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"abstract": "OBJECTIVE\nTo utilize transcatheter arterial steroid injection therapy (TASIT) via the hepatic artery to reduce hepatic macrophage activity in patients with severe acute hepatic failure.\n\n\nMETHODS\nThirty-four patients with severe acute hepatic failure were admitted to our hospital between June 2002 to June 2006 providing for the possibility of liver transplantation (LT). Seventeen patients were treated using traditional liver supportive procedures, and the other 17 patients additionally underwent TASIT with 1000 mg methylprednisolone per day for 3 continuous days.\n\n\nRESULTS\nOf the 17 patients who received TASIT, 13 were cured without any complications, 2 died, and 2 underwent LT. Of the 17 patients who did not receive TASIT, 4 were self-limiting, 7 died, and 6 underwent LT. Univariate logistic analysis revealed that ascites, serum albumin, prothrombin time, platelet count, and TASIT were significant variables for predicating the prognosis. Multivariate logistic regression analysis using stepwise variable selection showed that prothrombin time, platelet count, and TASIT were independent predictive factors.\n\n\nCONCLUSIONS\nTASIT might effectively prevent the progression of severe acute hepatic failure to a fatal stage of fulminant liver failure.",
"affiliations": "Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. kotoh-k@intmed3.med.kyushu-u.ac.jp",
"authors": "Kotoh|Kazuhiro|K|;Enjoji|Munechika|M|;Nakamuta|Makoto|M|;Yoshimoto|Tsuyoshi|T|;Kohjima|Motoyuki|M|;Morizono|Shusuke|S|;Yamashita|Shinsaku|S|;Horikawa|Yuki|Y|;Yoshimitsu|Kengo|K|;Tajima|Tsuyoshi|T|;Asayama|Yoshiki|Y|;Ishigami|Kousei|K|;Hirakawa|Masakazu|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v12.i41.6678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "12(41)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D018450:Disease Progression; D005260:Female; D006499:Hepatic Artery; D006801:Humans; D007269:Injections, Intra-Arterial; D017114:Liver Failure, Acute; D008264:Macrophages; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "6678-82",
"pmc": null,
"pmid": "17075983",
"pubdate": "2006-11-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "8320931;4693151;15561247;1716546;16534681;7004995;14742981;7035299;12820474;15588781;15692789;9635624;16279913;15288011;12695559;16142721;192431;16249741;7040555;15629511;8503773",
"title": "Arterial steroid injection therapy can inhibit the progression of severe acute hepatic failure toward fulminant liver failure.",
"title_normalized": "arterial steroid injection therapy can inhibit the progression of severe acute hepatic failure toward fulminant liver failure"
} | [
{
"companynumb": "JP-PFIZER INC-2021303460",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "011856",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POWDER FOR SOLUTION FOR INJECTION",
"drugdosagetext": "1000 MG, INFUSED FOR 2 H PER DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ACUTE HEPATIC FAILURE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
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"medicinalproduct": "METHYLPREDNISOLONE SODIUM SUCCINATE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatic failure",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KOTOH, K.. ARTERIAL STEROID INJECTION THERAPY CAN INHIBIT THE PROGRESSION OF SEVERE ACUTE HEPATIC FAILURE TOWARD FULMINANT LIVER FAILURE. WORLD JOURNAL OF GASTROENTEROLOGY. 2006?12 (41):6678?6682",
"literaturereference_normalized": "arterial steroid injection therapy can inhibit the progression of severe acute hepatic failure toward fulminant liver failure",
"qualification": "3",
"reportercountry": "JP"
},
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"receiptdate": "20210323",
"receivedate": "20210323",
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"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 19044445,
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"senderorganization": "FDA-Public Use",
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"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210420"
}
] |
{
"abstract": "A 12-year-old male patient suffering from congenital glaucoma developed bradycardia, left ventricular failure, and hypotension after induction of anesthesia. Electrocardiography and echocardiography revealed a complete normalization of ECG and a complete spontaneous recovery in the cardiac function 72 hours from the beginning of the clinical manifestations, while cardiac Magnetic Resonance Imaging was performed, and coronary Computed Tomography scan revealed a myocardial bridge of a tract of the left anterior descendent coronary artery. Diagnosis of Kounis syndrome (KS) was made, a relatively novel, under-recognized clinical condition, defined as the manifestation of an acute coronary syndrome accompanied by mast cell activation and platelet aggregation involving interrelated and interacting inflammatory cells in the setting of allergic, hypersensitivity, anaphylactic or anaphylactoid insults. We described one of the first pediatric cases of KS related to anesthetic medications. In children, this syndrome has been only described in isolated case reports or small case series. Thus, it appears critical to report new cases of KS in children to increase the awareness of this disease in pediatric healthcare workers so as to enhance its early recognition and optimal therapeutic strategy. Furthermore, it appears of paramount importance the implementation of universal guidelines accepted by allergology and cardiology societies, in order to standardize the management of pediatric and adult patients with KS. Finally, a close collaboration between pediatric allergists and cardiologists seems fundamental for an optimal multidisciplinary patient care.",
"affiliations": "Cardiology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Electrophysiology and Device Department, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.;Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Department of Pediatrics, Meyer Children's Hospital, Florence, Italy.;Cardiology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Cardiology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Cardiology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Department of Pediatrics, Meyer Children's Hospital, Florence, Italy.;Cardiology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.;Department of Pediatrics, Meyer Children's Hospital, Florence, Italy.",
"authors": "Capponi|Guglielmo|G|;Giovannini|Mattia|M|;Koniari|Ioanna|I|;Mori|Francesca|F|;Rubino|Chiara|C|;Spaziani|Gaia|G|;Calabri|Giovanni Battista|GB|;Favilli|Silvia|S|;Novembre|Elio|E|;Indolfi|Giuseppe|G|;De Simone|Luciano|L|;Trapani|Sandra|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fcvm.2021.676188",
