatigue, 2-degree thrombocytopenia and elevated blood pressure (considered as adverse reactions related to T-DM1). The MRI scan demonstrated cervical vertebrae and thoracic vertebrae metastases. In the six-line therapy, the patient was administered with afatinib at a dose of 30 mg once a day for rechallenge, which resulted in stable disease. After the failure of afatinib rechallenge, the patient was switched to chemotherapy with gemcitabine alone for two cycles along with intracavitary administration of recombinant human endostatin injection (ENDOSTAR) for the treatment of pleural effusion. A PET-CT scan performed on August 28, 2019, revealed progression of the lung, bone, and lymph node lesions with bulk pleural effusion (Figure 2). At the same time, the patient showed hypoproteinemia, cough, chest distress, and shortness of breath after activity. NGS analysis (Burning Rock Biotech, Guangzhou, China) of pleural effusion ctDNA showed HER2 exon 20 p.Y772_A775dup (38.86%) and HER2 amplification (copy number: 4.5) (Figure 3). Subsequently, he was treated with pyrotinib 400 mg once daily. The symptoms were markedly relieved after 2 weeks and were evaluated after 8 weeks of treatment using PET-CT. He achieved partial response according to the Response Evaluation Criteria in Solid Tumors 1.1 (Figure 2). Dynamic monitoring of the pleural effusion ctDNA (Burning Rock Biotech, Guangzhou, China) showed that the HER2 mutation ratio had decreased significantly (7.99%) and the amplification had disappeared (Figure 3). The levels of tumor CEA showed dynamic changes with different treatments (Figure 4). However, PET-CT performed on March 16, 2020, showed an increase in the size of the left lung lesion, indicating progressive disease. The PFS after treatment with pyrotinib was 7.5 months.Figure 2 Image scans revealed the clinical response to the treatment of pyrotinib.\n\nFigure 3 Molecular analysis of the patient before and after pyrotinib treatment. (A) NGS analysis based on pleural effusion showed ERBB2 exon 20 p.Y772_A775dup before pyrotinib treatment. (B) NGS analysis based on pleural effusion showed ERBB2 copy-number amplification is 4.5 before pyrotinib treatment. (C) NGS analysis based on pleural effusion showed ERBB2 exon 20 p.Y772_A775dup after pyrotinib treatment. (D) NGS analysis based on pleural effusion showed no copy number gain after pyrotinib treatment.\n\nFigure 4 Fluctuation of CEA level in the blood. CEA, carcinoembryonic antigen.\n\n\n\nDiscussion\nCompared with epidermal growth factor receptor mutations, HER2 alterations are rare in patients with NSCLC. Previous reports on the clinicopathological characteristics of HER2-mutant NSCLC have demonstrated that these alterations are more common in females, non-smokers, and patients with adenocarcinomas (median age: 62 years).14 Furthermore, the prognosis is poor with a median overall survival of 1.6–1.9 years.15 The most frequent metastatic sites are the lungs, brain, and liver, while some patients had more than two metastatic lesions.16 Our patient is a younger male with lymph node, bone, and pleural metastases, as well as slow progression of disease.\n\nPyrotinib is a novel irreversible tyrosine kinase inhibitor with activity against HER1, HER2, and HER4. Preclinical studies suggested that pyrotinib can significantly inhibit the growth of HER2 factor-driven tumor cells both in vivo and in vitro.17 This is achieved by blocking the cell cycle in the G1 phase through inhibition of the HER2 downstream signaling pathway. In a phase II study of 15 pretreated NSCLC patients with HER2 mutations, the administration of pyrotinib 400 mg resulted in an overall response rate of 53.3% and a median PFS of 6.4 months.12 Notably, there was no occurrence of grade 3 or 4 adverse events. This cohort included 10 patients with Y772_A775dup in exon 20 of HER2, but not coupled with HER2 amplification. To the best of our knowledge, this is the first report of the efficacy of pyrotinib in patients with co-existence of HER2 mutation and amplification. In our case, after treatment with pyrotinib 400 mg, the patient achieved partial response accompanied by rapid relief of clinical symptoms, and pyrotinib showed better tolerability compared with afatinib and T-DM1. In this patient’s anti-HER2 therapy, afatinib has demonstrated certain clinical effect, no matter it was used for the first time or challenged again. However, full dose afatinib yielded 3-degree diarrhea and rash, causing discontinuation of afatinib. Pembrolizumab monotherapy was ineffective in this patient at all. It was suggested that HER2 variations similar as EGFR or ALK alterations might influence the effect of PD-1/PD-L1 inhibitor monotherapy.18 Although T-DM1 was recommended at higher level by the guidelines, our patient did not respond to it and he experienced 2-degree thrombocytopenia and elevated blood pressure. But in the treatment of pyrotinib, he did not require dose reduction or treatment termination.\n\nIn the present case, the co-existence of HER2 exon 20 p.Y772_A775dup and HER2 amplification was firstly detected after failure of afatinib rechallenge with no HER2 amplification detected previously. A previous report of a 36-year-old Asian woman diagnosed with stage IV lung adenocarcinoma with a HER2 exon 20 insertion suggested that HER2 copy number gain may be a potential resistance mechanism to afatinib.19 It was reported that HER2 mutations with in-frame insertions in exon 20 and amplification resulted in constitutive activation of the downstream signaling pathways. All three anti-HER2 drugs, afatinib, T-DM1 and pyrotinib can block HER2 downstream signaling pathways, but among them, pyrotinib was the most potent at inhibiting tumor growth in vitro and in vivo using clinically relevant concentration.12 According to findings from early phase clinical trials, pyrotinib demonstrated encouraging antitumor activity and a manageable toxicity profile in patients with heavily pretreated HER2-mutant NSCLC, as well as other advanced solid tumors harboring activating HER2 alterations including amplification.12,13,20 These positive findings showed the potential of pyrotinib in targeting HER2 amplification and exon 20 insertions. Further studies are warranted to prove the efficacy of pyrotinib in HER2-altered NSCLC and other solid tumors. Moreover, many other HER2-targeted agents in NSCLC are in clinical trials, including neratinib, poziotinib, TAK788, DS-8201a and so on. With the continuous supplement of clinical evidence, NSCLC with HER2 alterations may soon enter the era of targeted therapy.\n\nConclusion\nOur case showed pyrotinib could be a potential treatment option for the subgroup of lung adenocarcinoma patients with coexistence of HER2 exon 20 p.Y772_A775dup and HER2 amplification who have developed progress after multi-line anti-HER2 therapy. It also indicated the value of capture-based NGS to monitor and guide therapy, even if the result of the initial test is negative.\n\nAcknowledgments\nThe authors sincerely thank the patient and his family. This work was supported by the Public Welfare Technology Research Project of Zhejiang Province (grant number LGJ18H160001) and the Medical and Health Science and Technology Project of Zhejiang Province (grant number 2017205840, grant number 2018274816).\n\nAbbreviations\nNSCLC, non-small cell lung cancer; NGS, next-generation sequencing; PFS, progression-free survival; HER1, human epidermal growth factor receptor 1; HER2, human epidermal growth factor receptor 2; HER4, human epidermal growth factor receptor 4; CT, computed tomography; PET-CT, positron emission tomography-computed tomography; T-DM1, ado-trastuzumab emtansine; CEA, carcinoembryonic antigen.\n\nEthics Approval and Consent to Participate\nThe study was approved by the ethical committee of the First Affiliated Hospital of Zhejiang University School of Medicine and the patient signed an informed consent to participate in the study. The First Affiliated Hospital of Zhejiang University School of Medicine approved to publish the case details.\n\nConsent for Publication\nPublication of the case was consent by the patient. Informed consent was obtained from the patient for use of his samples, imagings and the publication of this report.\n\nAuthor Contributions\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\nLi Yan is an employee of Burning Rock Biotech. The authors report no other potential conflicts of interest in this work.\n==== Refs\nReferences\n1. Hyman \nDM , Piha-Paul \nSA , Won \nH , et al. 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Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-erbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer\n. J Clin Oncol . 2017 ;35 :3105 –3112\n.28498781 \n10. Ma \nF , Zhu \nW , Guan \nY , et al. ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy\n. Oncotarget . 2016 ;7 (40 ):66020 –66031\n. doi:10.18632/oncotarget.11791 27602761 \n11. Ma \nF , Ouyang \nQ , Li \nW , et al. Pyrotinib or lapatinib combined with capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase II study\n. J Clin Oncol . 2019 ;37 (29 ):2610 –2619\n. doi:10.1200/JCO.19.00108 31430226 \n12. Wang \nY , Jiang \nT , Qin \nZ , et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib\n. Ann Oncol . 2019 ;30 (3 ):447 –455\n. doi:10.1093/annonc/mdy542 30596880 \n13. Zhou \nC , Li \nX , Wang \nQ , et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy: a multicenter, open-label, single-arm, phase II study\n. J Clin Oncol . 2020 ;O2000297 .\n14. Eng \nJ , Hsu \nM , Chaft \nJE , Kris \nMG , Arcila \nME , Li \nBT . Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers\n. Lung Cancer . 2016 ;99 :53 –56\n. doi:10.1016/j.lungcan.2016.05.030 27565914 \n15. Kris \nMG , Johnson \nBE , Berry \nLD , et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs\n. JAMA . 2014 ;311 (19 ):1998 –2006\n. doi:10.1001/jama.2014.3741 24846037 \n16. Auliac \nJB , Do \nP , Bayle \nS , et al. Non-small cell lung cancer patients harboring HER2 mutations: clinical characteristics and management in a real-life setting. Cohort HER2 EXPLORE GFPC 02-14\n. Adv Ther . 2019 ;36 (8 ):2161 –2166\n. doi:10.1007/s12325-019-01001-9 31154630 \n17. Li \nQ , Guan \nX , Chen \nS , et al. Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: a phase I trial\n. Clin Cancer Res . 2019 ;25 (17 ):5212 –5220\n. doi:10.1158/1078-0432.CCR-18-4173 31138588 \n18. Mazieres \nJ , Drilon \nA , Lusque \nA , et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the immunotarget registry\n. Ann Oncol . 2019 ;30 (8 ):1321 –1328\n. doi:10.1093/annonc/mdz167 31125062 \n19. Chuang \nJC , Stehr \nH , Liang \nY , et al. ERBB2-mutated metastatic non-small cell lung cancer: response and resistance to targeted therapies\n. J Thorac Oncol . 2017 ;12 (5 ):833 –842\n. doi:10.1016/j.jtho.2017.01.023 28167203 \n20. Li \nBT , Li \nT , Johnson \nML , et al. Safety and efficacy of pyrotinib in patients with NSCLC and other advanced solid tumors with activating HER2 alterations: A phase I basket trial\n. J Clin Oncol . 2020 ;38 (15_suppl ):3510 . doi:10.1200/JCO.2020.38.15_suppl.3510\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1178-6930", "issue": "13()", "journal": "OncoTargets and therapy", "keywords": "HER2 amplification; HER2 mutation; next-generation sequencing; non-small cell lung cancer; pyrotinib", "medline_ta": "Onco Targets Ther", "mesh_terms": null, "nlm_unique_id": "101514322", "other_id": null, "pages": "9849-9856", "pmc": null, "pmid": "33061462", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "28115222;26723242;15753357;29298799;28167203;25899785;24846037;27602761;32614698;28498781;31125062;23610105;31138588;30596880;29989854;29420467;31154630;31430226;27565914", "title": "Efficacy of Pyrotinib in a Heavily Pretreated Patient with Lung Adenocarcinoma Harboring HER2 Amplification and Exon 20 Insertions: A Case Report.", "title_normalized": "efficacy of pyrotinib in a heavily pretreated patient with lung adenocarcinoma harboring her2 amplification and exon 20 insertions a case report" }

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{ "abstract": "BACKGROUND\nEndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel.\n\n\nMETHODS\nHER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated.\n\n\nRESULTS\nFifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04).\n\n\nCONCLUSIONS\nThe EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization.\n\n\nBACKGROUND\nClinicalTrials.gov NCT01537536.", "affiliations": "Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Breast International Group (BIG aisbl), Brussels, Belgium.;Department of Radiology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medigene AG, Planegg, Germany.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Department of Biostatistics, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Univ. Paris-Sud, Villejuif, France.;Department of Radiology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.", "authors": "Ignatiadis|Michail|M|;Zardavas|Dimitrios|D|;Lemort|Marc|M|;Wilke|Celine|C|;Vanderbeeken|Marie-Catherine|MC|;D'Hondt|Veronique|V|;De Azambuja|Evandro|E|;Gombos|Andrea|A|;Lebrun|Fabienne|F|;Dal Lago|Lissandra|L|;Bustin|Fanny|F|;Maetens|Marion|M|;Ameye|Lieveke|L|;Veys|Isabelle|I|;Michiels|Stefan|S|;Paesmans|Marianne|M|;Larsimont|Denis|D|;Sotiriou|Christos|C|;Nogaret|Jean-Marie|JM|;Piccart|Martine|M|;Awada|Ahmad|A|", "chemical_list": "D014408:Biomarkers, Tumor; D015251:Epirubicin; D003520:Cyclophosphamide; D018719:Receptor, ErbB-2; D017239:Paclitaxel; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0154009", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2745493010.1371/journal.pone.0154009PONE-D-14-45860Research ArticleMedicine and Health SciencesOncologyCancer TreatmentMedicine and Health SciencesDiagnostic MedicineDiagnostic RadiologyMagnetic Resonance ImagingResearch and Analysis MethodsImaging TechniquesDiagnostic RadiologyMagnetic Resonance ImagingMedicine and Health SciencesRadiology and ImagingDiagnostic RadiologyMagnetic Resonance ImagingMedicine and Health SciencesClinical MedicineClinical ImmunologyHypersensitivityBiology and Life SciencesImmunologyClinical ImmunologyHypersensitivityMedicine and Health SciencesImmunologyClinical ImmunologyHypersensitivityMedicine and Health SciencesSurgical and Invasive Medical ProceduresBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsNeutropeniaBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsWhite Blood CellsNeutropeniaBiology and Life SciencesImmunologyImmune CellsWhite Blood CellsNeutropeniaMedicine and Health SciencesImmunologyImmune CellsWhite Blood CellsNeutropeniaMedicine and Health SciencesOncologyCancer TreatmentSurgical OncologyMedicine and Health SciencesClinical MedicineClinical OncologySurgical OncologyMedicine and Health SciencesOncologyClinical OncologySurgical OncologyMedicine and Health SciencesOncologyCancers and NeoplasmsBreast TumorsBreast CancerMedicine and Health SciencesOncologyCancer TreatmentChemotherapyMedicine and Health SciencesClinical MedicineClinical OncologyChemotherapyMedicine and Health SciencesOncologyClinical OncologyChemotherapyMedicine and Health SciencesPharmaceuticsDrug TherapyChemotherapyFeasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer Neoadjuvant EndoTAG-1 for Breast CancerIgnatiadis Michail 12*Zardavas Dimitrios 3Lemort Marc 4Wilke Celine 5Vanderbeeken Marie-Catherine 1D’Hondt Veronique 1De Azambuja Evandro 1Gombos Andrea 1Lebrun Fabienne 1Dal Lago Lissandra 1Bustin Fanny 1Maetens Marion 2Ameye Lieveke 6Veys Isabelle 7Michiels Stefan 8Paesmans Marianne 4Larsimont Denis 9Sotiriou Christos 12Nogaret Jean-Marie 7Piccart Martine 123Awada Ahmad 11 \nMedical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium2 \nBreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium3 \nBreast International Group (BIG aisbl), Brussels, Belgium4 \nDepartment of Radiology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium5 \nMedigene AG, Planegg, Germany6 \nDepartment of Biostatistics, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium7 \nDepartment of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium8 \nService de Biostatistique et d’Epidémiologie, Gustave Roussy, Univ. Paris-Sud, Villejuif, France9 \nDepartment of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumLonser Russell R. EditorOhio State University, UNITED STATESCompeting Interests: Medigene AG provided the EndoTAG-1 and an educational grant for this study. Celine Wilke is employed by Medigene AG. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.\n\nConceived and designed the experiments: MI DZ ML CW MCV VDH EDA AG FL LDL FB MM LA IV SM M Paesmans DL CS JMN M Piccart AA. Performed the experiments: MI DZ ML CW MCV VDH EDA AG FL LDL FB MM LA IV SM M Paesmans DL CS JMN M Piccart AA. Analyzed the data: MI DZ ML CW MCV VDH EDA AG FL LDL FB MM LA IV SM M Paesmans DL CS JMN M Piccart AA. Wrote the paper: MI DZ ML CW MCV VDH EDA AG FL LDL FB MM LA IV SM M Paesmans DL CS JMN M Piccart AA.\n\n* E-mail: michail.ignatiadis@bordet.be25 7 2016 2016 11 7 e015400916 1 2015 27 1 2016 © 2016 Ignatiadis et al2016Ignatiadis et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nEndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel.\n\nMethods\nHER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated.\n\nResults\nFifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04).\n\nConclusions\nThe EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization.\n\nTrial Registration\nClinicalTrials.gov NCT01537536\n\nIJB was the sponsor of this study and Medigene AG provided the EndoTAG-1 and an educational grant. Medigene AG provided support in the form of salaries for author CW, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nBreast cancer (BC) represents the most frequently diagnosed malignancy and the leading cause of cancer death among women in the western world [1]. Patients diagnosed with early stage disease have high survival rates with the local and systemic treatment options available. Neoadjuvant chemotherapy (NAC) was introduced as a way to improve surgical options for BC, being administered more commonly to patients with high risk factors such as larger tumors and/or lymph node involvement at diagnosis [2]. NAC has the potential to reduce tumor burden, thus achieving down-staging of the disease allowing breast-conserving surgery (BCS), treats micrometastatic tumor burden, and allows for in vivo assessment of tumor response to therapy [3]. Although no specific NAC regimen is considered as the gold standard, anthracycline-and taxane-based chemotherapy is often used, especially for patients with high-risk, node-positive disease [4].\n\nPathological complete response (pCR) after NAC has been associated with significantly longer recurrence free (RFS) and overall survival (OS) [5–9]. Moreover, in the case of triple negative breast cancer (TNBC), representing an aggressive BC subtype with poor clinical outcome, patients achieving pCR after NAC have excellent prognosis [10].\n\nIn terms of radiologic monitoring of response to NAC, dynamic contrast-enhanced magnetic resonance imaging (MRI) can discriminate non-vascularized NAC-induced fibrosis from residual vital tumor burden [11,12]. Moreover, MRI assessment during NAC can allow early identification of non-responders. Recent data supports that MRI performed during NAC provides an accurate way to monitor response in TNBC or HER2-positive disease [13]. Thus, MRI holds the potential to guide the NAC strategy, through in vivo monitoring of response to the treatment provided.\n\nEndoTAG-1 is a cationic liposomal paclitaxel that has shown activity in TNBC when used in combination with paclitaxel. In a randomized controlled phase II study, TNBC patients with 0–1 prior chemotherapy regimens for metastatic disease and a (neo)-adjuvant taxane free interval of > 6 months, the clinical benefit rate (complete or partial response at any time and stable disease ≥ 6 months) on combination of EndoTAG-1 and paclitaxel (n = 50 patients) was 53% compared to 31% and 36% on EndoTAG-1 and paclitaxel monotherapy, respectively [14]. EndoTAG-1 showed a similar safety profile to paclitaxel. On combination treatment, a slight increase in grade 3/4 adverse events (AEs) was observed compared to either monotherapy, with neutropenia being the most frequent AE.\n\nIn the study reported here, we investigated the combination of EndoTAG-1/Paclitaxel followed by Fluorouracil, Epirubicin, Cyclophosphamide (FEC) as NAC in HER2-negative BC. The trial is registered at clinicaltrials.gov (NCT01537536).\n\nPatients and Methods\nEligibility\nThis study was conducted at the Institute Jules Bordet (IJB), Brussels, Belgium. Patients were eligible if they had newly diagnosed histologically confirmed BC, candidate for NAC. Histology grade > 1 and HER2-negativity as assessed by either immunohistochemistry (IHC) or fluorescent in-situ hybridization (FISH) were also required. Additional inclusion criteria were female gender; age ≥18 years old; ECOG performance status ≤1; willingness to perform double-barrier-contraception during study and for 6 months post chemotherapy treatment; adequate organ function. Patients with pregnancy or nursing status, known positive HIV testing, known hypersensitivity to any component of the EndoTAG-1, taxanes or FEC formulations and history of malignancy other than breast cancer <5 years prior to enrollment were ineligible to this study.\n\nStudy Design\nThis was a prospective, single-center, open-label phase II clinical study investigating the feasibility and antitumor activity of EndoTAG-1/Paclitaxel combination therapy in patients with HER2 negative BC candidate for NAC, as measured by the decrease in MRI-estimated tumor volume at the end of EndoTAG-1/Paclitaxel administration. The TREND checklist (S1 Fig) and the full study protocol (S1 Text) are provided as supplementary information.\n\nPrimary endpoint of the study was the percent reduction in MRI-estimated Gd-enhancing tumor volume at the end of EndoTAG-1/Paclitaxel treatment compared to baseline. Secondary endpoints included the percent reduction in linear tumor size as measured on MRI; the percent reduction in MRI- measured transfer constant Ktrans (evaluating quality of tumour perfusion) at the end of EndoTAG-1/Paclitaxel administration (Ktrans was obtained using the pharmacokinetic modelling as described by. Tofts PS et al [15]); pathological complete response (pCR) rate, defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes at the time of surgery; residual cancer burden (RCB) scores, calculated according to the RCB index proposed by Symmans et al [16]; rate of breast-conserving surgery (BCS).\n\nThis study was approved by the local Ethical Review Board of IJB and it was conducted in compliance with Good Clinical Practices and the Helsinki Declaration. All patients provided written informed consent before entering the study.\n\nTreatment Planning and Response Assessments\nEndoTAG-1 (22 mg/m2) and paclitaxel (70 mg/m2) were administered at weekly intravenous (i.v.) infusions for 12 week on the same day. After this, three cycles of FEC100 regimen (Fluorouracil 500 mg/m2, Epirubicin 100 mg/m2, and Cyclophosphamide 500 mg/m2) were administered every three weeks. MRI assessment was performed before any given therapy and no more than three weeks after the last taxane administration before the first FEC administration.\n\nThe volume calculation for the MRI assessment was performed using a computer-assisted, threshold-based segmentation algorithm, user-correctable (Telemis Inc., Louvain-la-Neuve, Belgium) on subtraction images from a 3D sequence with a 2 mm slice thickness and a 448x336 matrix size. The computer-aided, user-controlled segmentation algorithm reduces inter-observer variability. In addition, data were acquired on a 3D sequence which is nearly isometric and the segmentation algorithm is 3D, voxel-based, so no extrapolation was done using empirical formula. Segmentation on subtracted images allows avoiding difficult segmentation problems with fat or other high-signal tissue. The radiologist was not blinded to treatment.\n\nStatistical Analysis\nWe planned a sample size of 20 patients, based on a one-sided t-test for the average percentage decrease in MRI-estimated volume at the end of EndoTAG-1/Paclitaxel treatment from baseline. The null hypothesis was that the EndoTAG-1/Paclitaxel combination has no or a negligible effect on volume reduction, defined as a decrease ≤50% from baseline, whereas the alternative hypothesis was that this combination would yield at least an 80% average decrease. A standard deviation estimate of 59% was obtained from the study of Delille JP et al, a multiregimen neoadjuvant chemotherapy study that included 14 patients and for which the average percent decrease was equal to 60% [17]. For a one-sided significance level of 0.1 and a power of 82%, at least 20 patients were required. Due to skewness in the distribution of the variables MRI-estimated tumor volume, MRI-measured greatest diameter and MRI-estimated Ktrans tumor perfusion, we have applied the nonparametric sign test to compare the baseline with the end of treatment values.\n\nRole of the Funding Source\nIJB was the sponsor of this study and Medigene AG provided the EndoTAG-1 and an educational grant.\n\nResults\nPatients\nA total of 15 patients were enrolled in this study, between December 2011 and May 2012 (Fig 1). The study did not reach the planned sample size because of safety concerns, as reported in the safety section. Six of these patients did not complete the initially planned number of treatments. Patient characteristics are summarized in Table 1. Median age was 47 years (range 29–63 years), 67% of the patients were premenopausal, 53% had a histological diagnosis of ductal carcinoma, 40% had tumors of histology Grade III and 80% of them had Ki67 ≥14%. Nine patients had ER-positive/HER2-negative BC and 6 had TNBC.\n\n10.1371/journal.pone.0154009.g001Fig 1 CONSORT Diagram.\n10.1371/journal.pone.0154009.t001Table 1 Patient and disease characteristics at baseline.\nCharacteristic\tNo of Patients\t%\t\nAge, years\t\nMedian\t47\t\nRange\t29–63\t\nMenopausal Status\t\nPremenopausal\t10\t67%\t\nPostmenopausal\t2\t13%\t\nMissing\t3\t20%\t\nHistology\t\t\t\nDuctal\t12\t80%\t\nLobular\t2\t13.3%\t\nMixed (Ductal and Lobular)\t1\t6.7%\t\nER/PR\t\nER+/PR+\t8\t53.3%\t\nER+/PR-\t1\t6.7%\t\nER-/PR+\t0\t0%\t\nER-/PR-\t6\t40%\t\nKi67\t\n<14\t3\t20%\t\n≥14\t12\t80%\t\nGrade\t\nI\t1\t7%\t\nII\t8\t53%\t\nIII\t6\t40%\t\ncT\t\nT1\t3\t20%\t\nT2\t8\t53.3%\t\nT3\t1\t7%\t\ncN\t\nN0\t8\t53.3%\t\nN1\t7\t46.7%\t\nType of Treatment\t\nRadiotherapy\t\nNo\t-\t-\t\nYes\t15\t100%\t\nAdjuvant Hormonal Therapy\t\nNo\t6\t40%\t\nYes\t9\t60%\t\nAdjuvant Chemotherapy\t\nNo\t15\t100%\t\nYes\t-\t-\t\nSafety\nAEs of grade 3 to 4 occurred in eight (53%) of the 15 patients, with six (40%) of them attributed to the EndoTAG-1/Paclitaxel chemotherapy (Table 2). Two patients experienced serious AEs: one grade 3 drug-hypersensitivity, related to the EndoTAG-1/Paclitaxel treatment and one grade 4 neutropenia, which was associated with the FEC treatment. Despite the premedication administered and the slow infusion rates, four patients experienced grade 3 hypersensitivity to EndoTAG-1 during the 1st, 2nd, 3rd and 6th weekly infusion respectively and required permanent discontinuation of the EndoTAG-1. The patients that have experienced grade 3 hypersensitivity to EndoTAG-1 during the 1st, 3rd and 6th weekly infusion continued with paclitaxel alone in order to complete 12 cycles of treatment and then received 3 cycles of FEC100. The patient that has experienced a grade 3 hypersensitivity reaction during the 2nd infusion continued with 3 cycles of FEC100 every 3 weeks and 3 cycles of docetaxel 100mg/m2 every 3 weeks. These grade 3 hypersensitivity events led to premature closure of patients' enrolment, before reaching the initially planned sample size of 20 patients. No fatal AE has been reported.\n\n10.1371/journal.pone.0154009.t002Table 2 Adverse events of grade 3 or 4.\nPatient ID\tAdverse Event\tGrade\tSerious\tRelation to Study Medication\t\n2\tFebrile Neutropenia\t4\tNo\tFEC\t\n2\tFebrile Neutropenia\t3\tNo\tFEC\t\n2\tAnemia\t3\tNo\tFEC\t\n2\tFebrile Neutropenia\t4\tNo\tFEC\t\n2\tNeutropenia\t3\tNo\tFEC\t\n5\tDrug Hypersensitivity\t3\tYes\tEndoTAG-1/Paclitaxel\t\n6\tDrug Hypersensitivity\t3\tNo\tEndoTAG-1/Paclitaxel\t\n7\tHepatic Enzyme Elevation\t3\tNo\tEndoTAG-1/Paclitaxel\t\n9\tDrug Hypersensitivity\t3\tNo\tEndoTAG-1/Paclitaxel\t\n9\tNeutropenia\t3\tNo\tEndoTAG-1/Paclitaxel\t\n9\tNeutropenia\t4\tNo\tFEC\t\n10\tHepatic Enzyme Elevation\t3\tNo\tEndoTAG-1/Paclitaxel\t\n10\tMucosal Inflammation\t3\tNo\tFEC\t\n11\tDrug Hypersensitivity\t3\tNo\tEndoTAG-1/Paclitaxel\t\n12\tNeutropenia\t4\tYes\tFEC\t\nAbbreviations: FEC: Fluorouracil, Epirubicin, Cyclophosphamide, ID: Identifier\n\nEfficacy\nThe efficacy data are shown collectively in Table 3. The MRI-estimated volume decreased from median 6.36 cm3 (min 1.56 to max 40.87) at baseline to median 0.36 cm3 (min 0 to max 20.26) at the end of treatment, which was a statistically significant decrease (P-value <0.001). The percent reduction in the MRI-estimated tumor volume was on average 81% (95% CI, 66% to 96%). A significant reduction in tumor size as defined by MRI-measured greatest diameter at the end of EndoTAG-1/Paclitaxel treatment was also noted (median 51%, p<0.001).\n\n10.1371/journal.pone.0154009.t003Table 3 Efficacy results.\nPatient ID\tDoses of EndoTAG-1/Paclitaxel\t% Decrease in MRI-tumor volume\t% Decrease in MRI-max diameter\t% decrease in tumour perfusion (Ktrans)\tpCR\tRCB\t\n\t\t\t\t\t\tContinuous\tClass\t\n1\t12\t-100.00\t-100.00\t-90.76\tYes\t0\t0\t\n2\t12\t-95.28\t-52.94\t-9.03\tNo\t1.641\t2\t\n3\t12\t-90.12\t-66.18\tNA\tNo\t1.395\t2\t\n4\t12\t-83.85\t-33.03\t-43.92\tNo\tNot assessed\tNot assessed\t\n5\t1\t-94.34\t-45.92\t-14.43\tYes\t0\t0\t\n6\t6\t-87.34\t-22.43\t-42.42\tYes\t0\t0\t\n7\t6\t-0.46\t-0.29\t-35.89\tNo\t3.993\t3\t\n8\t12\t-99.38\t-82.66\t-11.53\tYes\t0\t0\t\n9\t2\t-85.26\t-35.53\t-68.52\tNo\t1.828\t2\t\n10\t12\t-68.62\t-56.57\t0.41\tNo\tNot assessed\tNot assessed\t\n11\t1\t-50.43\t-43.78\t-30.97\tNo\t3.718\t3\t\n12\t12\t-98.51\t-51.09\t-91.55\tNo\t3.92\t3\t\n13\t12\t-100.00\t-63.60\tNA\tYes\t0\t0\t\n14\t12\t-100.00\t54.36\t-86.21\tNo\t1.687\t2\t\n15\t9\t-60.35\t-23.20\t-4.46\tNo\t4.299\t3\t\nAbbreviations: ID: Identifier, MRI: Magnetic Resonance Imaging, NA: Not Assessed, pCR: pathologic Complete Response, RCB: Residual Cancer Burden\n\nA significant percent reduction in MRI-estimated Ktrans tumor perfusion at the end of EndoTAG-1/Paclitaxel administration was also noted among 13 patients with available information about MRI-estimated Ktrans tumor perfusion (median change %, 36%, p<0.001). Eight (53%) patients underwent lumpectomy, and seven (47%) underwent mastectomy, with all 15 (100%) patients undergoing axillary node dissection. Five (33%) of the 15 patients enrolled in the study achieved pCR at the time of definite surgery, all of them having TNBC, thus translating into an 83% pCR rate among this BC phenotype. The patients achieving pCR received 1, 6, 12, 12, and 12 cycles of EndoTAG-1/Paclitaxel respectively as part of their NAC (see safety section). Of interest, per cent reduction of MRI-estimated tumor volume at the end of EndoTAG-1/Paclitaxel treatment was statistically associated with pCR (96% versus 73% for patient achieving and not achieving pCR respectively, p = 0.04). Lastly, a strong inverse correlation was noted between RCB seen as a continuous variable and the MRI-estimated change in tumour volume at the end of EndoTAG-1/Paclitaxel treatment (Pearson correlation r = -0.66, p = 0.01) among 13 evaluable patients.\n\nDiscussion\nIn this phase II study, we evaluated the feasibility of EndoTAG-1/Paclitaxel NAC in HER2 negative BC patients, followed by three cycles of FEC100. This regimen showed promising antitumor activity: EndoTAG-1/Paclitaxel NAC resulted in significant percent reduction in MRI estimated tumor volume and significant reduction in tumor size as defined by MRI-measured greatest diameter at the end of EndoTAG-1/Paclitaxel treatment as compared to baseline (p<0.001 both). Additionally, among 13 evaluable patients a significant percent reduction in MRI-estimated Ktrans tumor perfusion parameter at the end of EndoTAG-1/Paclitaxel administration was also noted (p<0.001).\n\nA pCR rate of 33% was achieved overall, with five out of six (83%) TNBC cases achieving pCR at definitive surgery. However, due to the small sample size of our study, results should be interpreted with particular caution. Based on results from three published meta-analyses, there is a strong association between pCR and clinical outcome for BC patients receiving NAC [10, 18, 19].\n\nOne interesting finding from this study is the significant association between percent MRI-assessed tumor volume reduction at the end of EndoTAG-1/Paclitaxel administration and pCR. Our study confirms results from previous studies demonstrating that assessment of treatment response using MRI during NAC is associated with pCR in BC patients. In the I-SPY trial, among 216 women receiving NAC, MRI assessment performed during treatment (after one cycle of anthracycline-based regimen and between the anthracycline-based and taxane regimen) was found to be a stronger predictor of pCR than clinical assessment [20]. MRI-assessed tumor volume proved to provide the most accurate prediction for pCR. Another study, assessing MRI response monitoring during NAC (4 different regimens used, with all HER2-positive cases treated with trastuzumab-based regimens), showed that this represents an accurate tool in TNBC or HER2-positive BC (n = 85), but not in ER-positive/HER2-negative subtype (n = 103) [13]. Indeed, the change in MRI-assessed change in largest tumor diameter between baseline and during NAC was a significant predictor of residual disease at surgery for these two BC subtypes. Evidence associating pCR with treatment response assessed through MRI at the end of NAC is also available. A multi-center, retrospective analysis of 746 BC patients receiving NAC assessed the ability of MRI at the end of treatment to predict pCR in the breast: an overall accuracy of 74% was found with variances among different BC subtypes [21]. In particular, higher accuracy was noted for patients with TNBC and HER2-positive BC (negative predictive value of 60% and 62% respectively) in comparison to the luminal cases, probably influenced by the different pCR rates seen among these different subtypes.\n\nIn our study, MRI assessment was performed after the completion of the EndoTAG-1/Paclitaxel part of NAC and before the completion of all NAC. In the phase III, randomized GeparTrio trial, early radiologic assessment of tumor response, was performed using ultrasound [22]. Patients not responding to two initial cycles of NAC were randomly assigned to either continuation of the same regimen (n = 321) or to an alternative treatment (n = 301), with no improvement in the pCR (pCR 5.3% versus 6.0% respectively). To our knowledge, there has been no randomized trial assessing MRI early on as a tool to guide treatment selection in the neoadjuvant setting. This might be further explored in appropriately designed clinical trials [23].\n\nIn terms of safety, it should be noted that 4 patients experienced grade 3 hypersensitivity reactions to EndoTAG-1 that led to permanent discontinuation of EndoTAG-1. Additionally, AEs that were observed during the subsequent chemotherapy following the EndoTAG-1 administration might have not occurred for some patients at least. Due to the drug hypersensitivity reactions, this trial had to be suspended. This study showed promising antitumor activity of EndoTAG-1/Paclitaxel followed by FEC chemotherapy in the neoadjuvant setting of HER2-negative BC. Significant reductions in MRI-assessed tumor volume and maximum diameter were seen, with high pCR rate within the subpopulation of TNBC patients. A significant association was found between percent reduction of MRI-assessed tumor volume after EndoTAG-1/Paclitaxel NAC with both pCR and RCB. If the issue with hypersensitivity reaction is resolved, further clinical development of this regimen should be pursued in TNBC patients.\n\nSupporting Information\nS1 Fig TREND checklist for the ‘Feasibility study of EndoTAG-1, a tumor endothelial targeting agent, in combination with paclitaxel followed by FEC as induction therapy in HER2-negative breast cancer’ study.\n(PDF)\n\nClick here for additional data file.\n\n S1 Text Protocol for the ‘Feasibility study of EndoTAG-1, a tumor endothelial targeting agent, in combination with paclitaxel followed by FEC as induction therapy in HER2-negative breast cancer’ study.\n(PDF)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Siegel R , DeSantis C , Virgo K , Stein K , Mariotto A , Smith T , et al\nCancer treatment and survivorship statistics, 2012 . 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Cancer . 2013 \n5 \n15 ;119 (10 ):1776 –83 . 10.1002/cncr.27995 \n23436342 \n22 Von Minckwitz G , Kummel S , Vogel P , Hanusch C , Eidtmann H , Hilfrich J , et al\nNeoadjuvant Vinorelbine-Capecitabine Versus Docetaxel-Doxorubicin-Cyclophosphamide in Early Nonresponsive Breast Cancer: Phase III Randomized GeparTrio Trial . JNCI J Natl Cancer Inst . 2008 \n4 \n8 ;100 (8 ):542 –51 . 10.1093/jnci/djn085 \n18398097 \n23 Ades F , Zardavas D , Aftimos P , Awada A . Anticancer drug development: moving away from the old habits . Curr Opin Oncol . 2014 \n5 ;26 (3 ):334 –9 .24614094\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "11(7)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D060828:Induction Chemotherapy; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D017239:Paclitaxel; D018719:Receptor, ErbB-2; D016896:Treatment Outcome", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0154009", "pmc": null, "pmid": "27454930", "pubdate": "2016", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article", "references": "21737257;23436342;22700443;17785706;21220595;10508281;11953845;25386936;22623692;11773300;23661583;24529560;11709566;9215816;18398097;24614094;18258991;22508812;16622270;15868426;18258986;24667715;12775851", "title": "Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer.", "title_normalized": "feasibility study of endotag 1 a tumor endothelial targeting agent in combination with paclitaxel followed by fec as induction therapy in her2 negative breast cancer" }