"fulltext": "\n==== Front\nFront Cardiovasc Med\nFront Cardiovasc Med\nFront. Cardiovasc. Med.\nFrontiers in Cardiovascular Medicine\n2297-055X\nFrontiers Media S.A.\n\n10.3389/fcvm.2021.676188\nCardiovascular Medicine\nCase Report\nCase Report: Perioperative Kounis Syndrome in an Adolescent With Congenital Glaucoma\nCapponi Guglielmo 1\n\nGiovannini Mattia 2\n\nKoniari Ioanna 3\nMori Francesca 2\n\nRubino Chiara 4\n\nSpaziani Gaia 1\nCalabri Giovanni Battista 1\nFavilli Silvia 1\nNovembre Elio 2\n\nIndolfi Giuseppe 4 5\n\nDe Simone Luciano 1 †\nTrapani Sandra 4 6 * †\n\n1Cardiology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy\n2Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy\n3Electrophysiology and Device Department, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom\n4Department of Pediatrics, Meyer Children's Hospital, Florence, Italy\n5Department of NEUROFARBA, Meyer Children's Hospital, University of Florence, Florence, Italy\n6Department of Health Sciences, Meyer Children's Hospital, University of Florence, Florence, Italy\nEdited by: Giovanni Biglino, University of Bristol, United Kingdom\n\nReviewed by: Ju Liu, Shandong University, China; Sezen Ugan Atik, Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, Turkey\n\n*Correspondence: Sandra Trapani sandra.trapani@unifi.it\nThis article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Cardiovascular Medicine\n\n†These authors share last authorship\n\n10 9 2021\n2021\n8 67618804 3 2021\n13 7 2021\nCopyright © 2021 Capponi, Giovannini, Koniari, Mori, Rubino, Spaziani, Calabri, Favilli, Novembre, Indolfi, De Simone and Trapani.\n2021\nCapponi, Giovannini, Koniari, Mori, Rubino, Spaziani, Calabri, Favilli, Novembre, Indolfi, De Simone and Trapani\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.\nA 12-year-old male patient suffering from congenital glaucoma developed bradycardia, left ventricular failure, and hypotension after induction of anesthesia. Electrocardiography and echocardiography revealed a complete normalization of ECG and a complete spontaneous recovery in the cardiac function 72 hours from the beginning of the clinical manifestations, while cardiac Magnetic Resonance Imaging was performed, and coronary Computed Tomography scan revealed a myocardial bridge of a tract of the left anterior descendent coronary artery. Diagnosis of Kounis syndrome (KS) was made, a relatively novel, under-recognized clinical condition, defined as the manifestation of an acute coronary syndrome accompanied by mast cell activation and platelet aggregation involving interrelated and interacting inflammatory cells in the setting of allergic, hypersensitivity, anaphylactic or anaphylactoid insults. We described one of the first pediatric cases of KS related to anesthetic medications. In children, this syndrome has been only described in isolated case reports or small case series. Thus, it appears critical to report new cases of KS in children to increase the awareness of this disease in pediatric healthcare workers so as to enhance its early recognition and optimal therapeutic strategy. Furthermore, it appears of paramount importance the implementation of universal guidelines accepted by allergology and cardiology societies, in order to standardize the management of pediatric and adult patients with KS. Finally, a close collaboration between pediatric allergists and cardiologists seems fundamental for an optimal multidisciplinary patient care.\n\nKounis syndrome\nperioperative\nmidazolam\nsevoflurane\ncoronary artery\npediatrics\n==== Body\npmcIntroduction\n\nKounis syndrome (KS) is defined as the manifestation of an acute coronary syndrome accompanied by mast cell activation and platelet aggregation involving interrelated and interacting inflammatory cells in the setting of allergic, hypersensitivity, anaphylactic or anaphylactoid insults (1, 2). However, the exact physiopathology of this syndrome has not been fully elucidated.\n\nAlthough this condition could potentially occur in every age, only a minority of cases (9.1%) are described in subjects younger than 20 years of age compared to older ages (68.0% at 40–70 years old) (3). The main reason could be attributed to an underestimation of this relatively novel syndrome in the pediatric age (4). Several triggers have been associated with KS, including drug administration, food consumption, and insect bites. Antibiotics (27.4%) and insect bites (23.4%) are demonstrated as the most common triggers eliciting this syndrome (1, 3). KS caused by anesthetic medications has already been reported as a cause of acute coronary syndrome (5–8). However, to the best of our knowledge, we describe one of the first pediatric cases of KS associated to anesthetic drugs (4, 8–14).\n\nCase Description\n\nA 12-year-old male suffering from congenital glaucoma was admitted to Meyer Children's University Hospital for the surgical revision of his ocular Baerveldt implant, a device that maintains a patent connection between the anterior chamber of the eye and an equatorial bleb capsule and improves the drainage of the aqueous out of the eye (15). This patient suffered from a pathologic mutation on CYP1B1, encoding a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily, that is involved in the proper development and balance of trabecular meshwork (16). Because of this chronic ocular disease, the patient had previously undergone other surgical procedures with no reported anesthesiologic complications. A previous surgery was performed 3 months before and the anesthesia was administered with inhaled sevoflurane and intravenous fentanyl, accompanied with intravenous ondansetron as antiemetic drug, without any clinical reaction. His past medical history was negative for any cardiac issue or atopic condition, and his family medical history was unremarkable.\n\nAbout 30 minutes after the induction phase of the anesthesia with intravenous midazolam bolus, followed by continuous inhaled sevoflurane, the patient experienced an episode of bradycardia associated with hypotension, apparently without reporting any clinical signs and symptoms (dyspnoea, chest pain, pulmonary or peripheral oedema). Specifically, his heart rate decreased from 90 to 40 bpm; however, this clinical manifestation seemed to respond to the administration of a bolus of atropine that further induced a transient episode of sinus tachycardia. At the same time, his blood pressure dropped to 80/45 mmHg. In the acute phase, the physical examination revealed a mild apical systolic murmur (2/6 on the Levine grading scale), without any other clinical manifestations of heart failure.\n\nAn electrocardiogram (ECG) showed sinus rhythm with ventricular repolarization abnormalities in the inferior lateral wall (Figure 1). Moreover, the echocardiographic study demonstrated global left ventricular (LV) hypokinesia and dilatation with preserved right ventricular function (Figure 1). Laboratory work-up documented an increase of creatine kinase-myocardial band (CK-MB) and troponin. Furthermore, N-terminal-prohormone B-type natriuretic peptide (NT-proBNP) was increased as well, consistent with LV dysfunction. Further blood investigations did not show any inflammatory markers increase, eosinophilia, electrolytic imbalance, and liver, or kidney dysfunction (Table 1).\n\nFigure 1 First electrocardiogram and echocardiogram after the onset of the clinical manifestations (A). The electrocardiogram shows sinus rhythm with 100 rpm, PR 0.14 s, QRS 0.08 s, QT/QTc 320/422 ms and diffuse alterations in ventricular repolarization with negative T waves in precordial leads (V4–V6), D2, D3 and aVF (B1–B4). The echocardiogram shows a diffusely hypokinetic left ventricle with an ejection fraction of 34%. Left ventricular inner dimension diastole 50 mm (Z score +2.3), left ventricular inner dimension systole 39 mm (Z score +4.25), left posterior ventricular wall diastole 6.6 mm (Z score −0.23), interventricular septum diastole 5.5 mm (Z score −1.22), right ventricular inner dimension diastole 14 mm (Z score +0.20) [Z score is derived from Kampman et al. (17)] (B1,B2). Moderate mitral valve regurgitation (left ventricular delta Pressure/delta Time 699 mmHg/s) (B3). Left and right coronary artery originating from left and right Valsalva sinus, respectively (B4).\n\nTable 1 Laboratory tests trend from the admission to the discharge of the patient.\n\n\tAdmission\t2 days\t4 days\tDischarge\tNormal\t\n\t\tafter admission\tafter admission\t\tvalues\t\nWBC (x 103/μL)\t\t\t6.36\t\t4.10–12.00\t\nRBC (x 106/μL)\t\t\t4.66\t\t4.30–5.80\t\nHb (g/dL)\t\t\t13.7\t\t12.60–17.00\t\nPLT (x 103/μL)\t\t\t230\t\t190–460\t\nN (%)\t\t\t54.4\t\t35.0–65.0\t\nL (%)\t\t\t32.7\t\t15.0–55.0\t\nM (%)\t\t\t7.9\t\t2.0–15.0\t\nE (%)\t\t\t2.6\t\t0.0–6.0\t\nB (%)\t\t\t0.5\t\t0.0–3.0\t\nCRP (mg/dL)\t<0.290\t\t\t\t0.0–0.5\t\nNa (mEq/L)\t\t\t139\t\t133–145\t\nK (mEq/L)\t\t\t3.8\t\t3.3–5.2\t\nCl (mEq/L)\t\t\t104\t\t95–110\t\nAST (IU/L)\t\t\t26\t\t8–60\t\nALT (IU/L)\t\t\t31\t\t7–55\t\nCreatinine (mg/dL)\t0.56\t\t\t\t0.40–0.80\t\nCK (IU/L)\t86\t81\t\t\t20–200\t\nCK-MB (ng/mL)\t7.5\t1.3\t\t\t0.5–3.6\t\nTroponin (μg/L)\t2.03\t0.21\t0.14\t\t0.00–0.09\t\nNT-proBNP(pg/mL)\t830\t1,300\t1,835\t601\t5–242\t\nALT, alanine transaminase; AST, aspartate transaminase; B, basophils; CK, creatine kinase; CK-MB, creatine kinase-myocardial band; Cl, chloride; CRP, C-reactive protein; E, eosinophils; Hb, hemoglobin; K, potassium; L, lymphocytes; M, monocytes; N, neutrophils; Na, sodium; NT-proBNP, N-terminal-prohormone B-type natriuretic peptide; PLT, platelets; RBC, red blood cells; WBC, white blood cells.\n\nThe patient was hemodynamically stable, but a close follow-up was planned, including a daily electrocardiogram and echocardiography for prompt evaluation of any additional ECG-ischemic changes or cardiomyopathy deterioration.\n\nTwo days after admission, in order to exclude other causes of cardiomyopathy, such as myocarditis, a cardiac contrast-enhancement magnetic resonance imaging (CE-MRI) demonstrated a significant improvement of LV function without any regional wall abnormality. Oedema was noticed on the anterior ventricular wall (Figure 2), possibly consistent with reversible myocardial injury potentially related to myocardial ischemia, while no signs of fibrosis were demonstrated after gadolinium enhancement. A daily cardiac evaluation revealed a complete normalization of ECG and a complete recovery in the cardiac function 72 hours from the beginning of the clinical manifestations, along with a marked reduction in CK-MB, troponin and NT-proBNP, at discharge, 6 days after admission (Figure 3), while the patient was in good clinical condition, in absence of drug therapy.\n\nFigure 2 (A) Cardiac contrast-enhancement magnetic resonance imaging demonstrates an increase of T2 signal on anterior left ventricular wall. (B1–B4) Coronary computed tomography reveals a right dominant coronary artery (B1), left common trunk coronary artery (B2), left circumflex coronary artery (B3) and left anterior descending (LAD) coronary artery (B4) without any dissection, lumen obstruction or anatomical variants. A tract of LAD coronary artery runs through the width of the myocardial wall for 12.3 mm and with a parietal thickness of 1.4 mm (B4).\n\nFigure 3 Trend of troponin, NT-proBNP (A) and ejection fraction (B) from the admission to the discharge of the patient. NT-proBNP, N-terminal-prohormone B-type natriuretic peptide.\n\nA coronary computed tomography (CT), 10 days after the onset of the clinical manifestations, excluded any lumen obstruction, dissection or other anatomical variants of the aorta and coronary arteries. However, it was clearly observed myocardial bridge of a tract of the left anterior descending (LAD) coronary artery (Figure 2). As a precaution, it was chosen not to perform a provocative stress test during the acute phase of the disease, but in order to exclude further stress-induced ischemia an exercise test was performed 21 days after the onset of the clinical manifestations. It showed a linear increase in heart rate and blood pressure, without ischemic signs, symptoms or ST-T ECG alterations.\n\nThe patient underwent skin prick testing with midazolam (5 mg/ml) and sevoflurane (100%) with negative results. According to current standards, histamine 10 mg/ml (Lofarma, Milan, Italy) and normal saline were used as positive and negative control substances, respectively.\n\nDiscussion\n\nKS is a rare and poorly characterized entity in children (2, 4, 8–14). In adults, this condition could be associated with other factors, such as previous allergy, hypertension, smoking, diabetes and hyperlipidemia, whereas these features may be less important in children and adolescents (3, 18, 19). The clinical suspicion is based on clinical signs and symptoms (including acute chest pain, chest discomfort, dyspnoea, bradycardia, hypotension, pallor, palpitations or clinical manifestations of a reaction) associated with a potential trigger. KS diagnosis should be highly suspected when these clinical findings are accompanied by ECG signs (including atrial fibrillation, sinus bradycardia, sinus tachycardia, ST-segment elevation or depression, T-wave flattening or inversion), an increase of myocardial injury biomarkers or possible evidence of coronary spasm/thrombosis on coronary angiography (1).\n\nThe differential diagnosis of KS includes other conditions related to myocardial injury, including spontaneous coronary artery dissection, fibromuscular dysplasia, myocardial bridging, myocarditis and takotsubo syndrome (20, 21).\n\nAccording to diagnostic criteria of myocarditis in our patient the diagnosis of infectious myocarditis could be excluded, due to the absence of fever or previous infectious clinical signs and symptoms, values of the blood tests, and findings of the MRI (22).\n\nSometimes, it can be difficult to distinguish takotsubo syndrome from KS and, as already reported, in some cases they can even coexist (23, 24). Interestingly, both these conditions share some common pathologic mechanisms: vascular hyperreactivity of coronary arteries and local/systemic cellular or humoral inflammatory response in inducing myocardial damage (25, 26).\n\nIn our patient, there was a close relationship between the administration of anesthetic medications and the onset of the clinical manifestations [probable association according to Naranjo scale (27)]. Furthermore, there was an increase of troponin and CK-MB, together with ECG abnormalities (diffuse repolarization abnormalities in inferior and lateral leads) and echocardiographic features (diffuse hypokinesia of LV wall). The latter characteristics strongly supported the diagnosis of KS.