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FEASIBILITY STUDY OF ENDOTAG-1, A TUMOR ENDOTHELIAL TARGETING AGENT, IN COMBINATION WITH PACLITAXEL FOLLOWED BY FEC AS INDUCTION THERAPY IN HER2-NEGATIVE BREAST CANCER. 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"INVESTIGATIONAL PRODUCT" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "22 MG/M2 WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INVESTIGATIONAL ANTINEOPLASTIC DRUGS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG/M2 WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IGNATIADIS M, ZARDAVAS D, LEMORT M, WILKE C, VANDERBEEKEN M-C, D^HONDT V, ET AL. FEASIBILITY STUDY OF ENDOTAG-1, A TUMOR ENDOTHELIAL TARGETING AGENT, IN COMBINATION WITH PACLITAXEL FOLLOWED BY FEC AS INDUCTION THERAPY IN HER2-NEGATIVE BREAST CANCER. PLOS-ONE 2016;11:NO. 7.", "literaturereference_normalized": "feasibility study of endotag 1 a tumor endothelial targeting agent in combination with paclitaxel followed by fec as induction therapy in her2 negative breast cancer", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160830", "receivedate": "20160830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12699829, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "BE-MYLANLABS-2016M1036391", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IGNATIADIS M, ZARDAVAS D, LEMORT M, WILKE C, VANDERBEEKEN M-C, D^HONDT V, ET AL. FEASIBILITY STUDY OF ENDOTAG-1, A TUMOR ENDOTHELIAL TARGETING AGENT, IN COMBINATION WITH PACLITAXEL FOLLOWED BY FEC AS INDUCTION THERAPY IN HER2-NEGATIVE BREAST CANCER. PLOS-ONE 2016;11:NO. 7.", "literaturereference_normalized": "feasibility study of endotag 1 a tumor endothelial targeting agent in combination with paclitaxel followed by fec as induction therapy in her2 negative breast cancer", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160830", "receivedate": "20160830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12699842, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "BE-MYLANLABS-2016M1036619", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG/M2 WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INVESTIGATIONAL PRODUCT" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "22 MG/M2 WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INVESTIGATIONAL ANTINEOPLASTIC DRUGS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/M2 EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IGNATIADIS M, ZARDAVAS D, LEMORT M, WILKE C, VANDERBEEKEN M-C, D^HONDT V, ET AL. FEASIBILITY STUDY OF ENDOTAG-1, A TUMOR ENDOTHELIAL TARGETING AGENT, IN COMBINATION WITH PACLITAXEL FOLLOWED BY FEC AS INDUCTION THERAPY IN HER2-NEGATIVE BREAST CANCER. PLOS-ONE 2016;11:NO. 7.", "literaturereference_normalized": "feasibility study of endotag 1 a tumor endothelial targeting agent in combination with paclitaxel followed by fec as induction therapy in her2 negative breast cancer", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160830", "receivedate": "20160830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12699830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "A 58-year-old man with Gleason 4+3 prostate cancer was initially treated by radical prostatectomy followed by salvage radiotherapy to the prostate bed for postoperative biochemical failure. One year later, F-fluorocholine PET/CT detected a pelvic lymph node recurrence, which was treated with radiation therapy and 6 months of androgen deprivation. PSA started to rise again 18 months later, but F-fluciclovine PET/CT failed to demonstrate the site of recurrence at a PSA of 0.63 ng/mL. However, Ga-PSMA PET/CT revealed a single positive 4-mm perirectal lymph node (PSA 0.80 ng/mL at time of scan), in retrospect anatomically apparent but negative on F-fluciclovine PET/CT.", "affiliations": "From the Division of Nuclear Medicine, Department of Radiology, McGill University, Montreal, Quebec, Canada.", "authors": "Chaussé|Guillaume|G|;Abikhzer|Gad|G|;Probst|Stephan|S|", "chemical_list": "D002264:Carboxylic Acids; D003503:Cyclobutanes; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D009842:Oligopeptides; C000718244:gallium 68 PSMA-11; C117460:fluciclovine F-18; D004492:Edetic Acid; D017430:Prostate-Specific Antigen", "country": "United States", "delete": false, "doi": "10.1097/RLU.0000000000002009", "fulltext": null, "fulltext_license": null, "issn_linking": "0363-9762", "issue": "43(4)", "journal": "Clinical nuclear medicine", "keywords": null, "medline_ta": "Clin Nucl Med", "mesh_terms": "D002264:Carboxylic Acids; D003503:Cyclobutanes; D004492:Edetic Acid; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D000072078:Positron Emission Tomography Computed Tomography; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D012008:Recurrence; D016879:Salvage Therapy", "nlm_unique_id": "7611109", "other_id": null, "pages": "250-251", "pmc": null, "pmid": "29465489", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Small Lymph Node Metastasis Detected by 68Ga-Prostate-Specific Membrane Antigen But Not 18F-Fluciclovine PET/CT in Low-Prostate-Specific Antigen Biochemical Recurrence of Prostate Cancer.", "title_normalized": "small lymph node metastasis detected by 68ga prostate specific membrane antigen but not 18f fluciclovine pet ct in low prostate specific antigen biochemical recurrence of prostate cancer" }

[ { "companynumb": "CA-BLUE EARTH DIAGNOSTICS LIMITED-BED-000012-2018", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUCICLOVINE F-18" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MCI, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POSITRON EMISSION TOMOGRAM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "019", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCICLOVINE F?18" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "False negative investigation result", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHAUSSE G ABIKHZER G PROBST S. SMALL LYMPH NODE METASTASIS DETECTED BY 68GA?PROSTATE?SPECIFIC MEMBRANE ANTIGEN BUT NOT 18F?FLUCICLOVINE PET/CT IN LOW?PROSTATE?SPECIFIC ANTIGEN BIOCHEMICAL RECURRENCE OF PROSTATE CANCER. JOURNAL OF NUCLEAR MEDICINE. 2018?43:250?251", "literaturereference_normalized": "small lymph node metastasis detected by 68ga prostate specific membrane antigen but not 18f fluciclovine pet ct in low prostate specific antigen biochemical recurrence of prostate cancer", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20180626", "receivedate": "20180626", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15065118, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]

{ "abstract": "A rare case of double Philadelphia chromosome-positive B Acute lymphoblastic Leukaemia (B-ALL) is reported here. A 60-year-old lady presented with one month history of fever, submandibular lymphadenopathy, loss of appetite and weight loss. Physical examination revealed multiple palpable cervical lymph nodes. Blood film showed leucocytosis with 72% blasts. Bone marrow assessment confirmed a diagnosis of B-ALL with presence of double Philadelphia (Ph) chromosomes. As she was very ill, she was initially treated with an attenuated regimen of induction chemotherapy consisting of rituximab, cyclophosphamide, vincristine and prednisolone (R-CVP) along with intrathecal chemotherapy comprising methotrexate, cytarabine and hydrocortisone. Bone marrow examination post-induction chemotherapy showed >5% blasts. She was subsequently re-induced with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) along with intrathecal chemotherapy, following which she went into complete remission. Consolidation chemotherapy consisting of methotrexate, methylprednisolone, cytarabine, intrathecal chemotherapy and imatinib was subsequently administered followed by maintenance chemotherapy consisting of vincristine, prednisolone and imatinib (IDEAMOP). She developed spontaneous bruises and relapsed four months into her maintenance chemotherapy with 90% blasts in the bone marrow which was treated with fludarabine, cytarabine and granulocyte colony stimulating factor (FLAG). Unfortunately she developed neutropenic sepsis which was complicated by invasive lung aspergillosis. Bone marrow examination post-FLAG showed 80% blasts. Despite aggressive antifungal therapy, her lung infection worsened and she finally succumbed to her illness 13 months after the initial diagnosis. We highlight a rare case of elderly B-ALL with double Ph chromosomes which carries a poor prognosis despite aggressive treatment for the disease and its complications.", "affiliations": "Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Pathology, Jalan Yaacob Latif, Bandar Tun Razak 56000 Cheras, Kuala Lumpur, Malaysia. tangyl@ppukm.ukm.edu.my.", "authors": "Tang|Yee-Loong|YL|;Raja Sabudin|Raja Zahratul Azma|RZ|;Leong|Chooi-Fun|CF|;Ko|Clarence Ching-Huat|CC|;Chia|Wai-Kit|WK|;Salwati|Shuib|S|;Wong|Chieh-Lee|CL|", "chemical_list": null, "country": "Malaysia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0126-8635", "issue": "37(3)", "journal": "The Malaysian journal of pathology", "keywords": null, "medline_ta": "Malays J Pathol", "mesh_terms": "D059786:Abnormal Karyotype; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma", "nlm_unique_id": "8101177", "other_id": null, "pages": "275-9", "pmc": null, "pmid": "26712675", "pubdate": "2015-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Double Philadelphia chromosome-positive B acute lymphoblastic leukaemia in an elderly patient.", "title_normalized": "double philadelphia chromosome positive b acute lymphoblastic leukaemia in an elderly patient" }

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DOUBLE PHILADELPHIA CHROMOSOME-POSITIVE B ACUTE LYMPHOBLASTIC LEUKAEMIA IN AN ELDERLY PATIENT. MALAYS J PATHOL. 2015;37(3):275-9.", "literaturereference_normalized": "double philadelphia chromosome positive b acute lymphoblastic leukaemia in an elderly patient", "qualification": "1", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20160404", "receivedate": "20160404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12235270, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016MY003464", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": 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"drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchopulmonary aspergillosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YEE-LOONG T, SABUDIN RZAR, CHOOI-FUN L, CHING-HUAT CK, WAI-KIT C, SHUIB S ET AL.. DOUBLE PHILADELPHIA CHROMOSOME-POSITIVE B ACUTE LYMPHOBLASTIC LEUKAEMIA IN AN ELDERLY PATIENT. MALAYSIAN JOURNAL OF PATHOLOGY. 2015?37 (3):275-9", "literaturereference_normalized": "double philadelphia chromosome positive b acute lymphoblastic leukaemia in an elderly patient", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20160118", "receivedate": "20160118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11925105, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "BACKGROUND\nDespite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%.\n\n\nMETHODS\nWe conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m(2) twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function.\n\n\nRESULTS\nAmong 25 BL patients, the median age was 44 years (23-70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 μg/ml, respectively, versus 131 and 193 μg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 μg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively.\n\n\nCONCLUSIONS\nThe integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. Clinicaltrials.gov NCT00392990.", "affiliations": "Division of Hematology/Oncology, Tufts Medical Center, Boston.", "authors": "Evens|A M|AM|;Carson|K R|KR|;Kolesar|J|J|;Nabhan|C|C|;Helenowski|I|I|;Islam|N|N|;Jovanovic|B|B|;Barr|P M|PM|;Caimi|P F|PF|;Gregory|S A|SA|;Gordon|L I|LI|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C506643:liposomal doxorubicin; D003561:Cytarabine; D011092:Polyethylene Glycols; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide; D008727:Methotrexate", "country": "England", "delete": false, "doi": "10.1093/annonc/mdt414", "fulltext": null, "fulltext_license": null, "issn_linking": "0923-7534", "issue": "24(12)", "journal": "Annals of oncology : official journal of the European Society for Medical Oncology", "keywords": "burkitt's lymphoma; cancer; liposomal doxorubicin; non-Hodgkin's lymphoma; prognosis; rituximab", "medline_ta": "Ann Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D003520:Cyclophosphamide; D003561:Cytarabine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011092:Polyethylene Glycols; D000069283:Rituximab; D013921:Thrombocytopenia; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult", "nlm_unique_id": "9007735", "other_id": null, "pages": "3076-81", "pmc": null, "pmid": "24146219", "pubdate": "2013-12", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural", "references": "15160953;18612102;9818074;12181251;23446093;12393404;22511498;23802659;8622041;21092025;23641015;12074766;3491184;22098541;21120644;21339382;16502413;8648381", "title": "A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma.", "title_normalized": "a multicenter phase ii study incorporating high dose rituximab and liposomal doxorubicin into the codox m ivac regimen for untreated burkitt s lymphoma" }

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"DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKITT^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperglycaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood sodium abnormal", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ejection fraction decreased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Convulsion", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoalbuminaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood phosphorus decreased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood magnesium decreased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", CARSON K, KOLESAR J, NABHAN C, HELENOWSKI I, ISLAM N, JOVANOVIC B, BAN P, CAIM P, GREGORY S AND GORDON G. A MULTICENTER PHASE II STUDY INCORPORATING HIGH-DOSE RITUXIMAB AND LIPOSOMAL DOXORUBICIN INTO THE CODOX-M/IVAC REGIMEN FOR UNTREATED BURKITT^S LYMPHOMA... ANNALS OF ONCOLOGY 2014 JUL 01;25(7):1449-.", "literaturereference_normalized": "a multicenter phase ii study incorporating high dose rituximab and liposomal doxorubicin into the codox m ivac regimen for untreated burkitt s lymphoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20140721", "receivedate": "20111220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 8302621, "safetyreportversion": 7, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "OBJECTIVE\nTo examine the efficacy and safety profile of antiepileptic repetitive transcranial magnetic stimulation (rTMS) for refractory status epilepticus (RSE) in the intensive care unit (ICU) setting. In addition, hypothetical concerns about electrical interference of rTMS with ICU equipment have been previously raised.\n\n\nMETHODS\nWe describe two cases of RSE treated with rTMS in the ICU.\n\n\nRESULTS\nIn one case, rTMS contributed to decreased seizure frequency; in the second case, rTMS transiently decreased seizure frequency. In both cases, rTMS was safe and did not interfere with the functioning of the ICU equipment.\n\n\nCONCLUSIONS\nrTMS is a potential therapy for RSE when conventional therapies have failed. Future studies should investigate the efficacy of various rTMS stimulation parameters, safety issues, and bioengineering considerations in the ICU setting.", "affiliations": "New York University Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA; New York University Langone Medical Center and School of Medicine, 550 First Avenue, New York, NY 10016 USA. Electronic address: anli.liu@nyumc.org.", "authors": "Liu|Anli|A|;Pang|Trudy|T|;Herman|Susan|S|;Pascual-Leone|Alvaro|A|;Rotenberg|Alexander|A|", "chemical_list": "D000927:Anticonvulsants", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1059-1311", "issue": "22(10)", "journal": "Seizure", "keywords": "Epilepsia partialis continua; Intensive care unit; Refractory status epilepticus; Transcranial magnetic stimulation", "medline_ta": "Seizure", "mesh_terms": "D000927:Anticonvulsants; D004569:Electroencephalography; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D013226:Status Epilepticus; D050781:Transcranial Magnetic Stimulation; D016896:Treatment Outcome", "nlm_unique_id": "9306979", "other_id": null, "pages": "893-6", "pmc": null, "pmid": "23876929", "pubdate": "2013-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "21914716;11528315;7922470;11843690;11897538;22981238;17068786;17493877;18832045;8450988;15016013;15946689", "title": "Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit.", "title_normalized": "transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit" }

[ { "companynumb": "US-ROCHE-1315756", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017533", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU A, PANG T, HERMAN S, PASCUAL-LEONE A, AND ROTENBERG A. TRANSCRANIAL MAGNETIC STIMULATION FOR REFRACTORY FOCAL STATUS EPILEPTICUS IN THE INTENSIVE CARE UNIT. SEIZURE 2013 DEC 01;22 (10):893-896.", "literaturereference_normalized": "transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170609", "receivedate": "20170609", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13639484, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "US-APOTEX-2015AP007605", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREGABALIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREGABALIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TITRATED TO HIGH THERAPEUTIC LEVEL", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSPHENYTOIN\\FOSPHENYTOIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSPHENYTOIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "075637", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.1 MG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM HYDROCHLORIDE INJECTION" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU A, PANG T, HERMAN S, PASCUAL-LEONE A, ROTENBERG A.. 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{ "abstract": "Atypical mycobacterioses are unusual infections of the skin and other organs caused by non-tuberculous mycobacteria. Fish tank granuloma and swimming pool granuloma are two forms of atypical mycobacterioses caused by Mycobacterium marinum. So far, only a few cases of these infections have been reported in organ transplant patients, and these usually are more severe when compared with atypical mycobacterioses in immunocompetent hosts. We report a kidney transplant patient with a rather mild form of atypical mycobacteriosis (fish tank granuloma) who responded well to treatment with doxycycline and will provide a review of all similar cases reported in the literature.", "affiliations": "Dermatology, Edouard Herriot Hospital, Lyon, FRA.;Dermatology, Edouard Herriot Hospital, Lyon, FRA.;Dermatology, Edouard Herriot Hospital, Lyon, FRA.", "authors": "Assiri|Ahmad|A|;Euvrard|Sylvie|S|;Kanitakis|Jean|J|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.6013", "fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.6013DermatologyNephrologyInfectious DiseaseCutaneous Mycobacterium Marinum Infection (Fish Tank Granuloma) in a Renal Transplant Recipient: Case Report and Literature Review Muacevic Alexander Adler John R Assiri Ahmad 1Euvrard Sylvie 1Kanitakis Jean 1\n1 \nDermatology, Edouard Herriot Hospital, Lyon, FRA \nJean Kanitakis jean.kanitakis@univ-lyon1.fr28 10 2019 10 2019 11 10 e601325 9 2019 28 10 2019 Copyright © 2019, Assiri et al.2019Assiri et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/23604-cutaneous-mycobacterium-marinum-infection-fish-tank-granuloma-in-a-renal-transplant-recipient-case-report-and-literature-reviewAtypical mycobacterioses are unusual infections of the skin and other organs caused by non-tuberculous mycobacteria. Fish tank granuloma and swimming pool granuloma are two forms of atypical mycobacterioses caused by Mycobacterium marinum. So far, only a few cases of these infections have been reported in organ transplant patients, and these usually are more severe when compared with atypical mycobacterioses in immunocompetent hosts. We report a kidney transplant patient with a rather mild form of atypical mycobacteriosis (fish tank granuloma) who responded well to treatment with doxycycline and will provide a review of all similar cases reported in the literature.\n\natypical mycobacteriosesmycobacterium marinumorgan transplantationimmunosuppressionskin infectiondoxycyclineThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nOrgan transplant recipients (OTRs) are at increased risk to develop infectious diseases because of the immunosuppressive treatment administered to prevent graft rejection. Atypical mycobacteriosis (AM) is a rare infection due to the non-tuberculous mycobacteria species. One of them, Mycobacterium marinum (M. marinum), is the cause of two clinical forms of AM, namely, fish tank (or aquarium) granuloma and swimming pool granuloma [1-2]. AM has rarely been reported in OTRs. We report here a renal transplant recipient who developed fish tank granuloma and briefly review the salient features of AM due to M. marinum in this group of patients.\n\nCase presentation\nA 72-year-old Caucasian male received a renal allograft at the age of 62 years because of liver-kidney polycystic disease and was thereafter treated with cyclosporin (200 mg/d), steroids (5 mg/d), and mycophenolic acid (720 mg/d). His post-transplant course was complicated by cutaneous warts, multiple actinic keratoses on sun-exposed areas, a squamous cell carcinoma on each ear, and porokeratosis of the shin. Nine years post-graft, he developed a rapidly-growing cutaneous lesion over the right index finger, for which his family physician prescribed an antibiotic treatment (amoxicillin/clavulanic acid, 3 g/d, and local fusidic acid ointment). However, this treatment proved ineffective; therefore, the patient was referred to our specialized outpatient clinic devoted to the care of cutaneous complications in OTR.\n\nOn admission, physical examination revealed an asymptomatic erythematous, scaly nodule over the proximal interphalangeal joint of the right index finger (Figure 1A). Detailed history revealed a minor trauma (cut) suffered by the patient while cleaning his fish tank one week prior to the disease onset. This fact was highly suggestive of the diagnosis of fish tank granuloma. Therefore, a biopsy was taken from the lesion under local anesthesia for histologic and bacteriologic examination.\n\nFigure 1 Asymptomatic erythematous, scaly nodule over the proximal interphalangeal joint of the right index finger\nA) An erythematous, scaly nodule over the right index finger; B) Almost complete regression of the lesion after a two-month treatment with doxycycline.\n\nMicroscopic examination of the skin biopsy showed a hyperplastic epidermis and a dense polymorphous dermal infiltrate made of lymphocytes, macrophages, neutrophils, and multinucleated giant cells, occasionally surrounding pre-necrotic foci in the mid-dermis (Figure 2A-C).\n\nFigure 2 Microscopic examination of the skin biopsy\nA) Histological examination of the lesion shows a hyperplastic epidermis and a dense cell infiltrate in the dermis; B-C) On higher magnification, the infiltrate consists of lymphocytes, macrophages, neutrophils, and multinucleated giant cells. The dermis contains granular, basophilic, pre-necrotic areas.\n\nMicroscopic examination at high magnification of tissue sections stained with periodic acid-Schiff (PAS) and Ziehl stains did not reveal microorganisms. The culture of the biopsy specimen was negative; however, polymerase chain reaction (PCR) (post-amplification sequencing of the heat-shock protein 65 gene (hsp65)) revealed an amplicon characteristic of M. marinum (or ulcerans), thereby confirming the diagnosis of fish tank granuloma. Before the results of the bacteriological examination were available, the patient was prescribed minocycline, 200 mg/d. Almost complete regression of the lesion was noted after one month (Figure 1B). After a second month on minocycline, the patient was switched to doxycycline (200 mg/d), which he received for an additional three months. The treatment resulted in complete regression of the lesion, although the patient reported some stiffness and a decrease of skin sensitivity of his index finger. The immunosuppressive treatment of the patient was reduced (cyclosporin dosage was lowered to 125 mg/d); however, this was followed by a slight decrease in his renal function.\n\nDiscussion\nFish tank granuloma is a clinical form of AM due to M. marinum. This microorganism was first isolated from carcasses of saltwater fishes in the aquarium of Philadelphia in 1926 [3]. Its role in tuberculosis of freshwater (platy) fishes was recognized in 1942 and the microorganism was named M. platypoecilus [4]. In 1951, the first observations of human infection (swimming pool granuloma) were reported in swimmers in contaminated pools in Sweden, and the responsible agent was named M. balnei [5]. It was later recognized that M. balnei and M. platypoecilus were identical, and they were renamed M. marinum [6].\n\nM. marinum is a slow-growing, non-tuberculous mycobacterium belonging to the Runyon group I, requiring seven to 10 days to grow when cultured at 30° - 33°C [2, 6]. It has a worldwide distribution but is mainly found in temperate climates in stagnating water (such as swimming pools and fish tanks but also in ponds, rivers, beaches, mud, and the sea). The hosts include saltwater or freshwater fishes, snails, dolphins, and shellfishes.\n\nM. marinum is pathogenic in traumatized, abraded skin, although a history of trauma is not always recorded by the patients. Infection occurs in contaminated swimming pools, by handling infected fish, or following (minor) trauma in an aquarium, even though this may pass unnoticed. The usual incubation period is two to six weeks but may take as long as nine months [7].\n\nCutaneous infections due to M. marinum have been mainly reported in immunocompetent hosts [8-9] but have been also rarely reported in OTR. Our literature review revealed 11 such cases (including the one presented here); they included five patients with renal, two with combined pancreas and kidney, two with lung, one with liver, and one with hematopoietic stem-cell transplantation [10-19] (Table 1).\n\nIn these transplantation-associated cases, there was no gender predilection (6 women/5 men). The mean age of patients was 50 years (range: 30 - 72), and the mean delay of disease onset after the (latest) transplantation procedure was 2.9 years (range: 5 months - 9 years). A history of exposure to fish or fish tank water was mentioned in nine cases.\n\nTable 1 Cases of Mycobacterium marinum Skin Infections in Organ Transplant Recipients (OTR)\nAza: azathioprine; Az: azithromycin; bid: twice a day; Cip: ciprofloxacin; Clar: clarithromycin; CyA: cyclosporin; Dxc: doxycycline; Eth: ethambutol, F: female; INH: isoniazid; IVIg: intravenous immunoglobulins; K: kidney; L: left; Lu: lung; Li: liver; M: male; Mi: minocycline; MMF: mycophenolate mofetil; Mox: moxifloxacin; OD: once a day; P: pancreas; Post-tx: post-treatment; Pred: prednisone; R: right; Rif: rifampicin; Tac: tacrolimus; Tmp-Smx: trimethoprim-sulfamethoxazole; tx: transplantation\n\nCase/ Ref #\tAge/ Gender\tOrgan Transplant /Treatment\tTransmission\tDisease onset post-tx (delay)\tClinical appearance\tTreatment\tOutcome\t\n1 [10]\t30/M\tK/Aza, Pred\tfish tank\t3 years\tLinear, tender, ulcerated nodules on extremities\tEth, 1 g/day, + Rif, 600 mg/day - recurrence after Rif was stopped, retreated with Eth +Tmp-Smx\tnot reported\t\n2 [11]\t52/F\tK/CyA, Aza\tfish tank\t1.5 years\tSporotrichoid nodules on the lateral aspect of R fifth finger, hand, forearm, and arm\tDoxy, 400 mg/day, but progressed, then Rif, 600 mg/day, + Eth, 800 mg/day for 3 months\tcure\t\n3 [12]\t48/M\tK/CyA, MMF, Pred\tfishing, swimming\t1 year\tLinear, tender, ulcerated, 1 - 2 cm nodules on L forearm\tEth, 1.2 g/day, + Cip, 750 mg bid for 6 months, recurrence treated with 3 additional months of Emb + Cip\tcure\t\n4 [16]\t52/F\tLu/CyA, Aza, Pred\tfish tank\t2.5 years\tTender, firm, < 1.5 cm nodules on R hand and forearm\tEth, 800 mg/day, + Az, 500 mg/day, + Minoc, 100 mg bid for 6 months: surgical excision of lesions because of tissue irritation\tcure\t\n5 [15]\t45/F\tP-K/CyA, Aza\tunknown\t8 years\tUlcerated, tender 3 cm nodules on arms and L foot\tEth, Rif, INH, addition of protionamide total treatment  4 months\tcure (died of cerebral hemorrhage)\t\n6 [14]\t37/M\tK-P/Tac, MMF, Pred\tfish tank\t1.5 years\tErythematous, tender, ulcerated nodules in ascending pattern on L forearm\tClar, 500 mg bid, + Rif, 300 mg/day\timproved at 4 months of ongoing therapy\t\n7 [13]\t50/F\tK/Tac, MMF, Pred\tunknown \t3 months after latest (3rd) tx  \tSporotrichoid, ulcerated painful nodules on L arm\tTriple tuberculostatic therapy for 3 months\tLesions subsided \t\n8 [18]\t50/F\tLi/Tac, MMF, Pred \tcontact with marine fish (fishing)\t2.5 years  \tMultiple painless ulcerated nodules on the nose spreading to face, upper limbs, and R leg \tRif, 300 mg OD, Eth, 800 mg every 3 days, and Mox, 400 mg OD, for 1 year\tCure\t\n9 [19]\t63/M\tStem cell/ cytarabine, idarubicin, busulfan, melphalan, fludarabine, anti-thymocyte globulin\tfish tank\t5 months  \tDiffuse sporotrichoid nodules on upper and lower limbs, scrotum, forehead – multiorgan involvement\tClar, Rif, tigecycline, switched to Clar, Rif, and Eth for one year\tImproved at 6 months of ongoing therapy\t\n10 [17]\t52/F\tLu/Tac, Pred, MMF IVIg, rituximab for rejection 3 months post-tx\tfish tank\t2.5 years\tErythematous, tender nodules of distal extensor of forearm, 2 proximal subcutaneous nodules in sporotrichoid distribution \tClar, 500 mg bid, + Eth, 900 mg OD\tImproved at 6 months of treatment\t\n 11 (this case)\t72/M\tK/CyA, Pred, MMF\tfish tank\t9 years\tSingle painless nodule on the R index finger   \tDxc, 200 mg bid\tCure after one month\t\nClinically, cutaneous M. marinum infection manifests with nodules or pustules that may progress to ulcers, abscesses, or warty plaques [1, 8-9]. It may spread proximally along the lymphatic vessels in a sporotrichoid pattern, mimicking sporotrichosis [13-14]. The lesions predominate on the extremities since the growth of the microorganism is inhibited at 37°C. Swimming pool granuloma develops on trauma-prone body zones, such as the elbows, knees, feet, and tip of the nose, whereas fish tank granuloma predominates on the dominant hand (as in our patient). Locoregional lymphadenopathy is usually absent. The infection may extend to deeper tissues, causing tenosynovitis, osteomyelitis, septic arthritis, and may even disseminate to internal organs, especially in immunocompromised patients [1, 20].\n\nOTR with AM presented with multiple, occasionally painful, nodular or pustular lesions with a tendency to ulcerate and to extend locally in an ascending sporotrichoid pattern (Table 1). The lesions affected the upper extremities (75% of cases) and less often in the lower limbs (four cases, i.e., 36%), possibly as a result of disease dissemination [10, 15, 18-19].\n\nA documented systemic dissemination was reported in a patient with hematopoietic stem cell transplantation for acute myeloid leukemia followed by two courses of aggressive chemotherapy [19]. Apart from cutaneous lesions (which predominated on the lower limbs), the patient also had intramuscular and intraosseous involvement (shown on MRI) and hypermetabolic lesions seen on positron emission tomography (PET) scan in the brain, lung, scalp, face, nasal cavity, scrotum, and testis. Despite the widespread disease, the lesions improved after six months of treatment, given for one year. \n\nThree patients had multiple skin lesions over several body sites, possibly as a result of systemic dissemination (rather than to multiple sites of inoculation) [10, 15, 18]. Our patient differed from these cases as he had a mild disease (limited to a single asymptomatic nodule) which developed rather late (nine years) after transplantation.\n\nThe diagnosis of AM can be suspected by history (contact with fishes or with a fish tank, swimming in contaminated swimming pools) and is confirmed by isolation of the responsible microorganism from the lesions. This can be achieved with cultures, which are positive in 70% - 80% of cases, and also allows for an antibiogram to be performed [1]. Histologically, the lesions are characterized by a non-caseating granulomatous skin infiltrate. Mycobacterial microorganisms are seldom found, even after specific (Ziehl) histochemical stains, as in our case. Of note, a monoclonal antibody to M. marinum, detecting an antigen of 56-kDa, is available for immunohistochemical use on tissue sections. PCR with specific primers appears as the most sensitive and specific diagnostic method [9] and allowed diagnostic confirmation in the case of our patient.\n\nThe treatment of cutaneous infections due to M. marinum is not standardized and depends on several factors, including mainly the severity of the infection and the immune status of the patient. In immunocompetent patients, the lesions are often superficial and may regress spontaneously or after antibiotic monotherapy [2]. In immunocompromised hosts, such as OTR, the infection is usually more severe; therefore, treatment with at least two antibiotics is advised so as to avoid the development of resistance. Clarithromycin and trimethoprim-sulfamethoxazole are both efficacious and safe. Cyclins (minocycline, doxycycline) are also effective at a dose of 200 mg/d. Cyclins may be combined with rifampicin or ethambutol in severe cases or in the setting of immunosuppression [2, 8-9]. Clarithromycin and rifampicin, clarithromycin and ethambutol, or ethambutol and rifampicin in combination have also been used with good results in such cases [20]. On average, the duration of the treatment is three months or six weeks after clinical healing [2], but a much longer treatment duration (up to 12 months) may be necessary in case of a deep extension or dissemination [2, 18-19]. In OTR, M. marinum infections were treated with at least two antibiotics with rare exceptions (such as our patient, who had mild disease). In another OTR treated with doxycycline as monotherapy, progression was noted, prompting a switch to rifampicin and ethambutol [13]. Ethambutol was the most common antibiotic used in OTR (nine cases), followed by rifampicin (seven cases), and clarithromycin (three cases). The most commonly used drug combination was ethambutol and rifampicin (five patients), including all four cases of disseminated infection. Other antimicrobials used included azithromycin, ciprofloxacin, moxifloxacin, isoniazid, protionamide, and trimethoprim-sulfamethoxazole (Table 1). In addition to antimicrobial treatment, deep lesions may be surgically excised. Prevention of an AM infection includes the use of gloves when cleaning fish tanks, rapid disinfection of wounds, and adequate chlorination of swimming pools. \n\nConclusions\nAtypical mycobacterioses of the skin are unusual infections, even in organ transplant recipients in whom they usually manifest with more severe signs compared with immunocompetent patients. In that respect, the case of our renal transplant patient with fish tank granuloma due to Mycobacterium marinum was unusual as the disease was mild and could be treated effectively with doxycycline as monotherapy. The diagnosis of AM is not straightforward, but a detailed history (namely, concerning occupation, hobbies, and activities) helps to identify such cases.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Aquarium-borne Mycobacterium marinum skin infection. Report of 15 cases and review of the literature Eur J Dermatol Bonamonte D De Vito D Vestita M Delvecchio S Ranieri LD Santantonio M Angelini G 510 516 23 2013 24002023 \n2 Treatment of Mycobacterium marinum cutaneous infections Expert Opin Pharmacother Rallis E Koumantaki-Mathioudaki E 2965 2978 8 2007 18001256 \n3 Spontaneous tuberculosis in salt water fish J Infect Dis Aronson D 315 320 39 1926 https://www.jstor.org/stable/30083276 \n4 Tuberculosis of the Mexican platyfish (Platypoecilus maculatus) J Infect Dis Baker A Hagan WA 248 252 70 1942 https://www.jstor.org/stable/30089670 \n5 Swimming pool injuries, mycobacteria, and tuberculosis-like disease Public Health Rep Greenberg AE  Kupka E 902 904 72 1957 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2031358/ 13465956 \n6 Mycobacterium marinum Clin Dermatol Gluckman SJ 273 276 13 1995 8521369 \n7 Incubation period and sources of exposure for cutaneous Mycobacterium marinum infection: case report and review of the literature Clin Infect Dis Jernigan J Farr B 439 443 31 2000 10987702 \n8 Mycobacterium marinum infections in Denmark from 2004 to 2017: a retrospective study of incidence, patient characteristics, treatment regimens and outcome Sci Rep Holden IK Kehrer M Andersen AB Wejse C Svensson E Johansen IS 6738 8 2018 29712930 \n9 Nontuberculous mycobacterial infections of the skin: a retrospective study of 25 cases J Am Acad Dermatol Dodiuk-Gad R Dyachenko P Ziv M 413 420 57 2007 17368631 \n10 Disseminated Mycobacterium marinum infection after renal transplantation Ann Intern Med Gombert ME Goldstein EJ Corrado ML Stein AJ Butt KM 486 487 94 1981 7011140 \n11 Sporotrichoid form of M. marinum infection in a patient treated with cyclosporin following kidney transplantation (Article in French) Ann Dermatol Venereol Dompmartin A Lorier E de Raucourt S Vergnaud M Ryckelynck JP Hurault de Ligny B Leroy D 377 379 118 1991 https://www.ncbi.nlm.nih.gov/pubmed/1897820 1897820 \n12 Mycobacterium marinum infection in a renal transplant recipient Transplantation Farooqui MA Berenson C Lohr JW 1495 1496 67 1999 10385095 \n13 Fish, flesh and a good red herring: a case of ascending upper limb infection in a renal transplant patient. Clin Nephrol Lovric S Becker JU Kayser D Wagner A Haubitz M Kielstein JT 402 404 72 2009 \n14 Mycobacterium marinum infections in transplant recipients: case report and review of the literature Transpl Infect Dis Pandian TK Deziel PJ Otley C Eid AJ Razonable RR 358 336 10 2008 18482202 \n15 Skin tuberculosis with atypical mycobacteria 8 years after combined pancreas and kidney transplantation Am J Nephrol Schmekal B Janko O Zazgornik J Schinko H Bogner S Syre G Biesenbach G 566 568 22 2002 12381960 \n16 Mycobacterium marinum infection in a lung transplant recipient J Heart Lung Transplant Torres F Hodges T Zamora MR 486 489 20 2001 11295588 \n17 Sporotrichoid Mycobacterium marinum infection after lung transplantation for alpha-1 antitrypsin deficiency J Surg Transplant Sci Javvaji SR Javvaji S Grossman ME 1013 3 2015 http://jscimedcentral.com/Surgery/surgery-3-1013.pdf \n18 First report of disseminated mycobacterium skin infections in two liver transplant recipients and rapid diagnosis by hsp65 gene sequencing J Clin Microbiol Lau SK Gurrem SO Ngan AH Yeung CK Yuen KY Woo PC 3733 3738 49 2011 21880973 \n19 Disseminated Mycobacterium marinum infection in hematopoietic stem cell transplant recipient Transplant Infect Dis Jacobs S George A Papanicolaou GA Lacouture ME Tan BH Jakubowski AA Kaltsas A 410 414 14 2012 \n20 Osteomyelitis Infection of Mycobacterium marinum: A Case Report and Literature Review Case Rep Infect Dis Nguyen HH Fadul N Ashraf MS Siraj DS 905920 2015 2015 25664190\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "11(10)", "journal": "Cureus", "keywords": "atypical mycobacterioses; doxycycline; immunosuppression; mycobacterium marinum; organ transplantation; skin infection", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e6013", "pmc": null, "pmid": "31815077", "pubdate": "2019-10-28", "publication_types": "D002363:Case Reports", "references": "10385095;8521369;24002023;21880973;11295588;18001256;29712930;7011140;10987702;1897820;25664190;18482202;19863885;12381960;17368631;13465956;22093773", "title": "Cutaneous Mycobacterium Marinum Infection (Fish Tank Granuloma) in a Renal Transplant Recipient: Case Report and Literature Review.", "title_normalized": "cutaneous mycobacterium marinum infection fish tank granuloma in a renal transplant recipient case report and literature review" }