\n\nOkur et al. defined the cardiac MRI criteria for KS type 1 diagnosis: early phase subendocardial contrast defect, T2 weight images showing high-intensity signal consistent with oedema of all lesion areas, lack of the late gadolinium enhancement, and no transmural involvement (28). This study reported different percentages of left-wall myocardial involvement with a prevalence in interventricular septum (53.8%), followed by LV lateral wall (30.7%). It is interesting to note that MRI in our patient highlighted an augmented T2 signal in the anterior LV wall without late gadolinium enhancement, probably supporting vasospasm in the left anterior descending coronary artery, concordant with the ECG data.\n\nCoronary angiography is the gold standard to demonstrate the anatomy of coronary arteries and to exclude other causes of lumen obstruction. The coronary-CT of our patient demonstrated myocardial bridging of a tract of LAD coronary artery. Drug reactions and the narrowing of the coronary lumen due to myocardial bridging have already been reported as participating co-factors leading to myocardial ischemia (29). Indeed, it seems unlikely a direct role of a myocardial bridging as the unique cause of the transient myocardial damage, even if it could be accounted as a potential favoring condition.\n\nIn a recent retrospective analysis, allergic reactions due to sedative e/o analgesic medications during pediatric pre-procedural sedation were described with an incidence of about 1:4,219, with midazolam being the third most frequently reported drug (1:2,035) (30). Midazolam can also be associated with severe adverse events, for example, anaphylactic and anaphylactoid reactions (31–34). Moreover, an acute coronary syndrome has already been described in the literature as a side effect of this anesthetic drug in a previous case report of KS in an adult patient during the preoperative phase of a transurethral prostatectomy (5). Furthermore, inhaled anesthetic medications, such as isoflurane, have already been reported as a possible precipitating factor of acute coronary vasospasm in a 59-year-old man and in a 2-year-old boy (6, 8). Sevoflurane was used in our case and, of note, our patient had received anesthesia comprising sevoflurane without clinical reactions 3 months before. However, he was suggested to strictly avoid drugs potentially associated to the event in the future.\n\nAs occurred in our case, diagnosis of KS can be difficult when the patient is not able to report signs and symptoms. In such conditions the suspicion and the diagnosis establishment should be based mostly on the close association between a trigger, for example a drug, and the occurrence of ECG signs, the increase of myocardial injury biomarkers or possible evidence of coronary spasm/thrombosis on coronary angiography (1).\n\nIn anaphylaxis, cutaneous manifestations can lack in a minority of cases. In a cohort of adult and pediatric patients with this disease, skin was affected in 84% of them, followed by clinical manifestations involving cardiovascular (72%) or respiratory (68%) systems (35, 36). In severe anaphylaxis the phenomenon has been hypothesized due to the state of shock that prevents or delays the released anaphylactic mediators from reaching and acting on the skin, thus inducing redness, rash and/or itching (37, 38). The absence of skin lesions can also occur in KS, in which rash has been described in 26.8% of cases, preceded by chest pain (86.8%) and anaphylaxis (53%) (3, 39, 40). Indeed, the latter event may be particularly true especially if the blood pressure is low as in the described patient.\n\nSkin prick tests could be useful in demonstrating IgE-mediated hypersensitivity (41). However, especially for some drugs, in case of negative results is not possible to completely rule out the diagnosis of hypersensitivity. Interestingly, skin tests themselves can induce KS and caution has to be paid to carry them out, especially when the diagnostic performance for the specific allergen is suboptimal (42). Unfortunately, serum tryptase dosage was not performed in our patient. However, although positive serum tryptase could be a useful biomarker in case of anaphylaxis and KS, negative results cannot rule them out completely (2).\n\nIn this case we highlighted the importance of recognition of KS in pediatric patients, differentiating this condition from other ones associated with acute ventricular systolic disfunction. Firstly, a hypersensitivity reaction should be taken into consideration as a potential cause of an acute coronary syndrome; secondly we pointed out the critical role of observing closely the patient, as the situation could evolve unpredictably to a cardiopulmonary emergency. Moreover, when a myocarditis or another cause are suspected, they benefit from a specific management (22). In the context of diagnostic investigations, in addition to ECG and echocardiography, cardiac MRI and coronary CT scan were performed, which were fundamental to assess our patient. In addition, his blood investigations did not show inflammatory markers increase.\n\nIn the present report, after the management of the acute phase, the stable clinical condition and the rapid improvement of systolic function allowed us to avoid the administration of specific drugs.\n\nConclusion\n\nIn conclusion, we described one of the first pediatric cases of KS related to anesthetic medications. Cases reported of this syndrome are increasing progressively in the literature, and more and more drugs/agents have been identified as potential triggers of this clinical condition. The treatment of KS could be challenging, and it is mainly based on the treatment of the allergic reaction and of the cardiological clinical manifestations. In children, this syndrome has been only described in isolated case reports or small case series. Thus, it appears critical to report new cases of KS in children to increase the awareness of this disease in pediatric healthcare workers so as to enhance its early recognition and optimal therapeutic strategy. Furthermore, it appears of paramount importance the implementation of universal guidelines accepted by allergology and cardiology societies, in order to standardize the management of pediatric and adult patients with KS. Finally, a close collaboration between pediatric allergists and cardiologists seems fundamental for an optimal multidisciplinary patient care.\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\nWritten informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nGC, MG, LDS, and ST conceptualized the work. GC, MG, IK, FM, SF, LDS, and ST drafted the manuscript. GC, MG, FM, CR, GS, GBC, SF, EN, GI, LDS, and ST performed the investigations. GC, MG, IK, FM, CR, GS, GBC, SF, EN, GI, LDS, and ST critically revised the manuscript. All authors approved the final version of the manuscript as submitted and agreed to be accountable for all aspects of the work.\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\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors want to thank Prof. Nicholas George Kounis (Department of Cardiology, Patras University School of Medicine, Patras, Greece) for critical review of the manuscript.\n==== Refs\nReferences\n\n1. Kounis NG . Kounis syndrome: An update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med. (2016) 54 :1545–59. 10.1515/cclm-2016-0010 26966931\n2. Giovannini M Koniari I Mori F Ricci S De Simone L Favilli S . Kounis syndrome: a clinical entity penetrating from pediatrics to geriatrics. J Geriatr Cardiol. (2020) 17 :294–9. 10.11909/j.issn.1671-5411.2020.05.011 32547613\n3. Abdelghany M Subedi R Shah S Kozman H . Kounis syndrome: A review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome. Int J Cardiol. (2017) 232 :1–4. 10.1016/j.ijcard.2017.01.124 28153536\n4. Biteker M Duran NE Biteker FS Ertürk E Aykan AÇ Civan HA . Kounis Syndrome secondary to amoxicillin/clavulanic acid use in a child. Int J Cardiol. (2009) 136 :e3–5. 10.1016/j.ijcard.2008.04.064 18632172\n5. Ateş AH Kul S . Acute coronary syndrome due to midazolam use: Kounis syndrome during a transurethral prostatectomy. Turk Kardiyol Dern Ars. 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Kounis syndrome following the performance of skin test to amoxicillin. Int J Cardiol. (2014) 174 :856–7. 10.1016/j.ijcard.2014.04.191 24801079\n\n",
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"abstract": "Agents that block vascular endothelial growth factor (VEGF) and its downstream pathway have been reported to be associated with nephrotoxicity including hypertension, proteinuria, and renal dysfunction. Bevacizumab, a monoclonal antibody against VEGF, is known to cause thrombotic microangiopathy (TMA), while tyrosine kinase inhibitors (TKIs) that block VEGF downstream are mainly associated with minimal change disease or focal segmental glomerulosclerosis. The question regarding the source of the diverse phenotypes of nephrotoxicity associated with these agents remains enigmatic. Nintedanib, a multitargeted TKI, blocks fibroblast growth factor and platelet-derived growth factor receptor as well as VEGF receptor, and is indicated for the treatment of idiopathic pulmonary fibrosis. We describe a case of a 45-year-old male who presented with isolated proteinuria of 1.3 g/g Cr 3 years after beginning nintedanib treatment. The kidney biopsy revealed histological features consistent with renal TMA. He underwent single lung transplantation 6 months later, which enabled cessation of nintedanib, and, 1 month later, his proteinuria results were negative. Unlike other types of TKIs, the pathological findings of nintedanib-induced nephrotoxicities have been limitedly reported. This is the first case of isolated proteinuria likely caused by nintedanib-induced TMA.",
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"authors": "Inoue|Daisuke|D|;Nishi|Hiroshi|H|;Honda|Kenjiro|K|;Ishii|Taisuke|T|;Abe|Hiroyuki|H|;Sato|Masaaki|M|;Nangaku|Masaomi|M|",
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] |
{
"abstract": "BACKGROUND\nTacrolimus is a cornerstone of immunosuppression after transplantation but is highly susceptible to changes from interacting variables and has a narrow therapeutic index. Clotrimazole troches are commonly used as a non-systemic antifungal to prevent oral candidiasis. Studies suggest that clotrimazole troches, though minimally absorbed systemically, may affect tacrolimus concentrations by inhibition of metabolic enzyme activity in the intestines. However, the magnitude of the impact of clotrimazole on tacrolimus dosing requirements to maintain goal levels is not well described.\n\n\nMETHODS\nTo assess this, tacrolimus dose adjustments and trough concentrations were retrospectively examined in 95 heart transplant recipients before and after the discontinuation of clotrimazole.\n\n\nRESULTS\nThe median percent tacrolimus dose change was an increase of 66.7% (IQR 28.6%, 100%) after clotrimazole discontinuation, and the median trough concentration percent change from baseline to the first trough after clotrimazole discontinuation (in the absence of a dose change) was -42.5% (IQR -52.3%, -30.9%). Five cases of allograft rejection were observed.\n\n\nCONCLUSIONS\nIn conclusion, clotrimazole troches exert a meaningful interaction with tacrolimus that requires close monitoring and dose adjustment. The data from this single-center study provide novel information that could guide providers on the degree of tacrolimus dose adjustment needed when discontinuing clotrimazole prophylaxis after heart transplantation.",
"affiliations": "Division of Pharmacy Services, Mayo Clinic Hospital, Rochester, Minnesota.;Division of Pharmacy Services, Mayo Clinic Hospital, Rochester, Minnesota.;Division of Pharmacy Services, Mayo Clinic Hospital, Rochester, Minnesota.;Division of Biomedical Statistics and Informatics, Mayo Clinic Hospital, Rochester, Minnesota.;Division of Cardiovascular Diseases, Mayo Clinic Hospital, Rochester, Minnesota.;Division of Infectious Diseases, Mayo Clinic Hospital, Rochester, Minnesota.",
"authors": "Laub|Melissa R|MR|http://orcid.org/0000-0002-6251-9153;Crow|Stacy A|SA|;Personett|Heather A|HA|;Dierkhising|Ross|R|;Boilson|Barry|B|;Razonable|Raymund|R|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D003022:Clotrimazole; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12979",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "clotrimazole; heart transplant; prophylaxis; tacrolimus; thrush",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000284:Administration, Oral; D000935:Antifungal Agents; D002180:Candidiasis, Oral; D003022:Clotrimazole; D004347:Drug Interactions; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12979",
"pmc": null,
"pmid": "30120865",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effects of clotrimazole troches on tacrolimus dosing in heart transplant recipients.",
"title_normalized": "effects of clotrimazole troches on tacrolimus dosing in heart transplant recipients"
} | [
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{
"abstract": "Although gastric metastases have been estimated to occur in less than 2% of cancer patients, an increased use of upper digestive tract endoscopy allows for a higher detection of secondary gastric tumors. We describe the case of a 66-year-old male patient presenting with mild pain in the sternum and upper abdominal area. Physical examination revealed a right parietal skull tumor, with no other significant clinical changes. Upon exclusion of an acute coronary syndrome, upper digestive tract endoscopy was performed, showing the presence of an ulcerated tumor located in the gastric fundus. Histopathologic examination of the biopsy sample and immunohistochemical tests suggested a pulmonary origin of the gastric tumor. Whole body computer tomography showed the presence of tumors in the gastric fundus, left lung, liver, kidneys, bones and brain. Transbronchial biopsy of the lung tumor certified the diagnosis of non-small cell lung cancer, with the same immunohistochemical profile as the gastric tumor. Hence, it was considered the origin of the metastases. Biopsy of the skull tumor also had the identical tumor histology. Whole brain radiotherapy was performed for the brain metastases and subsequent chemotherapy was administered. Although non-specific, gastrointestinal signs and symptoms occurring in lung cancer patients should alert the clinicians as to the possibility of gastrointestinal metastases and prompt endoscopic evaluation.",