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{ "abstract": "BACKGROUND\nTo evaluate the anatomical outcome of patients after vitrectomy due to persisting symptomatic vitreomacular traction (VMT), including full-thickness macular holes (FTMHs) of less than 400 µm, after ocriplasmin treatment.\n\n\nMETHODS\nRetrospective, single centre, consecutive interventional case series. Patients were treated with a single intravitreal injection of ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU).\n\n\nMETHODS\nresolution of VMT, closure of FTMH and anatomical outcome of vitrectomy after unsuccessful treatment with ocriplasmin.\n\n\nRESULTS\nFive patients were treated with ocriplasmin injection. VMT persisted in all but one case. Four patients underwent pars-plana vitrectomy (PPV) for treatment of persistent VMT and FTMH (n=2, size of macular hole <400 µm) in spectral-domain optical coherence tomography (SD-OCT). FTMHs were closed in both cases within the first week postoperatively. After PPV, in three eyes newly developed subretinal fluid was detected, which persisted up to several months postoperatively.\n\n\nCONCLUSIONS\nData on ocriplasmin remain controversial. We report on four cases with resolution of VMT following PPV after unsuccessful ocriplasmin treatment. Newly developed subretinal fluid has been described after ocriplasmin treatment, predominantly in cases with resolution of VMT. We also detected this newly developed subretinal fluid after vitrectomy, which persisted for several weeks up to 7 months in two cases with FTMHs. This may be attributable to loosening of the photoreceptor complex due to enzyme activity of ocriplasmin. Long-term effects of ocriplasmin are still to be evaluated using SD-OCT.", "affiliations": "Department of Ophthalmology, Charite -Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.;Department of Ophthalmology, Charite -Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.;Department of Ophthalmology, Charite -Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.;Department of Ophthalmology, Charite -Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.;Department of Ophthalmology, Charite -Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.", "authors": "Hager|A|A|;Seibel|I|I|;Riechardt|A|A|;Rehak|M|M|;Joussen|A M|AM|", "chemical_list": "D005343:Fibrinolytic Agents; D010446:Peptide Fragments; C054561:microplasmin; D005341:Fibrinolysin", "country": "England", "delete": false, "doi": "10.1136/bjophthalmol-2014-305620", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1161", "issue": "99(5)", "journal": "The British journal of ophthalmology", "keywords": "Macula; Retina; Vitreous", "medline_ta": "Br J Ophthalmol", "mesh_terms": "D000368:Aged; D001485:Basement Membrane; D058450:Endotamponade; D005260:Female; D005341:Fibrinolysin; D005343:Fibrinolytic Agents; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments; D020419:Photoreceptor Cells, Vertebrate; D012167:Retinal Perforations; D055213:Retinal Pigment Epithelium; D012189:Retrospective Studies; D058471:Subretinal Fluid; D000267:Tissue Adhesions; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D014821:Vitrectomy; D020255:Vitreous Detachment", "nlm_unique_id": "0421041", "other_id": null, "pages": "635-8", "pmc": null, "pmid": "25403647", "pubdate": "2015-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Does ocriplasmin affect the RPE-photoreceptor adhesion in macular holes?", "title_normalized": "does ocriplasmin affect the rpe photoreceptor adhesion in macular holes" }

[ { "companynumb": "DE-THROMBOGENICS NV-SPO-2014-1455", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OCRIPLASMIN" }, "drugadditional": null, "drugadministrationroute": "031", "drugauthorizationnumb": "125422", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "0.125 MG, ONE TIME DOSE", "drugenddate": "20130828", "drugenddateformat": "102", "drugindication": "VITREOUS ADHESIONS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130828", "drugstartdateformat": "102", "drugstructuredosagenumb": ".125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "JETREA" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cystoid macular oedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "A HAGER, I SEIBEL, A REICHARDT, M REHAK AND A M JOUSSEN. DOES OCRIPLASMIN AFFECT THE RPE-PHOTORECEPTOR ADHESION IN MACULAR HOLES?. BR J OPHTALMOL. 2014;0:4", "literaturereference_normalized": "does ocriplasmin affect the rpe photoreceptor adhesion in macular holes", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20141202", "receivedate": "20141202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10620524, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "Atypical antipsychotics are efficacious for chemoprophylaxis against chemotherapy-induced nausea and vomiting, but perioperative investigations have been scant. We sought to examine the association between chronic atypical antipsychotic therapy and the likelihood of postoperative nausea and vomiting.\n\n\n\nIn this single-center, propensity-matched, retrospective, observational study, elective noncardiac surgical cases from January 2014 to December 2017 were examined with regard to the primary outcome of rescue antiemetic administration in the postanesthesia care unit as a measure of postoperative nausea and vomiting. Chronic administration of olanzapine, aripiprazole, and risperidone was the exposure of interest. Other independent variables included outpatient antiemetics, modified Apfel score, age, American Society of Anesthesiologists physical status score, case length, and exposures to emetogenic and chemoprophylactic agents. Logistic regression was performed using case-level data. Conditional logistic regression was performed after 1:2 propensity matching, sampling without replacement. Monte Carlo simulation was performed to compute the mean patient-level treatment effect on the treated.\n\n\n\nOf 13,660 cases, 154 cases with patients receiving atypical antipsychotics were matched against 308 cases without, representing 115 and 273 unique patients, respectively. In a well-balanced cohort, the mean patient-level odds of being administered rescue antiemetic was lower for patients chronically taking the 3 atypical antipsychotics under consideration as compared to those not on atypical antipsychotics, with an odds ratio of 0.29 (95% CI, 0.11-0.75; P = .015).\n\n\n\nChronic atypical antipsychotic therapy is associated with reduced risk of postanesthesia care unit antiemetic administration. These findings support the need for prospective studies to establish the safety and efficacy of postoperative nausea and vomiting chemoprophylaxis with these agents.", "affiliations": "From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia.;From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia.;From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia.;From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia.;Department of Information Systems and Operations Management, Emory University Goizueta Business School, Atlanta, Georgia.;Department of Information Systems and Operations Management, Emory University Goizueta Business School, Atlanta, Georgia.;From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia.", "authors": "Jabaley|Craig S|CS|;Gray|Dennis W|DW|;Budhrani|Gaurav S|GS|;Lynde|Grant C|GC|;Adamopoulos|Panagiotis|P|;Easton|George S|GS|;O'Reilly-Shah|Vikas N|VN|", "chemical_list": "D000932:Antiemetics; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D018967:Risperidone; D000077152:Olanzapine", "country": "United States", "delete": false, "doi": "10.1213/ANE.0000000000003990", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-2999", "issue": "130(1)", "journal": "Anesthesia and analgesia", "keywords": null, "medline_ta": "Anesth Analg", "mesh_terms": "D000328:Adult; D000368:Aged; D000762:Anesthesia Recovery Period; D000932:Antiemetics; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D020250:Postoperative Nausea and Vomiting; D057216:Propensity Score; D065840:Protective Factors; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D018967:Risperidone; D013997:Time Factors", "nlm_unique_id": "1310650", "other_id": null, "pages": "141-150", "pmc": null, "pmid": "30585903", "pubdate": "2020-01", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Chronic Atypical Antipsychotic Use Is Associated With Reduced Need for Postoperative Nausea and Vomiting Rescue in the Postanesthesia Care Unit: A Propensity-Matched Retrospective Observational Study.", "title_normalized": "chronic atypical antipsychotic use is associated with reduced need for postoperative nausea and vomiting rescue in the postanesthesia care unit a propensity matched retrospective observational study" }

[ { "companynumb": "GE-OTSUKA-2019_043220", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABILIFY" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Jabaley CS, Gray DW, Budhrani GS, Lynde GC, Adamopoulos P, Easton GS et al.. Chronic Atypical Antipsychotic Use Is Associated With Reduced Need for Postoperative Nausea and Vomiting Rescue in the Postanesthesia Care Unit: A Propensity-Matched Retrospective Observational Study. Anesthesia and analgesia. 2020;130(1):141-50", "literaturereference_normalized": "chronic atypical antipsychotic use is associated with reduced need for postoperative nausea and vomiting rescue in the postanesthesia care unit a propensity matched retrospective observational study", "qualification": "1", "reportercountry": "GE" }, "primarysourcecountry": "GE", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19916389, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "A 56-year-old Caucasian woman presented with epigastric pain, watery diarrhoea, bloating and flatulence following treatment with duloxetine and venlafaxine for anxiety and depression. Abdominal examination was benign. Blood work revealed haemoglobin of 96 g/L (115-160 g/L), iron 6 μmol/L (10-33 μmol/L), transferrin saturation 0.08 (0.20-0.55), ferritin 26 μg/L (15-180 μg/L), albumin 46 g/L (35-50 g/L), pre-albumin 293 mg/L (170-370 mg/L), total IgA 2.64 g/L (0.78-3.58 g/L) and anti-tTG IgA 5 units (<20 units). Faecal occult blood tests were 3/3 positive and stool cultures were negative. CT enterography was normal. Colonic biopsy revealed collagenous colitis, while duodenal biopsy showed collagenous sprue with blunted to completely flattened villi and markedly thickened subepithelial collagen table entrapping capillaries and lymphocytes. The patient started a gluten-free diet, loperamide and ferrous gluconate. Her symptoms resolved and a faecal immunochemical test performed 6 months later was negative.", "affiliations": "St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.;St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.;St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.", "authors": "Yau|Alan Hoi Lun|AH|;Xiong|Wei|W|;Ko|Hin Hin|HH|", "chemical_list": "D003094:Collagen", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D018798:Anemia, Iron-Deficiency; D001706:Biopsy; D046729:Colitis, Collagenous; D003094:Collagen; D064068:Collagenous Sprue; D003106:Colon; D003967:Diarrhea; D055050:Diet, Gluten-Free; D004386:Duodenum; D004760:Enterocolitis; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa; D008875:Middle Aged", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26347238", "pubdate": "2015-09-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23368698;16979955;3775341;5478450;19855376;21523258;10360997;19641452;21716082;23402093;25056300;6548902;18502544;10666840", "title": "Collagenous enterocolitis manifesting as watery diarrhoea and iron-deficiency anaemia.", "title_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia" }

[ { "companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-106237", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090745", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MF", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090745", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis microscopic", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coeliac disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iron deficiency anaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAU AHL, XIONG W, KO HH. COLLAGENOUS ENTEROCOLITIS MANIFESTING AS WATERY DIARRHOEA AND IRON-DEFICIENCY ANAEMIA. 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COLLAGENOUS ENTEROCOLITIS MANIFESTING AS WATERY DIARRHOEA AND IRON-DEFICIENCY ANAEMIA. BMJ CASE REPORTS. 2015?1-3.", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151113", "receivedate": "20151113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11734528, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "CA-PFIZER INC-PV202200000910", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "20699", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HCL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anxiety disorder", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malabsorption", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Colitis microscopic", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocytic oesophagitis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Gastritis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Intestinal intraepithelial lymphocytes increased", "reactionmeddraversionpt": "25.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "Yau, A.. Collagenous enterocolitis manifesting as watery diarrhoea and iron-deficiency anaemia. BMJ Case Reports. 2015;10.1136/bcr-2015-211200", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20220624", "receivedate": "20220624", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 21005626, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CA-MACLEODS PHARMACEUTICALS US LTD-MAC2022036138", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, QD(DOSE REDUCTION)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "204889", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enterocolitis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Yau AH, Xiong W, Ko HH. Collagenous enterocolitis manifesting as watery diarrhoea and iron-deficiency anaemia. BMJ case reports", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20220617", "receivedate": "20220617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20975882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CA-HERITAGE PHARMACEUTICALS-2015HTG00065", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HYDROCHLORIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Iron deficiency anaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Colitis microscopic", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malabsorption", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAU AHL, XIONG W, KO HH. COLLAGENOUS ENTEROCOLITIS MANIFESTING AS WATERY DIARRHOEA AND IRON-DEFICIENCY ANAEMIA. BMJ CASE REPORTS (DOI:10.1136/BCR-2015-211200). 2015?ARTICLE NUMBER 211200", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151130", "receivedate": "20151130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11786315, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "CA-ATLANTIDE PHARMACEUTICALS AG-2022ATL000050", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "078865", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anxiety", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "078865", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anxiety", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis microscopic", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iron deficiency anaemia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malabsorption", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Yau AH, Xiong W, Ko HH. Collagenous enterocolitis manifesting as watery diarrhoea and iron-deficiency anaemia. BMJ Case Rep. 2015", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20220617", "receivedate": "20220617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20973275, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "CA-ALEMBIC PHARMACUETICALS LIMITED-2015SCAL000981", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE DR CAPSULE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "078932", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HYDROCHLORIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE DR CAPSULE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enterocolitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAU AHL, XIONG W, KO HH.. COLLAGENOUS ENTEROCOLITIS MANIFESTING AS WATERY DIARRHOEA AND IRON-DEFICIENCY ANAEMIA. BMJ-CASE-REP. 2015;2015:200-211", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160803", "receivedate": "20160803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12617355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "CA-ENDO PHARMACEUTICALS INC-2015-004295", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "90027", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE HCL TABLETS 37.5MG" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis microscopic", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAU A, XIONG W, KO H. COLLAGENOUS ENTEROCOLITIS MANIFESTING AS WATERY DIARRHOEA AND IRON-DEFICIENCY ANAEMIA. BMJ CASE REPORTS. 2015?21120:.", "literaturereference_normalized": "collagenous enterocolitis manifesting as watery diarrhoea and iron deficiency anaemia", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CA", "receiptdate": "20151123", "receivedate": "20151123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11769781, "safetyreportversion": 10, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "Stevens-Johnson syndrome and toxic epidermal necrolysis comprise a spectrum of severe mucocutaneous hypersensitivity reactions. A paucity of data limits current understanding of the etiology, treatment options, and prognosis of this entity in the infantile population compared to that in the adult and pediatric literature. We describe the case of an 8-week-old male with toxic epidermal necrolysis treated successfully with intravenous immunoglobulin and amniotic membrane transplant. This patient is the youngest surviving infant with toxic epidermal necrolysis to be reported.", "affiliations": "Dermatology Program, Boston Children's Hospital, Boston, Massachusetts.;Harvard Medical School, Boston, Massachusetts.;Dermatology Program, Boston Children's Hospital, Boston, Massachusetts.;Dermatology Program, Boston Children's Hospital, Boston, Massachusetts.;Dermatology Program, Boston Children's Hospital, Boston, Massachusetts.", "authors": "Nassim|Janelle S|JS|https://orcid.org/0000-0002-2035-3095;Karim|Sabrina A|SA|;Grenier|Pierre-Olivier|PO|;Schmidt|Birgitta|B|;Jones|Krystal M|KM|", "chemical_list": "D016756:Immunoglobulins, Intravenous", "country": "United States", "delete": false, "doi": "10.1111/pde.14376", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "38(1)", "journal": "Pediatric dermatology", "keywords": "drug reaction; mucous membrane disorders; neonatal; therapysystemic", "medline_ta": "Pediatr Dermatol", "mesh_terms": "D000328:Adult; D000650:Amnion; D002648:Child; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007223:Infant; D008297:Male; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "8406799", "other_id": null, "pages": "202-205", "pmc": null, "pmid": "33125180", "pubdate": "2021-01", "publication_types": "D002363:Case Reports", "references": null, "title": "Infantile toxic epidermal necrolysis: Successful treatment of an 8-week-old with intravenous immunoglobulin and amniotic membrane transplant.", "title_normalized": "infantile toxic epidermal necrolysis successful treatment of an 8 week old with intravenous immunoglobulin and amniotic membrane transplant" }

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Infantile Toxic Epidermal Necrolysis: Successful Treatment Of An 8-Week-Old With Intravenous Immunoglobulin And Amniotic Membrane Transplant. 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Infantile toxic epidermal necrolysis: Successful treatment of an 8-week-old with intravenous immunoglobulin and amniotic membrane transplant. Pediatr Dermatol. 2021;38:202-205", "literaturereference_normalized": "infantile toxic epidermal necrolysis successful treatment of an 8 week old with intravenous immunoglobulin and amniotic membrane transplant", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211011", "receivedate": "20210910", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19812301, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "OBJECTIVE\nA growing number of studies have suggested that exercise may promote therapeutic effects in patients with idiopathic inflammatory myopathy. This prospective case series study aimed to report on the effects of exercise in patients with persistent active myositis.\n\n\nMETHODS\nThree patients with persistent active polymyositis were submitted to a 12-week supervised exercise program comprising both aerobic and strength exercises.\n\n\nRESULTS\nAfter the intervention, the patients presented improvements in selected parameters of muscle function and aerobic conditioning. In addition, an overall improvement was detected in the quality of life, as measured by both the 36-item Short-Form Health Survey and the Health Assessment Questionnaire questionnaires. Importantly, exercise did not increase serum levels of creatine kinase and aldolase.\n\n\nCONCLUSIONS\nThe findings herein suggest that a combined aerobic and strength training program may be tolerable and potentially effective in improving muscle function, aerobic conditioning, and quality of life in patients with persistent active polymyositis.", "affiliations": "From the *School of Medicine, Rheumatology Division; and †School of Physical Education and Sport, Brazil.", "authors": "Mattar|Melina Andrade|MA|;Gualano|Bruno|B|;Roschel|Hamilton|H|;Perandini|Luiz Augusto|LA|;Dassouki|Thalita|T|;Lima|Fernanda Rodrigues|FR|;Shinjo|Samuel Katsuyuki|SK|;de Sá Pinto|Ana Lúcia|AL|", "chemical_list": "D003402:Creatine Kinase; D005634:Fructose-Bisphosphate Aldolase", "country": "United States", "delete": false, "doi": "10.1097/RHU.0000000000000056", "fulltext": null, "fulltext_license": null, "issn_linking": "1076-1608", "issue": "20(1)", "journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases", "keywords": null, "medline_ta": "J Clin Rheumatol", "mesh_terms": "D000328:Adult; D003402:Creatine Kinase; D015444:Exercise; D005081:Exercise Therapy; D005260:Female; D005634:Fructose-Bisphosphate Aldolase; D006801:Humans; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength; D017285:Polymyositis; D011446:Prospective Studies; D011788:Quality of Life; D055070:Resistance Training; D011795:Surveys and Questionnaires; D016896:Treatment Outcome", "nlm_unique_id": "9518034", "other_id": null, "pages": "11-5", "pmc": null, "pmid": "24356483", "pubdate": "2014-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Exercise as an adjuvant treatment in persistent active polymyositis.", "title_normalized": "exercise as an adjuvant treatment in persistent active polymyositis" }