"affiliations": "Department of Oncology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Surgery, 'Sf. Ioan' Clinical Emergency Hospital, Carol Davila University, Faculty of Dental Medicine, 042122 Bucharest, Romania.;Department of Dermatology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Histopathology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Gastroenterology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Oncology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Oncology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Oncology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.;Department of Pathology, Emergency University Military Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 020021 Bucharest, Romania.;Department of Surgery, 'Sf. Pantelimon' Clinical Emergency Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 021659 Bucharest, Romania.;Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Medical School, 10679 Athens, Greece.;Department of Toxicology, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, 020956 Bucharest, Romania.;Department of Oncology, Elias University Clinical Hospital, Carol Davila University, Medicine and Pharmacy Faculty, 011461 Bucharest, Romania.",
"authors": "Nitipir|Cornelia|C|;Ginghina|Octav|O|;Popa|Liliana|L|;Andrei|Florin|F|;Tudor|Nicolaie|N|;Radu|Irina|I|;Iaciu|Cristian|C|;Orlov|Cristina|C|;Vasilescu|Florina|F|;Balalau|Cristian|C|;Leon|Grigoris|G|;Negrei|Carolina|C|;Barbu|Maria Alexandra|MA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2018.1565",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "8(4)",
"journal": "Molecular and clinical oncology",
"keywords": "gastric metastases; immunohistochemistry; non-small cell lung cancer",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "595-599",
"pmc": null,
"pmid": "29541469",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": "21098094;11577478;6274500;11156325;18512073;8153934;21565397;16810769;24697130;8739742;17010474;11437044;19696259;25663915;5939878;2311070;17186432;22090788;21519812;22634567;8277608;17468816;22183069;21160891;14487721;3028602;27833973;1190198;16899604;24179627;10847441;26742998;21864934;18594328;16177864",
"title": "A rare case of advanced lung cancer presenting as a symptomatic gastric tumor.",
"title_normalized": "a rare case of advanced lung cancer presenting as a symptomatic gastric tumor"
} | [
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{
"abstract": "BACKGROUND\nIt is common clinical experience that, after structured withdrawal, some patients with chronic migraine and medication overuse headache (CM with MOH) are more prone than others to relapse and to be in need of further structured treatments. Our aim was to explore similarities and differences between frequent relapsers (FRs) and non-frequent relapsers (NFRs) by considering their point of view, perceptions, and perspective of their subjective experience with relapse into CM with MOH.\n\n\nMETHODS\nPatients were consecutively recruited on occasion of a structured withdrawal treatment and were interviewed individually about their headache experience and their perspectives on relapse into CM with MOH. We considered FR those patients requiring 2 or more structured withdrawals for MOH within 3 years. A narrative approach with no preconceived coding schemes was employed. To facilitate coding, categorization and organization of data the software QRS NVivo 11.0 was used: themes were defined as common to FR and NFR, or peculiar (by frequency or content) to one of the 2 groups.\n\n\nRESULTS\nSixteen patients (13 women; mean age of 53) were interviewed: 7 were classified as FRs. A total of 22 themes emerged from 552 single quotations (the 10 most relevant covered 82% of the entire body of quotations). Four themes were commonly reported by both FR and NFR patients, and 6 were peculiar to one group only. Common aspects included issues connected to the dilemma between disclosing, concealing and the feelings of isolation around MOH, the idea of being addicted to medication, presence of anxiety, and the attempt to use non-pharmacological therapies as an alternative to medication. Peculiar aspects included causal attribution (FRs attributed headache to uncontrollable factors); future expectations at the time point of withdrawal (FRs were generally resigned); high-performance functioning (FRs believed they are \"forced\" to reach high levels of performance as a consequence of others' inability); coping strategies (FRs tended to \"passively accept\" problems and showed avoidance-related behaviors). Moreover, FRs were less frequently aware of their problems and described more frequently depressive symptoms.\n\n\nCONCLUSIONS\nOur results highlight that some differences between FR and NFR patients with CM and MOH exist. Frequent relapsers among patients with CM and MOH reported some important peculiarities of the lived experience of having chronic migraine; clinicians should recognize these psychosocial aspects such as social relationships, future expectations, the experience of illness, medication management, and how the withdrawal experience is regarded, as they may be associated with frequent relapse into MOH.",
"affiliations": "Public Health and Disability Unit, Neurological Institute \"C. Besta\" IRCCS Foundation, Neurology, Milan, Italy.;e-Campus University, Novedrate, Italy.;Public Health and Disability Unit, Neurological Institute \"C. Besta\" IRCCS Foundation, Neurology, Milan, Italy.;Public Health and Disability Unit, Neurological Institute \"C. Besta\" IRCCS Foundation, Neurology, Milan, Italy.;Headache and Neuroalgology Unit, Neurological Institute \"C. Besta\" IRCCS Foundation, Milan, Italy.;John R. Graham Headache Center, Department of Neurology, Brigham and Women's Faulkner Hospital, Boston, MA, USA.;Headache and Neuroalgology Unit, Neurological Institute \"C. Besta\" IRCCS Foundation, Milan, Italy.;Public Health and Disability Unit, Neurological Institute \"C. Besta\" IRCCS Foundation, Neurology, Milan, Italy.",
"authors": "Scaratti|Chiara|C|;Covelli|Venusia|V|;Guastafierro|Erika|E|;Leonardi|Matilde|M|;Grazzi|Licia|L|;Rizzoli|Paul B|PB|;D'Amico|Domenico|D|;Raggi|Alberto|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/head.13385",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "58(9)",
"journal": "Headache",
"keywords": "chronic migraine; medication-overuse headache; qualitative study; relapse; withdrawal",
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D000368:Aged; D001007:Anxiety; D003863:Depression; D005260:Female; D051271:Headache Disorders, Secondary; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D036301:Qualitative Research; D012008:Recurrence; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "1373-1388",
"pmc": null,
"pmid": "30125944",