[ { "companynumb": "PHHY2014BR107121", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG, PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYMYOSITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG/KG, PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYMYOSITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polymyositis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATTAR MA, GUALANO B, ROSCHEL H, PERANDINI LA, DASSOUKI T, LIMA FR, ET AL.. EXERCISE AS AN ADJUVANT TREATMENT IN PERSISTENT ACTIVE POLYMYOSITIS.. JCR: JOURNAL OF CLINICAL RHEUMATOLOGY. 2014;20 (1):11-15", "literaturereference_normalized": "exercise as an adjuvant treatment in persistent active polymyositis", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20140828", "receivedate": "20140828", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10415252, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "BACKGROUND\nClozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Although the molecule presents with a range of well-known side-effects, its discontinuation/withdrawal syndrome has been only anecdotally described.\n\n\nOBJECTIVE\nthe 2005-2018 European Medicines Agency (EMA) dataset of Adverse Drug Reactions (ADRs) was analyzed to identify and describe possible clozapine withdrawal- and misuse-/abuse-/dependence-related issues.\n\n\nMETHODS\nA descriptive analysis of clozapine-related ADRs was performed when available, data on ADRs' outcome, dosage, and possible concomitant drug(s) were considered.\n\n\nRESULTS\nOut of 11,847 clozapine-related ADRs, some 599 (5.05%) were related to misuse/abuse/dependence/withdrawal issues, including 258 withdrawal-related (43.1%); 241 abuse-related (40.2%); and 80 intentional product misuse-related (13.3%) ADRs. A small number of overdose- and suicide-related ADRs were reported as well. Clozapine was typically (69.2%) identified alone, and most (84.7%) fatalities/high-dosage intake instances were reported in association with a history of substance abuse.\n\n\nCONCLUSIONS\nPrevious suggestions about the possibility of a clozapine discontinuation/withdrawal occurrence are here supported, but further studies are needed. However, the misuse/abuse cases here identified might be difficult to interpret, given the lack of studies highlighting the possible recreational use of clozapine. The high-dosage intake, fatal outcomes and clozapine/polydrug abuse issues reported here may, however, be a reason for concern.", "affiliations": "Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, UK.;Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, UK.;Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, UK.;Swansea University Medical School, Institute of Life Sciences 2, Swansea University, Singleton Park, Swansea SA2 8PP, UK.", "authors": "Chiappini|Stefania|S|0000-0002-6810-1540;Schifano|Fabrizio|F|;Corkery|John Martin|JM|0000-0002-3849-817X;Guirguis|Amira|A|0000-0001-8255-0660", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/brainsci10020105", "fulltext": "\n==== Front\nBrain Sci\nBrain Sci\nbrainsci\nBrain Sciences\n2076-3425 MDPI \n\n10.3390/brainsci10020105\nbrainsci-10-00105\nArticle\nFocus on Clozapine Withdrawal- and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database\nhttps://orcid.org/0000-0002-6810-1540Chiappini Stefania 1 Schifano Fabrizio 1* https://orcid.org/0000-0002-3849-817XCorkery John Martin 1 https://orcid.org/0000-0001-8255-0660Guirguis Amira 2 1 Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, UK; stefaniachiappini9@gmail.com (S.C.); j.corkery@herts.ac.uk (J.M.C.)\n2 Swansea University Medical School, Institute of Life Sciences 2, Swansea University, Singleton Park, Swansea SA2 8PP, UK; amira.guirguis@swansea.ac.uk\n* Correspondence: f.schifano@herts.ac.uk\n16 2 2020 \n2 2020 \n10 2 10514 1 2020 14 2 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Clozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Although the molecule presents with a range of well-known side-effects, its discontinuation/withdrawal syndrome has been only anecdotally described. Aims: the 2005–2018 European Medicines Agency (EMA) dataset of Adverse Drug Reactions (ADRs) was analyzed to identify and describe possible clozapine withdrawal- and misuse-/abuse-/dependence-related issues. Method: A descriptive analysis of clozapine-related ADRs was performed when available, data on ADRs’ outcome, dosage, and possible concomitant drug(s) were considered. Results: Out of 11,847 clozapine-related ADRs, some 599 (5.05%) were related to misuse/abuse/dependence/withdrawal issues, including 258 withdrawal-related (43.1%); 241 abuse-related (40.2%); and 80 intentional product misuse-related (13.3%) ADRs. A small number of overdose- and suicide-related ADRs were reported as well. Clozapine was typically (69.2%) identified alone, and most (84.7%) fatalities/high-dosage intake instances were reported in association with a history of substance abuse. Conclusions: Previous suggestions about the possibility of a clozapine discontinuation/withdrawal occurrence are here supported, but further studies are needed. However, the misuse/abuse cases here identified might be difficult to interpret, given the lack of studies highlighting the possible recreational use of clozapine. The high-dosage intake, fatal outcomes and clozapine/polydrug abuse issues reported here may, however, be a reason for concern.\n\nclozapineadverse drug reactionsmisusewithdrawaldependenceoverdose\n==== Body\n1. Introduction\nClozapine was first synthesized in 1959 [1] and made available on the European market in 1971 for the treatment of schizophrenia [2]. If compared with remaining first-generation antipsychotic agents, clozapine is characterized by a lack of extrapyramidal side-effects [2]. After having been withdrawn from the European market in 1976 due to fatal cases of agranulocytosis, clozapine was approved by the Food and Drug Administration (FDA) in 1989 for treatment-resistant schizophrenia [2,3]. It was then approved in the USA in 2002 for reducing recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Other unlicensed uses include treatment-resistant bipolar disorder, aggression in patients with psychosis, and other brain disorders unresponsive to remaining treatments [4].\n\n1.1. Pharmacodynamic Considerations\nClozapine is a dibenzodiazepine designated as a Multi-Acting Receptor-Targeted Antipsychotic (MARTA), deriving its therapeutic effects from its action across various neurotransmitter systems [4,5]. In fact, a combination of pharmacological effects is unique to clozapine: (1) although the molecule presents with affinity levels for a range of dopamine/DA receptors (e.g., D1, D2, D3, D4, and D5; [6]), the blockade of dopamine 2 and 4 receptors is particularly relevant, with a preferential affinity for D4 over D2 receptors; this blockade seems to be effective in reducing positive symptoms of psychosis and stabilizing affective symptoms [4]; (2) 5-hydroxytryptamine/5-HT 2A receptor antagonism, causing enhancement of DA release in certain brain regions, and thus reducing motor side-effects and possibly improving cognitive and affective symptoms associated with schizophrenia [4]. Conversely, the clinical effects of the reported interactions at 5HT2C; 5HT1A; 5-HT6; and 5-HT7 receptors [6] might be less clear; (3) α2C-adrenergic receptor blockade; this may contribute to the clozapine-related improvement of cognitive function [7]; (4) significant antimuscarinic and antihistaminergic H1 effects, which may well contribute to the central effect [8]; and (5) possible modulatory actions on a dysfunctional glutamatergic system, improving schizophrenia symptoms and contrasting illness progression [1,4,9,10,11]. More precisely, clozapine interacts with the N-methyl-D-aspartate (NMDA) receptor complex, affecting either the glycine site of the NMDA receptor or tentatively inhibiting the glycine transporter [12]. Moreover, both clozapine and its major metabolite N-desmethylclozapine behave as: (i) delta-opioid receptor agonists [13,14,15,16,17]; (ii) cannabinoid CB1 receptor agonists [18]; and (iii) antagonists at muscarinic receptors [8]. Indeed, these i-iii pharmacological activities are, per se, typically associated with the occurrence of pleasurable effects [19,20,21,22], which could suggest a theoretical potential for clozapine to be misused by vulnerable individuals. Finally, further pharmacological clozapine activities which should be better understood in terms of their clinical effects may include both interaction with GABA-B receptors [22]; and antagonistic actions at D (2)/D (3)/D (4) receptors [23].\n\nThe therapeutic response depends on plasma clozapine concentrations, which may be influenced by many factors such as age, gender, and smoking [5], and should normally reach 350 ng/mL [4,5]; levels greater than 700 ng/mL are often not well tolerated [4]. Clozapine is metabolized by CYP450 enzymes, specifically by CYP450 1A2, 2D6 and 3A4 enzymes [5], and its metabolism may be influenced by CYP450 1A2 inhibitors, such as fluvoxamine and ciprofloxacin [14]. Remaining interactions may occur with both strong CYP450 2D6 inhibitors (e.g., bupropion, duloxetine, paroxetine, fluoxetine) and strong CYP450 3A4 (e.g., ketoconazole) inhibitors [4,15].\n\n1.2. Clozapine Abuse Issues and Substance Use Disorders\nSubstance use disorders (SUDs), typically involving alcohol, cannabis, and cocaine, commonly occur in patients with schizophrenia, supposedly due to epidemiological and genetic determinants of risk for both psychosis and addiction [1,16]. This co-occurrence (‘dual diagnosis’) has a negative effect on the course of schizophrenia, due to increased rates of hospitalization, decreased compliance with medication, increased violence and suicide, general deterioration of the patients’ condition, and overall increased societal costs [1,17]. In particular, the positive symptoms of schizophrenia are generally exacerbated by the intake of stimulant drugs, such as cocaine, amphetamine derivatives [24], and synthetic cathinones [25]. Due to clozapine’s effectiveness, there has been support for considering the molecule in limiting substance use in patients with schizophrenia [26], to achieve both a reduction in substance use [27,28] and an improvement in positive/negative schizophrenia symptoms [29]. Additionally, differently from other antipsychotics, such as quetiapine, which has showed in recent years to be a strong potential for misuse and abuse [30,31,32,33], the recreational use of clozapine has not been noted in the literature. Conversely, clozapine withdrawal is a phenomenon which has already been described, even at therapeutic dosages [9]. However, the risk of withdrawal may arguably be significant only when a psychoactive molecule is being misused/ingested at higher dosages. Since SUD patients may be vulnerable to misuse prescribed medications, one could argue that it is relevant to identify and assess any possible clozapine misuse/abuse/withdrawal and dependence issues.\n\n1.3. Aims\nWe aimed here at identifying and describing the number of European Medicines Agency (EMA) database cases of misuse, abuse, dependence, and withdrawal specifically relating to clozapine; suicide-related cases and fatalities were also considered.\n\n2. Methods\n2.1. Data Source and Acquisition\nEudraVigilance (EV) manages and analyzes information on suspected Adverse Drug Reactions (ADRs) to medicines that have been authorized in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 [34]. In order to investigate the aspects above, EV was specifically requested to provide all Level 2A data [34] comprising case reports of clozapine-related misuse, abuse, dependence, and withdrawal ADRs, which were obtained in the form of line listings, relating to the 2005–June 2018 time-frame. Differently from the publicly available data from the EV website, Level 2A data were presented as Excel sheets divided into information sections reporting in a standardized format according to the Medical Dictionary for Regulatory Activities (MedDRA), which is the internationally agreed list of terms that supports the coding of ADRs [35], which are identified through Preferred Terms (PT). Indeed, MedDRA is a comprehensive and highly standardized medical terminology developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) (https://www.meddra.org/) in the late 1990s to facilitate the international sharing of regulatory information for medical products. Such listings showed all information related to the ADR, the patient, the drug, the reporter, and the diagnosis. In line with previous studies from our group [36,37,38,39], the ADRs considered here were, per se, voluntary and unsolicited communications [34] reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorization Holders for those ADRs occurring outside the EEA. Individual Case Safety Reports, such as voluntary reports, refer to the format and content for the reporting of one or several suspected ADRs in relation to a medicinal product that occur in a single patient at a specific point of time [40]. ‘Suspect’ ADRs were selected, meaning clozapine was considered as ‘suspected’ for the reaction reported [34]. Within the standardized MedDRA Query (SMQ) ‘drug abuse, dependence and withdrawal’ section, we identified the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug diversion, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, product use issue, substance abuse, and withdrawal syndrome. For the definition of ‘abuse’; ‘addiction’; ‘dependence’; and ‘misuse’ please refer to references [35,36,37,38,39,40]. Moreover, in accordance with MedDRA, ‘withdrawal’ is identified in association with the abrupt cessation or reduction in intake of a drug in a habituated person. A substance-specific syndrome may follow, with withdrawal symptoms varying according to the psychoactive substance used and generally opposite the acute effects of drug. These include nonspecific symptoms e.g., nausea, diarrhea or constipation, profuse sweating, increase in respiratory rate, and tachycardia; remaining common symptoms include anxiety, restlessness, irritability, insomnia, and impaired attention [35].\n\n2.2. Data Analysis\nEach case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. All rows of the case have the same ‘EV Local Report Number’, unequivocally identifying an individual case. Thus, the number of suspected ADRs can be different from the number of case reports as one case report may refer to several suspected ADRs. Moreover, the number of patients can be different from the number of case reports as a patient may have been described in more than one case. Finally, ADRs’ numbers differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA.\n\nPatients’ data were analyzed using a range of parameters, including: socio-demographic characteristics (age and gender); source/reporter country (EEA or non-EEA) and reporter qualification (i.e., pharmacist, physician); outcomes (fatal, recovered, resolved); clozapine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded [37]. The analysis included cases of overdoses, suicides, and fatalities.\n\nSuicidal behavior was here defined as ‘completed suicide’, ‘intentional self-injury’, ‘suicidal behavior’, ‘suicidal ideation’, ‘suicide attempt’, ‘self-injurious ideation’, and ‘intentional self-injury.’ ‘Overdose’, including ‘intentional overdose’, was not necessarily interpreted as being a suicidal attempt [35]. The analysis included here both a descriptive study of the dataset and the Confidence Interval (CI) values [41].\n\n2.3. Ethics’ Issues\nComplying with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001 on the protection of privacy and integrity of individuals, certain data elements, including names/identifiers of individuals involved or country-specific information were not disclosed by the EMA to safeguard the identity of individuals [42]. The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.\n\n3. Results\nThe EMA dataset included a total of 13,596 clozapine-related ADRs. A total of 11,847 ADRs were considered as ‘suspect’, i.e., as suspected to be related with clozapine. Of those, 599/11,847 (5.05% CI 95% 597–601) related to misuse/abuse/dependence/withdrawal ADRs and were associated with 559 unique subjects. These included: 258 ADRs (258/599 = 43.1% CI 95% 256–260) relating to ‘withdrawal syndrome’ issues; 241 abuse-related ADRs (241/599 = 40.2% CI 95% 239–242); and 80 ADRs (80/599 = 13.3% CI 95% 76–84) relating to ‘intentional product misuse.’ A small number of overdose- (n = 29) and suicidal behavior-related ADRs (n = 29) were reported here, resulting in death, respectively, in two and 11 cases (Table 1).\n\nPatients were typically males (379/559 = 67.8% CI 95% 378–380), in the 18–65 years age range. Most typical senders were pharmaceutical companies (303/559 = 54.2% CI 95% 301.5–304.5) and regulatory authorities (241/559 = 43.11% CI 95% 239–243) (Table 2).\n\nThe number of cases increased year by year, with a peak in 2008 (120/559 cases) (Figure 1).\n\nOral intake occurred here in 533/559 cases (95.3% CI 95% 532.5–533.5); when recorded, clozapine dosages varied from 12.5 mg/day to high/unlicensed levels (i.e., 2800–5600 mg/day; Figure 2). Only a few cases (n = 7), however, reported high (e.g., >1000 mg) levels. When the relating clinical data were made available, these cases were typically described as ‘intentional self-injury’, ‘completed suicide’, and ‘drug abuse’).\n\nClozapine was the sole molecule reported in 387/559 (69.2% of cases; CI 95% 386–388); remaining drugs included: first/second generation antipsychotics (55/559 cases; 9.8%); benzodiazepines (clonazepam, diazepam, and lorazepam; 54/559 cases; 9.7%); antidepressants (citalopram, escitalopram, sertraline, and venlafaxine; 33/559 cases; 5.9%); and mood stabilizers (valproic acid, carbamazepine, lamotrigine, lithium, and gabapentin; 20/559 cases; 3.6%). Illicit drugs most typically reported here were opioids (15/559 cases), amphetamines (10/559), cannabis, and alcohol (each in seven cases). In 30 cases, two or more prescribed/recreational drugs were recorded in association with clozapine (Table 3).\n\nThe ADRs required in most cases a prolonged hospitalization (298/559 = 53.3% CI 95% 296.5–299.5), while some 46 cases (46/559 = 8.2%) resulted in death (Table 2 and Table 4). Of these 46 clozapine-related fatalities, 39 (84.7%) were associated with a previous history of substance abuse (Table 4).\n\nIn a number of cases, reporters had omitted some relevant details, including diagnosis, drugs involved, and, more importantly, both the white blood cell (WBC) and the absolute neutrophil count (ANC) results. Out of a total of 599 ADRs, referring to 559 individual cases, some 149 ADRs (42 individual cases) mentioned that the WBC count had been carried out. However, the results were reported in only 123 ADRs (32 individual cases). For 68 of these ADRs, the WBC/ANC count was within the normal range; while 42 and 13 ADRs were, respectively, associated with either leukopenia or increased WBC count levels. However, since modifications overtime of WBC count levels were not reported, it would be problematic to unequivocally conclude from here if clozapine had been stopped in association with the occurrence of WBC count abnormalities.\n\nA total of 28 cases reported here catatonia, six of which were specifically described as being associated with clozapine withdrawal issues; further reporters’ comments relating to overdose, suicidal behavior, withdrawal, and abuse issues are listed in Table 5.\n\n4. Discussion\nTo the best of our knowledge, this is the largest collection of literature data relating to clozapine withdrawal and misuse/abuse/dependence cases. Our analysis found 599 ADRs of interest (relating to 559 individuals), representing 5.05% of all 11,847 reports submitted to the EMA EV between 2005 and 2018 and judged as ‘suspect.’ In contrast with the related knowledge on this topic, mostly focused on small case reports/series [10,43,44,45,46,47,48], current findings referred to high numbers of patients presenting with clozapine withdrawal and misusing issues.\n\nClozapine ADRs of interest showed a peak in 2008, but an overall increase was observed between 2010 and 2018. One could argue that this upward trend may have been associated with a range of factors, including the increasing rates of worldwide availability of clozapine due to an overwhelming evidence of its effectiveness [2,49,50,51] and/or a major awareness of the relevant and significant impact of pharmacovigilance processes and issues, resulting in a rise of spontaneous reporting practices related to safety monitoring of medicinal products in general [52].\n\nWithdrawal cases collected here were recorded according to the related PTs defined in the MedDRA dictionary [35], where withdrawal is described as “the abrupt cessation of a drug use in a habituated person; and a substance specific syndrome following cessation or reduction in intake of a psychoactive substance previously used regularly”. Clozapine withdrawal/discontinuation ADRs were the most frequently reported and, as such, current findings confirmed and expanded on previous anecdotal data [6,53,54]. In association with a sudden discontinuation of clozapine, which may be required in cases of blood dyscrasia or suspected myocarditis, instances of withdrawal have already been reported [6,44,54,55]. It is of clear interest that a case of clozapine withdrawal neonatal syndrome was specifically mentioned here as well. The clozapine multi-receptor agonism/antagonism is likely responsible for the occurrence of discontinuation/withdrawal symptoms. Indeed, the clozapine pharmacodynamic profile may well include: (a) a dopaminergic super-sensitivity, with the risk of a dopaminergic psychosis and symptoms such as dystonias, dyskinesias, and catatonia [38,56,57,58,59]; (b) a cholinergic rebound, inducing in vulnerable patients a rapid worsening of psychosis, agitation, confusion, insomnia, and symptoms including nausea, vomiting, diarrhea, headache, diaphoresis, and abnormal movements, such as dystonias and dyskinesias [6,54,56,57,60,61,62,63,64]. Consistent with this, symptoms appear to regress rapidly with the help of anti-cholinergic drugs; (c) a serotonergic syndrome, which may occur even without the concomitant use of a serotonergic agent [10,39,61]. In fact, acting as a 5-HT2A antagonist, long-term clozapine use may be associated with receptor downregulation, and thus, its abrupt discontinuation might lead to receptors’ upregulation [65,66]; (d) a sudden decrease in gamma-aminobutyric acid (GABA) activity, with the development of catatonic symptoms which may include, mutism, waxy flexibility, staring, posturing, mannerisms, negativism, and also restless, irrelevant speech, and psychomotor agitation [6,67]. The clozapine agonist action on GABA receptors can explain both the drug-drug interaction between clozapine and benzodiazepines, and the flumazenil therapeutic effect in clozapine intoxication cases [6]; and (e) a modification of norepinephrine levels, with clozapine abrupt discontinuation in chronic patients possibly resulting in an increase in suicidal behavior [1,68]. As it may occur with remaining psychotropics, such as antidepressants [69,70], the existence of a discontinuation syndrome following an abrupt stoppage of, or marked reduction in, the dosage of a drug taken on a regular basis does not necessarily mean that a drug causes dependence. Discontinuation should be seen here as distinct from the withdrawal scenario associated with alcohol and other addictive substances, a scenario which commonly presents together with craving, drug seeking behavior, and the inability to stop drug use [71,72]. Thus, if a discontinuation of clozapine is needed, the molecule should be gradually tapered off over several weeks rather than abruptly discontinued, except in cases of emergency (e.g., agranulocytosis), and only with close clinical monitoring [10,67,73]. There are no established guidelines regarding which antipsychotic to choose after withdrawal of clozapine [73], although anticholinergics and olanzapine may be the treatment of choice for preventing withdrawal [53].\n\nThe reporters’ narrative here formally submitted in a few cases was consistent with both drug seeking and diversion behavior (e.g., “…clozapine as a drug of abuse…”; and “…patient possibly has used Leponex as drug of abuse or he bought Leponex for drug abuse by others…”.). Considering the current misuse/abuse issues, the number of clozapine related ADRs (e.g., 326 ADRs; referring to: ‘drug abuse’, ‘drug abuser’, ‘drug diversion’, ‘intentional product misuse’, ‘product use issue’, and ‘substance abuse’) here identified may be difficult to interpret. In fact, in comparing quetiapine- and other second-generation antipsychotic-related intentional abuse exposures reported to the US National Poison Data System, Klein et al. [74] suggested that clozapine and olanzapine were significantly associated with frequent instances of severe central effects, including: lethargy/drowsiness/slurred speech; agitation/irritability; confusion and hallucinations. However, no use of clozapine as a recreational drug was reported. One could argue that at least a proportion of these ADRs involved subjects suffering from both schizophrenia and a co-occurring SUD. Furthermore, current findings here did not identify any idiosyncratic intake modalities (e.g., intravenous use) that are typical of a substance misuse behavior. Hypothetically, putative levels of clozapine misuse liability might be tentatively explained considering the range of its pharmacodynamics activities, and the occurrence of rewarding and pleasurable effects due to the agonism at both delta-opioid [13,17,75] and cannabinoid CB1 receptors [18]; and the antagonism at muscarinic receptors [76,77]. Additionally, although clozapine was here ingested on its own in some 69% of cases, remaining antipsychotics and benzodiazepines were the drugs most frequently reported in association. Polypharmacy ingestion may have facilitated the occurrence of synergistic reactions, and hence the EMA ADRs’ reporting, due to possible increase in clozapine plasma concentrations associated with metabolism inhibition [14]. Relatively small recreational drugs’ numbers were identified here as well, and this may have been associated with complex pharmacological interactions. Indeed, clozapine pre-treatment may increase cocaine concentrations, but significantly reduce subjective responses to cocaine [78].\n\nRegarding the ADRs’ outcomes, present figures seem to be a reason for concern, since most cases (298/559 = 53.3%) required a prolonged hospitalization. Furthermore, some 46 (8.2% of 559 subjects) fatalities were here reported, and these mostly occurred in the context of: high dosage clozapine intake; suicidal behavior; and/or polydrug abuse. Although the EMA suggests a maximum clozapine dosage of up to 900 mg/day and warns about side-effects occurring at doses over 450 mg/day [79], cases reported here were at times associated with massive dosages (e.g., in the range of 2800–5600 mg), although most of these cases were associated with overdose/suicide instances. These rates are a reason for concern but seem to be consistent with the suggestion that those subjects diagnosed with treatment-resistant schizophrenia, and hence, who are typically being prescribed with clozapine, present with a higher risk of attempted/completed suicide in comparison to the general population [80]. Clozapine overdose may be lethal due to changes in heart rhythm, respiratory depression, and altered state of consciousness [4,81,82]; clozapine high-dosage ingestion may be associated with a mortality rate of approximately 12% [83], with fatalities most typically being associated with cardiac insufficiency and aspiration pneumonia observed with dosages higher than 2 g [45,46,47,48]. Although cases of full recovery after ingestion of either high dosages [46] and/or associated with very high plasma levels (>9000 ng/mL) [45] have been reported, ingestion of 400 mg in a patient not previously treated may be life-threatening [46].\n\n4.1. Limitations\nOverall, pharmacovigilance systems such as the EV in Europe, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom and the FDA Adverse Event Reporting System (FAERS) are considered important because the analysis of suspected ADRs may deal with early detection of possible drug safety signals [34]. However, the study of ADRs alone may not be enough to prove causality between a certain suspected reaction and a specific medicine. Any case report should be considered and assessed together with all available data, including case reports worldwide, clinical trials, epidemiological studies, and toxicological investigations.\n\nUnfortunately, the dataset did not typically report here any clinical data, including information on the current/past psychopathology and the medications that were prescribed in association. Furthermore, the study of ADRs may be influenced by the molecule’s availability and extent of use, although precise data on the worldwide prescription rates for clozapine were not here identified or available. Moreover, in being voluntarily reported/submitted, the number of ADRs could have been conditioned by both the nature of the reaction and the public awareness of a safety concern, with underreporting possibly having here occurred. Additionally, some data could have been unavailable, invalid or redacted.\n\n4.2. Conclusions\nCurrent findings focused on a range of clozapine withdrawal and misuse/abuse/dependence issues. It was here confirmed, on a large-scale basis, that, following the abrupt reduction of clozapine dosage a discontinuation/withdrawal syndrome may occur. This may involve possible severe and long-lasting symptoms [10,59,67,84]. Moreover, although this may be an unusual event, it is here suggested that cases of misuse/abuse/dependence could occur in patients with a concomitant SUD and this is despite clozapine being of clinical value for the treatment of dual diagnosis. Conversely, current findings emphasized a range of severe and fatal health consequences associated with clozapine high-dosage intake, and patients taking clozapine should be educated thoroughly about the risks associated with polydrug intake. In being a prescribed drug of highly significant clinical value [85], increased awareness is essential towards prevention, diagnosis, and treatment of cases of clozapine abuse/recreational use in patients diagnosed with schizophrenia [86].\n\nAuthor Contributions\nS.C. conceived the paper, the main conceptual ideas, proof outline and designed the study. S.C. wrote the first draft and led on the analysis of the results with the support of A.G. and J.M.C. under the supervision of F.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nF.S. was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2013 to 2019; he is currently an EMA Advisory Board (psychiatry) member. J.M.C. is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.\n\nFigure 1 Total Number of clozapine-related misuse, abuse, dependence, withdrawal cases reported to EudraVigilance (EV) per year (2005–June 2018).\n\nFigure 2 Dosages of clozapine reported to the EudraVigilance (EV) dataset of clozapine-related misuse, abuse, dependence, withdrawal ADRs.\n\nbrainsci-10-00105-t001_Table 1Table 1 Analysis of the EudraVigilance (EV) clozapine-related misuse/abuse/dependence and withdrawal ADRs (2005–June 2018).\n\nEudraVigilance (EV) Clozapine-Related Misuse/Abuse/Dependence and Withdrawal ADRs (2005–June 2018)\t\nn\n\t\nTotal “suspect” clozapine-related ADRs\t11,847\t\nClozapine-related ‘abuse, dependence and withdrawal’ ADRs\t599 (CI 95% 595–603) \n(n individual cases = 559) \t\nDrug abuse\t198\t\nDrug abuser\t1\t\nSubstance abuse\t42\t\nDependence\t7\t\nDrug dependence\t6\t\nDrug diversion\t1\t\nIntentional product misuse\t80\t\nProduct use issue\t4\t\nDrug withdrawal convulsions\t1\t\nDrug withdrawal neonatal syndrome\t1\t\nDrug withdrawal syndrome\t91\t\nWithdrawal syndrome\t165\t\nFurther issues emerging from the analysis of clozapine ADRs’ dataset\t\n\t\nIntentional overdose\t12\t\nOverdose\t17\t\nCompleted suicide\t9\t\nIntentional self-injury\t4\t\nSuicidal behavior\t1\t\nSuicidal ideation\t4\t\nSuicide attempt\t7\t\nSelf-injurious ideation\t4\t\nbrainsci-10-00105-t002_Table 2Table 2 Description of clozapine-related misuse, abuse, dependence and withdrawal cases. F: female; M: male; N: no; Y: yes.\n\nClozapine-Related Misuse, Abuse, Dependence and Withdrawal Cases\tn of Unique Patients\t\n\n\t559\t\n\nAge range (years)\n\t3 neonates, \n1 child (5 years), \n2 adolescents (15–16 years), \n78 adults (18–65 years), \n1 elderly (67 years), \n474 Not specified \t\n\nGender\n\t171 F, \n379 M, \n9 Not Specified\t\n\nSender\n\t241 Regulatory authority, \n303 Pharmaceutical company, \n9 Other (distributor, study sponsor, contract research organization), \n6 Not Specified\t\n\nOutcome\n\t\n\t\nResulted in death\t46 Y, 448 N, 65 Not Specified\t\nLife threatening\t35 Y, 447 N, 77 Not Specified\t\nRequired a prolonged hospitalization\t298 Y, 219 N, 42 Not Specified\t\nDisabling\t8 Y, 467 N, 84 Not Specified\t\nbrainsci-10-00105-t003_Table 3Table 3 Clozapine alone or in combination rates of identification, as recorded by the EudraVigilance (EV) dataset of misuse, abuse, dependence, and withdrawal cases.\n\nClozapine-Related Misuse, Abuse, Dependence and Withdrawal Cases Recorded by the EudraVigilance (EV) Dataset\tTot (n = 559)\t\nClozapine ingested as a lone drug\t387 (69.2%)\t\nClozapine identified in combination with remaining drugs\t172 (30.7%)\t\n\nPrescribing drugs\n\t\n\t\nOther antipsychotics\t55\t\nBenzodiazepines\t54\t\nAntidepressants\t33\t\nMood stabilizers\t20\t\nZ-drugs\t4\t\n\nRecreational drugs\n\t\n\t\nOpioids\t15\t\nAmphetamine derivatives\t10\t\nCannabis\t7\t\nAlcohol\t7\t\nCocaine\t4\t\nKetamine\t1\t\nbrainsci-10-00105-t004_Table 4Table 4 Description of the clozapine-related fatalities’ cases reported to the EudraVigilance (EV) dataset (2005–June 2018). F: female; M: male.\n\n\n\t\n\tClozapine Dosage (mg)\tConcomitant Drugs\tMedical History\tReactions according to the MedDRA Dictionary (Preferred Terms-PT)\t\n1\tM, Adult (30 yy)\t200 mg\tBenzodiazepines Alcohol\t\n\tIntentional product misuse; Antipsychotic drug level increased (clozapine plasmatic 1.1 mg/mL); Blood pressure decreased; Loss of consciousness; Poisoning; Dysarthria; Loss of consciousness; Blood alcohol increased\t\n2\tM, Adult (48 yy)\tN/A\tCocaine \nOpioids \nZ-drugs\tHypertension; Schizophrenia; Chronic obstructive pulmonary disease; \nArteriosclerosis\tSubstance abuse; Toxicity to various agents\t\n3\tM, Adult (25 yy)\t300 mg\tBenzodiazepines \nOpioids\t\n\tCardiac arrest; Arrhythmia \nToxicity to various agents (methadone and clozapine); \nDrug abuse; Drug level increased (methadone and clozapine)\t\n4\tM, Adult (44 yy)\tN/A\tOpioids\tHypertension; Alcoholism; \nDepression; Epigastric discomfort; Anxiety\tPulmonary embolism; \nDrug abuse\t\n5\tM, Adult\t400 mg\tAlcohol\t\n\tLiver function test abnormal; \nBlood alkaline phosphatase increased; Gamma-glutamyl transferase increased; Asphyxia; Alcohol abuse; \nDrug abuse (heroin)\t\n6\tM, Adult (24yy)\tN/A\tAlcohol\tAnemia\tDrug abuse (Clozaril abuse)\t\n7\tF\t300 mg\t\n\tAlcoholism; Mental impairment; Depression; Treatment noncompliance; \nDeep vein thrombosis\tDeath; Withdrawal syndrome; \nAcute psychosis; Cognitive disorder; Amnesia; Speech disorder; Gait disturbance; Chills\t\n8\tF, Adult (54yy)\t350 mg\tBenzodiazepines\t\n\tWithdrawal syndrome; Insomnia; Completed suicide\t\n9\tM, Adult (66 yy)\tN/A\t\n\t\n\tCompleted suicide; Drug abuse\t\n10\tF, Adult (25yy)\tN/A\tAntidepressants\t\n\tCompleted suicide; Drug abuse\t\n11.\tM, Adult (31yy)\tN/A\t\n\t\n\tCompleted suicide; Drug abuse\t\n12\tM\tN/A\t\n\tObesity; Gastroesophageal reflux; Drug abuse\tDrug abuse; Death\t\n13\tF\tN/A\tCocaine \nBenzodiazepines \nOpioids\tDrug dependence\tDrug abuse (cocaine, leponex and probably benzodiazepines); Death; Hyperthermia malignant; \nCardiac arrest; Circulatory collapse; Delirium\t\n14\tM\tN/A\t\n\tHepatitis\tDrug abuse (possible use of non-prescribed drugs); Death\t\n15\tM\tN/A\t\n\tSalivary hypersecretion; \nDrug abuse (crack cocaine, marijuana, alcohol); Extrapyramidal disorder\tNonspecific reaction; Treatment noncompliance; \nDrug abuse (mixed polysubstance abuse); Death\t\n16\tF\tN/A\tMood stabilizers \nAntipsychotics\t\n\tDrug abuse\t\n17\tM\t1000 mg\t\n\tHypercholesterolemia; \nSubstance abuse; Hypertension; Schizophrenia; \nGastro-esophageal reflux disease\tHematemesis; Drug abuse; \nCardiac arrest; Completed suicide; Toxicity to various agents; Intentional overdose; \nResuscitation; Seizure; \nTachycardia\t\n18\tF, Adult (27yy)\tN/A\t\n\t\n\tDrug abuse\t\n19\tM, Adult (30yy)\tN/A\t\n\t\n\tMyocardial infarction; Drug abuse; Eye swelling; Glossodynia; Tongue coated; \nSwollen tongue\t\n20\tF\tN/A\t\n\t\n\tIntentional self-injury; Meningioma; Drug abuse; \nHypoglycemia; Peripheral venous disease; Hepatic steatosis; Scar; Pneumonia; \nBronchitis; Arteriosclerosis coronary artery; Purulent discharge; Pulmonary congestion; Death\t\n21\tM, Adult (26yy)\t800 mg\t\n\t\n\tCoronary artery disease; Drug abuse; Hallucination, auditory; Epilepsy; Depressed mood\t\n22\tM, Adult (31yy)\tN/A\t\n\t\n\tDeath; Substance abuse\t\n23\tM\tN/A\t\n\tSurgery; Intentional self-injury; Bipolar disorder\tAgitation; Death; Drug abuse; \nSuicidal ideation; Nasal septum deviation \t\n24\tM, Adult (30yy)\tN/A\t\n\t\n\tAutonomic nervous system imbalance; Catatonia; Drug withdrawal syndrome; Dyskinesia; Neuroleptic malignant syndrome; \nPsychotic disorder\t\n25\tM, Adult (36yy)\tN/A\t\n\t\n\tAlcohol abuse; Drug abuse; \nMyocardial infarction; Coronary artery disease\t\n26\tM\t200 mg\t\n\t\n\tDrug abuse; Obesity\t\n27\tM, Adult (34yy)\t350 mg\t\n\t\n\tCirculatory collapse; Intentional product misuse; \nCardiopulmonary failure\t\n28\tM, Adult (33yy)\tN/A\tBenzodiazepines \nOpioids\t\n\tDeath; Drug abuse (heroin, temazepam)\t\n29\t\n\tN/A\t\n\tArm amputation; Drug dependence (including cannabis, benzodiazepines and heroin); Limb reduction defect; Alcohol use\tDrug abuse; Loss of consciousness; Hypothermia\t\n30\tM, Adult (31yy)\tN/A\t\n\t\n\tAbnormal behavior; Myocardial infarction; \nDrug abuse (heroin, cocaine); \nPsychomotor hyperactivity; \nPeripheral coldness; \nUnresponsive to stimuli; \nArteriosclerosis coronary artery; Blood glucose decreased\t\n31.\tF, Adult (72yy)\t200 mg\tOpioids\tSchizophrenia; Depression; Somnolence; Anxiety\tMovement disorder; Sudden death; Drug abuse\t\n32.\tM, Adult (27yy)\t400 mg\tAntipsychotics\tAsthma; Nicotine dependence; Drug abuse; Obesity; Substance use; Diabetes mellitus; Mental disorder; Alcohol use\tAsphyxia; Substance abuse\t\n33.\tM, Adult (50 yy)\t550 mg\t\n\t\n\tHypoxic-ischemic encephalopathy; Drug abuse (cocaine); Pulmonary hemosiderosis; Pulmonary edema; Cardiac arrest; \nLeft ventricular hypertrophy; \nArteriosclerosis coronary artery; Aortic arteriosclerosis; \nMyocardial fibrosis; Hepatic steatosis; Spleen congestion\t\n34.\tM, Adult (29yy)\t1000 mg\tOpioids\tSchizophrenia\tSubstance abuse (heroin)\t\n35.\tF, Adult\tN/A\tAntidepressants\t\n\tDrug abuse\t\n36.\tM, Adult (34yy)\t700 mg\t\n\tSchizophrenia; Nicotine dependence; \nDrug abuse\tCardiac arrest; Substance abuse\t\n37.\tF, Adult (28yy)\tN/A\tAntidepressants\t\n\tDrug abuse\t\n38.\tM\t100 mg\t\n\tBlood cholesterol increased; Bipolar disorder; Gastroesophageal reflux; Schizoaffective disorder; Diabetes mellitus\tSudden death; Drug abuse (cocaine and another illicit drug)\t\n39.\tF, Adult (50yy)\tN/A\tAlcohol\tDrug abuse; Drug dependence\tCompleted suicide; Toxicity to various agents; Drug abuse (propofol)\t\n40.\tM\tN/A\t\n\tProduct use issue; Psychotic disorder\tProduct use issue; Drug level increased (clozapine levels in the 600,000 s); Death; Adverse event; Psychotic disorder; \nIntentional product misuse\t\n41.\tM\tN/A\t\n\t\n\tDrug withdrawal syndrome; Memory impairment; Disorientation; \nCompleted suicide\t\n42.\tF, Adult (28yy)\tN/A\tAntidepressants\t\n\tToxicity to various agents; Drug abuse\t\n43.\tM, Adult (31yy)\t700 mg\t\n\tAnxiety; Psychotic disorder; Depression\tCompleted suicide (suicide due to overdose on clozapine); \nIntentional product misuse; \nOverdose; Adverse event\t\n44.\tM\tN/A\t\n\t\n\tCompleted suicide (patient jumped to his death); Withdrawal syndrome (periodically he would refrain from taking the medication, thus suffering withdrawal/Initially withdrawal symptoms would consist of disorientation after 2–3 days and memory impairment after 4–7 days)\t\n45.\tM\tN/A\t\n\t\n\tDeath; Withdrawal syndrome (withdrawal symptoms from the capsule form of Clozaril antipsychotic medication)\t\n46.\tM, Adult (58yy)\t100 mg\t\n\tAlcohol use; Hypertension\tDrug abuse; Vomiting; \nAsphyxia; Prescription drug used without a prescription (abuse of clozapine 100 mg tablets)\t\nbrainsci-10-00105-t005_Table 5Table 5 Reporter’ comments recorded in the line listing; EudraVigilance (EV) clozapine-related misuse/abuse/dependence and withdrawal ADRs (2005-June 2018).\n\n\n\tComments in the ADRs Reported in the Dataset\t\n\nOverdose and suicidal behaviour ADRs\n\t\n“Clozapine overdose in suicidal attempt”\n\n“Patient stopped treatment and then took an overdose of about 2800 mg”\n\n“Clozapine levels in the 600,000’s possible overdose”\n\n“Clozapine overdose of 3000 mg/took two weeks supply of Clozaril as 4200 mg (300 mg × 14 dd)”\n\n“Clozapine overdose”\n\n“Took an overdose of 5600 mg”\n\n“The patient took 1300 mg for intentional self-injury”\n\n“Suicide due to overdose on clozapine”\n\n\n\t\n\nWithdrawal and clozapine discontinuation ADRs\n\t\n“Clozaril withdrawal due to non-compliance”\n\n“Withdrawal reaction cholinergic rebound”\n\n“Anticholinergic withdrawal syndrome”\n\n“Withdrawal psychotic episode”\n\n“Sudden withdrawal with Clozaril”\n\n“Clozaril withdrawal psychosis”\n\n“Psychotic decompensation after clozapine discontinuation”\n\n“Relapse psychosis”\n\n“Experiencing extremely negative reactions due to going off this medication”\n\n“Serotonin syndrome associated with clozapine withdrawal”\n\n“Withdrawal agitation”\n\n“Tachycardia and high BP possibly due to Clozaril withdrawal”\n\n“Acute clozapine withdrawal”\n\n“Withdrawal symptoms from Clozaril”\n\n“Compatible with withdrawal effects arising from the abrupt discontinuation of clozapine”\n\n\n\t\n\nAbuse of clozapine\n\t\n“Abusing Clozaril taking more than he needs”\n\n“Clozaril was prescribed for family members”\n\n“Took his wife’s Clozaril to help him sleep”\n\n“He depended on clozapine”\n\n“Died because of clozapine and alcohol”\n\n“Clozapine as a drug of abuse”\n\n“Clozaril misuse”\n\n“Abuse of Leponex”\n\n“Patient possibly has used Leponex as drug of abuse or he bought Leponex for drug abuse by others”\n==== Refs\nReferences\n1. 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The art of clozapine therapy and “clozaphobia” BMJ 2019 364 l484 10.1136/bmj.l484 30723070\n\n", "fulltext_license": "CC BY", "issn_linking": "2076-3425", "issue": "10(2)", "journal": "Brain sciences", "keywords": "adverse drug reactions; clozapine; dependence; misuse; overdose; withdrawal", "medline_ta": "Brain Sci", "mesh_terms": null, "nlm_unique_id": "101598646", "other_id": null, "pages": null, "pmc": null, "pmid": "32079135", "pubdate": "2020-02-16", "publication_types": "D016428:Journal Article", "references": "19909228;30722037;12591093;25655145;12564740;15602101;28735357;9219487;22503785;30782143;31573374;24978;28331860;7543218;29413518;28767928;8117587;21753741;31982601;8938913;31068753;12665390;28210359;29620695;20689404;9229045;16774655;30286103;27141293;30723070;29620694;19588385;29618978;28396815;23764370;10786215;15995876;16782758;9754851;21925742;9504382;21254789;28416205;7961573;26826542;31674690;29210868;19239909;15034917;23706777;20587767;17868938;12511175;18004134;23104931;16683856;22495953;19230235;29234517;27464323;30472164;28554948;21563869;10891628;11215836;10653215;26417330;30774595;10229061;23753931;30065280;29690558;25721705;24708834", "title": "Focus on Clozapine Withdrawal- and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database.", "title_normalized": "focus on clozapine withdrawal and misuse related cases as reported to the european medicines agency ema pharmacovigilance database" }

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FOCUS ON CLOZAPINE WITHDRAWAL AND MISUSE-RELATED CASES AS REPORTED TO THE EUROPEAN MEDICINES AGENCY (EMA) PHARMACOVIGILANCE DATABASE.. BRAIN SCIENCES. 2020?10(2):1-18", "literaturereference_normalized": "focus on clozapine withdrawal and misuse related cases as reported to the european medicines agency ema pharmacovigilance database", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200427", "receivedate": "20200427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17713311, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "Three cases of supraventricular tachycardia (SVT) associated with the use of furosemide infusion (FI) in children following cardiac surgery are reported. The SVT occurred three to seven hours after starting an infusion at 1.0 mg.kg-1.hr-1. All three patients had a diuresis of 8-10 ml.kg-1.hr-1 compared with a mean average of 2.5 ml.kg-1.hr-1 in 22 other patients who had received a similar infusion. A rapid fluid shift was the most likely mechanism of the tachycardia. Sotalol was effective in controlling the tachycardia in the two patients in whom it was tried. We now recommend a starting dose of 0.3 mg.kg-1.hr-1 in using furosemide as a continuous infusion, with hourly increments of 0.1 mg.kg-1.hr-1 until the desired diuresis is obtained.", "affiliations": "Department of Pediatrics, University of British Columbia, Vancouver, Canada.", "authors": "Wilson|N J|NJ|;Adderley|R J|RJ|;McEniery|J A|JA|", "chemical_list": "D005665:Furosemide", "country": "United States", "delete": false, "doi": "10.1007/BF03007589", "fulltext": null, "fulltext_license": null, "issn_linking": "0832-610X", "issue": "38(4 Pt 1)", "journal": "Canadian journal of anaesthesia = Journal canadien d'anesthesie", "keywords": null, "medline_ta": "Can J Anaesth", "mesh_terms": "D002315:Cardiopulmonary Bypass; D005260:Female; D005665:Furosemide; D006330:Heart Defects, Congenital; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D013617:Tachycardia, Supraventricular", "nlm_unique_id": "8701709", "other_id": null, "pages": "502-5", "pmc": null, "pmid": "2065418", "pubdate": "1991-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "5358152;4182436;728311;686480;636561;3882391;3369300;5576449;3711429;4177503;3987321;6618550;4705138;6650766;3943393;1147715;7002435", "title": "Supraventricular tachycardia associated with continuous furosemide infusion.", "title_normalized": "supraventricular tachycardia associated with continuous furosemide infusion" }

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SUPRAVENTRICULAR TACHYCARDIA ASSOCIATED WITH CONTINUOUS FUROSEMIDE INFUSION. CANADIAN JOURNAL OF ANAESTHESIA. 1991?38:4:502?505", "literaturereference_normalized": "supraventricular tachycardia associated with continuous furosemide infusion", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20210409", "receivedate": "20210409", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19117722, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated-conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF. Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25-83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1- <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate. Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage. Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.", "affiliations": "Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Institute of Rheumatology, Zenjinkai Shimin-No-Mori Hospital, Miyazaki, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Institute of Rheumatology, Zenjinkai Shimin-No-Mori Hospital, Miyazaki, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Matsubara Mayflower Hospital, Kato, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.", "authors": "Nozaki|Yuji|Y|;Hidaka|Toshihiko|T|;Ri|Jinhai|J|;Itami|Tetsu|T|;Tomita|Daisuke|D|;Okada|Akinori|A|;Ashida|Chisato|C|;Ikeda|Fusayo|F|;Yamamoto|Atsuhiro|A|;Funahashi|Keiko|K|;Kinoshita|Koji|K|;Matsubara|Tsukasa|T|;Funauchi|Masanori|M|;Matsumura|Itaru|I|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fmed.2021.643459", "fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.643459\nMedicine\nOriginal Research\nReal-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizumab Pegol With Rheumatoid Arthritis\nNozaki Yuji 1*\n\nHidaka Toshihiko 2\nRi Jinhai 1\nItami Tetsu 1\nTomita Daisuke 1\nOkada Akinori 1\nAshida Chisato 1\nIkeda Fusayo 1\nYamamoto Atsuhiro 1\nFunahashi Keiko 2\n\nKinoshita Koji 1\n\nMatsubara Tsukasa 3\nFunauchi Masanori 1\nMatsumura Itaru 1\n1Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan\n2Institute of Rheumatology, Zenjinkai Shimin-No-Mori Hospital, Miyazaki, Japan\n3Matsubara Mayflower Hospital, Kato, Japan\nEdited by: Enrique Roberto Soriano, Italian Hospital of Buenos Aires, Argentina\n\nReviewed by: Javier Eduardo Rosa, Italian Hospital of Buenos Aires, Argentina; Jose A. Gómez-Puerta, Hospital Clínic de Barcelona, Spain\n\n*Correspondence: Yuji Nozaki yuji0516@med.kindai.ac.jp\nThis article was submitted to Rheumatology, a section of the journal Frontiers in Medicine\n\n21 4 2021\n2021\n8 64345918 12 2020\n22 2 2021\nCopyright © 2021 Nozaki, Hidaka, Ri, Itami, Tomita, Okada, Ashida, Ikeda, Yamamoto, Funahashi, Kinoshita, Matsubara, Funauchi and Matsumura.\n2021\nNozaki, Hidaka, Ri, Itami, Tomita, Okada, Ashida, Ikeda, Yamamoto, Funahashi, Kinoshita, Matsubara, Funauchi and Matsumura\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nObjective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated–conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF.\n\nPatients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25–83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1– <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate.\n\nResults: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage.\n\nConclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.\n\ncytokines\nrheumatoid arthritis\nbiological\nX ray\nDAS28-ESR\ncertolizumab pegol\n==== Body\nIntroduction\n\nThe treatment of rheumatoid arthritis (RA) has greatly progressed with the use of new biological agents including tumor necrosis factor (TNF) inhibitors, which have been observed to be efficacious for RA when administered in combination with the chemotherapy agent methotrexate (MTX). The recommended dose of MTX in the USA and Europe is 15–25 mg/week (1–3); the maximum dose in Japan is 16 mg/week. High-dose MTX has been demonstrated to increase the effectiveness of TNF inhibitors in early-stage RA and established RA. For example, in the Combination Therapy with Adalimumab in Subjects with Early Rheumatoid Arthritis (CONCERTO) study, high-dose (i.e., 20 mg/week) MTX administered in a regimen with the TNF inhibitor adalimumab (ADA) resulted in a three-fold higher remission rate than low-dose (2.5 mg/week) MTX with ADA in bio-naive patients with early-stage RA (4). However, high-dose MTX cannot be used for all patients for reasons such as tolerability concerns, contraindications related to its antimetabolite action, and lack of effectiveness (4).\n\nCertolizumab pegol (CZP) is used to treat RA. CZP is a pegylated–conjugated Fab′ fragment of a humanized anti-TNF antibody that has high affinity to TNF. CZP does not have an Fc region; its use may therefore avoid the risk of Fc-mediated effects such as complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which have been observed in vitro; attachment of the polyethylene glycol moiety of CZP to the Fab' fragment yields a molecule with a plasma half-life of ~2 weeks (5). Patients with early-stage RA have been treated with MTX in combination with CZP, and the effectiveness and safety of such a regimen were assessed in the Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA) study (6). In the randomized, placebo-controlled J-RAPID trial, CZP with MTX (average 11.4 ± 3.1 mg/week) provided a rapid reduction in RA signs and symptoms and the inhibition of structural joint damage in Japanese patients with active RA who had an inadequate response to MTX (7).\n\nHowever, there has been no investigation of the effects of the dose of MTX on the efficacy of CZP and bone destruction in patients with established RA. We conducted the present prospective study to determine whether a concomitant dose of MTX affected CZP's treatment of RA and the retention rate. We divided CZP-treated patients with RA into those treated or not treated with concomitant MTX. We also classified the patients who were treated with concomitant MTX into two groups based on their average weekly dose of MTX: the low-dose (LD) patients who received 1– <7 mg MTX and the high-dose (HD) patients who received ≥8 mg MTX. We prospectively examined the effects of these concomitant MTX dose by using registry data on actual clinical use.\n\nPatients and Methods\n\nPatients\n\nWe examined the cases of 95 Japanese individuals diagnosed with RA based on the American College of Rheumatology (ACR) criteria (8) who had had active RA for ≥6 months despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARD). We excluded patients who had any of the following: other connective tissue disease with joint symptoms; hepatitis B, hepatitis C, or human immunodeficiency virus; a serious or opportunistic infection within 6 months prior to study enrollment; active tuberculosis; or chronic infectious diseases.\n\nThe enrolled patients were 25–83 years old and received a stable MTX dose (up to 16 mg/week). They meet the following additional criteria: ≥6 or more swollen joint count (SJC) and ≥6 tender joint count (TJC) and ≥2 of the following: a C-reactive protein (CRP) value ≥2.0 mg/dl; an erythrocyte sedimentation rate (ESR) ≥28 mm/h; a global health score ≥20 mm on a 0–100 mm patient's visual analog scale (PtVAS) in which 0 is the best score and 100 is the worst; radiography-documented evidence of bone erosion; and positive status for rheumatoid factor (RF) or anticyclic citrullinated peptide antibodies (ACPA). All of the patients underwent screening for latent and active tuberculosis.\n\nWe divided the 95 RA patients treated with CZP into those concomitantly treated with (n = 65) vs. without (n = 30) MTX. We also divided the CZP + MTX-treated patients into those treated with low-dose (1– <8 mg) MTX (n = 24; the LD group) or high-dose (≥8 mg) MTX (n = 41, the HD group). Concomitant treatment with an oral corticosteroid was permitted, e.g., a stable dose ≤10 mg of prednisolone(PSL)/day or an equivalent.\n\nThe treatment regimens were as follows. For weeks 0, 2, and 4, the patients received CZP (200 or 400 mg) subcutaneously with or without a 400 mg CZP loading dose. The patients were then treated every other week with 200 or 400 mg CZP, with or without a concomitant high or low dose of MTX through the follow-up. For the patients being treated with PSL, decreased treatment effectiveness was observed with the dose.\n\nCompliance With Ethical Standards\n\nThe patients were enrolled from March 2009 to April 2020 and were treated at Matsubara Mayflower Hospital, Zenjinkai Shimin-no-mori Hospital, and Kindai Hospital in Japan. The study was conducted in accord with the principles of the Helsinki Declaration of 1983 and was approved by the Research Ethics Committee of Kindai University of Medicine (30–2688). For this prospective cohort study, the patients' fully informed consents were obtained with written agreement.\n\nClinical Assessments\n\nAt baseline, the patients' demographic characteristics were obtained (e.g., sex, age, disease duration, and current therapy). At each control visit, the laboratory tests below were performed. Each patient's value of RF (U/ml), ACPA (U/ml), and matrix metalloproteinase-3 (MMP-3; ng/ml) were also measured at baseline.\n\nThe following data were obtained at each visit from baseline to 12 months: the patients' scores on the Disease Activity Score assessing 28 joints with the erythrocyte sedimentation rate (DAS28-ESR), their TJC and SJC among 28 joints (both assessed by the patient's treating physician), the PtVAS score, and two laboratory parameters, i.e., CRP (mg/dl) and ESR (mm/h). We used the established definitions for evaluating RA disease activity. Regarding the categories of DAS28-ESR disease activity (9), we divided the patients into those at remission (DAS28-ESR <2.6) and those not in remission: low, 2.6 ≤ DAS28-ESR <3.2; moderate, DAS28-ESR 3.2–5.1; or high disease activity, DAS28-ESR >5.2. We defined clinical remission as the achievement of a DAS28-ESR value <2.6 and ≤1 on all four of the following ACR/European League against Rheumatism (EULAR) Boolean-based criteria (10): the number of TJC and SJC, the CRP and the PtVAS (the 100-mm visual analog scale data were converted to centimeters).\n\nAs the endpoint for the patients' clinical response to the treatments, we used their DAS28-ESR scores at 1, 3, 6, and 12 months. We also evaluated the patients' EULAR responses (11) at 1, 3, 6, and 12 months. Each patient's physical function was evaluated at baseline based on the Health Assessment Questionnaire Disability Index (HAQDI) (12).\n\nRadiographic Assessment\n\nAt baseline and at 12 months, plain radiographs of the patient's hands and feet were obtained, evaluated, and scored using both the Steinbrocker class and the modified Sharp/van der Heijde scoring system (13, 14). Two readers who were blinded to the patients' sequence and treatment reviewed the baseline and 12 months radiographs, and previous radiographs were reread concurrently with year 2 films.\n\nWe also calculated the mean changes from the baseline in the erosion score (ES), the modified total Sharp score (mTSS), and the joint space narrowing (JSN) score with the possible range of 0–390. We defined radiographic non-progression as an mTSS score ≤0.5. The smallest detectable change, an estimate of the measurement error between readers of the films (15), was also used.\n\nSafety\n\nEach patient's treating physician recorded any adverse events (AEs) and made necessary treatment adjustments in accord with the study protocol. Any adverse reaction resulting in any of the following outcomes was considered a serious AE: hospitalization or prolongation of hospitalization, a life-threatening condition or death, a significant or permanent disability, a malignancy, a congenital abnormality, or a birth defect. Chest radiographs, electrocardiograms, and laboratory values, i.e., hematological, blood chemistry, and urinalysis values, were also evaluated.\n\nStatistical Analyses\n\nContinuous variables were examined with summary statistics of the mean and standard deviation (SD) or the median and interquartile range (IQR) when appropriate. The categorical variables are shown as percentages. We used the Mann–Whitney test to compare independent means and the χ2 test to evaluate the relationships between categorical variables. The survival (retention) rate of this CZP-treated cohort was assessed by obtaining the Kaplan–Meier curves, and we used the log-rank test to examine the differences in retention curves. When data were missing, they were imputed (with the use of linear extrapolation for mTSS data) and with the last observation carried forward (LOCF) for all other effectiveness variables. Continuous variables were assessed using analysis of variance (ANOVA). Tukey's post-hoc analyses were computed when significant F ratios were obtained. Statistical significance was defined as a p < 0.05. All of the statistical analyses were performed with the GraphPad Prism program (GraphPad Software, San Diego, CA, USA) or JMP software (SAS, Cary, NC).\n\nResults\n\nThe Patients' Characteristics\n\nWe retrospectively analyzed the cases of 95 RA patients treated with CZP with (n = 65) or without concomitant MTX (n = 30). Of the patients treated with MTX, 41 were treated with high-dose MTX (the HD group), and the other 24 patients were treated with low-dose MTX (the LD group) continuously throughout the study period. These groups' baseline characteristics, laboratory findings, and treatment are summarized in Table 1.\n\nTable 1 The 95 RA patients' baseline clinical and laboratory data, and treatment information.\n\n\tCZP with MTX (LD)\tCZP with MTX (HD)\tCZP with MTX\tCZP without MTX\tAll CZP\tp\t\nNo. of patients\t24\t41\t65\t30\t95\t\t\nAge, years\t53.0 ± 15.9\t49.7 ± 15.2\t50.7 ± 15.4\t54.6 ± 16.8\t51.7 ± 15.8\t0.3\t\nFemale, (%)\t87.0\t68.3\t75.4\t79.3\t73.0\t0.3\t\nDisease duration, months\t69.0 [16.0–129.0]\t60.0 [13.5–114.0]\t66.0 [15.0–119.5]\t54.0 [28.0–106.0]\t62.0 [22.0–114.0]\t0.6\t\nBio naïve, %\t59.1\t61.0\t60.3\t67.9\t61.2\t0.8\t\nRF, positive (%)\t76.2\t66.7\t70.4\t73.1\t70.7\t0.8\t\nRF titers, IU/ml [IQR]\t51.0 [12.8–109.0]\t30.0 [5.8–94.2]\t40.5 [6.1–94.2]\t61.5 [8.5–163.5]\t45.5 [7.3–122.7]\t0.6\t\nACPA, (%)\t73.3\t73.1\t73.2\t76.5\t74.1\t1.0\t\nACPA titers, Al/ml [IQR]\t37.2 [1.4–72.9]\t35.7 [1.7–143.7]\t37.2 [1.7–128.9]\t55.7 [0.3–122.0]\t37.8 [1.4–120.0]\t0.9\t\nCRP, mg/dl [IQR]\t0.7 [0.2–2.6]\t1.0 [0.2–2.9]\t1.0 [0.2–2.6]\t1.3 [0.4–2.5]\t1.0 [0.3–2.6]\t0.9\t\nESR, mm/h [IQR]\t34.9 ± 21.1\t39.1 ± 29.1\t37.6 ± 26.4\t43.7 ± 31.1\t39.5 ± 27.9\t0.5\t\nMMP-3, ng/ml [IQR]\t107.5 [53.7–432.5]\t126.1 [52.8–126.1]\t121.2 [52.9–287.9]\t156.1 [105.8–330.4]\t130.9 [66.8–336.8]\t0.7\t\nTender joints, range 0–28 [IQR]\t7.0 [2.0–10.0]\t6.0 [2.0–10.0]\t6.0 [1.0–10.0]\t6.5 [4.0–11.5]\t6.0 [2.0–10.8]\t0.9\t\nSwollen joints, range 0–28 [IQR]\t5.0 [2.0–12.0]\t5.0 [2.0–10.0]\t5.0 [2.0–10.8]\t5.0 [2.0–10.8]\t5.0 [2.0–10.8]\t1.0\t\nPt VAS, 0–100 mm\t50.0 [25.0–71.0]\t50.0 [20.0–76.0]\t50.0 [23.5–70.8]\t62.5 [40.0–70.0]\t51.2 ± 27.4\t0.6\t\nDAS28-ESR\t5.0 ± 0.4\t5.0 ± 0.3\t5.2 ± 1.6\t5.0 ± 1.8\t5.1 ± 1.7\t0.8\t\nCDAI score\t25.2 ± 16.8\t24.0 ± 15.4\t24.4 ± 15.8\t25.1 ± 12.6\t24.6 ± 14.9\t0.9\t\nTotal sharp score 0–448 [IQR]\t25.3 [10.6–53.3]\t7.3 [0.0–30.6]\t14.5 [2.0–42.3]\t5.5 [1.0–46.8]\t12.5 [1.8–42.3]\t1.0\t\nJoint narrowing score [IQR]\t10.3 [0.5–33.4]\t5.0 [0.0–19.4]\t7.5 [0.0–23.8]\t3.5 [0.6–9.3]\t6.0 [0.4–21.2]\t0.2\t\nErosive score [IQR]\t7.8 [1.0–26.5]\t5.3 [0.0–13.9]\t7.3 [0.4–23.5]\t2.5 [0.5–7.9]\t4.0 [0.5–20.8]\t0.2\t\nSteinbrocker stage (I/II/III/IV)\t(19.1/42.9/23.8/14.3)\t(39.5/29.0/15.8/15.8)\t(30.4/33.9/19.6/16.1)\t(29.2/33.3/20.8/16.7)\t(30.0/33.8/20.0/16.2)\t0.8\t\nSteinbrocker class (I/II/III/IV)\t(31.3/50.0/18.8/0.0)\t(40.9/54.5/5.0/0.0)\t(45.8/45.8/6.8/1.7)\t(35.7/50.0/14.3/0.0)\t(42.6/47.1/9.2/1.1)\t0.4\t\nHAQDI, range 0–3\t1.0 [0.2–1.6]\t1.0 [0.4–1.5]\t1.0 [0.4–1.6]\t1.1 [0.6–2.0]\t1.0 [0.6–1.8]\t0.5\t\nCZP loading, %\t78.9\t81.8\t79.8\t80.4\t80.0\t0.7\t\nMTX, %, mg/week [IQR]\t100, 6.0 [4.0–6.0]\t100, 10.0 [8.0–10.0]\t100, 8.0 [6.0–10.0]\t0, 0\t69.1, 6.0 [0.0–8.0]\t<0.0001*\t\nPSL, %, mg/day [IQR]\t34.8, 0.0 [0.0–2.5]\t51.2, 0.5 [0.0–4.3]\t46.9, 0.0 [0.0–4.0]\t58.6, 3.3 [0.0–7.1]*\t50.5, 0.0 [0.0–5.0]\t0.1\t\nValues are median [25th−75th centiles] or mean (SD), unless otherwise indicated.\n\n* p < 0.0001, CZP without MTX vs. other groups, CZP with MTX (LD) vs. other groups, CZP with MTX (HD) vs. other groups.\n\nACPA, anticitrullinated peptide antibody; CDAI, clinical disease activity index; CRP, C-reactive protein; DAS, disease activity score; ESR, erythrocyte sedimentation rate; HAQDI, Health Assessment Questionnaire Disability Index; IQR, interquartile range; MMP-3, matrix metalloproteinase-3; MTX, methotrexate; PSL, prednisolone; Pt-VAS, patient visual analog scale; RF, rheumatoid factor.\n\nOur analyses revealed no significant between-group background differences in age, sex, disease duration, percentage of bio-naive patients, the proportions of Steinbrocker stages and classes, steroid dose, positive percentage or titers of RF and ACPA, the DAS28-ESR, CDAI, and HAQDI, or the total Sharp score at baseline.\n\nRetention Rate\n\nFigure 1 illustrates the retention rates in the RA patients treated with CZP and with/without concomitant high- or low-dose MTX for the 12-month study period. Figure 1 also provides the overall retention rate over the study period, based on withdrawal from treatment for any of the following reasons: lack of effectiveness, one or more AEs, the patient's request, or sustained remission. At 12 months, the retention rates of all of the CZP treatments were 88.9% (Figure 1), and those in the without- and with-MTX groups were 84.6 and 87.1%, respectively. At 12 months, there was no significant difference between the CZP retention rates of the LD and HD groups at 79.3 and 88.3%, respectively.\n\nFigure 1 Retention rates. Kaplan–Meier curves for all CZP treatments, low- (2– <8 mg) and high-dose MTX (≥8 mg), with MTX, and without and with MTX group regarding the time of withdrawal due to lack of effectiveness, adverse effects, or the patient's request from the start of CZP to 12 months. CZP, certolizumab pegol; MTX, methotrexate.\n\nClinical Effectiveness\n\nThe changes in the patients' baseline values demonstrated the disease activity at 1, 3, 6, and 12 months are summarized in Table 2: those of the DAS28-ESR and CDAI scores; the TJC28, SJC28, and PtVAS as clinical parameters; and the laboratory data of CRP, ESR, RF, and MMP-3. In all of the treatment groups, significant reductions were observed in the values of the DAS28-ESR, CDAI, TJC, SJC, and PtVAS as the clinical parameters and CRP as the laboratory data at 1, 3, 6, and 12 months compared to baseline. On the other hand, there were no significant differences in the MMP-3 value or RF titer at 1 month or during the 12-month treatment period compared to the baseline in any of the treatment groups.\n\nTable 2 Clinical parameters and laboratory values during follow-up.\n\n\tCZP+MTX (LD)\tCZP+MTX (HD)\tCZP with MTX\tCZP without MTX\tALL CZP\t\t\n\tBaseline\t1 m\t3 m\t6 m\t12 m\tBaseline\t1 m\t3 m\t6 m\t12 m\tBaseline\t1 m\t3 m\t6 m\t12 m\tBaseline\t1 m\t3 m\t6 m\t12 m\tBaseline\t1 m\t3 m\t6 m\t12 m\tp-value\t\nClinical parameters\t\nDAS28-ESR\t5\t4.1\t3.6**\t3.3†\t2.7#\t4.9\t3.3†\t2.8#\t2.8#\t2.4#\t5\t3.6#\t3.0#\t2.9#\t2.5#\t5.2\t3.8#\t3.3#\t3.3#\t3.1#\t5\t3.6#\t3.1#\t3.0#\t2.7#\t0.7\t\nCDAI score\t25.2\t16.8\t11.5**\t9.7†\t6.0#\t23.5\t10.0#\t7.7#\t6.4#\t4.9#\t23.9\t12.1#\t8.9#\t7.6#\t5.4#\t25.4\t12.8#\t9.9#\t8.6#\t7.5#\t24.4\t12.3#\t9.2#\t7.9#\t6.0#\t0.8\t\nTender joints, range 0–28 [IQR]\t8.4\t5.8\t4.3\t3.4*\t1.8#\t7.4\t3.5#\t2.2#\t2.3#\t1.6#\t7.7\t4.1#\t2.8#\t2.7#\t1.7#\t7.9\t3.8#\t3.0#\t2.5#\t2.0#\t7.7\t4.0#\t2.9#\t2.6#\t1.8#\t0.8\t\nSwollen joints, range 0–28 [IQR]\t6.5\t3.7\t2.3**\t1.4†\t1.3#\t6.6\t2.5#\t2.1#\t2.3#\t1.1#\t6.5\t2.9#\t2.2#\t2.0#\t1.2#\t6.9\t3.8#\t2.5#\t1.6#\t1.6#\t6.6\t3.1#\t2.3#\t1.9#\t1.3#\t0.9\t\nPt VAS, 0–100 mm\t49.2\t38.2\t27.9*\t25.1*\t16.2#\t49.2\t21.6†\t18.4#\t17.4#\t11.6#\t49.2\t27.2#\t21.5#\t20.1#\t14.1#\t55.8\t29.7#\t24.0#\t24.9#\t21.2#\t51\t27.9#\t22.2#\t21.5#\t16.2#\t0.6\t\nLaboratory parameters\t\nCRP, mg/dl [IQR]\t1.7\t0.7*\t0.4*\t0.3**\t0.2**\t2\t0.6**\t0.4†\t0.6**\t0.4†\t2\t0.6#\t0.4#\t0.5#\t0.3#\t1.9\t0.8#\t0.5#\t0.7#\t0.5#\t1.9\t0.7#\t0.5#\t0.5#\t0.4#\t0.8\t\nESR, mm/h [IQR]\t34.9\t24.6\t21.8*\t19.4**\t19.3*\t37.8\t21.9**\t18.5†\t20.4**\t17.5†\t37.4\t23.4†\t20.0#\t20.0#\t18.1#\t42.4\t31.0†\t27.7#\t27.9#\t28.1#\t38.9\t25.7#\t22.0#\t22.4#\t21.1#\t0.5\t\nRF titer, IU/ml [IQR]\t70.6\t51.6\t52.4\t60.2\t38\t87.8\t92.5\t86.8\t80.9\t77.7\t80.1\t72.9\t72.1\t73.4\t63.9\t113.1\t89\t93.2\t101.1\t127.9\t89.8\t77.7\t78.4\t81.9\t84.2\t0.5\t\nMMP-3, ng/ml [IQR]\t214.8\t235.8\t101.2\t119\t97.5*\t201.2\t77.3\t58.7\t98.8*\t83.4**\t214.5\t162\t76.9*\t105.6**\t88.1†\t227.3\t111\t119.6\t122.0*\t80.9†\t218.2\t146.9\t94.7\t110.4#\t86.1#\t0.6\t\nSerial changes in DAS28-ESR, CDAI, TJC, SJC, PtVAS as the clinical parameters and CRP, ESR, RF, and MMP-3 as the laboratory data from baseline in the patients with CZP in the combination of MTX who were classified into the following two groups according to the average weekly dose of concomitant MTX as LD group, 1 to <8 mg and HD group, 8 mg ≤. Statistical analysis was by a log-rank t-test. Values are median [25th−75th centiles] as tender joints, swollen joints, Pt VAS, CRP, RF titers, MMP-3, and the dosage of MTX and PSL or mean (SD) as DAS28-ESR, CDAI score, and ESR unless otherwise indicated. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; MTX, methotrexate; PSL, prednisolone; Pt-VAS, patient visual analog scale; RF, rheumatoid factor.\n\n* p < 0.05,\n\n** p < 0.005,\n\n† p < 0.001 and\n\n# p < 0.0001, baseline vs. the value at 1, 3, 6, and 12 months.\n\nP-values at baseline were also analyzed and no significant differences in all treatment groups by ANOVA analysis.\n\nFigure 2 provides the DAS-ESR values from baseline as the clinical response in the patients in each group. In the all-CZP-treatment cohort, the DAS28-ESR shows an early decline from baseline, and there were significant reductions at 1, 3, 6, and 12 months (Figures 2A–C). No significant difference in the DAS28-ESR was detected between the CZP without- and with-MTX groups over the 12 months (Figure 2B). However, the DAS28-ESR values were significantly lower in the group of patients treated with CZP and LD-MTX compared to those treated with HD-MTX at 1 and 3 months, although the difference between these groups disappeared at 6 and 12 months (Figure 2C).\n\nFigure 2 Clinical and laboratory data from baseline in certolizumab pegol (CZP) without and with methotrexate (MTX) in the clinical course. Serial changes in DAS28-ESR from baseline in (A) all CZP treatments, (B) with and without MTX, and (C) the low- and high-dose MTX. *p < 0.05 and †p < 0.001, baseline vs. the value at 1, 3, 6, and 12 months. DAS28-ESR, Disease Activity Score assessing 28 joints with erythrocyte sedimentation rate.\n\nWe evaluated the proportions of disease activity by assessing the DAS28-ESR in the all-CZP cohort, the LD and HD-MTX groups, and the groups with and without MTX (Figure 3A). At 12 months, the proportions of patients with low disease activity (LDA) including remission based on DAS28-ESR criteria were as follows: LD-MTX, 68.4%; HD-MTX, 82.9%; with MTX, 77.8%; without MTX, 55.5%; and all CZP treatments, 60.9% (Figure 3B). We also evaluated remission based on ACR/EULAR Boolean-based criteria at 12 months, and we observed no significant differences: LD-MTX, 35.0%; HD-MTX, 34.3%; with MTX, 34.6%; without MTX, 19.1%; and all CZP treatments, 30.3% (Figure 3C).\n\nFigure 3 Disease activity in DAS28-ESR and ACR/EULAR Boolean-based criteria. By comparing the RA patients' DAS28-ESR scores at baseline and at 1, 3, 6, and 12 months, it is possible to define (A) disease activity, (B) low disease activity including remission, and (C) Boolean-based criteria in RA patients with the low- and high-dose MTX, with MTX, and without and with MTX, and all CZP treatments. The disease activity and criteria in DAS28-ESR were categorized as follows. DAS28 criteria: ■ high: 5.1 <DAS28; moderate, 3.2 ≤ DAS28 ≤ 5.1; low, 2.6 ≤ DAS28 <3.2; □ remission: DAS28 < 2.6. ACR/EULAR Boolean-based remission: TJC, SJC, PtVAS, and CRP all ≤1. CRP, C-reactive protein; EULAR, European League Against Rheumatism; PtVAS, patient's visual analog scale; RA, rheumatoid arthritis; SJC, swelling joint count; TJC, tender joint count.\n\nFigure 4 shows the EULAR responses at 1, 3, 6, and 12 months in all five groups. The rate of responders (good or moderate response) at 12 months was as follows: LD-MTX, 83.3%; HD-MTX, 88.2%; with MTX, 86.6%; without MTX, 91.0%; and all CZP treatments, 87.9%. At 1 and 3 months, the rate of good responders tended to be lower in the LD group compared to the HD group. The proportion of non-responder patients at 12 months were as follows: LD-MTX, 16.4%; HD-MTX, 15.4%; with MTX, 13.5%; without MTX, 9.1%; and all CZP treatments, 12.0%. There were no significant differences among any of the groups in the rate of responders or the rate of non-responders in EULAR response during the study period.\n\nFigure 4 Disease activity in EULAR response. By comparing the RA patients' DAS28-ESR scores at baseline and at 1, 3, 6, and 12 months, it is possible to define the EULAR response in RA patients in the low- and high-dose MTX, with MTX, and without and with MTX, and all CZP treatments. The EULAR responses were categorized as follows. ■ no response: DAS28 improvement ≤0.6 and DAS28 improvement >0.6 and ≤1.2 in present DAS28 >5.1. Moderate response: DAS28 improvement >0.6 and ≤1.2 in present DAS28 ≤3.2, and >3.2 and ≤5.1; DAS28 improvement >1.2 in present DAS28 >5.1, and >3.2 and ≤5.1. □ Good response: DAS28 improvement >1.2 in present DAS28 ≤3.2.\n\nRadiographic Progression\n\nSeventy-eight radiographs were assessed in the 95 patients treated with concomitant MTX (LD, n = 23 and HD, n = 35) and in 20 patients without MTX at 12 months (Figure 5). Regarding the joint space narrowing (JSN) score, erosion number, and TSS at baseline, all of the groups had similar values (Table 1). As shown in Figure 5A, at 12 months, there were no significant differences in all-CZP treatment cohort, LD and HD-MTX groups, and groups with and without MTX in the mean changes in JSN at 0.4 (0.1–0.8), 0.0 (−0.8–0.8), 0.4 (0.1–0.8), 0.5 (0.1–0.9), and 0.0 (−0.8–0.8); or in erosions at 0.4 (0.1–0.8), 0.1 (−0.5–0.7), 0.4 (−0.1–0.9), 0.5 (0.1–1.0), and 0.1 (−0.5–0.7); or in the TSS at 0.7 (0.2–1.3), 0.3 (−0.9–1.6), 0.9 (0.3–1.6), 0.8 (0.2–1.4), and 0.3 (−0.9–1.6), respectively. The percentages of patients with no progression of joint damage (i.e., improved or no change; ΔmTSS ≤0.5) were as follows: LD-MTX, 45.5%; HD-MTX, 68.6%, with MTX, 63.0%; without MTX, 72.2%; and all CZP treatments, 67.2% (Figure 5B).\n\nFigure 5 Joint damage in radiographic assessment. The progression of joint damage in RA patients in the low- and high-dose MTX, with MTX, and without and with MTX, and all CZP treatments according to the modified total Sharp score (mTSS) at 12 months. (A) The change in mTSS from baseline. (B) The rate of patients with progression, no change, or improvement in the mTSS (ΔmTSS ≤0.5).\n\nAdverse Events\n\nTable 3 lists the treatment AEs: pneumonia, herpes zoster, and interstitial lung disease as serious AEs, and upper respiratory infection, thrombocytopenia, and rash during the 12 months after the start of CZP administration. During the 12-month study period, there was no significant difference in the cumulative rate of any of the AEs among any of the patient groups: LD-MTX, 17.1%; HD-MTX, 25.0%; with MTX, 21.5%; without MTX, 23.3%; and all CZP treatments, 21.1%. Serious infections occurred in 7.7% of the CZP with MTX group [pneumonia (n = 3), interstitial lung disease (n = 1)] and in 10.0% of the CZP without MTX group (one patient with pneumonia and herpes zoster). There were no significant differences in the rate of serious AEs between the HD and LD groups (7.3 and 4.2%). However, the incidence of any AE tended to be lower incidences in the LD group than the HD group. None of the patients treated with CZP experienced any AE that was serious enough to result in treatment discontinuation.\n\nTable 3 Adverse events observed over 12 months resulting in CZP administration.\n\nTreatment group\tCZP+MTX (LD)\tCZP+MTX (HD)\tCZP +MTX\tCZP without MTX\tAll CZP\tp\t\nNo. of patients\t24\t41\t65\t30\t95\t\t\nAny AEs, n (%)\t7 (17.1)\t6 (25.0)\t14 (21.5)\t7 (23.3)\t20 (21.1)\t0.9\t\nUpper respiratory infection, n (%)\t5 (12.2)\t3 (12.5)\t8 (12.3)\t3 (10.0)\t10 (10.5)\t0.7\t\nThrombocytopenia, n (%)\t0 (0.0)\t1 (2.4)\t1 (1.5)\t0 (0.0)\t1 (1.1)\t1.0\t\nRash, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1 (3.3)\t1 (1.1)\t0.8\t\nSerious AE, n (%)\t1 (4.2)\t3 (7.3)\t5 (7.7)\t3 (10.0)\t7 (7.4)\t0.6\t\nPneumonia, n (%)\t1 (4.2)\t2 (4.9)\t3 (4.6)\t1 (3.3)\t4 (4.2)\t0.9\t\nHerpes zoster, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1 (4.5)\t1 (1.1)\t0.5\t\nInterstitial lung disease, n (%)\t0 (0.0)\t1 (2.4)\t1 (1.5)\t0 (0.0)\t1 (1.1)\t0.3\t\nDeath, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1.00\t\nAE, adverse event; CZP, certolizumab pegol; MTX, methotrexate.\n\nDiscussion\n\nIn this study, there were no differences in clinical effectiveness and radiographic inhibition in patients treated with CZP, with the high or low MTX doses or without concomitant MTX in Japanese patients with RA. MTX has very good cost effectiveness and a good efficacy/toxicity ratio, but its toxicity remains a concern. The potential AEs associated with MTX (e.g., nausea, headache, fatigue, mucositis, and alopecia) have been examined in part because they are a major cause of drug withdrawal (16–18). MTX-associated hepatotoxicity is frequent in RA patients, but mild and transient, not needing either drug interruption or dose adjustment in the majority of these cases (19). The exact mechanism of MTX toxicity is not yet clear. The same or differing metabolic pathways may be involved in the mechanisms underlying the efficacy and toxicity of MTX.\n\nThe use of a TNF antagonist has been advised when active disease remains after the optimization of non-biological therapy with DMARDs. For RA patients with high disease activity and risk factors associated with poor prognosis (e.g., high ACPA or RF titer, erosive disease), the early initiation of biological therapy to reduce joint damage and functional decline is recommended (20). Combination therapy with a TNF inhibitor and MTX has been demonstrated to significantly improve the clinical manifestations of RA, toward the goal of achieving remission or low disease activity (1, 2, 20, 21).\n\nThe CONCERTO study of the TNF inhibitor adalimumab in early RA revealed a trend toward improved efficacy when the dose of MTX was increased from 2.5 mg/week to 20 mg/week (4). Conversely, in MTX-naive patients with early RA and one or more poor-prognosis factors, CZP + MTX was shown to significantly reduce structural damage and decrease disease activity, although there was no clear association between the MTX dose and joint suppression (22). The HIKARI study demonstrated significant clinical benefit, functional improvement, and structural protection in Japanese patients with RA treated with the TNF inhibitor etanercept without concomitant MTX (23).\n\nOur present study is the first to confirm that the treatment of RA in a Japanese population with CZP without MTX (either as CZP monotherapy or in combination with a non-MTX DMARD) was effective in controlling their clinical signs/symptoms and reducing the radiographic progression of joint damage due to RA, and our results confirm the safety of CZP.\n\nOne of the reported effects of the concomitant use of MTX is a reduction in the antidrug antibody (ADA) formation. Krieckaert et al. demonstrated that the rate of appearance of antiadalimumab (AAA) as an ADA was ~30% with concomitant MTX at ≤10 mg, but the rate of AAA appearance was <20% at concomitant MTX doses ≥12.5 mg (24). In their investigation of Japanese patients, Miyasaka observed that the rate of AAA positivity was high at 44%, indicating that there is a higher rate of AAA formation in Japanese RA patients (25).\n\nCertolizumab pegol is the only PEGylated TNF inhibitor. Polyethylene glycol (PEG) is a polyetherized repeating subunit of ethylene glycol of various molecular weights (5). PEG is commonly attached to proteins to increase their half-life in vivo. Certolizumab pegol is also a TNF inhibitor in which PEGs may optimize the delivery of neutralizing moieties by specifically targeting inflamed tissues in RA patients. In the inflamed synovium in RA, the disrupted endothelial tissue does not have the same barriers to diffusion as normal tissues and, therefore, may not be as effective as normal tissues (26).\n\nAnti-CZP antibodies have been detected in 5–6.4% of RA patients treated with CZP monotherapy or with concomitant MTX (27). In the J-RAPID study, anti-CZP antibodies were observed in 1.2% of the 200- and 400-mg CZP groups, although the MTX dose was set at 6–8 mg/week in accord with the approved dose in Japan at the time of this clinical trial (7). The lower incidence of ADA among RA patients treated with CZP might have affected the retention rate, clinical effectiveness, and bone destruction.\n\nThe results of the RA (RAPID)2 randomized controlled trial demonstrated that a loading dose of 400 mg at weeks 0, 2, and 4, then CZP (200 or 400 mg) every other week in combination with MTX provided significant and rapid improvements in the signs and symptoms of RA after 24 weeks of treatment (28). We attempted to perform a subanalysis to determine the effectiveness of loading treatment, but the number of patients was not sufficient for a statistical analysis of loading vs. non-loading as the initial treatment between groups receiving a low or high dose of concomitant MTX. It is difficult to treat some RA patients because of the above-mentioned problems presented by MTX, and it can be difficult to increase the MTX dose; these difficulties contribute to a reduced retention rate and effectiveness (29–31).\n\nWe observed no significant differences among any of the five present patient groups in the rates of retention and clinical remission, in structural protection (by analyses of the mTSS with the scores of erosion and joint space narrowing), or the non-progression rate. The reduction in DAS28-ESR was significantly greater in the CZP with high-dose MTX group compared to the CZP with low-dose group at 1 and 3 months, but there was no significant difference at 6 months. The rate of low disease activity (remission and good responders) tended to be higher in the patients treated with CZP and high-dose MTX compared to those treated with low-dose MTX. Conversely, there was no significant difference in the Boolean-based criteria between the CZP with HD vs. LD groups. In the patients treated without MTX, the rates of achieving LDA and the Boolean-based criteria tended to be lower than those of the other groups. These findings suggested that rheumatologists and patients should both take part in decisions about treatment goals based on the disease activity, progression of structural damage, and the safety issues when considering a CZP-only regimen or a combination with MTX (low or high dose) in light of potential complications such as interstitial pneumonia, liver and renal dysfunction, gastrointestinal disorder, and blood disorder.\n\nThis study has some limitations to address. The lack of randomization and blinding may have resulted in bias due to the selection of the patients and their indications. In clinical practice, only patients with RA who fail to respond to MTX would receive CZP with MTX, and thus, our CZP with MTX groups are likely to have included more MTX-resistant patients than the CZP without MTX group. This may have affected the therapeutic effectiveness. Second, only Japanese RA patients were analyzed in this clinical study. In addition, the mean MTX dose (8 mg) in our cohort is low compared to similar RA studies from the European Union and USA (15–17 mg/week) (1–3). However, the mean MTX dose was 7.4 mg/week in phase II/III clinical trials conducted in Japan (7), and the dose used herein is a standard dose in Japan considering body weight and MTX metabolism (32).\n\nThe study population was rather small (n = 95), which may have resulted in low statistical power and low precision of the analysis. Gender, disease duration, RF and ACPA positivity, and disease activity at baseline may also be variables that influence efficacy and retention, and our adjustment for confounders may be inadequate due to the small sample size. Because this was a retrospective study, there were no predetermined treatment discontinuation criteria. Discontinuation of treatment at the discretion of each physician may also lead to bias. A randomized controlled trial is essential to establish the effectiveness of CZP treatment with or without MTX. Nevertheless, the results of our analyses demonstrated that CZP treatment with and without MTX were effective to reduce the disease activity of RA and the progression of bone destruction.\n\nTo date, there have been no reports on the effectiveness of CZP treatment with or without MTX or on the dose of MTX used to treat RA patients in a real-world setting, and our present investigation is the first clinical study. In all of the relevant treatment guidelines, MTX is described as effective, well-tolerated by patients, affordable, and recommended. However, high-dose MTX cannot be administered to all patients due to contraindications related to its antimetabolite action, tolerability concerns, or lack of effectiveness.\n\nIn this study, the rates of retention and clinical remission and the inhibitory effect on radiographic joint damage were not significantly different among the all-CZP-treatment group, the with-MTX group, the without-MTX group, and the high- and low-dose MTX groups. As real-world data in the era of biological agents in patients with RA, despite the limitations of a retrospective, non-blinded, and non-randomized study, and limited to a selected Japanese population, there were no differences in clinical effectiveness and radiographic inhibition in patients treated with CZP, with the high or low MTX doses, or without concomitant MTX. However, the present study has a short follow-up period as well as administered low-dose MTX. Since its selected population is Japanese, these results might be only valid in a population especially sensitive to higher doses of MTX such as the Asian RA patients. Further studies are needed, and the clinical effectiveness and radiographic assessment should be evaluated in prospective, randomized, large cohort, and longer term in the global trials. In summary, CZP shows the potential to be a useful biological agent to control the disease activity and bone destruction in patients with RA who cannot tolerate a sufficient dose of MTX.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Research Ethics Committee of Kindai University of Medicine (30–2688). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nYN designed, performed, analyzed the study, drafted the manuscript, and analyzed the data. JR, DT, TI, AO, CA, FI, and AY are evaluated and scored using Steinbrocker class and the modified Sharp/van der Heijde scoring system. TH, TM, KF, KK, MF, and IM edited the manuscript. All authors contributed to the manuscript's revision, read, and approved the submitted version or confirms being the sole contributor of this work and has approved it for publication.\n\nConflict of Interest\n\nYN has received honoraria or research grant from AbbVie GK, Astellas Pharma, Asahi Kasei, AYUMI Pharmaceutical, Chugai Pharmaceutical Co., Eisai Co., Daiichi-Sankyo, MSD, Mitsubishi Tanabe Pharma Corp., Takeda, Ono, Otsuka Co., Pfizer, Janssen, and UCB Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1. Weinblatt ME Keystone EC Furst DE Moreland LW Weisman MH Birbara CA . Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 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(2014) 24 :715–24. 10.3109/14397595.2013.864224 24313916\n8. Arnett FC Edworthy SM Bloch DA McShane DJ Fries JF Cooper NS . The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. (1988) 31 :315–24. 10.1002/art.1780310302 3358796\n9. Prevoo ML van 't Hof MA Kuper HH van Leeuwen MA van de Putte LB van Riel PL . Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. (1995) 38 :44–8. 10.1002/art.1780380107 7818570\n10. Felson DT Smolen JS Wells G Zhang B van Tuyl LH Funovits J . American college of rheumatology/European league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. (2011) 70 :404–13. 10.1136/ard.2011.149765 21292833\n11. Smolen JS Landewé R Breedveld FC Dougados M Emery P Gaujoux-Viala C . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. (2010) 69 :964–75.20444750\n12. Fries JF Spitz P Kraines RG Holman HR . Measurement of patient outcome in arthritis. Arthritis Rheum. (1980) 23 :137–45. 10.1002/art.1780230202 7362664\n13. Kaye JJ Fuchs HA Moseley JW Nance EP Jr Callahan LF Pincus T . Problems with the Steinbrocker staging system for radiographic assessment of the rheumatoid hand and wrist. Invest Radiol. (1990) 25 :536–44. 10.1097/00004424-199005000-00011 2345085\n14. van der Heijde DM van Riel PL Nuver-Zwart IH Gribnau FW vad de Putte LB . Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet. (1989) 1 :1036–8. 10.1016/S0140-6736(89)92442-2 2565997\n15. Bruynesteyn K Boers M Kostense P van der Linden S van der Heijde D . Deciding on progression of joint damage in paired films of individual patients: smallest detectable difference or change. Ann Rheum Dis. (2005) 64 :179–82. 10.1136/ard.2003.018457 15286006\n16. Prey S Paul C . Effect of folic or folinic acid supplementation on methotrexate-associated safety and effectiveness in inflammatory disease: a systematic review. Br J Dermatol. (2009) 160 :622–8. 10.1111/j.1365-2133.2008.08876.x 18945303\n17. Schnabel A Gross WL . Low-dose methotrexate in rheumatic diseases – Effectiveness, side effects, and risk factors for side effects. Semin Arthritis Rheum. (1994) 23 :310–27. 10.1016/0049-0172(94)90027-2 8036521\n18. Romão VC Lima A Bernardes M Canhão H Fonseca JE . Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res. (2014) 60 :289–310. 10.1007/s12026-014-8564-6 25391609\n19. Visser K van der Heijde DM . Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol. (2009) 27 :1017–25.20149325\n20. St Clair EW van der Heijde DM Smolen JS Maini RN Bathon JM Emery P . Active-Controlled study of patients receiving infliximab for the treatment of rheumatoid arthritis of early onset study group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum. (2004) 50 :3432–43. 10.1002/art.20568 15529377\n21. The Japan College of Rheumatology and the Institute of Data Analysis. Study of Effectiveness and Safety of MTX at More Than 8 mg/week: Evaluation of 3 RA Patients Cohorts (IORRA, REAL and NinJa). Available online at: http://www.twmu.ac.jp/IOR/recruit/iorra.html\n22. Atsumi T Yamamoto K Takeuchi T Yamanaka H Ishiguro N Tanaka Y . The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression. Ann Rheum Dis. (2016) 75 :75–83. 10.1136/annrheumdis-2015-207511 26139005\n23. Yamamoto K Takeuchi T Yamanaka H Ishiguro N Tanaka Y Eguchi K . Effectiveness and safety of certolizumab pegol without methotrexate co-administration in Japanese patients with active rheumatoid arthritis: the HIKARI randomized, placebo-controlled trial. Mod Rheumatol. (2014) 24 :552–60. 10.3109/14397595.2013.843764 24981319\n24. Krieckaert CL Nurmohamed MT Wolbink GJ . Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. (2012) 71 :1914–5. 10.1136/annrheumdis-2012-201544 22586169\n25. Miyasaka N . CHANGE study investigators. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheumatol. (2008) 18 :252–62. 10.3109/s10165-008-0045-0 18330677\n26. Wang D Sima M Mosley RL Davda JP Tietze N Miller SC . Pharmacokinetic and biodistribution studies of a bone-targeting drug delivery system based on N-(2-hydroxypropyl) methacrylamide copolymers. Mol Pharm. (2006) 3 :717–25. 10.1021/mp0600539 17140259\n27. Keystone E Heijde Dv Mason D Jr Landewé R Vollenhoven RV Combe B . Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. (2008) 58 :3319–29. 10.1002/art.23964 18975346\n28. Smolen J Landewé RB Mease P Brzezicki J Mason D Luijtens K . Effectiveness and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis. (2009) 68 :797–804. 10.1136/ard.2008.101659 19015207\n29. Nozaki Y Inoue A Kinoshita K Funauchi M Matsumura I . Effectiveness of iguratimod vs. salazosulfapyridine as the first-line csDMARD for rheumatoid arthritis. Mod Rheumatol. (2020) 30 :249–58. 10.1080/14397595.2019.1572267 30676812\n30. Inoue A Nozaki Y Hirooka Y Kinoshita K Chiba Y Funauchi M . The effectiveness and retention rate of iguratimod in Japanese rheumatoid arthritis patients with/without methotrexate in daily medical care. Life. (2020) 10 :261. 10.3390/life10110261 33138014\n31. Nozaki Y Nagare Y Ashida C Tomita D Okada A Inoue A . Infliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients: REVIVE study results. Biologics. (2018) 12 :171–182. 10.2147/BTT.S187998 30568425\n32. Takahashi C Kaneko Y Okano Y Ooshima H Takeuchi T . THU0118 methotrexate polyglutamates in erythrocytes correlates with clinical response in Japanese patients with rheumatoid arthritis. Ann Rheum Dis. (2014) 73 (Suppl. 2 ):218–9. 10.1136/annrheumdis-2014-eular.3527\n\n", "fulltext_license": "CC BY", "issn_linking": "2296-858X", "issue": "8()", "journal": "Frontiers in medicine", "keywords": "DAS28-ESR; X ray; biological; certolizumab pegol; cytokines; rheumatoid arthritis", "medline_ta": "Front Med (Lausanne)", "mesh_terms": null, "nlm_unique_id": "101648047", "other_id": null, "pages": "643459", "pmc": null, "pmid": "33968956", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "17636564;8036521;7362664;25391609;2565997;12528101;24550168;2345085;3358796;19015207;33138014;15529377;21292833;22586169;7818570;20149325;20444750;18945303;30568425;17140259;18330677;30676812;15286006;26139005;24981319;28153828;24313916;16385520;18975346;15208176", "title": "Real-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizumab Pegol With Rheumatoid Arthritis.", "title_normalized": "real world methotrexate dose on clinical effectiveness and structural damage of certolizumab pegol with rheumatoid arthritis" }