"pubdate": "2018-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "A Qualitative Study On Patients With Chronic Migraine With Medication Overuse Headache: Comparing Frequent And Non-Frequent Relapsers.",
"title_normalized": "a qualitative study on patients with chronic migraine with medication overuse headache comparing frequent and non frequent relapsers"
} | [
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{
"abstract": "Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with immune checkpoint inhibitors (ICIs) are at risk of pneumonitis as well as pneumonia (combined henceforth as ICI-related pulmonary complications). Little is known about the cellular and molecular mechanisms underlying ICI-related pulmonary complications. We characterized lymphocytes from bronchoalveolar lavage (BAL) fluid and peripheral blood from seven AML/MDS patients with pulmonary symptoms after ICI-based therapy (ICI group) and four ICI-naïve AML/MDS patients with extracellular bacterial or fungal pneumonias (controls). BAL T cells in the ICI group were clonally expanded, and BAL IFNγ+ IL-17- CD8+ T and CXCR3+ CCR6+ Th17/Th1 cells were enriched in the ICI group. Our data suggest that these cells may play a critical role in the pathophysiology of ICI-related pulmonary complications. Understanding of these cell populations may also provide predictive and diagnostic biomarkers of ICI-related pulmonary complications, eventually enabling differentiation of pneumonitis from pneumonia in AML/MDS patients receiving ICI-based therapies.",
"affiliations": "Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"authors": "Kim|Sang T|ST|;Sheshadri|Ajay|A|;Shannon|Vickie|V|;Kontoyiannis|Dimitrios P|DP|;Kantarjian|Hagop|H|;Garcia-Manero|Guillermo|G|;Ravandi|Farhad|F|;Im|Jin S|JS|;Boddu|Prajwal|P|;Bashoura|Lara|L|;Balachandran|Diwakar D|DD|;Evans|Scott E|SE|;Faiz|Saadia|S|;Ruiz Vazquez|Wilfredo|W|;Divenko|Margarita|M|;Mathur|Rohit|R|;Tippen|Samantha P|SP|;Gumbs|Curtis|C|;Neelapu|Sattva S|SS|;Naing|Aung|A|;Wang|Linghua|L|;Diab|Adi|A|;Futreal|Andrew|A|;Nurieva|Roza|R|;Daver|Naval|N|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.590494",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.590494\nImmunology\nOriginal Research\nDistinct Immunophenotypes of T Cells in Bronchoalveolar Lavage Fluid From Leukemia Patients With Immune Checkpoint Inhibitors-Related Pulmonary Complications\nKim Sang T. \n1\n\n†\n Sheshadri Ajay \n2\n\n†\n Shannon Vickie \n2\n\n†\n Kontoyiannis Dimitrios P. \n3\n Kantarjian Hagop \n4\n Garcia-Manero Guillermo \n4\n Ravandi Farhad \n4\n Im Jin S. \n5\n Boddu Prajwal \n4\n Bashoura Lara \n2\n Balachandran Diwakar D. \n2\n Evans Scott E. \n2\n Faiz Saadia \n2\n Ruiz Vazquez Wilfredo \n5\n Divenko Margarita \n6\n Mathur Rohit \n7\n Tippen Samantha P. \n8\n Gumbs Curtis \n8\n Neelapu Sattva S. \n7\n Naing Aung \n9\n Wang Linghua \n8\n Diab Adi \n10\n Futreal Andrew \n8\n Nurieva Roza \n6\n\n*\n Daver Naval \n4\n\n*\n \n1\nDepartment of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n2\nDepartment of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n3\nDepartment of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n4\nDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n5\nDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n6\nDepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n7\nDepartment of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n8\nDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n9\nDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\n\n10\nDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States\n\nEdited by: Xi Wang, Capital Medical University, China\n\nReviewed by: Penghui Zhou, Dana–Farber Cancer Institute, United States; Thomas Cluzeau, Centre Hospitalier Universitaire de Nice, France\n\n*Correspondence: Roza Nurieva, rnurieva@mdanderson.org; Naval Daver, NDaver@mdanderson.org\n†These authors have contributed equally to this work\n\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n\n21 1 2021 \n2020 \n11 59049401 8 2020 07 12 2020 Copyright © 2021 Kim, Sheshadri, Shannon, Kontoyiannis, Kantarjian, Garcia-Manero, Ravandi, Im, Boddu, Bashoura, Balachandran, Evans, Faiz, Ruiz Vazquez, Divenko, Mathur, Tippen, Gumbs, Neelapu, Naing, Wang, Diab, Futreal, Nurieva and Daver2021Kim, Sheshadri, Shannon, Kontoyiannis, Kantarjian, Garcia-Manero, Ravandi, Im, Boddu, Bashoura, Balachandran, Evans, Faiz, Ruiz Vazquez, Divenko, Mathur, Tippen, Gumbs, Neelapu, Naing, Wang, Diab, Futreal, Nurieva and DaverThis 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.Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with immune checkpoint inhibitors (ICIs) are at risk of pneumonitis as well as pneumonia (combined henceforth as ICI-related pulmonary complications). Little is known about the cellular and molecular mechanisms underlying ICI-related pulmonary complications. We characterized lymphocytes from bronchoalveolar lavage (BAL) fluid and peripheral blood from seven AML/MDS patients with pulmonary symptoms after ICI-based therapy (ICI group) and four ICI-naïve AML/MDS patients with extracellular bacterial or fungal pneumonias (controls). BAL T cells in the ICI group were clonally expanded, and BAL IFNγ+ IL-17− CD8+ T and CXCR3+ CCR6+ Th17/Th1 cells were enriched in the ICI group. Our data suggest that these cells may play a critical role in the pathophysiology of ICI-related pulmonary complications. Understanding of these cell populations may also provide predictive and diagnostic biomarkers of ICI-related pulmonary complications, eventually enabling differentiation of pneumonitis from pneumonia in AML/MDS patients receiving ICI-based therapies.\n\npneumonitisTh17/Th1 cellscheckpoint inhibitoracute myeloid leukemiaimmune-related adverse eventUniversity of Texas MD Anderson Cancer Center10.13039/100007313\n==== Body\nHighlights\n- Th17/Th1 and IFNγ+ IL-17− CD8+ T cells were enriched in bronchoalveolar lavage fluid from leukemia patients with ICI-related pulmonary complications.\n\n- Bronchoalveolar lavage T cells were clonally expanded in patients with ICI-related complications compared with controls in terms of T cell receptor repertoire.\n\nIntroduction\nPatients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are susceptible to serious infections, including pneumonia. Although immune checkpoint inhibitor (ICI)-based therapies, specifically epigenetic agent azacytidine in combination with a PD-1 inhibitor, have demonstrated encouraging responses and improved overall survival in patients with frontline or relapsed MDS or relapsed AML, ICIs are associated with immune-related adverse events, including pneumonitis (1–5). Studies have demonstrated that 10–12% of patients with a hematologic malignancy treated with ICI(s) developed pneumonitis (1, 6). Thus, AML/MDS patients receiving ICI-based therapies are at risk to develop pneumonia (due to disease and treatment-related neutropenia and immunosuppression) as well as pneumonitis (combined henceforth as ICI-related pulmonary complications). Because ICI-related pulmonary complications are life-threatening (7), understanding the pathophysiology is critical for prompt diagnosis and early intervention. Detailed characterization of the immune cells in the inflamed lung and peripheral blood (PB) from patients with AML/MDS treated with ICI-based therapies, the first step in elucidating these pathophysiologic mechanisms, would be particularly valuable. In the current study, we characterized lymphoid immune cell populations in bronchoalveolar lavage (BAL) fluid and in PB from AML/MDS patients who received ICI(s), developed pulmonary symptoms, and underwent a diagnostic bronchoscopy. As a control, we analyzed BAL fluid and PB from ICI-naïve AML/MDS patients with pulmonary symptoms who had a confirmed extracellular bacterial or fungal pneumonia.