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{ "abstract": "OBJECTIVE\nThe optimal timing of anti-tumor necrosis factor (anti-TNF) initiation in patients with ulcerative colitis (UC) remains unclear. Very little is known about the clinical outcomes after the early versus late initiation of anti-TNF therapy, especially in Asian UC patients. Here we aimed to assess whether earlier anti-TNF treatment initiation results in favorable clinical outcomes in Korean UC patients.\n\n\nMETHODS\nUsing the Korean National Health Insurance claims database, we studied patients who were diagnosed with UC and received anti-TNF therapy for more than 6 months between 2010 and 2016. Using a Cox proportional hazard model, clinical outcomes including colectomy, UC-related emergency room (ER) visits, UC-related hospitalizations, and the need for corticosteroids were compared between early (≤2 years of diagnosis) and late (>2 years of diagnosis) initiators of anti-TNF therapy.\n\n\nRESULTS\nAmong 17167 UC patients, 698 patients who received anti-TNF therapy for more than 6 months were included (420 infliximab, 242 adalimumab, and 36 golimumab). Of the 698 patients, 299 (42.8%) initiated anti-TNF therapy within 2 years of diagnosis. There were no significant differences in the risk of colectomy [adjusted hazard ratio (aHR), 0.41; 95% confidence interval (CI), 0.04-3.90], ER visits (aHR, 0.98; 95% CI, 0.50-1.92), hospitalization (aHR, 0.76; 95% CI, 0.57-1.01), and corticosteroid use (aHR, 1.04; 95% CI, 0.71-1.50) between early and late initiators of anti-TNF therapy.\n\n\nCONCLUSIONS\nPatients receiving early anti-TNF therapy had similar clinical outcomes to those of late initiators, suggesting that early anti-TNF therapy initiation offers little benefit in patients with UC.", "affiliations": "Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea.;Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. soheepark@yuhs.ac.;Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea.", "authors": "Han|Minkyung|M|https://orcid.org/0000-0002-5011-5557;Jung|Yoon Suk|YS|https://orcid.org/0000-0002-1963-7170;Cheon|Jae Hee|JH|https://orcid.org/0000-0002-2282-8904;Park|Sohee|S|https://orcid.org/0000-0001-8513-5163", "chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab", "country": "Korea (South)", "delete": false, "doi": "10.3349/ymj.2020.61.5.382", "fulltext": "\n==== Front\nYonsei Med J\nYonsei Med. J\nYMJ\nYonsei Medical Journal\n0513-5796 1976-2437 Yonsei University College of Medicine \n\n10.3349/ymj.2020.61.5.382\nOriginal Article\nGastroenterology & Hepatology\nSimilar Clinical Outcomes of Early and Late Anti-TNF Initiation for Ulcerative Colitis: A Nationwide Population-Based Study\nhttps://orcid.org/0000-0002-5011-5557Han Minkyung 1* https://orcid.org/0000-0002-1963-7170Jung Yoon Suk 2* https://orcid.org/0000-0002-2282-8904Cheon Jae Hee 3 https://orcid.org/0000-0001-8513-5163Park Sohee 4 1 Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea.\n2 Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.\n3 Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.\n4 Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea.\nCorresponding author: Sohee Park, PhD, Department of Biostatistics, Graduate School of Public Health, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: 82-2-2228-1532, Fax: 82-2-392-7734, soheepark@yuhs.acCorresponding author: Jae Hee Cheon, MD, PhD, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: 82-2-2228-1990, Fax: 82-2-393-6884, geniushee@yuhs.ac*Minkyung Han and Yoon Suk Jung contributed equally to this work.\n\n\n01 5 2020 \n24 4 2020 \n61 5 382 390\n13 2 2020 07 3 2020 25 3 2020 © Copyright: Yonsei University College of Medicine 20202020Yonsei University College of MedicineThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nThe optimal timing of anti-tumor necrosis factor (anti-TNF) initiation in patients with ulcerative colitis (UC) remains unclear. Very little is known about the clinical outcomes after the early versus late initiation of anti-TNF therapy, especially in Asian UC patients. Here we aimed to assess whether earlier anti-TNF treatment initiation results in favorable clinical outcomes in Korean UC patients.\n\nMaterials and Methods\nUsing the Korean National Health Insurance claims database, we studied patients who were diagnosed with UC and received anti-TNF therapy for more than 6 months between 2010 and 2016. Using a Cox proportional hazard model, clinical outcomes including colectomy, UC-related emergency room (ER) visits, UC-related hospitalizations, and the need for corticosteroids were compared between early (≤2 years of diagnosis) and late (>2 years of diagnosis) initiators of anti-TNF therapy.\n\nResults\nAmong 17167 UC patients, 698 patients who received anti-TNF therapy for more than 6 months were included (420 infliximab, 242 adalimumab, and 36 golimumab). Of the 698 patients, 299 (42.8%) initiated anti-TNF therapy within 2 years of diagnosis. There were no significant differences in the risk of colectomy [adjusted hazard ratio (aHR), 0.41; 95% confidence interval (CI), 0.04–3.90], ER visits (aHR, 0.98; 95% CI, 0.50–1.92), hospitalization (aHR, 0.76; 95% CI, 0.57–1.01), and corticosteroid use (aHR, 1.04; 95% CI, 0.71–1.50) between early and late initiators of anti-TNF therapy.\n\nConclusion\nPatients receiving early anti-TNF therapy had similar clinical outcomes to those of late initiators, suggesting that early anti-TNF therapy initiation offers little benefit in patients with UC.\n\nUlcerative colitisanti-TNFearly useclinical outcome\n==== Body\nINTRODUCTION\nUlcerative colitis (UC) is an inflammatory bowel disease that results in chronic inflammation of the large intestine due to immune dysregulation.1 UC is an incurable disease with alternating periods of remission and relapse. Due to this chronic clinical course, most patients with UC require life-long medical treatment. The medical treatment of UC has changed dramatically over the past decade, with the introduction of biological agents that target tumor necrosis factor-alpha (TNF-α).2 Pivotal randomized controlled trials (RCTs) demonstrated the efficacy of anti-TNF agents, including infliximab, adalimumab, and golimumab, for inducing and maintaining remission in patients with moderately to severely active UC.3456 Anti-TNF therapy targeting mucosal healing may also lead to changes in the natural course of UC. Indeed, previous RCTs demonstrated that anti-TNF therapy reduces the risk of colectomy and hospitalization.78\n\nHowever, the optimal timing of anti-TNF initiation in UC patients remains a challenging issue. Several studies have proven the benefit of earlier anti-TNF initiation on the clinical outcomes of patients with Crohn's disease (CD),91011 while very little is known about the effects of earlier anti-TNF initiation on the natural history of UC. The results of CD patients may not be generalized for UC patients, as the two diseases have different features. To date, only a few studies have examined the effect of earlier anti-TNF initiation on the clinical outcomes of UC.121314 However, the number of UC patients included in previous studies was insufficient to draw a clear conclusion. Furthermore, all previous studies on this topic were performed in Western countries,121314 and their results may not be generalizable in Asian UC patients. To better understand the association between anti-TNF initiation timing and clinical outcomes of UC, an analysis of population-based Asian data of a large number of patients is warranted.\n\nTherefore, in this nationwide population-based study of data from the South Korean health insurance claims database, we evaluated the impact of early initiation of anti-TNF therapy on the clinical outcomes [abdominal surgery, UC-related emergency room (ER) visits, UC-related hospitalization, and new corticosteroid use] of patients with UC during maintenance therapy in the real-life clinical setting.\n\nMATERIALS AND METHODS\nStudy design and data source\nThis study analyzed data from the National Health Insurance (NHI) claims database of South Korea, a mandatory nationwide health insurance program established by the Korean government that covers all forms of health-care utilization, including outpatient care, pharmaceutical services, and hospitalization, for the entire population of South Korea (approximately 51 million people). Medical institutions must electronically submit all information regarding health-care utilization for reimbursement; this information is registered in a comprehensive database operated by the Health Insurance and Review Agency (HIRA). The HIRA database contains information on personal demographics, outpatient and inpatient medical use, prescriptions, diagnostic and surgical procedures, as well as diagnoses identified by the International Classification of Diseases 10th revision (ICD-10) codes.151617 The source population for this study was NHI claims data registered between 2008 and 2016.\n\nPatient ascertainment and definitions\nTo improve the diagnostic accuracy of UC, only patients with data on both appropriate diagnostic codes and UC-related medicine prescriptions were included. The ICD-10 codes K51.0–51.9 indicate UC. UC-related medicine prescriptions were defined as prescriptions of 5-aminosalicylic acids (5-ASA) for ≥1 month, immunomodulators (azathioprine or 6-mercaptopurine) at least once, and/or biologics at least once.151617 To rule out the use of drugs for other autoimmune diseases, the included medications were confined to prescriptions received from a gastroenterology clinic. During the study period, the biologics approved for UC treatment in South Korea were infliximab, adalimumab, and golimumab. However, the actual use of golimumab was rare during the study period, as this anti-TNF agent was only approved in May 2015.\n\nThe date of UC registration in the HIRA database was considered as the date of diagnosis. Given that previous prevalent cases could confound the incidence rate, we set a washout period of 2 years; as a result, patients who were diagnosed with UC from January 1, 2010 to December 31, 2016 were analyzed.\n\nPatients were stratified by the time to their first dose of induction anti-TNF agent after diagnosis. Based on the previous studies,131418 early initiation of anti-TNF therapy was defined as starting infliximab, adalimumab, or golimumab within 2 years of diagnosis, whereas late initiation of anti-TNF therapy was defined as starting >2 year after diagnosis.\n\nTo properly assess the effectiveness of anti-TNF therapy on long-term clinical outcomes, patients who received anti-TNF therapy for less than 6 months were excluded from the analysis. Since the effects of anti-TNF therapy may differ between patients undergoing colectomy or not, patients with a history of colectomy before starting anti-TNF therapy were also excluded from the analysis.\n\nClinical outcomes\nThe primary objective of this study was to determine if the early initiation of anti-TNF therapy within 2 years of UC diagnosis affected the need for colectomy, UC-related ER visits, UC-related hospitalization, or new corticosteroid use during anti-TNF maintenance therapy. These clinical outcomes were determined based on the previous studies.121314 Colectomy was identified using the procedural code. ER visits were defined as patient visits to the ER with UC as the primary diagnosis. Hospitalization was defined as admission for ≥3 days in the department of gastroenterology. Finally, new corticosteroid use was defined as moderate to high dose of corticosteroid use (≥30 mg prednisolone, ≥50 mg methylprednisolone, or ≥200 mg hydrocortisone) for more than 2 months after the first anti-TNF agent prescription.\n\nStatistical analysis\nIncidence rates for colectomy, ER visits, hospitalization, and corticosteroid use were calculated per 100 person-years with 95% confidence intervals (CIs) using Poisson distribution. The crude risk of outcomes between early and late initiators was compared using Kaplan-Meier method and log-rank tests. We used Cox proportional hazards models to adjust for potential confounding variables. Baseline covariates including sex, age, first anti-TNF agent, region, and hospital scale were adjusted as time-fixed covariates. The cumulative use period of anti-TNF agents and concomitant medications, including 5-ASA and immunomodulators, were adjusted as time-dependent covariates. The results are presented as hazard ratios (HRs) with corresponding 95% CIs. All analyses were performed using the SAS Enterprise Guide (SAS Institute, Inc., Cary, NC, USA), and p-values<0.05 were considered statistically significant.\n\nEthical considerations\nAs the information in the HIRA database is encrypted, the database does not contain personal identifiers. The study protocol was approved by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine (IRB no. 4-2017-0927).\n\nRESULTS\nBaseline patient demographics\nWe identified that 17167 patients were diagnosed with UC in 2010–2016; among them, 1125 patients started their first anti-TNF agents during the study period. Of these 1125 patients, 419 were excluded as they received anti-TNF therapy for less than 6 months, while another 8 were excluded for having undergone colectomy before the start of anti-TNF therapy. Ultimately, 698 patients were included in the study, of whom 399 were early initiators of anti-TNF (≤2 years) and 299 were late initiators of anti-TNF (>2 years) (Fig. 1). The median period from UC diagnosis to the first anti-TNF agent in all 698 patients was 1.7 years (interquartile range, 0.8–2.9 years). Among the 399 early initiators, 264 (66.2%), 118 (29.6%), and 17 (4.2%) patients started with infliximab, adalimumab, and golimumab, respectively; among the 299 late initiators, 156 (52.2%), 124 (41.5%), and 19 (6.3%) patients started with infliximab, adalimumab, and golimumab, respectively (p<0.001). The proportion of patients who started with infliximab was higher in early initiators than in late initiators.\n\nTable 1 shows the baseline characteristics of early and late initiators of anti-TNF. Sex did not differ between the two groups. Age at diagnosis of UC and at the start of anti-TNF was younger, and the mean period of anti-TNF use was longer in early versus late initiators. The rate of steroid use at the start of anti-TNF was higher in early initiators than in late initiators. The rate of concomitant immunomodulator use did not differ between early and late initiators, whereas the rate of previous immunomodulator exposure was lower in early initiators than in late initiators. The proportion of patients who first started anti-TNF in the Seoul region and at tertiary hospitals was lower in early versus late initiators.\n\nComparison of clinical outcomes between early and late initiators\nThe rates of colectomy, ER visits, hospitalization, and corticosteroid use (per 100 patient-years) were not significantly different between early and late initiators (Table 2). The median time to colectomy, ER visit, hospitalization, and corticosteroid use after anti-TNF initiation also did not differ significantly between early and late initiators. Only five patients underwent colectomy during the study period (four early, one late initiator).\n\nFig. 2 compares the clinical outcomes of Kaplan-Meier method and log-rank test. There were no significant differences in the cumulative probabilities of colectomy (p=0.415) (Fig. 2A), UC-related ER visits (p=0.967) (Fig. 2B), or corticosteroid use (p=0.789) (Fig. 2D) between early and late initiators. However, early initiators showed significantly higher cumulative probabilities of hospitalization compared to late initiators of anti-TNF (p=0.041) (Fig. 2C).\n\nCox proportional hazard regression analysis of factors associated with clinical outcomes\nThe HRs of univariate and multivariable Cox proportional hazards models are summarized in Table 3. Univariate analysis showed that late initiation of anti-TNF therapy was associated with a reduced risk of hospitalization (HR, 0.75; 95% CI, 0.57–0.99). However, the significant association disappeared after adjusting for confounding variables [adjusted HR (aHR), 0.76; 95% CI, 0.57–1.01]. Additionally, on multivariable Cox regression analysis, there were no significant differences in the risk of colectomy (aHR, 0.41; 95% CI, 0.04–3.90), ER visits (aHR, 0.98; 95% CI, 0.50–1.92), and corticosteroid use (aHR, 1.04; 95% CI, 0.71–1.50) between early and late initiators.\n\nAnti-TNF use period (years) was associated with a reduced risk of hospitalization (aHR, 0.56; 95% CI, 0.43–0.74) and steroid use (aHR, 0.65; 95% CI, 0.48–0.88). The use of 5-ASA at the start of anti-TNF was associated with an increased risk of steroid use (aHR, 2.61; 95% CI, 1.25–5.41).\n\nDISCUSSION\nThis nationwide population-based study was able to confirm that UC patients receiving early anti-TNF therapy had similar clinical outcomes to those of late initiators. More specifically, we found no significant differences in the risk of colectomy, ER visits, hospitalization, or corticosteroid use between early and late initiators of anti-TNF therapy. Only three studies to date have directly evaluated the effect of earlier initiation of anti-TNF therapy on the clinical outcomes of UC. Similar to our results, none of those studies found more favorable outcomes of early versus late initiators.121314 A retrospective Hungarian study involving 42 UC patients demonstrated no difference in hospitalization or colectomy rate with time to anti-TNF exposure.12 Similarly, a Dutch population-based study of 66 CD patients and 16 UC patients observed no beneficial effect of early anti-TNF initiation (<16 months) versus late anti-TNF initiation (>16 months) with respect to surgery, abscess formation, fistula formation, extraintestinal manifestations (EIMs), or mucosal healing.13 However, in this Dutch study, CD and UC were analyzed together. A retrospective Canadian study of 115 UC patients (78 infliximab, 37 adalimumab) also revealed that early anti-TNF initiation, defined as starting treatment within 3 years of diagnosis, was not associated with colectomy (aHR, 2.02; 95% CI, 0.57–7.20), hospitalization (aHR, 1.66; 95% CI, 0.84–3.30), or secondary loss of response (aHR, 0.86; 95% CI, 0.52–1.42).14 However, drawing a firm conclusion from the results of these three prior studies is difficult, as the number of included patients was too small. Since our study included a relatively larger sample size (698 patients), it can more reliably support the results of previous studies showing no benefit of earlier anti-TNF initiation in UC patients. Our findings are also in line with those of a recent U.S. study that evaluated the effects of vedolizumab stratified by disease duration.18 In this study, UC patients treated early with vedolizumab (≤2 years, n=109) did not show different rates of clinical remission, corticosteroid-free remission, or endoscopic remission from those who were treated late with vedolizumab (>2 years, n=328).18\n\nThese results are in contrast with evidence from studies of CD in which early anti-TNF initiation improved clinical outcomes, such as reducing the risk of bowel stricture development or abdominal surgery.9101119 Although the reason for the difference in the effect of early anti-TNF therapy between UC and CD cannot be clearly elucidated, there are several potential explanations. First, differences in the pathophysiological mechanisms of UC and CD may be a contributing factor. In CD, early control of the inflammatory burden with aggressive medical treatment reduces the development of irreversible mechanical complications, such as fibrostenotic strictures and penetrating disease, that require surgical treatment.919 In contrast, UC is characterized by mucosal rather than transmural inflammation; therefore, fibrostenotic or penetrating disease is very rare.20 Patients with UC usually require colectomy due to refractoriness to medical treatments or the development of colorectal cancer (CRC) or colorectal dysplasia rather than mechanical complications. One of the reasons for early anti-TNF treatment showing no beneficial clinical outcome in patients with UC may be that patients with UC are much less likely to develop irreversible bowel damage than those with CD. Second, symptom differences between UC and CD may also be a contributing factor. UC flares usually present dramatically with bloody diarrhea, urgency, and tenesmus, which are difficult to overlook. A Japanese study demonstrated that self-reported symptoms by patients are useful to estimate endoscopic activity in UC.21 In contrast, patients with CD are often asymptomatic, even in uncontrolled CD-related inflammation conditions, reducing the likelihood that they receive medical attention or undergo hospitalization.22 Given these differences, it may be more difficult to determine the appropriate timing of anti-TNF initiation in CD than in UC; for patients with CD, the timing may depend largely on the physician's decision. Indeed, our preceding studies showed that variation in the prescription rate of anti-TNF agents was greater in CD than that in UC.17 Since clinical symptoms better reflect the real severity and inflammatory burden of UC than CD, delays in anti-TNF treatment may occur less often in UC than in CD, and early anti-TNF treatment may be less helpful in UC than in CD. Our findings suggest that, for patients with UC, a conventional step-up strategy may be more reasonable than top-down or accelerated step-up strategies. Third, there might be differences in disease severity between early and late initiators of anti-TNF therapy. Patients requiring early anti-TNF therapy are more likely to have more severe disease. Indeed, in the aforementioned Canadian study, patients treated with early anti-TNF therapy had more severe endoscopic disease at anti-TNF therapy induction (mean Mayo endoscopy subscore, 2.46 vs. 1.86; p<0.001); when adjusted for endoscopic disease activity, the timing of anti-TNF initiation did not affect the risk of colectomy or hospitalization.14 Likewise, in our study, early initiators may have had more severe disease than late initiators, although information on disease severity was not captured in the HIRA database. High steroid use and younger age at the start of anti-TNF in early initiators (Table 1) may support our hypothesis. UC patients with severe serologic and endoscopic activities reportedly have poor prognosis, such as an increased risk of colectomy and hospitalization.2324 Given that anti-TNF therapy for early initiators with more severe disease who have poorer outcomes may equalize the clinical outcomes of late initiators with less severe disease, early anti-TNF therapy may have been helpful for early initiators. Based on our findings, the necessity of early anti-TNF agent use should not be overlooked, even in UC patients with severe activity who do not respond to corticosteroids or immunomodulators in the early disease stages. There is strong evidence that anti-TNF agents should be used early as a rescue therapy for corticosteroid-refractory patients with severe or fulminant UC.23 However, our results suggest that, conversely, other therapeutic options, such as 5-ASAs and immunomodulators, should be optimized for patients with mild to moderate disease. It is also important to select patients who are more likely to develop stenosis or CRC, so that anti-TNF use is not delayed in these high-risk patients. Fourth, longer follow-up periods may be needed to observe disease modifications in UC. In this study, we only examined data from 2010 to 2016. Whether early intervention with anti-TNF agents can change the natural course of UC should be explored further in long-term longitudinal studies.\n\nInterestingly, we found that the use of 5-ASA at the start of anti-TNF was associated with an increased risk of steroid use. Although it is difficult to explain the reasons for this result in a clear manner, a possible explanation is that this drug might have been discontinued in patients whose prognosis was expected to be good. In addition, some patients may have discontinued 5-ASA due to side effects, and they might have received an earlier step-up therapy with immunomodulators or anti-TNF agents, although the disease activity is not severe.\n\nTo the best of our knowledge, this is the largest study to date to assess the impact of early initiation of anti-TNF on the clinical outcomes of UC patients. Furthermore, this is also the first population-based study on this topic in Asia. Nonetheless, our study had several limitations. First, disease extent and severity (e.g. clinical, serologic, and endoscopic activities), which can affect clinical outcomes, were not considered, as these information could not be captured in the HIRA database. Although anti-TNF agents are approved only for patients with moderate to severe disease activity (Mayo score, 6–12; endoscopy subscore≥2) in South Korea, due to the non-randomized design of this study, early initiators might have had more severe and extensive diseases than late initiators did. Therefore, the effects of early anti-TNF use might have been offset. Second, detailed clinical outcomes, such as mucosal healing, EIMs, compliance with the use of anti-TNF, loss of response requiring anti-TNF agent dose escalation, and reasons for discontinuation of anti-TNF therapy, were not assessed. Third, we did not evaluate the safety issue and cost effectiveness according to anti-TNF induction timing. Fourth, we did not verify the accuracy of UC diagnosis and UC-related ER visits. Although we defined ER visits as patient visits to the ER with UC as the primary diagnosis, it may be difficult to accurately view them as true UC-related ER visits. However, we consider our definition of UC diagnosis to be quite reliable. When defining UC, we considered the prescription of UC medications as well as the diagnostic code. Moreover, our study included only patients who received anti-TNF therapy from a gastroenterology clinic to rule out the use of anti-TNF agents for other autoimmune diseases. Finally, although our study included the largest number of UC patients, there were limitations in comparing the colectomy rates. Since colectomy is very rarely required in UC, much larger cohorts are needed to increase the statistical power to determine the difference in colectomy rates.\n\nIn conclusion, similar clinical outcomes, including colectomy, ER visits, hospitalization, and the need for corticosteroids, were observed for early and late initiators of anti-TNF therapy among South Korean patients with UC. These results suggest that indiscriminate early anti-TNF treatment should be avoided for patients with UC. The timing of anti-TNF initiation must be carefully determined for each patient according to the disease severity and refractoriness to other therapeutic options. Further long-term large-scale studies are warranted to clarify the ability of early use of anti-TNF agents to alter the natural course of and prevent disease progression in UC.\n\nThe authors have no potential conflicts of interest to disclose.\n\nAUTHOR CONTRIBUTIONS:\nConceptualization: Yoon Suk Jung and Jae Hee Cheon.\n\nData curation: Minkyung Han.\n\nFormal analysis: Minkyung Han.\n\nInvestigation: all authors.\n\nMethodology: all authors.\n\nProject administration: Minkyung Han and Yoon Suk Jung.\n\nResources: all authors.\n\nSoftware: Minkyung Han and Yoon Suk Jung.\n\nSupervision: all authors.\n\nValidation: all authors.\n\nVisualization: Minkyung Han and Yoon Suk Jung.\n\nWriting—original draft: Yoon Suk Jung.\n\nWriting—review & editing: all authors.\n\nApproval of final manuscript: all authors.\n\n\n\n\nFig. 1 Patient enrollment flow chart. UC, ulcerative colitis; TNF, tumor necrosis factor.\nFig. 2 Kaplan-Meier survival analysis of clinical outcomes from initiating anti-tumor necrosis factor agents. (A) Cumulative probabilities of intestinal surgery. (B) Emergency room visits. (C) Hospitalization. (D) New steroid use. UC, ulcerative colitis.\nTable 1 Baseline Characteristics of the Study Population\nCharacteristics\tEarly initiators of anti-TNF agents (n=399)\tLate initiators of anti-TNF agents (n=299)\tp value\t\nSex, male\t255 (63.9)\t191 (63.9)\t1.000\t\nAge at diagnosis of UC (yr)\t36.4±16.1\t39.7±15.0\t0.006\t\nAge at anti-TNF agent initiation (yr)\t37.3±16.1\t43.1±15.1\t<0.001\t\nPeriod from UC diagnosis to first anti-TNF agent use (yr)\t0.9±0.6\t3.4±1.1\t<0.001\t\nAnti-TNF agent use duration (yr)\t2.0±1.4\t1.6±1.0\t<0.001\t\nFirst anti-TNF agent\t\t\t<0.001\t\n Infliximab\t264 (66.2)\t156 (52.2)\t\t\n Adalimumab\t118 (29.6)\t124 (41.5)\t\t\n Golimumab\t17 (4.2)\t19 (6.3)\t\t\nMedication use at anti-TNF agent initiation\t\t\t\t\n 5-ASA\t277 (69.4)\t191 (63.9)\t0.144\t\n Steroid\t176 (44.1)\t97 (32.4)\t0.002\t\n Immunomodulator\t175 (43.9)\t129 (43.1)\t0.911\t\nConcomitant immunomodulators (±30 days)\t240 (60.2)\t189 (63.2)\t0.457\t\nPrevious immunomodulator exposure\t288 (72.2)\t253 (84.6)\t<0.001\t\nRegion at first anti-TNF agent use\t\t\t0.016\t\n Seoul\t156 (39.1)\t145 (48.5)\t\t\n Outside Seoul\t243 (60.9)\t154 (51.5)\t\t\nHospital size at first anti-TNF agent use\t\t\t0.010\t\n Tertiary\t269 (67.4)\t229 (76.6)\t\t\n General/community/clinic\t130 (32.6)\t70 (23.4)\t\t\n5-ASA, 5-aminosalicylic acid; TNF, tumor necrosis factor; UC, ulcerative colitis.\n\nData are presented as number (%) or mean±SD.\n\nTable 2 Outcomes of Early versus Late Initiators of Anti-TNF Agents\nOutcome\tEarly initiators of anti-TNF agents (n=399)\tLate initiators of anti-TNF agents (n=299)\tp value\t\nColectomy outcomes\t\t\t\t\n Colectomy (n, %)\t4 (1.0)\t1 (0.3)\t0.399\t\n Surgery rate (per 100 patient-years, 95% CI)\t0.42 (0.13–0.98)\t0.19 (0.01–0.84)\t0.479\t\n Median time to surgery (yr, IQR)\t1.37 (0.66–2.13)\t1.64 (1.64–1.64)\t1.000\t\nER visit outcomes\t\t\t\t\n ER visit (n, %)\t26 (6.5)\t15 (5.0)\t0.502\t\n ER visit rate (per 100 patient-years, 95% CI)\t2.76 (1.83–3.96)\t2.91 (1.67–4.65)\t0.870\t\n Median time to ER visit (yr, IQR)\t0.99 (0.38–2.04)\t0.96 (0.64–2.18)\t0.936\t\nHospitalization outcomes\t\t\t\t\n Hospitalization (n, %)\t143 (35.8)\t77 (25.8)\t0.006\t\n Hospitalization rate (per 100 patient-years, 95% CI)\t21.73 (18.36–25.49)\t18.75 (14.87–23.26)\t0.298\t\n Median time to hospitalization (yr, IQR)\t0.27 (0.11–0.90)\t0.40 (0.13–0.79)\t0.664\t\nNew steroid use (after 2 months) outcomes\t\t\t\t\n New steroid use (n, %)\t74 (18.6)\t50 (16.7)\t0.600\t\n New steroid use rate (per 100 patient-years, 95% CI)\t8.91 (7.03–11.10)\t10.97 (8.20–14.29)\t0.258\t\n Median time to new steroid use (yr, IQR)\t0.60 (0.27–1.14)\t0.64 (0.31–1.19)\t0.941\t\nCI, confidence interval; ER, emergency room; IQR, interquartile range; TNF, tumor necrosis factor.\n\nTable 3 Cox Regression Analysis of Clinical Outcomes\nVariable\tColectomy\tER visit\tHospitalization\tNew steroid use\t\nCrude HR (95% CI)\tAdjusted HR (95% CI)\tCrude HR (95% CI)\tAdjusted HR (95% CI)\tCrude HR (95% CI)\tAdjusted HR (95% CI)\tCrude HR (95% CI)\tAdjusted HR (95% CI)\t\nInitiation of anti-TNF\t\t\t\t\t\t\t\t\t\n Early (≤2 yr)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Late (>2 yr)\t0.41 (0.05–3.71)\t0.41 (0.04–3.90)\t1.01 (0.53–1.94)\t0.98 (0.50–1.92)\t0.75 (0.57–0.99)\t0.76 (0.57–1.01)\t1.05 (0.73–1.51)\t1.04 (0.71–1.50)\t\nSex\t\t\t\t\t\t\t\t\t\n Female\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Male\t-\t-\t1.04 (0.55–1.96)\t1.10 (0.57–2.11)\t1.02 (0.78–1.34)\t1.05 (0.79–1.39)\t1.29 (0.89–1.89)\t1.29 (0.88–1.90)\t\nAge at anti-TNF agent initiation (yr)\t1.01 (0.95–1.06)\t1.00 (0.95–1.06)\t0.99 (0.97–1.01)\t0.99 (0.97–1.01)\t0.99 (0.99–1.01)\t0.99 (0.99–1.01)\t0.99 (0.99–1.01)\t0.99 (0.98–1.01)\t\nAnti-TNF use period* (yr)\t0.61 (0.21–1.79)\t0.56 (0.19–1.69)\t0.87 (0.61–1.24)\t0.85 (0.59–1.22)\t0.57 (0.43–0.75)\t0.56 (0.43–0.74)\t0.69 (0.51–0.93)\t0.65 (0.48–0.88)\t\nFirst anti-TNF agent\t\t\t\t\t\t\t\t\t\n Infliximab\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Adalimumab\t1.80 (0.30–10.93)\t1.73 (0.27–10.94)\t1.85 (0.96–3.56)\t1.90 (0.98–3.70)\t0.96 (0.72–1.28)\t0.98 (0.73–1.32)\t1.34 (0.92–1.97)\t1.36 (0.93–2.01)\t\n Golimumab\t-\t-\t1.28 (0.17–9.71)\t1.31 (0.17–10.04)\t0.53 (0.22–1.29)\t0.55 (0.22–1.35)\t1.64 (0.70–3.80)\t1.61 (0.69–3.76)\t\n5-ASAs use*\t\t\t\t\t\t\t\t\t\n No\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Yes\t-\t-\t1.31 (0.51–3.38)\t1.40 (0.53–3.67)\t0.98 (0.66–1.44)\t1.08 (0.73–1.61)\t2.31 (1.13–4.75)\t2.61 (1.25–5.41)\t\nImmunomodulators use*\t\t\t\t\t\t\t\t\t\n No\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Yes\t0.23 (0.03–2.11)\t0.21 (0.02–1.88)\t1.19 (0.63–2.22)\t1.21 (0.64–2.27)\t1.01 (0.77–1.33)\t1.06 (0.81–1.39)\t0.88 (0.62–1.26)\t0.89 (0.62–1.27)\t\nRegion†\t\t\t\t\t\t\t\t\t\n Outside Seoul\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Seoul\t1.92 (0.32–11.51)\t1.20 (0.19–7.51)\t1.00 (0.54–1.86)\t1.09 (0.55–2.13)\t0.96 (0.74–1.26)\t1.04 (0.78–1.40)\t0.85 (0.59–1.22)\t0.81 (0.55–1.19)\t\nHospital scale†\t\t\t\t\t\t\t\t\t\nGeneral/community/clinics\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t1.00 (ref)\t\n Tertiary\t-\t-\t0.84 (0.43–1.62)\t0.85 (0.41–1.74)\t0.88 (0.66–1.17)\t0.90 (0.66–1.23)\t1.08 (0.72–1.60)\t1.21 (0.79–1.86)\t\n5-ASA, 5-aminosalicylic acid; CI, confidence interval; ER, emergency room; HR, hazard ratio; TNF, tumor necrosis factor.\n\n*Time-dependent covariate, †Region and hospital scale use was defined as the hospital where a patient's first anti-TNF agent was prescribed.\n==== Refs\n1 Lee SH Kwon JE Cho ML Immunological pathogenesis of inflammatory bowel disease Intest Res 2018 16 26 42 29422795 \n2 Ooi CJ Hilmi I Banerjee R Chuah SW Ng SC Wei SC Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn’s disease in Asia Intest Res 2019 17 285 310 31146509 \n3 Rutgeerts P Sandborn WJ Feagan BG Reinisch W Olson A Johanns J Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005 353 2462 2476 16339095 \n4 Sandborn WJ van Assche G Reinisch W Colombel JF D’Haens G Wolf DC Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2012 142 257 265 22062358 \n5 Sandborn WJ Feagan BG Marano C Zhang H Strauss R Johanns J Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2014 146 85 95 23735746 \n6 Sandborn WJ Feagan BG Marano C Zhang H Strauss R Johanns J Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis Gastroenterology 2014 146 96 109 23770005 \n7 Sandborn WJ Rutgeerts P Feagan BG Reinisch W Olson A Johanns J Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab Gastroenterology 2009 137 1250 1260 19596014 \n8 Feagan BG Sandborn WJ Lazar A Thakkar RB Huang B Reilly N Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis Gastroenterology 2014 146 110 118 24067881 \n9 Ma C Beilman CL Huang VW Fedorak DK Kroeker KI Dieleman LA Anti-TNF therapy within 2 years of Crohn's disease diagnosis improves patient outcomes: a retrospective cohort study Inflamm Bowel Dis 2016 22 870 879 26818419 \n10 Safroneeva E Vavricka SR Fournier N Pittet V Peyrin-Biroulet L Straumann A Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease Aliment Pharmacol Ther 2015 42 977 989 26271358 \n11 Frei R Fournier N Zeitz J Scharl M Morell B Greuter T Early initiation of anti-TNF is associated with favourable long-term outcome in Crohn's disease: 10-year-follow-up data from the Swiss IBD cohort study J Crohns Colitis 2019 13 1292 1301 30854548 \n12 Mandel MD Balint A Golovics PA Vegh Z Mohas A Szilagyi B Decreasing trends in hospitalizations during anti-TNF therapy are associated with time to anti-TNF therapy: results from two referral centres Dig Liver Dis 2014 46 985 990 25156871 \n13 Nuij V Fuhler GM Edel AJ Ouwendijk RJ Rijk MC Beukers R Benefit of earlier anti-TNF treatment on IBD disease complications? J Crohns Colitis 2015 9 997 1003 26223842 \n14 Ma C Beilman CL Huang VW Fedorak DK Wong K Kroeker KI Similar clinical and surgical outcomes achieved with early compared to late anti-TNF induction in mild-to-moderate ulcerative colitis: a retrospective cohort study Can J Gastroenterol Hepatol 2016 2016 2079582 27478817 \n15 Jung YS Han M Kim WH Park S Cheon JH Incidence and clinical outcomes of inflammatory bowel disease in South Korea, 2011-2014: a nationwide population-based study Dig Dis Sci 2017 62 2102 2112 28593437 \n16 Jung YS Han M Park S Kim WH Cheon JH Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study J Crohns Colitis 2017 11 954 962 28333358 \n17 Han M Jung YS Cheon JH Park S Regional variations in the use of biologics and immunomodulators among Korean patients with inflammatory bowel diseases J Gastroenterol Hepatol 2019 34 1166 1174 30672608 \n18 Faleck DM Winters A Chablaney S Shashi P Meserve J Weiss A Shorter disease duration is associated with higher rates of response to vedolizumab in patients with Crohn's disease but not ulcerative colitis Clin Gastroenterol Hepatol 2019 17 2497 2505 30625408 \n19 Oh EH Oh K Han M Seo H Chang K Lee SH Early anti-TNF/immunomodulator therapy is associated with better long-term clinical outcomes in Asian patients with Crohn's disease with poor prognostic factors PLoS One 2017 12 e0177479 28542298 \n20 Ordás I Eckmann L Talamini M Baumgart DC Sandborn WJ Ulcerative colitis Lancet 2012 380 1606 1619 22914296 \n21 Tsuda S Kunisaki R Kato J Murakami M Nishio M Ogashiwa T Patient self-reported symptoms using visual analog scales are useful to estimate endoscopic activity in ulcerative colitis Intest Res 2018 16 579 587 30301332 \n22 Vavricka SR Spigaglia SM Rogler G Pittet V Michetti P Felley C Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease Inflamm Bowel Dis 2012 18 496 505 21509908 \n23 Monterubbianesi R Aratari A Armuzzi A Daperno M Biancone L Cappello M Infliximab three-dose induction regimen in severe corticosteroid-refractory ulcerative colitis: early and late outcome and predictors of colectomy J Crohns Colitis 2014 8 852 858 24472490 \n24 Oussalah A Evesque L Laharie D Roblin X Boschetti G Nancey S A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization Am J Gastroenterol 2010 105 2617 2625 20736936\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0513-5796", "issue": "61(5)", "journal": "Yonsei medical journal", "keywords": "Ulcerative colitis; anti-TNF; clinical outcome; early use", "medline_ta": "Yonsei Med J", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D008297:Male; D016016:Proportional Hazards Models; D012044:Regression Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "0414003", "other_id": null, "pages": "382-390", "pmc": null, "pmid": "32390361", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": "26818419;24472490;23770005;30672608;31146509;30854548;29422795;25156871;20736936;30625408;22062358;28333358;23735746;28593437;19596014;22914296;28542298;26223842;27478817;24067881;21509908;16339095;26271358;30301332", "title": "Similar Clinical Outcomes of Early and Late Anti-TNF Initiation for Ulcerative Colitis: A Nationwide Population-Based Study.", "title_normalized": "similar clinical outcomes of early and late anti tnf initiation for ulcerative colitis a nationwide population based study" }

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{ "abstract": "With the development of invasive medical procedures, an increasing number of healthcare-associated infective endocarditis cases have been reported. In particular, non-nosocomial healthcare-associated infective endocarditis in outpatients with recent medical intervention has been increasingly identified.\n\n\n\nA 66-year-old man with diabetes mellitus and a recent history of intermittent urethral self-catheterization was admitted due to a high fever. Repeated blood cultures identified Pseudomonas aeruginosa, and transesophageal echocardiography uncovered a new-onset severe aortic regurgitation along with a vegetative valvular structure. The patient underwent emergency aortic valve replacement surgery and was successfully treated with 6 weeks of high-dose meropenem and tobramycin. Historically, most cases of P. aeruginosa endocarditis have occurred in the right side of the heart and in outpatients with a history of intravenous drug abuse. In the case presented, the repeated manipulations of the urethra may have triggered the infection. Our literature review for left-sided P. aeruginosa endocarditis showed that non-nosocomial infection accounted for nearly half of the cases and resulted in fatal outcomes as often as nosocomial cases. A combination therapy with anti-pseudomonal beta-lactams or carbapenems and aminoglycosides may be the preferable treatment. Medical treatment alone may be effective, and surgical treatment should be carefully considered.\n\n\n\nWe presented a rare case of native aortic valve endocarditis caused by P. aeruginosa. This case illustrates the importance of identifying the causative pathogen(s), especially for outpatients with a recent history of medical procedures.", "affiliations": "Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. highgear@hp-infect.med.osaka-u.ac.jp.;Department of Cardiovascular Surgery, Osaka University Hospital, Osaka, Japan.;Department of Anesthesiology and Intensive Care Medicine, Osaka University Hospital, Osaka, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.", "authors": "Hagiya|Hideharu|H|;Tanaka|Takeshi|T|;Takimoto|Kohei|K|;Yoshida|Hisao|H|;Yamamoto|Norihisa|N|;Akeda|Yukihiro|Y|;Tomono|Kazunori|K|", "chemical_list": "D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem; D014031:Tobramycin", "country": "England", "delete": false, "doi": "10.1186/s12879-016-1757-y", "fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 175710.1186/s12879-016-1757-yCase ReportNon-nosocomial healthcare-associated left-sided Pseudomonas aeruginosa endocarditis: a case report and literature review Hagiya Hideharu +81-6-6879-5093highgear@hp-infect.med.osaka-u.ac.jp 1Tanaka Takeshi tanaken0612@hotmail.com 2Takimoto Kohei mm7706tk@gmail.com 3Yoshida Hisao falco60v@yahoo.co.jp 1Yamamoto Norihisa norihisa65@hp-infect.med.osaka-u.ac.jp 1Akeda Yukihiro akeda@biken.osaka-u.ac.jp 1Tomono Kazunori tomono@hp-infect.med.osaka-u.ac.jp 11 Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871 Japan 2 Department of Cardiovascular Surgery, Osaka University Hospital, Osaka, Japan 3 Department of Anesthesiology and Intensive Care Medicine, Osaka University Hospital, Osaka, Japan 20 8 2016 20 8 2016 2016 16 43120 10 2015 4 8 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWith the development of invasive medical procedures, an increasing number of healthcare-associated infective endocarditis cases have been reported. In particular, non-nosocomial healthcare-associated infective endocarditis in outpatients with recent medical intervention has been increasingly identified.\n\nCase presentation\nA 66-year-old man with diabetes mellitus and a recent history of intermittent urethral self-catheterization was admitted due to a high fever. Repeated blood cultures identified Pseudomonas aeruginosa, and transesophageal echocardiography uncovered a new-onset severe aortic regurgitation along with a vegetative valvular structure. The patient underwent emergency aortic valve replacement surgery and was successfully treated with 6 weeks of high-dose meropenem and tobramycin. Historically, most cases of P. aeruginosa endocarditis have occurred in the right side of the heart and in outpatients with a history of intravenous drug abuse. In the case presented, the repeated manipulations of the urethra may have triggered the infection. Our literature review for left-sided P. aeruginosa endocarditis showed that non-nosocomial infection accounted for nearly half of the cases and resulted in fatal outcomes as often as nosocomial cases. A combination therapy with anti-pseudomonal beta-lactams or carbapenems and aminoglycosides may be the preferable treatment. Medical treatment alone may be effective, and surgical treatment should be carefully considered.\n\nConclusions\nWe presented a rare case of native aortic valve endocarditis caused by P. aeruginosa. This case illustrates the importance of identifying the causative pathogen(s), especially for outpatients with a recent history of medical procedures.\n\nKeywords\nHealthcare-associated infective endocarditisPatent foramen ovaleRight-to-left shuntUrethral self-catheterizationissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nInfective endocarditis (IE) continues to be associated with high morbidity and mortality, even with advancements in medical care. Most cases of IE occur outside of the healthcare setting, but an increasing number of healthcare-associated IE (HCA-IE) are consistently being reported [1]. According to a recent prospective, multicenter, cohort study, 16 % of IE cases (127/793) were categorized as HCA-IE [2]. Further, a clinically important new type of IE, non-nosocomial healthcare-associated IE (NNHCA-IE), which is defined as IE cases originating from outpatients who underwent medical cares in community settings, has been identified in recent years [2]. These cases of NNHCA-IE account for between 9.3 and 15.7 % of all cases of IE [3–6].\n\nPseudomonas aeruginosa is typically associated with nosocomial infections. Whereas, the organism is historically known to cause community-acquired IE, which develops primarily in the right side of the heart of patients with a history of intravenous drug (IVD) abuse [7, 8]. Due to an increase in invasive medical interventions, cases of P. aeruginosa-induced HCA-IE have also recently increased [9]. However, the incidence of P. aeruginosa endocarditis is still significantly low compared to the incidence of endocarditis due to other pathogens [10], and the clinical characteristics of the infection are not well known. Herein, we report a case of left-sided NNHCA-IE caused by P. aeruginosa, along with a review of the recent literature.\n\nCase presentation\nA 66-year-old man with a history of diabetes mellitus, benign prostatic hypertrophy, and hypertension had recently undergone percutaneous coronary intervention and was transferred to a hospital owing to a high fever and temporary loss of consciousness. The patient had been diagnosed with diabetes mellitus 8 months prior to the hospital admission with markedly elevated blood glucose and hemoglobin A1c levels (12.4 %). After the initiation of intensive insulin therapy, the patient’s serum glucose level was well controlled. The patient had undergone transurethral resection of the prostate 9 years earlier for treatment of urinary retention secondary to benign prostatic hypertrophy. However, urinary retention persisted, and the patient’s symptoms had been managed by an indwelling urinary catheter at home for 6 months. Ten days prior to the onset of fever, he had begun intermittent urethral self-catheterization.\n\nThe patient’s vital signs on admission were relatively stable. Although focal neurological symptoms were absent, magnetic resonance imaging of the head showed multiple acute emboli in the left parietal and posterior lobes. Blood and urine culture detected antimicrobial-susceptible P. aeruginosa, and treatment of ceftazidime (4 g per day) was initiated. Because of his sustained fever, blood cultures were redrawn on day 7, and they were positive for ceftazidime-resistant P. aeruginosa. Antibiotic therapy was changed to levofloxacin (500 mg per day) and continued for 2 weeks. During the hospitalization, transthoracic echocardiography (TTE) was performed twice (on day 1 and day 4), but no remarkable findings were observed. The patient’s symptoms resolved with antibiotic treatment, and he was discharged.\n\nThree days after discharge, the high fever remerged, and the patient was readmitted. Physical examination did not show any abnormalities, but laboratory results showed elevated levels of white blood cells (9300/μL) and serum protein (12.5 mg/dL). Blood culture again detected P. aeruginosa, and magnetic resonance imaging of the head showed newly formed, multiple emboli accompanying micro-hemorrhages at the cerebral cortex and cerebellum bilaterally. IE was suspected, but TTE performed on the day of readmission did not reveal any structural abnormalities. Three days later, however, transesophageal echocardiography (TEE) revealed a movable, hypoechoic lesion at the aortic valve, along with new-onset severe aortic regurgitation (Fig. 1a). A patent foramen ovale (PFO) was also discovered (Fig. 1b). The patient was transferred to our hospital for emergency surgical treatment.Fig. 1 Transesophageal echocardiography findings. Vegetative lesions are visualized at the right coronary cusp (3 × 12 mm) and the noncoronary cusp (6 × 12 mm) of the aortic valve with the presence of newly developed severe aortic regurgitation (a). An interatrial shunt, suggesting the presence of patent foramen ovale, as demonstrated on color Doppler ultrasonography (b). LA left atrium, LV left ventricle, Ao ascending aorta\n\n\n\nOn arrival, a pan-diastolic murmur was auscultated, but there was no apparent peripheral embolic finding. Full body computed tomography did not reveal any other infectious foci. P. aeruginosa was repeatedly identified in blood cultures, and the antimicrobial susceptibility testing of the pathogen revealed the following minimum inhibitory concentrations: piperacillin, ≥128 μg/mL; ceftazidime, ≥32 μg/mL; cefepime, 16 μg/mL; aztreonam, ≥32 μg/mL; imipenem/cilastatin, 1 μg/mL; meropenem, ≤0.5 μg/mL; gentamicin, 4 μg/mL; tobramycin, ≤1 μg/mL; amikacin, 8 μg/mL; ciprofloxacin, ≤0.25 μg/mL; and levofloxacin, ≤0.5 μg/mL. An emergency operation for aortic valve replacement and PFO closure was performed, and a combination therapy of high-dose meropenem (6 g divided into 3 doses per day) and a single daily dose of tobramycin (300 mg per day, approximately 3.5 mg/kg/day) was initiated perioperatively. The post-operative clinical course was uneventful, and the patient completed a 6-week course of the combination antibiotic therapy. The dose of tobramycin was adjusted to target trough levels of 1 to 2 μg/mL, and the patient did not develop renal dysfunction during the treatment. The patient recovered well without recurrence after 1 year.\n\nDiscussion\nP. aeruginosa endocarditis is a clinically rare condition. In an international study including 61 hospitals in 28 countries, the pathogen accounted for only 0.4 % (11/2761 cases) of all cases of IE [10]. Compared to right-sided disease, the left-sided P. aeruginosa endocarditis progresses rapidly with varied complications and serious outcomes [10]. According to a recent literature review summarizing 40 cases of the left-sided P. aeruginosa endocarditis in non-IVD abusers, the overall mortality was about 64 % (23/36 cases) [11]. However, most of the cases were reported more than 10 years previously, and current incidence and clinical features of this rare but fatal infection are uncertain.\n\nFor better comprehension of the left-sided P. aeruginosa endocarditis, we performed a review of literature published in the last decade (2005 to June 2015) in the MEDLINE database. Due to its low incidence, previous reports referring to HCA-IE did not particularly focus on this pathogen [2–5]. To the best of our knowledge, this is the first attempt to categorize such cases by their clinical backgrounds. A summary of 26 cases identified in the review (15 reports), including the presented case, is shown in Table 1 [11–25].Table 1 A summary of cases of left-sided infective endocarditis caused by Pseudomonas aeruginosa reported during the last decade (2005–2015)\n\nNo. [ref]\tYear\tAge/Sex\tIVD\tUnderlying disease or intervention\tSuspected source\tInfected valves\tSize and lesion\tComplications\tTreatment\tAntibiotics\tOutcome\t\nCommunity-acquired IE\t\n 1 [12]\t2009\t49/M\tYes\tCKD\tIVD\tProsthetic mitral/aortic\t10 mm/5 mm\tUnknown\tSurgical\tBL + AG\tSurvival\t\n 2 [13]\t2013\t41/M\tNo\tNone\tUnknown\tNative mitral\t20 mm\tn.d.\tSurgical\tBL + AG\tSurvival\t\n 3 [14]\t2013\t85/F\tNo\tHT, DM\tUnknown\tNative mitral\t4–8 mm\tAVB\tMedical\tBL + AG\tDeath\t\nNon-nosocomial healthcare-associated IE (NNHCA-IE)\t\n 4 [15]\t2005\t56/F\tNo\tDM\tUnknown\tNative mitral\t17 mm\tMeningitis\tMedical\tBL + AG\tSurvival\t\n 5 [16]\t2008\t66/M\tNo\tCardiac surgery (AVR)\tUnknown\tProsthetic mitral\t11 × 12 mm\tSub-endocardial abscess\tSurgical\tBL\tDeath\t\n 6 [11]\t2011\t71/M\tNo\tCardiac surgery (CABG), CAD,\tUrinary tract (cystoscopy)\tNative mitral\t6 × 10 mm\tCerebral embolism\tSurgical\tCPM + FQ\tSurvival\t\n 7 [11]\t2011\t65/M\tNo\tCardiac surgery (AD), DM\tInfected toe\tProsthetic aortic\tn.d.\tAortic root graft abscess\tSurgical\tBL + AG\tSurvival\t\n 8 [11]\t2011\t45/M\tNo\tCardiac surgery (AVR, MVR, TAP), HD\tCardiac surgery\tProsthetic mitral\tn.d.\tn.d.\tMedical\tn.d.\tDeath\t\n 9 [11]\t2011\t61/M\tNo\tCardiac surgery (e.g. AVR)\tCardiac surgery\tProsthetic aortic\tn.d.\tn.d.\tSurgical\tBL + AG\tDeath\t\n 10 [17]\t2012\t63/M\tNo\tDM, CHF, Implanted pacemaker, CKD\tUnknown\tNative mitral\t5 mm\tAortic root abscess\tSurgical\tBL + AG\tDeath\t\n 11 [18]\t2012\t73/M\tNo\tMM, HT, DM, Af, chemotherapy\tInfection of the lower limb\tNative mitral\t10 mm\tn.d.\tMedical\tBL + FQ\tDeath\t\n 12 [19]\t2012\t49/F\tNo\tDM, CAD, CKD (HD), HT\tDialysis catheter\tNative aortic\t20 mm\tn.d.\tMedical\tBL + AG\tSurvival\t\n 13a\n\t2015\t66/M\tNo\tDM, BPH, HT, CAD\tUrinary tract\tNative aortic\t6 × 12 mm\tCerebral infarction\tSurgical\tCPM + AG\tSurvival\t\nNosocomial healthcare-associated IE (NHCA-IE)\t\n 14 [20]\t2008\t45/F\tNo\tSevere burn\tBurn injury\tNative aortic\tn.d.\tNone\tMedical\tn.d.\tDeath\t\n 15 [20]\t2008\t47/F\tNo\tSevere burn\tBurn injury\tNative mitral\t3 × 10 mm\tCerebral and renal embolism\tMedical\tn.d.\tDeath\t\n 16 [20]\t2008\t31/M\tNo\tSevere burn\tBurn injury\tNative mitral\t3 × 5 mm\tCerebral embolism\tMedical\tn.d.\tDeath\t\n 17 [21]\t2009\t69/M\tNo\tCardiac surgery (AVR)\tUnknown\tProsthetic aortic\tn.d.\tUnknown\tSurgical\tFQ + AG\tSurvival\t\n 18 [22]\t2012\t35/M\tNo\tRenal transplantation\tSurgery\tNative aortic\t6 × 13 mm\tSplenic infarction\tMedical\tCPM + FQ\tSurvival\t\n 19 [23]\t2014\t83/M\tNo\tHD, CHF, Malignancy\tUnknown\tProsthetic aortic\t8 mm\tHeart failure\tMedical\tCPM + COL\tDeath\t\n 20 [23]\t2014\t55/M\tNo\tImmunosuppressive therapy\tUnknown\tNative aortic\t14 mm\tSplenic infarction\tSurgical\tCPM + COL\tDeath\t\n 21 [24]\t2014\t60/M\tNo\tMyocardial infarction\tUnknown\tNative mitral\tn.d.\tSplenomegaly\tSurgical\tBL + AG\tSurvival\t\nUncertain cases\t\n 22 [25]\t2009\tUnknown\tYes\tUnknown\tIVD\tProsthetic aortic\t3 mm\tYes\tMedical\tBL + AG\tSurvival\t\n 23 [25]\t2009\tUnknown\tYes\tUnknown\tIVD\tNative mitral\t4 mm\tYes\tMedical\tBL + AG\tSurvival\t\n 24 [25]\t2009\tUnknown\tYes\tUnknown\tIVD\tNative aortic\t6 mm\tYes\tSurgical\tBL + AG\tSurvival\t\n 25 [25]\t2009\tUnknown\tYes\tUnknown\tIVD\tProsthetic mitral\t10 mm\tYes\tSurgical\tBL + AG\tSurvival\t\n 26 [25]\t2009\tUnknown\tYes\tUnknown\tIVD\tNative aortic\t15 mm\tYes\tMedical\tBL + FQ\tDeath\t\n\nAD aortic dissection, AF atrial fibrillation, AG aminoglycoside, AVB atrioventricular block, AVR aortic valve replacement, BL anti-pseudomonal beta-lactam, BPH benign prostatic hypertrophy, CABG coronary artery bypass grafting, CAD coronary artery disease, CHF chronic heart failure, CKD chronic kidney disease, COL colistin, CPM carbapenem, DM diabetes mellitus, FQ fluoroquinolone, HT hypertension, IE infective endocarditis, IVD intravenous drug use, MM multiple myeloma, MVR mitral valve replacement, SSS sick sinus syndrome, TAP tricuspid annuloplasty, n.d. not described\n\nNon-nosocomial healthcare-associated cases are those that occurred in outpatients who had received medical care prior to the onset of infection\n\n\naCase No. 13 is the present case\n\n\n\nThere were 3 cases of community-acquired IE, 10 cases of NNHCA-IE, and 8 cases of nosocomial healthcare-associated IE (NHCA-IE). Five cases were inconclusive for their onset. Most cases were related to previous history of medical intervention. Involvements of the native valves were common (65.4 %, 17/26 cases), and systemic and cardiac complications occurred in approximately one-third (8/26 cases) and one-fifth (5/25 cases) of the cases, respectively. The mortality rate among patients with NNHCA-IE (50 %, 5/10 cases) was almost as high as that among patients with NHCA-IE (62.5 %, 5/8 cases). For outpatients, we generally do not suspect P. aeruginosa as a potential pathogen for IE, and thus, anti-pseudomonal agents are not empirically prescribed. We stress the importance of identifying the causative pathogen(s) in every cases of IE, especially in cases with a recent history of medical intervention.\n\nThe primary pathogen entry was undetermined in nearly half of the cases. Our patient repeatedly underwent urinary tract manipulations, and P. aeruginosa was noted in his urine sample. In addition, the urinary tract is reported to be a major site of pathogen entry in native valve endocarditis [26]. Moreover, it is known that genitourinary instrumentation accounts for the third most common etiology of HCA-IE, following vascular and digestive origination [2]. Thus, we suspect the damaged urethral mucosa was the pathogen entry site in the presented case. A similar case was also described in a recent NNHCA-IE case [11].\n\nCompared to IVD abusers, who primarily develop right-sided infection, patients without a history of IVD abuse are prone to left-sided infection. A recent report demonstrated that 63 % (17/27 cases) of patients diagnosed with P. aeruginosa endocarditis without a history of IVD abuse developed left-sided heart infections [9]. Our review also revealed IVD abuse was less frequently associated with the left-sided P. aeruginosa endocarditis (23 %, 6/26 cases). This may be explained by the fact that a high-velocity blood jet stream damages the endocardium, and thus, the left side of the heart is more vulnerable to infection. Although the clinical significance is unknown, the presence of PFO may have been partially responsible for the left-sided involvement in this case.\n\nOptimal treatment for the left-sided P. aeruginosa endocarditis has yet to be determined. Effectiveness of combination therapy with carbapenem and aminoglycosides for the infection has been reported [27], and therefore, we treated our patient with meropenem and tobramycin. Of the 26 cases reviewed, combination antibiotic therapy was prescribed in 21 cases (81 %). Monotherapy with ceftazidime was given in 1 case, but the patient died eventually [16]. Four cases did not mention antibiotic treatment. Among 14 successful cases, 5 patients underwent medical treatment alone, and 4 of them were treated with a combination of anti-pseudomonal beta-lactams and aminoglycosides. Of 9 successful cases with surgical treatment, the similar combined treatment was given in 6 cases. Although the effectiveness of antimicrobial combination therapy remains controversial, it may be preferable when the potential emergence of drug resistant strains during treatment is considered [28], as seen in our case. Thus, we consider that anti-pseudomonal beta-lactams or carbapenems combined with aminoglycosides can be a choice for cases of left-sided P. aeruginosa endocarditis.\n\nThe need for surgical intervention in the treatment for left-sided P. aeruginosa endocarditis should be carefully considered, as recent literature reports that the disease can be successfully treated medically [25, 27]. However, the results of our review show that the mortality rate in patients receiving medical treatment alone (62 %, 8/13 cases) was twice as high as that in patients receiving surgical treatment (31 %, 4/13 cases). The patients were not randomized, and critically ill patients or patients who had severe concomitant diseases tended to be treated by a medical approach alone. Thus, it is actually difficult to compare the survival rates of patients with medical or surgical treatment. However, medical treatment alone may be insufficient for left-sided P. aeruginosa endocarditis in some cases. A prospective, randomized study is warranted to elucidate the appropriate treatment strategy for this type of infection.\n\nConclusions\nIn conclusion, we described a rare case of left-sided NNHCA-IE caused by P. aeruginosa. The repeated manipulation of the urethra by intermittent self-catheterization was suspected as the cause of the infection. A literature review of cases of left-sided P. aeruginosa endocarditis revealed that non-nosocomial cases accounted for nearly half of the cases, and resulted in fatal outcomes as often as that noted in nosocomial cases. Optimal treatment is undetermined, but combination therapy with anti-pseudomonal beta-lactams or carbapenems and aminoglycosides would be preferable, according to the results of our review. Surgical indication for the disease should be carefully determined in every case.\n\nAbbreviations\nCA-IE, community-acquired IE; HCA-IE, healthcare-associated IE; IE, infective endocarditis; IVD, intravenous drug; NHCA-IE, nosocomial healthcare-associated IE; NNHCA-IE, non-nosocomial healthcare-associated IE; PFO, patent foramen ovale; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.\n\nAcknowledgements\nWe would like to thank all medical staff who cared for the patient.\n\nFunding\nNone to report.\n\nAvailability of data and materials\nNone to describe.\n\nAuthors’ contributions\nHH mainly collected data and drafted the manuscript. TT and KT managed the patient at the clinical site and gave advice in drafting. HY, NY, YA, and KT participated in interpretation and discussion. KT finally approved the article. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval and consent to participate\nInvolvement of the ethical committee was not considered necessary, since this case report was not classified as a research study.\n==== Refs\nReferences\n1. Fernandez-Hidalgo N Almirante B Tornos P Pigrau C Sambola A Igual A Contemporary epidemiology and prognosis of health care-associated infective endocarditis Clin Infect Dis 2008 47 1287 1297 10.1086/592576 18834314 \n2. Lomas JM Martinez-Marcos FJ Plata A Ivanova R Galvez J Ruiz J Healthcare-associated infective endocarditis: an undesirable effect of healthcare universalization Clin Microbiol Infect 2010 16 1683 1690 10.1111/j.1469-0691.2010.03043.x 19732086 \n3. Benito N Miro JM de Lazzari E Cabell CH del Rio A Altclas J Health care-associated native valve endocarditis: importance of non-nosocomial acquisition Ann Intern Med 2009 150 586 594 10.7326/0003-4819-150-9-200905050-00004 19414837 \n4. Wu KS Lee SS Tsai HC Wann SR Chen JK Sy CL Non-nosocomial healthcare-associated infective endocarditis in Taiwan: an underrecognized disease with poor outcome BMC Infect Dis 2011 11 221 10.1186/1471-2334-11-221 21849057 \n5. Yang F Zhang B Yu J Shao L Zhou P Zhu L Epidemiology and the prognosis of healthcare-associated infective endocarditis in China: the significance of non-nosocomial acquisition Emerg Microbes Infect 2015 4 10.1038/emi.2015.38 26251828 \n6. Murdoch DR Corey GR Hoen B Miro JM Fowler VG Jr Bayer AS Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study Arch Intern Med 2009 169 463 473 10.1001/archinternmed.2008.603 19273776 \n7. Reyes MP Palutke WA Wylin RF Pseudomonas endocarditis in the Detroit Medical Center. 1969–1972 Medicine (Baltimore) 1973 52 173 194 10.1097/00005792-197305000-00001 20407410 \n8. Cohen PS Maguire JH Weinstein L Infective endocarditis caused by gram-negative bacteria: a review of the literature, 1945–1977 Prog Cardiovasc Dis 1980 22 205 242 10.1016/0033-0620(80)90010-9 6986059 \n9. Lin TI, Huang YF, Liu PY, Chou CA, Chen YS, Chen YY, et al. Pseudomonas aeruginosa infective endocarditis in patients who do not use intravenous drugs: analysis of risk factors and treatment outcomes. J Microbiol Immunol Infect. 2014.\n10. Morpeth S Murdoch D Cabell CH Karchmer AW Pappas P Levine D Non-HACEK gram-negative bacillus endocarditis Ann Intern Med 2007 147 829 835 10.7326/0003-4819-147-12-200712180-00002 18087053 \n11. Dawson NL Brumble LM Pritt BS Yao JD Echols JD Alvarez S Left-sided Pseudomonas aeruginosa endocarditis in patients without injection drug use Medicine (Baltimore) 2011 90 250 255 10.1097/MD.0b013e3182252133 21694647 \n12. Daas H Abuhmaid F Zervos M Successful treatment of Candida parapsilosis and Pseudomonas aeruginosa infection using medical and surgical management in an injecting drug user with mitral and aortic valve endocarditis: a case report J Med Case Rep 2009 3 6598 10.1186/1752-1947-3-6598 19830113 \n13. Yilmaz M Sunar H Mert A Community-acquired left-sided Pseudomonas aeruginosa endocarditis in a patient without intravenous drug use Infection 2013 41 243 245 10.1007/s15010-012-0306-x 22865392 \n14. Setoguchi M Iwasawa E Hashimoto Y Isobe M A patient with infective endocarditis caused by community-acquired Pseudomonas aeruginosa infection Intern Med 2013 52 1259 1262 10.2169/internalmedicine.52.9059 23728567 \n15. Venkatesan A Spalding C Speedie A Sinha G Rumbaugh JA Pseudomonas aeruginosa infective endocarditis presenting as bacterial meningitis J Infect 2005 51 e199 e202 10.1016/j.jinf.2005.02.019 16291269 \n16. Reinsch N Plicht B Lind A Janosi RA Buck T Kamler M Recurrent infective endocarditis with uncommon Gram-negative Pasteurella multocida and Pseudomonas aeruginosa: a case report J Heart Valve Dis 2008 17 710 713 19137805 \n17. Aggarwal A Ritter N Reddy L Lingutla D Nasar F El-Daher N Recurrent Pseudomonas aortic root abscess complicating mitral valve endocarditis Heart Lung 2012 41 181 183 10.1016/j.hrtlng.2011.01.008 21414666 \n18. Todaro J Bollmann PW Nussbacher A Camargo LF Santos BF Alvarenga D Multiple myeloma complicated with pseudomonas endocarditis Einstein (Sao Paulo) 2012 10 498 501 10.1590/S1679-45082012000400017 23386092 \n19. Hassan KS Al-Riyami D Infective endocarditis of the aortic valve caused by Pseudomonas aeruginosa and treated medically in a patient on haemodialysis Sultan Qaboos Univ Med J 2012 12 120 123 10.12816/0003099 22375270 \n20. Regules JA Glasser JS Wolf SE Hospenthal DR Murray CK Endocarditis in burn patients: clinical and diagnostic considerations Burns 2008 34 610 616 10.1016/j.burns.2007.08.002 18029099 \n21. Kato Y Ohashi H Tsutsumi Y Murakami T Takahashi Y Prosthetic valve endocarditis caused by metallo-beta-lactamase-producing Pseudomonas aeruginosa J Card Surg 2009 24 347 349 10.1111/j.1540-8191.2008.00791.x 19438796 \n22. Nasim A Baqi S Akhtar SF Pseudomonas aeruginosa endocarditis in renal transplant recipients Transpl Infect Dis 2012 14 180 183 10.1111/j.1399-3062.2011.00667.x 21883760 \n23. Durante-Mangoni E Andini R Agrusta F Iossa D Mattucci I Bernardo M Infective endocarditis due to multidrug resistant gram-negative bacilli: single centre experience over 5 years Eur J Intern Med 2014 25 657 661 10.1016/j.ejim.2014.05.015 24954705 \n24. Polovina M Potpara T Milosevic I Stepanovic J Jovanovic M Pavlovic M Mitral valve endocarditis caused by Pseudomonas aeruginosa: a case report J Infect Dev Ctries 2014 8 676 679 10.3855/jidc.3816 24820475 \n25. Reyes MP Ali A Mendes RE Biedenbach DJ Resurgence of Pseudomonas endocarditis in Detroit, 2006–2008 Medicine (Baltimore) 2009 88 294 301 10.1097/MD.0b013e3181b8bedc 19745688 \n26. Meyers BR Sherman E Mendelson MH Velasquez G Srulevitch-Chin E Hubbard M Bloodstream infections in the elderly Am J Med 1989 86 379 384 10.1016/0002-9343(89)90333-1 2929625 \n27. Gavin PJ Suseno MT Cook FV Peterson LR Thomson RB Jr Left-sided endocarditis caused by Pseudomonas aeruginosa: successful treatment with meropenem and tobramycin Diagn Microbiol Infect Dis 2003 47 427 430 10.1016/S0732-8893(03)00135-4 14522517 \n28. Fichtenbaum CJ Smith MJ Treatment of endocarditis due to Pseudomonas aeruginosa with imipenem Clin Infect Dis 1992 14 353 354 10.1093/clinids/14.1.353 1571451\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2334", "issue": "16(1)", "journal": "BMC infectious diseases", "keywords": "Healthcare-associated infective endocarditis; Patent foramen ovale; Right-to-left shunt; Urethral self-catheterization", "medline_ta": "BMC Infect Dis", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001021:Aortic Valve; D004359:Drug Therapy, Combination; D017548:Echocardiography, Transesophageal; D004696:Endocarditis; D004697:Endocarditis, Bacterial; D054092:Foramen Ovale, Patent; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D057928:Intermittent Urethral Catheterization; D008279:Magnetic Resonance Imaging; D008297:Male; D000077731:Meropenem; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D013845:Thienamycins; D014031:Tobramycin; D018608:Ultrasonography, Doppler", "nlm_unique_id": "100968551", "other_id": null, "pages": "431", "pmc": null, "pmid": "27543116", "pubdate": "2016-08-20", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "22865392;21883760;21849057;18087053;6986059;24954705;19273776;21414666;19414837;19830113;2929625;19137805;16291269;14522517;19745688;19732086;23728567;22375270;18834314;23386092;21694647;25442867;26251828;20407410;1571451;24820475;19438796;18029099", "title": "Non-nosocomial healthcare-associated left-sided Pseudomonas aeruginosa endocarditis: a case report and literature review.", "title_normalized": "non nosocomial healthcare associated left sided pseudomonas aeruginosa endocarditis a case report and literature review" }

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{ "abstract": "OBJECTIVE\nFew studies have examined the relationship between antipsychotic polypharmacy and metabolic syndrome in schizophrenia. Some studies suggest that antipsychotic polypharmacy may be associated with greater metabolic risk, whereas other studies suggest that this is uncertain. To date, there have been no studies in Egypt or the Arab world that have investigated this relationship. We sought to compare subjects with schizophrenia receiving antipsychotic polypharmacy and monotherapy as regards metabolic outcomes and to investigate medication-related factors associated with metabolic syndrome.\nWe recruited 118 subjects with schizophrenia and compared between those receiving antipsychotic polypharmacy (86 subjects) and monotherapy (32 subjects) as regards demographic, clinical, metabolic, and antipsychotic medication characteristics. We examined the effect of antipsychotic-related factors an outcome of metabolic syndrome.\nThe prevalence of metabolic syndrome in our sample was 38.1%. Except for gender, there was no statistically significant difference as regards demographic and clinical characteristics, rates of metabolic syndrome, or for individual metabolic parameters. We found a statistically significant difference (P < 0.05) between the 2 groups as regards the number, dose, and duration of intake and for the number of subjects receiving typical antipsychotics (oral and depot) and a number of individual antipsychotic medications. Using logistic regression, receiving haloperidol depot was the only antipsychotic-related factor predictive for metabolic syndrome.\nThe prevalence of metabolic syndrome does not differ in schizophrenia whether patients are receiving polypharmacy and monotherapy nor do they differ for individual metabolic parameters. Most antipsychotic-related characteristics did not predict for metabolic syndrome.", "affiliations": null, "authors": "Aly El-Gabry|Dina M|DM|;Abdel Aziz|Karim|K|;Okasha|Tarek|T|;Azzam|Hanan|H|;Okasha|Ahmed|A|", "chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D006220:Haloperidol", "country": "United States", "delete": false, "doi": "10.1097/JCP.0000000000000815", "fulltext": null, "fulltext_license": null, "issn_linking": "0271-0749", "issue": "38(1)", "journal": "Journal of clinical psychopharmacology", "keywords": null, "medline_ta": "J Clin Psychopharmacol", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003430:Cross-Sectional Studies; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D004534:Egypt; D005260:Female; D006220:Haloperidol; D006801:Humans; D016015:Logistic Models; D008297:Male; D024821:Metabolic Syndrome; D008875:Middle Aged; D019338:Polypharmacy; D015995:Prevalence; D012559:Schizophrenia; D055815:Young Adult", "nlm_unique_id": "8109496", "other_id": null, "pages": "27-33", "pmc": null, "pmid": "29210867", "pubdate": "2018-02", "publication_types": "D016428:Journal Article", "references": null, "title": "Antipsychotic Polypharmacy and Its Relation to Metabolic Syndrome in Patients With Schizophrenia: An Egyptian Study.", "title_normalized": "antipsychotic polypharmacy and its relation to metabolic syndrome in patients with schizophrenia an egyptian study" }

[ { "companynumb": "EG-JNJFOC-20180208790", "fulfillexpeditecriteria": "1", "occurcountry": "EG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALIPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALIPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "015923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIMOZIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIMOZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "015923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metabolic syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALY EL-GABRY D, AZIZ KA, OKASHA T, AZZAM H, OKASHA A. ANTIPSYCHOTIC POLYPHARMACY AND ITS RELATION TO METABOLIC SYNDROME IN PATIENTS WITH SCHIZOPHRENIA AN EGYPTIAN STUDY. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY FEB-2018?38 (1):27-33.", "literaturereference_normalized": "antipsychotic polypharmacy and its relation to metabolic syndrome in patients with schizophrenia an egyptian study", "qualification": "1", "reportercountry": "EG" }, "primarysourcecountry": "EG", "receiptdate": "20180216", "receivedate": "20180216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14541709, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "A 75-year-old female presented for left total hip reimplantation and suffered pulseless electrical activity arrest upon lateral positioning and administering vancomycin. Resuscitation was achieved according to Advanced Cardiac Life Support protocol. Post-event echocardiography showed hypertrophic cardiomyopathy with asymmetrical septal thickening, an under-filled left ventricle, dynamic left ventricular outflow obstruction, and severe mitral regurgitation related to systolic anterior motion of the mitral valve. Laboratory analysis showed a tryptase level of 209 ng/mL. After multispecialty evaluation, it was concluded that the patient's arrest was due to vancomycin anaphylaxis in the setting of previously undiagnosed hypertrophic cardiomyopathy leading to acute left ventricular outflow tract obstruction. After medical optimization of the patient's cardiomyopathy and an evaluation of potential intraoperative allergic triggers, the patient underwent a successful hip reimplantation without incident. This case presents a novel combination of events leading to intraoperative cardiac arrest. Rapid identification and an understanding of the cause(s) of cardiac arrest in this setting are critical for effective perioperative care.", "affiliations": "Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905. Electronic address: Smith.Bradford@mayo.edu.;Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University, Nashville, TN 37232. Electronic address: andrew.s.nickels@vanderbilt.edu.;Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905. Electronic address: Sviggum.Hans@mayo.edu.", "authors": "Smith|Bradford B|BB|;Nickels|Andrew S|AS|;Sviggum|Hans P|HP|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D014640:Vancomycin; D008790:Metoprolol; D004837:Epinephrine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0952-8180", "issue": "31()", "journal": "Journal of clinical anesthesia", "keywords": "Anaphylaxis; Hypertrophic cardiomyopathy; Left ventricular outflow obstruction; Pulseless electrical activity; Vancomycin anaphylaxis", "medline_ta": "J Clin Anesth", "mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D002312:Cardiomyopathy, Hypertrophic; D004452:Echocardiography; D004837:Epinephrine; D005260:Female; D006323:Heart Arrest; D006615:Hip; D006801:Humans; D007431:Intraoperative Complications; D008790:Metoprolol; D014640:Vancomycin; D014694:Ventricular Outflow Obstruction", "nlm_unique_id": "8812166", "other_id": null, "pages": "212-4", "pmc": null, "pmid": "27185714", "pubdate": "2016-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A rare combination of undiagnosed hypertrophic cardiomyopathy revealed by intraoperative anaphylaxis resulting in acute left ventricular outflow obstruction and cardiac arrest.", "title_normalized": "a rare combination of undiagnosed hypertrophic cardiomyopathy revealed by intraoperative anaphylaxis resulting in acute left ventricular outflow obstruction and cardiac arrest" }

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A RARE COMBINATION OF UNDIAGNOSED HYPERTROPHIC CARDIOMYOPATHY REVEALED BY INTRAOPERATIVE ANAPHYLAXIS RESULTING IN ACUTE LEFT VENTRICULAR OUTFLOW OBSTRUCTION AND CARDIAC ARREST. 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"reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertrophic cardiomyopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SMITH BB, NICKELS AS, SVIGGUM HP. A RARE COMBINATION OF UNDIAGNOSED HYPERTROPHIC CARDIOMYOPATHY REVEALED BY INTRAOPERATIVE ANAPHYLAXIS RESULTING IN ACUTE LEFT VENTRICULAR OUTFLOW OBSTRUCTION AND CARDIAC ARREST. J-CLIN-ANESTH 2016;31:212-4.", "literaturereference_normalized": "a rare combination of undiagnosed hypertrophic cardiomyopathy revealed by intraoperative anaphylaxis resulting in acute left ventricular outflow obstruction and cardiac arrest", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170424", "receivedate": "20170424", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13472968, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-MYLANLABS-2017M1022840", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30ML OF 0.5%", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Left ventricle outflow tract obstruction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertrophic cardiomyopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SMITH BB, NICKELS AS, SVIGGUM HP. A RARE COMBINATION OF UNDIAGNOSED HYPERTROPHIC CARDIOMYOPATHY REVEALED BY INTRAOPERATIVE ANAPHYLAXIS RESULTING IN ACUTE LEFT VENTRICULAR OUTFLOW OBSTRUCTION AND CARDIAC ARREST. J-CLIN-ANESTH 2016;31:212-4.", "literaturereference_normalized": "a rare combination of undiagnosed hypertrophic cardiomyopathy revealed by intraoperative anaphylaxis resulting in acute left ventricular outflow obstruction and cardiac arrest", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170413", "receivedate": "20170413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13436336, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-DEPOMED, INC.-US-2017DEP000938", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertrophic cardiomyopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Left ventricle outflow tract obstruction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SMITH BB, NICKELS AS, SVIGGUM HP. A RARE COMBINATION OF UNDIAGNOSED HYPERTROPHIC CARDIOMYOPATHY REVEALED BY INTRAOPERATIVE ANAPHYLAXIS RESULTING IN ACUTE LEFT VENTRICULAR OUTFLOW OBSTRUCTION AND CARDIAC ARREST. JOURNAL OF CLINICAL ANESTHESIA. 2016;31:212-214", "literaturereference_normalized": "a rare combination of undiagnosed hypertrophic cardiomyopathy revealed by intraoperative anaphylaxis resulting in acute left ventricular outflow obstruction and cardiac arrest", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170512", "receivedate": "20170512", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13540483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-03031", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { 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null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INDUCTION OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INDUCTION OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201510", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NERVE BLOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201510", "drugstartdateformat": "610", "drugstructuredosagenumb": "30", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "SPACER PLACEMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201510", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypertrophic cardiomyopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Left ventricle outflow tract obstruction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201510" } }, "primarysource": { "literaturereference": "SMITH B,NICKELS A,SVIGGUM H. A RARE COMBINATION OF UNDIAGNOSED HYPERTROPHIC CARDIOMYOPATHY REVEALED BY INTRAOPERATIVE ANAPHYLAXIS RESULTING IN ACUTE LEFT VENTRICULAR OUTFLOW OBSTRUCTION AND CARDIAC ARREST. JOURNAL OF CLINICAL ANESTHESIA 2016?31:212-214.", "literaturereference_normalized": "a rare combination of undiagnosed hypertrophic cardiomyopathy revealed by intraoperative anaphylaxis resulting in acute left ventricular outflow obstruction and cardiac arrest", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180424", "receivedate": "20180424", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14799413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "BACKGROUND\nWe present a 51 year old, African American, female who presented with persistent hypoxemia. She had been taking dapsone for many years for prophylaxis against Pneumocystic Jiroveci with no symptoms but eventually developed methemoglobinemia only after a splenectomy. From our literature review there are no documented cases that have demonstrated this relationship between dapsone, splenic function and methemoglobin and we hope to share our perplexing case and shed light on the interaction.\n\n\nMETHODS\nOur patient has type 1 diabetes and underwent multiple pancreas transplants and an initial kidney transplant during her disease course. One year prior to her presentation she underwent a distal pancreatectomy and an incidental splenectomy during the same procedure. She had been taking dapsone for approximately 17 years due to her allergy to sulfamethoxazole/trimethoprim and her immunosuppressive regimen included tacrolimus, sirolimus, and low dose prednisone. She had presented for a routine, post-surgery follow up visit when she was diagnosed with hypoxemia. After an extensive but unsuccessful work up for persistent hypoxemia, she presented to our clinic for a second opinion. Repeat testing of the arterial blood gas in clinic showed a significant methemoglobin (MHb) level of 16.6 mg/dl.\n\n\nCONCLUSIONS\nAlthough methemoglobinemia is a well-known risk of dapsone exposure, we report a case that suggests that splenectomy can interact with dapsone to further increase the risk of methemobloginemia. We believe that our patient did not develop methemoglobinemia initially, despite being on dapsone for many years because her spleen was able to remove older more susceptible erythrocytes from the circulation leaving the more robust younger erythrocytes. With the splenectomy, the number of older erythrocytes in the peripheral circulation increased and resulted in an accumulation of MHb leading to the low oxygen saturations. Her dapsone was immediately stopped and she was started on vitamin C with a 3 day follow up revealing resolution of her methemoglobinemia and normal oxygen saturation on room air.", "affiliations": "St. Joseph's Hospital and Medical Center, USA.;Arizona Pulmonary Specialists, USA.", "authors": "Ballachanda Subbaiah|Taaran Cariappa|TC|;Feldman|Jeremy P|JP|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2017.05.001", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30174-510.1016/j.rmcr.2017.05.001Case ReportBlue after splenectomy Ballachanda Subbaiah Taaran Cariappa MDtaaran.cariappa@gmail.coma∗Feldman Jeremy P. MDba St. Joseph's Hospital and Medical Center, USAb Arizona Pulmonary Specialists, USA∗ Corresponding author. taaran.cariappa@gmail.com09 5 2017 2017 09 5 2017 21 164 166 27 12 2016 3 5 2017 4 5 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nWe present a 51 year old, African American, female who presented with persistent hypoxemia. She had been taking dapsone for many years for prophylaxis against Pneumocystic Jiroveci with no symptoms but eventually developed methemoglobinemia only after a splenectomy. From our literature review there are no documented cases that have demonstrated this relationship between dapsone, splenic function and methemoglobin and we hope to share our perplexing case and shed light on the interaction.\n\nDescription\nOur patient has type 1 diabetes and underwent multiple pancreas transplants and an initial kidney transplant during her disease course. One year prior to her presentation she underwent a distal pancreatectomy and an incidental splenectomy during the same procedure. She had been taking dapsone for approximately 17 years due to her allergy to sulfamethoxazole/trimethoprim and her immunosuppressive regimen included tacrolimus, sirolimus, and low dose prednisone. She had presented for a routine, post-surgery follow up visit when she was diagnosed with hypoxemia. After an extensive but unsuccessful work up for persistent hypoxemia, she presented to our clinic for a second opinion. Repeat testing of the arterial blood gas in clinic showed a significant methemoglobin (MHb) level of 16.6 mg/dl.\n\nDiscussion\nAlthough methemoglobinemia is a well-known risk of dapsone exposure, we report a case that suggests that splenectomy can interact with dapsone to further increase the risk of methemobloginemia. We believe that our patient did not develop methemoglobinemia initially, despite being on dapsone for many years because her spleen was able to remove older more susceptible erythrocytes from the circulation leaving the more robust younger erythrocytes. With the splenectomy, the number of older erythrocytes in the peripheral circulation increased and resulted in an accumulation of MHb leading to the low oxygen saturations.\n\nHer dapsone was immediately stopped and she was started on vitamin C with a 3 day follow up revealing resolution of her methemoglobinemia and normal oxygen saturation on room air.\n\nKeywords\nMethemoglobinemiaDapsoneSplenectomySolid organ transplantHypoxemia\n==== Body\n1 Introduction\nMethemoglobin (MHb) is an abnormal form of hemoglobin (Hb) and is created in the body when deoxygenated Hb is transformed by oxidation so that the iron present in the heme moiety is converted from the usual ferrous state to the ferric state [1]. Dapsone is a well-recognized cause of methemoglobinemia. As many as 13% of stem cell recipients exposed to dapsone will develop MHb [2]. We present a patient who was taking dapsone for many years without any symptoms but developed methemoglobinemia only after a splenectomy. From our literature review there are no documented cases that have demonstrated this relationship between dapsone, splenic function and MHb and we hope to share our perplexing case and shed light on the interaction.\n\n2 Case history\nWe introduce a 51 year old, African American, female who was referred to the pulmonologist's office because of persistent hypoxemia.\n\nHer past medical history is significant for type 1 diabetes for which she received a pancreas transplant along with a kidney transplant, 17 years prior. She subsequently required 2 more pancreas transplants, 10 and 11 years after the initial transplant. One year prior to presenting to our office she underwent a distal pancreatectomy for an intra-ductal mucinous neoplasm and an incidental splenectomy during the same procedure. She had been taking dapsone for approximately 17 years due to her allergy to sulfamethoxazole/trimethoprim. Her immunosuppressive regimen included tacrolimus, sirolimus, and low dose prednisone.\n\nHer hypoxemia was first noted on a routine check-up 6 months after her splenectomy. Her oxygen saturations were noted to be persistently between 80 and 85%. With two liters per minute of oxygen her saturations increased to 92%. Her initial work up consisted of a chest x-ray revealing an incidental nodule in her left upper lobe. A ventilation/perfusion scan and a duplex ultrasonography of her lower extremities revealed no signs of thromboembolic events. Echocardiography with bubble study revealed normal cardiac function and with estimated pulmonary artery pressure of 27 mmHg and no signs of right to left shunting. She also has a right heart catheterization which was normal. Pulmonary function testing (PFTs) showed a restrictive disease pattern with a moderately decreased diffusion capacity of carbon monoxide. 8 months after she was initially found to be have low oxygen saturations she sought a second opinion. A room air arterial blood gas was checked which showed pH: 7.41; pCO2: 35; pO: 295.5; HCO3: 21.8. Her oxygen saturation was 85.2 with an A-a gradient of 8.9. Her Hgb was 12.3mg/dl and her MHb level was found to be 16.6 mg/dl.\n\n3 Discussion\nHeme is a tetramer molecule. Under conditions of oxidative stress, partial oxidation of the heme subunits occurs, causing the remaining non-oxidized portions of the heme molecule to have a very high affinity for oxygen. Because of this they do not easily release oxygen to the tissues, thus shifting the oxygen dissociation curve to the left [3]. Because erythrocytes are continuously exposed to oxygen, a physiologic amount of MHb is produced [4]. It is maintained at low levels; usually less than 1% by compensatory mechanisms.\n\nNicotinamide adenine dinucleotide (NADH) dependent cytochrome b5 reductase is the major enzyme responsible for reducing MHB. Nicotinamide adenine dinucleotide phosphate (NADPH) also participates in the reduction of MHb. Two non-enzymatic antioxidants include ascorbic acid and glutathione [5].\n\nErythrocytes are uniquely susceptible to oxidative stress. Red blood cells are equipped with NADH and NADPH but are unable to respond to increased oxidative stress by increasing enzyme production because of a lack of cellular organelles. As erythrocytes age, the amount of enzyme they contain degrades over time making the older cells more prone to oxidative stress than the younger cells [6].\n\nMethemoglobinemia occurs when the MHb is being produced at a rate that is faster than the rate at which it can be reduced back to Hb by the regulatory mechanisms of the body. It can be hereditary or acquired. Acquired Methemoglobinemia is induced by exposure to chemicals or drugs. The most common agents seen in the medical field are nitrates, nitrites, naphthalene, phenazopyridine, dapsone, benzocaine and aniline dyes [7].\n\nDapsone (diaminodiphenylsulfone) is an antibiotic that decreases folate synthesis by inhibiting the enzyme dihydropteroate synthetase and is used to treat leprosy, malaria, and dermatitis herpetiformis and provide prophylaxis of Pneumocystis Jiroveci infections. It undergoes reversible acetylation by N-acetyltransferase (NAT2) to monoacetyl dapsone and via the cytochrome P450 mediated N-hydroxylation to dapsone hydroxylamine in the liver. Dapsone monohydroxylamine is rapidly taken up by erythrocytes and is primarily responsible for the development of methemoglobinemia and hemolysis. The acetylated metabolites are pharmacologically inactive [8].\n\nIn normally healthy subjects, symptoms of cyanosis begin to appear when the level of MHb is around 15%. Headaches, tachycardia, fatigue, weakness and dizziness appear at levels of 30–40%. Hypoxia leading to acidosis, paralysis, arrhythmias, convulsions and coma are present at 60% and death at 70–80% [9]. The severity of the patient's methemoglobinemia is relative to the patient's Hb level.\n\nMany scientific authors in the past have suggested that exposure to dapsone metabolites results in an acceleration of the aging process of normal erythrocytes which in turn increases splenic sequestration and consequent breakdown [10]. L. Ciccoli and M. Ferrali in their study published in 1999 showed that acute intoxication of laboratory rats with aniline and dapsone compounds resulted in a marked increase in the content of free iron and methemoglobin within erythrocytes. Sub chronic administration of the same compounds resulted in marked iron overload in the spleen and the kupffer cells of the liver. Splenic weight was markedly increased and the free iron pool in both the liver and spleen were also increased further indicating increased erythrocyte breakdown in the spleen [11].\n\nThe primary treatment in cases of acquired methemoglobinemia is to stop the offending agent. A decision to hospitalize patients and use specific therapeutic agents is made based on the degree of symptoms as well as the level of methemoglobin. The best described pharmacological therapies for methemoglobinemia are methylene blue and vitamin C as reducing agents and cimetidine as an inhibitor of the N-hydroxylation of dapsone to dapsone hydroxylamine which causes methemoglobinemia.\n\nIn life threatening circumstances treatment of methemoglobinemia, intravenous methylene blue is considered to be the treatment of choice [12]. When methylene blue is unavailable high doses of inteavenous vitamin C can be used [13]. Blood transfusions and hyperbaric oxygen have also been used in some cases. Since cimetidine works slowly it is not useful for acute dapsone associated methemoglobinemia.\n\nFor outpatient treatment of acute methemoglobinemia, oral methylene blue and vitamin C are the primary options. Cimetidine has mostly been studied for chronic use to improve the therapeutic/toxic ratio to dapsone and decrease the level of dapsone induced methemoglobinemia [14].\n\n4 Conclusion\nAlthough metmemoglobinemia is a well-known risk of dapsone exposure we report a case that suggests that splenectomy can interact with dapsone to further increase the risk methemobloginemia. We believe that our patient did not develop methemoglobinemia despite being on dapsone for many years because her spleen was able to remove older more susceptible erythrocytes from the circulation leaving the more robust younger erythrocytes which were able to prevent MHb formation because of their adequate enzyme levels. With the splenectomy the number of older erythrocytes in the peripheral circulation increased and resulted in an accumulation of MHb leading to low oxygen saturations. Once recognized, her dapsone was immediately stopped and she was started on vitamin C. 3 days later, at her follow up clinic visit, she was noted to have oxygen saturations close to 100% on room air. She was later placed on atovaquone for continued Pneumocystic Jiroveci prophylaxis.\n==== Refs\nReferences\n1 Zosel A. Rychter K. Leikin J.B. Dapsone-induced methemoglobinemia: case report and literature review Am. J. Ther. 14 6 2007 Nov-Dec 585 587 18090884 \n2 Lee I. Barton T.D. Goral S. Doyle A.M. Bloom R.D. Chojnowski D. Korenda K. Blumberg E.A. Complications related to dapsone use for Pneumocystis jirovecii pneumonia prophylaxis in solid organ transplant recipients Am. J. Transpl. Off. J. Am. Soc. Transpl. Am. Soc. Transpl. Surg. 5 11 2005 2791 2795 \n3 Jaffé E.R. Methaemoglobinaemia Clin. Haematol. 10 1 1981 99 122 7011627 \n4 Jaffe E.R. Hultquist D.E. Cytochrome b5 Reductase Deficiency and Enzymopenic Hereditary Methemoglobinemia seventh ed. The Metabolic and Molecular Bases of Inherited Disease 1995 McGraw-Hill New York 2267 2280 \n5 Coleman M.D. Coleman N.A. Drug-induced methaemoglobinaemia. Treatment issues Drug Saf. 14 6 1996 394 405 8828017 \n6 Bernstein S.C. Bowman J.E. Noche L.K. Interaction of sickle cell trait and glucose-6-phosphate dehydrogenase deficiency in Cameroon Hum. Hered. 30 1 1980 7 11 7353892 \n7 Wright Robert O. Lewander William J. Woolf Alan D. Methemoglobinemia: etiology, pharmacology, and clinical management Ann. Emerg. Med. 34 5 1999 646 656 10533013 \n8 Barclay J.A. Ziemba S.E. Ibrahim R.B. Dapsone-induced methemoglobinemia: a primer for clinicians Ann. Pharmacother. 45 9 2011 1103 1115 21852596 \n9 Curry S. Methemoglobinemia Ann. Emerg. Med. 11 4 1982 214 221 7073040 \n10 Grossman S.J. Jollow D.J. Role of dapsone hydroxylamine in dapsone-induced hemolytic anemia J. Pharmacol. Exp. Ther. 244 1 1988 118 125 3335994 \n11 Ciccoli L. Ferrali M. Rossi V. Signorini C. Alessandrini C. Comporti M. Hemolytic drugs aniline and dapsone induce iron release in erythrocytes and increase the free iron pool in spleen and liver Toxicol. Lett. 110 1–2 1999 57 66 10593595 \n12 Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes Anesth. Analgesia 108 3 2009 837 845 \n13 Rino Pedro Bonifacio Ascorbic acid for the treatment of methemoglobinemia: the experience of a large tertiary care pediatric hospital Am. J. Ther. 21 4 2014 240 243 24914501 \n14 Rhodes L.E. Cimetidine improves the therapeutic/toxic ratio of dapsone in patients on chronic dapsone therapy Br. J. Dermatol. 132 2 1995 257 262 7888363\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "21()", "journal": "Respiratory medicine case reports", "keywords": "Dapsone; Hypoxemia; Methemoglobinemia; Solid organ transplant; Splenectomy", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "164-166", "pmc": null, "pmid": "28616377", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "7073040;19224791;10593595;7888363;10533013;24914501;7353892;16212642;21852596;18090884;3335994;7011627;8828017", "title": "Blue after splenectomy.", "title_normalized": "blue after splenectomy" }

[ { "companynumb": "US-ALVOGEN-2017-ALVOGEN-092553", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DAPSONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "205429", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG HYPERSENSITIVITY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAPSONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Methaemoglobinaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BALLACHANDA SUBBAIAH TC, FELDMAN JP. BLUE AFTER SPLENECTOMY. RESPIR MED CASE REP. 2017 MAY 9;21:164-166.", "literaturereference_normalized": "blue after splenectomy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170703", "receivedate": "20170703", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13709837, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Valproic acid is an effective, frequently used anticonvulsant drug. Typical adverse effects include weight gain, hair loss, and nausea. Hyperpigmentation, onycholysis, and onychomadesis are nail changes that can be seen after valproic acid use. Changes occur at the distal and proximal portions of the nail bed in onycholysis and onychomadesis, respectively. Onychomadesis is a very rare disease of childhood with the exception of systemic and genetic diseases. Here, we present a child aged 23 months, the youngest and the earliest isolated patient with onychomadesis, which occurred after valproic acid treatment and worried the family but resolved spontaneously. The improvement of this very rare adverse effect of antiepileptic drugs after cessation of valproic acid without treatment is emphasized.", "affiliations": "Division of Pediatric Neurology, Bezmialem Vakif University School of Medicine, İstanbul, Turkey.;Division of Pediatric Neurology, Bezmialem Vakif University School of Medicine, İstanbul, Turkey.;Division of Pediatric Neurology, Bezmialem Vakif University School of Medicine, İstanbul, Turkey.", "authors": "Güler|Serhat|S|;Işık|İlhan|İ|;İşcan|Akın|A|", "chemical_list": null, "country": "Turkey", "delete": false, "doi": "10.5152/TurkPediatriArs.2015.2630", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "52(2)", "journal": "Turk pediatri arsivi", "keywords": "Adverse effect; epilepsy; onychomadesis; valproic acid", "medline_ta": "Turk Pediatri Ars", "mesh_terms": null, "nlm_unique_id": "9803140", "other_id": null, "pages": "98-100", "pmc": null, "pmid": "28747841", "pubdate": "2017-06", "publication_types": "D002363:Case Reports", "references": "10523137;17430758;20199458", "title": "Onychomadesis: A rare adverse effect in early-period valproic acid therapy.", "title_normalized": "onychomadesis a rare adverse effect in early period valproic acid therapy" }

[ { "companynumb": "MT-BION-006557", "fulfillexpeditecriteria": "1", "occurcountry": "MT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "073484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG/DAY IN TWO DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "FEBRILE CONVULSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": "3", "patientonsetage": "2", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Onycholysis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GULER S, ISIK I, ISCAN A. ONYCHOMADESIS: A RARE ADVERSE EFFECT IN EARLY PERIOD VALPROIC ACID THERAPY. TURK PEDIATRIARS. 2017 JUN 1;52(2):98-100.", "literaturereference_normalized": "onychomadesis a rare adverse effect in early period valproic acid therapy", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "MT", "receiptdate": "20170814", "receivedate": "20170814", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13862815, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Acute respiratory distress syndrome (ARDS) is a disorder that involves the activation of alveolar macrophages triggering the innate immune system. The parenchymal lung injury seen in ARDS is a result of many proinflammatory elevations including interleukin-6. There remains no effective standard of care of ARDS, and current treatments at this time currently do not target the immunological mechanisms or pathways involved. Treatments involving this pathway should be further investigated as targeted treatment. We discuss a case of a patient with multiple myeloma who was hospitalized with drug-induced ARDS who had a rapid response to an anti-interleukin-6 monoclonal antibody.", "affiliations": "Hackensack University Medical Center, Hackensack, NJ, USA.;Hackensack University Medical Center, Hackensack, NJ, USA.;Hackensack University Medical Center, Hackensack, NJ, USA.", "authors": "Petrillo|Alessandra|A|https://orcid.org/0000-0002-9060-1496;Biran|Noa|N|;Sadikot|Sean|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2020/8832986", "fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420 2090-6439 Hindawi \n\n10.1155/2020/8832986\nCase Report\nUse of Anti-Interleukin-6 Receptor Monoclonal Antibody in Drug-Induced Acute Respiratory Distress Syndrome\nhttps://orcid.org/0000-0002-9060-1496Petrillo Alessandra alessandra.petrillo@hackensackmeridian.org Biran Noa Sadikot Sean Hackensack University Medical Center, Hackensack, NJ, USA\nAcademic Editor: Ricardo Jorge Dinis-Oliveira\n\n\n2020 \n22 7 2020 \n2020 883298622 5 2020 26 6 2020 4 7 2020 Copyright © 2020 Alessandra Petrillo et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Acute respiratory distress syndrome (ARDS) is a disorder that involves the activation of alveolar macrophages triggering the innate immune system. The parenchymal lung injury seen in ARDS is a result of many proinflammatory elevations including interleukin-6. There remains no effective standard of care of ARDS, and current treatments at this time currently do not target the immunological mechanisms or pathways involved. Treatments involving this pathway should be further investigated as targeted treatment. We discuss a case of a patient with multiple myeloma who was hospitalized with drug-induced ARDS who had a rapid response to an anti-interleukin-6 monoclonal antibody.\n==== Body\n1. Introduction\nAcute respiratory distress syndrome (ARDS) is a disorder for which there is no standard of care therapy and with a mortality rate of 27%, 35%, and 45% for mild, moderate, severe disease, respectively [1]. It is mediated via a systemic inflammatory response involving all organ systems. The innate immune system elicits a systemic response in ARDS involving neutrophils, macrophages, and dendritic cells [2]. Alveolar macrophages lead to the elevation of inflammatory cytokines including interleukin-1beta (IL-1B), tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and interleukin-8 (IL-8) through the recruitment of neutrophils and macrophages in response to injury [2]. This inflammatory response leads to damaged lung epithelia and endothelia resulting in impaired alveolar-capillary barrier. Accumulation of protein-rich fluid accumulates in alveoli causing impaired gas exchange, subsequently leading to hypoxemia [2]. Current anti-inflammatory therapies that have been investigated for the treatment of ARDS include most commonly corticosteroids [3]. Other treatments have also been used, which include neutrophil elastase inhibitors [4], granulocyte-macrophage colony-stimulating factor (GM-CSF) [5], statins [6], omega-3 fatty acids [7], surfactant [8], inhaled B-agonists [9], and nitric oxide [10]. All treatments mentioned have not shown a mortality benefit. Supportive therapies such as mechanical ventilation [11] and prone positioning [12] are currently the only management for ARDS at this time [2].\n\nTocilizumab is a humanized monoclonal antibody to IL-6 receptor currently FDA approved for patients with rheumatoid arthritis, giant cell arteritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, and cytokine release syndrome in the setting of chimeric antigen receptor (CAR) T cells [13, 14]. Here, a patient with drug-induced ARDS and pneumonitis with multiorgan failure secondary to a chemotherapeutic agent carfilzomib experienced a rapid and clinically significant resolution of drug-induced ARDS after tocilizumab therapy.\n\n2. Case Report\nThe patient is a 62-year-old female with a past medical history of hypothyroidism who was diagnosed with free kappa multiple myeloma, Durie-Salmon IIIA Revised International Staging System (R-ISS), in 2019 after she presented with acute kidney injury and multiple vertebral compression fractures. Criteria for Durie-Salmon IIIA include one or more of the following: hemoglobin < 8.5 g/dL, serum calcium value > 12 mg/dL, advanced lytic lesions, or high M-component production rates IgG value > 7 g/dL and IgA value > 5 g/dL. Class A refers to a relatively normal renal function or serum creatinine value < 2.0 mg/dL [15].\n\nThe patient received induction therapy with carfilzomib (a second-generation proteasome inhibitor), cyclophosphamide (an alkylating agent), and dexamethasone in a twice weekly dosing schedule in a 28-day cycle. She completed her first full cycle without complication. During cycle 2, the cyclophosphamide was replaced by the oral immunomodulatory agent lenalidomide. On cycle 2 day 10, she was admitted with a fever of 102.5°F in respiratory distress requiring nasal cannula. Computed tomography (CT) chest at that time revealed patchy bilateral ground glass opacities consistent with pneumonia versus pulmonary edema. The respiratory pathogen panel was negative, an infectious etiology was not found, and she responded very quickly to stress dose steroids and was discharged two days later. Treatment was restarted a week later. The evening after rechallenge of carfilzomib, lenalidomide, and dexamethasone (cycle 3 day 1), she was found to be in acute respiratory failure by her husband and upon arrival in the emergency department she was found to have Po2 of 54, BP 93/58, and WBC 31.3.\n\nChest X-ray at the time of presentation showed new extensive multilobar airspace disease related to pneumonia or edema. Despite a trial of bilevel positive airway pressure and the rapid initiation of high-dose steroids and empiric antibiotics, the patient required intubation for respiratory distress. CT chest was consistent with complete opacification of both lungs. She experienced high fevers and multiorgan failure requiring 3 vasopressors, nitric oxide with prone positioning, and hemodialysis. Physical exam was significant for anisocoria and coarse breath sounds bilaterally. Laboratory evaluation revealed WBC 35,000; ferritin 2,500; CRP 17.7; and negative blood cultures. The patient was subsequently administered tocilizumab 500 mg IV 100 mL/hr over 60 minutes 1x. Within 24-48 hrs, vasopressor requirements lessened, anisocoria resolved, oxygen requirements improved, and laboratory evaluation revealed WBC 24,000; CRP 3.4; and ferritin 1000. Her chest X-ray showed significant improvement in diffuse airspace opacification. She was eventually extubated and is currently doing well.\n\n3. Discussion\nCurrent treatments for ARDS involve mechanisms which reduce shunt fraction, increase oxygen delivery, decrease oxygen consumption, and avoid further injury [1]. Mechanical ventilation with low tidal volume and high positive end-expiratory pressure (PEEP) and proning remain the most common and standard of care treatments for severe ARDS. Low tidal volume reduces lung stretch along with a reduction in inflammatory cytokines [11]. High PEEP is used to reduce lung collapse at end expiration and improve oxygenation [1]. However, methods to determine selection of the optimal PEEP level without leading to injury and lung overdistention is still unclear [1]. Prone positioning helps to alleviate lung compression from mediastinal and abdominal structures, improves oxygenation through redistribution of lung edema to less perfused areas, and reduces transpulmonary pressures that lead to tissue injury [1]. However, prone positioning is associated with increased risk of adverse events such as pressure ulcers, endotracheal obstruction, and catheter dislodgement [1]. Of these treatments, the mortality of ARDS remains at 45% for severe cases.\n\nThe case presented here involves a patient with drug-induced ARDS who demonstrated a response with an IL-6 receptor inhibitor as seen with her clinical improvement and measured with ferritin and CRP (Figure 1) At this time, her multiple myeloma was well controlled with carfilzomib as seen in (Figure 2) with a dose-dependent decrease in myeloma marker free kappa chain. In addition, her chest X-ray showed dramatic improvement after tocilizumab (Figure 3). She was discharged from the ICU within 48 hours of treatment. Her recovery was unanticipated given her initial severe presentation.\n\n4. Conclusion\nThe patient in this case was in multiorgan failure at the time and had poor response to steroids. This left the patient without options for treatment of her drug-induced ARDS, and therefore, an IL-6 receptor inhibitor was considered to reduce the inflammatory response.\n\nTreatment for ARDS should be centered around a targeted approach to the inflammatory mediators involved in the process. IL-6 plays a key role in leading to endothelial injury subsequently causing hypoxemia. Targeting IL-6 levels through means of IL-6 receptor inhibition would therefore assist in mechanisms for treatment to prevent cytokine-induced injury that subsequently leads to ARDS. Tocilizumab has also been used in Still's disease complicated with ARDSs and most recently in SARS-CoV-2 (COVID-19)-induced ARDS [16, 17]. It can be hypothesized, based on the clinical response seen in this patient, that tocilizumab played a critical role in modulating the pathophysiological immune response of ARDS. Therefore, tocilizumab should be investigated in the future for the targeted treatment of inflammatory diseases aside from cytokine release syndrome, such as ARDS.\n\nAcknowledgments\nI thank both Dr. Noa Biran and Dr. Sean Sadikot for their clinical expertise and assistance in writing this case report.\n\nAbbreviations\nCAR:Chimeric antigen receptor.\n\nData Availability\nNo additional data is available.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Inflammatory markers ferritin and CRP were both measured prior to and after the administration of an anti-IL-6 receptor monoclonal antibody. Administration of tocilizumab shows a time-dependent decrease in both ferritin and CRP within 48-72 hours. Baseline ferritin decreased from 2,500 to almost 1,000, whereas baseline CRP decreased from 17 to 2.0.\n\nFigure 2 Multiple myeloma marker responses to carfilzomib. Demonstration of cycle-dependent decline in free kappa and kappa/lambda ratios.\n\nFigure 3 Chest X-ray prior to and following tocilizumab. Improvement of bilateral ground glass opacities following interleukin-6 receptor inhibitor.\n==== Refs\n1 Diamond M. Peniston Feliciano H. L. Sanghavi D. Mahapatra Sidharth Acute respiratory distress syndrome (ARDS) [Updated 2020 Jan 5]. StatPearls [Internet] 2020 Treasure Island (FL) StatPearls Publishing https://www.ncbi.nlm.nih.gov/books/NBK436002/ \n2 Han S. Mallampalli R. K. The acute respiratory distress syndrome: from mechanism to translation Journal of Immunology 2015 194 3 855 860 10.4049/jimmunol.1402513 2-s2.0-84921473064 25596299 \n3 Peter J. V. John P. Graham P. L. Moran J. L. George I. A. Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis BMJ 2008 336 7651 1006 1009 10.1136/bmj.39537.939039.BE 2-s2.0-43249117658 18434379 \n4 Iwata K. Doi A. Ohji G. Effect of neutrophil elastase inhibitor (sivelestat sodium) in the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): a systematic review and meta-analysis Internal Medicine 2010 49 22 2423 2432 10.2169/internalmedicine.49.4010 2-s2.0-78549232682 21088343 \n5 Paine R. III Standiford T. J. Dechert R. E. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury Critical Care Medicine 2012 40 1 90 97 10.1097/CCM.0b013e31822d7bf0 2-s2.0-84055173351 21926600 \n6 The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network Rosuvastatin for sepsis-associated acute respiratory distress syndrome The New England Journal of Medicine 2014 370 23 2191 2200 10.1056/nejmoa1401520 2-s2.0-84901759539 24835849 \n7 Rice T. W. Wheeler A. P. Thompson B. T. Enteral omega-3 fatty acid, γ -linolenic acid, and antioxidant supplementation in acute lung injury JAMA 2011 306 1574 1581 10.1001/jama.2011.1435 2-s2.0-80054003232 21976613 \n8 Anzueto A. Baughman R. P. Guntupalli K. K. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome The New England Journal of Medicine 1996 334 22 1417 1422 10.1056/NEJM199605303342201 2-s2.0-9344262898 8618579 \n9 The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Randomized, placebo-controlled clinical trial of an aerosolized β 2 -Agonist for treatment of acute lung injury American Journal of Respiratory and Critical Care Medicine 2011 184 5 561 568 10.1164/rccm.201012-2090oc 2-s2.0-79960430979 21562125 \n10 Dellinger R. P. Zimmerman J. L. Taylor R. W. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome Critical Care Medicine 1998 26 1 15 23 10.1097/00003246-199801000-00011 2-s2.0-0031975630 9428538 \n11 The Acute Respiratory Distress Syndrome Network Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome The New England Journal of Medicine 2000 342 1301 1308 10.1056/nejm200005043421801 2-s2.0-0343893748 10793162 \n12 Guérin C. Reignier J. Richard J.-C. Prone positioning in severe acute respiratory distress syndrome The New England Journal of Medicine 2013 368 2159 2168 10.1056/NEJMoa1214103 2-s2.0-84878602907 23688302 \n13 National Cancer Institute NCI Drug Dictionary http://www.cancer.gov/publications/dictionaries/cancer-drug/def/tocilizumab \n14 GCA, SJIA, PJIA Treatment | ACTEMRA® (Tocilizumab) Learn more about Actemra https://www.actemra.com \n15 International Myeloma Foundation Durie-Salmon staging system http://www.myeloma.org/durie-salmon-staging \n16 Kaneko Y. Kameda H. Ikeda K. Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment: a randomised, double-blind, placebo-controlled phase III trial Annals of the Rheumatic Diseases 2018 77 12 1720 1729 10.1136/annrheumdis-2018-213920 2-s2.0-85054333198 30279267 \n17 Campochiaro C. Della-Torre E. Cavalli G. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single- centre retrospective cohort study European Journal of Internal Medicine 2020 76 43 49 10.1016/j.ejim.2020.05.021 32482597\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2020()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "8832986", "pmc": null, "pmid": "32774934", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "18434379;24835849;21976613;8618579;30279267;25596299;32482597;10793162;23688302;21562125;21926600;21088343;9428538", "title": "Use of Anti-Interleukin-6 Receptor Monoclonal Antibody in Drug-Induced Acute Respiratory Distress Syndrome.", "title_normalized": "use of anti interleukin 6 receptor monoclonal antibody in drug induced acute respiratory distress syndrome" }

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null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PETRILLO A, BIRAN N, SADIKOT S. USE OF ANTI?INTERLEUKIN?6 RECEPTOR MONOCLONAL ANTIBODY IN DRUG?INDUCED ACUTE RESPIRATORY DISTRESS SYNDROME. CASE REP CRIT CARE. 2020?UNKNOWN:01?04. DOI:10.1155/2020/8832986", "literaturereference_normalized": "use of anti interleukin 6 receptor monoclonal antibody in drug induced acute respiratory distress syndrome", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210719", "receivedate": "20210708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19505374, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "US-CELGENEUS-USA-20210600619", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Acute respiratory distress syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Acute respiratory distress syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Acute respiratory distress syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARFILZOMIB" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ALESSANDRA P. USE OF ANTI?INTERLEUKIN?6 RECEPTOR MONOCLONAL ANTIBODY IN DRUG?INDUCED ACUTE RESPIRATORY DISTRESS SYNDROME. CASE REPORTS IN CRITICAL CARE. 2020 JUL 22?.", "literaturereference_normalized": "use of anti interleukin 6 receptor monoclonal antibody in drug induced acute respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210609", "receivedate": "20210608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19391133, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Chemotherapy-induced neutropenia often occurs in our routine work and presents an obstacle for adequate (dose and continuance) treatment, which may affect patients' outcome. Granulocyte colony-stimulating factors (GCSFs) effectively prevent myelosuppression and thus improve the standard treatment. Through their application cases of chemotherapy-induced neutropenia have been reduced. Still these factors cannot remove entirely the danger of encountering neutropenia, which can cause dangerous complications. We present a case of a fulminate anaerobic infection with unknown origin in a patient with metastatic breast cancer after standard treatment with chemotherapy supported by GCSFs.", "affiliations": "Clinic of Hematology and Oncology, Department of Medical Oncology, Medical Military Academy, Sofia, Bulgaria.", "authors": "Petrova|Mila|M|;Mihaylova|Zhasmina|Z|;Fakirova|Albena|A|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/imcrj.s9383", "fulltext": null, "fulltext_license": null, "issn_linking": "1179-142X", "issue": "3()", "journal": "International medical case reports journal", "keywords": "anaerobic infection; granulocyte colony-stimulating factors; neutropenia; phlegmon", "medline_ta": "Int Med Case Rep J", "mesh_terms": null, "nlm_unique_id": "101566269", "other_id": null, "pages": "35-7", "pmc": null, "pmid": "23754885", "pubdate": "2010", "publication_types": "D002363:Case Reports", "references": "19756002;19652050;19773618;19627169;19756005", "title": "Fulminate anaerobic bacteremia after chemotherapy for metastatic breast cancer despite the prophylactic use of GCSF.", "title_normalized": "fulminate anaerobic bacteremia after chemotherapy for metastatic breast cancer despite the prophylactic use of gcsf" }

[ { "companynumb": "BG-AMGEN-BGRSP2020137543", "fulfillexpeditecriteria": "2", "occurcountry": "BG", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200905", "drugstartdateformat": "610", "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20090224", "drugstartdateformat": "102", "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200905", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteochondrosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Dysuria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Back pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2009" } }, "primarysource": { "literaturereference": "FAKIROVA, A.. FULMINATE ANAEROBIC BACTEREMIA AFTER CHEMOTHERAPY FOR METASTATIC BREAST CANCER DESPITE THE PROPHYLACTIC USE OF GCSF. INTERNATIONAL MEDICAL CASE REPORTS JOURNAL. 2010?3:35?37", "literaturereference_normalized": "fulminate anaerobic bacteremia after chemotherapy for metastatic breast cancer despite the prophylactic use of gcsf", "qualification": "3", "reportercountry": "BG" }, "primarysourcecountry": "BG", "receiptdate": "20200901", "receivedate": "20200901", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18217952, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]