\n\nMaterials and Methods\nPatient Selection\nFrom March 2017 to January 2018, we reviewed for inclusion in our study 40 AML/MDS patients who underwent diagnostic bronchoscopy due to radiographic abnormalities and/or pulmonary symptoms, including fever, cough, and shortness of breath. We excluded six patients who had undergone stem cell transplantation and five patients who had received non-ICI immunotherapy. Another four patients declined to participate. Among the remaining 25 patients, 10 had received ICI therapy and 15 had not. Three of the 10 patients who had received ICI therapy were excluded; one had had pneumonia 6 weeks prior to the bronchoscopy, one had completed ICI therapy more than 12 weeks prior to the bronchoscopy, and one had lung lesions that turned out to be lymphoma. Thus, the ICI group comprised seven patients. An expert multidisciplinary committee consisting of two pulmonologists (AS and VS), one rheumatologist (SK), one infectious disease specialist (DK), and one hematologist (ND) adjudicated the presence of pneumonitis or pneumonia in these seven patients. Pneumonitis was considered the leading diagnosis if 1) radiologic patterns favored pneumonitis over pneumonia (e.g., diffuse ground-glass opacities), 2) the natural history and type of symptoms were more consistent with pneumonitis, 3) there was a clear response to corticosteroids but not antibiotics, or 4) there was histopathologic confirmation of pneumonitis or organizing pneumonia in the absence of microbiological cultures. Pneumonia was considered the leading diagnosis if 1) radiologic patterns favored pneumonia over pneumonitis (e.g., lobar consolidation), 2) the natural history and type of symptoms were more consistent with pneumonia, 3) there was a clear response to antibiotics but not corticosteroids, or 4) there was a positive microbiological culture from a lower respiratory specimen. Four patients in the ICI group met the criteria for pneumonia (hereafter, ICI-pneumonia) and three patients were determined to have pneumonitis (hereafter, ICI-pneumonitis). Two patients in the ICI-pneumonitis group had positive BAL culture results (one for Stenotrophomonas and one for Enterococcus faecalis), but the expert multidisciplinary committee determined that these were colonizations rather than active infections.\n\nOf the 15 patients who had not received ICI therapy, eight patients were excluded because the BAL culture results were negative. Because the immune response in viral infections is distinct from that of extracellular bacterial/fungal infections, we excluded another two patients whose BAL culture results were positive for a virus. Another patient was excluded because the positive BAL culture result was clinically determined to be colonization by the expert multidisciplinary committee. The remaining four patients, whose extracellular bacterial/fungal infection was confirmed microbiologically and clinically, comprised the control group.\n\nThe patient selection process is summarized in \nFigure 1\n. Samples were collected and distributed under protocol PA15-0551 approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center and all patients provided written informed consent.\n\nFigure 1 Selection process for patients in the immune checkpoint inhibitor (ICI) group and the control group. AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; SCT, stem cell transplantation; BAL, bronchoalveolar lavage.\n\nSample Collection\nResidual BAL fluid (10–35 ml) from all participants was obtained and transported on ice to the laboratory. PB samples (15–30 ml) were collected from available patients 3 ± 3 days (mean ± SD) after the bronchoscopy. One participant in the control group (Cont_2) declined to provide a PB sample.\n\nCell Isolation\nAfter centrifugation at 1,600 rpm, the BAL fluid was stored at −80°C. BAL cells were washed with 1× phosphate buffered saline (Gibco) and cryopreserved in the presence of 90% fetal bovine serum and 10% dimethyl sulfoxide (Sigma-Aldrich). Peripheral blood mononuclear cells (PBMCs) were isolated using the Ficoll gradient technique (Sigma-Aldrich) and cryopreserved like BAL cells.\n\nT Cell Receptor Sequencing\nDNA was extracted from cryopreserved BAL cells and PBMCs using the QIAamp DNA Mini Kit (Qiagen), and the complementarity determining region 3 of the T cell receptor beta (TCRβ) chain was amplified using the ImmunoSeq hsTCRB Kit (Adaptive Biotechnologies) and sequenced using the MiSeq platform (Illumina). Sequencing data were analyzed using the ImmunoSEQ Analyzer (Adaptive Biotechnologies), by which a series of diversity metrics were generated, including observed richness, Pielou evenness, and Simpson D (8). The clonality metric was defined as 1-Pielou evenness, where the values of clonality approach 0 when all sequences are equally abundant and perfectly even, and the values approach 1 when a single sequence makes up the entire sample.\n\nFlow Cytometry\nCryopreserved BAL cells and PBMCs were thawed, washed, and stained with flow cytometry antibodies to CD3, CD4, CD8, CD19, CD25, CD27, CD45A, CD56, CD127, CCR4, CCR6, CCR7, CXCR3, CXCR5, PD-1, and γδTCR. For intracellular staining, BAL cells and PBMCs were stimulated with cell activation cocktail (BioLegend) containing phorbol 12-myristate 13-acetate (PMA), ionomycin, and bredfeldin for 4 h. Cells were stained for surface molecules, fixed with BD CytoFix/CytoPerm, permeabilized with BD PERM/wash solution, and stained with antibodies to IFNγ and IL-17A. For transcription factor analysis, cells were first stained for surface molecules, then fixed and permeabilized with eBioscienceTM FoxP3/transcription staining buffer set. After permeabilization, cells were stained with T-bet, GATA3, RORγt, and FoxP3. Stained samples were acquired using an LSR II FORTESSA X-20 (BD Biosciences) and analyzed using FlowJo software (TreeStar). Detailed information about the flow cytometry antibodies is available in \nSupplementary Table 1\n.\n\nIdentification of Immune Cell Subsets\nLive immune cells were detected by gating live-dead. The lymphocytes were further examined by forward scatter and side scatter (SSC). Natural killer (NK) and NK T cells were identified by CD56 and CD3 expression. Within the CD3+ CD56− cell population, we further gated to identify CD4+ T cells and CD8+ T cells. For CD4+ T cells, after gating regulatory T (Treg) cells (CD25hi CD127lo) (9), we further divided non-Treg cells into CD45RA+ naïve T cells, CXCR5-expressing follicular helper T cells (Tfh) (10), and CD45RA− CXCR5− cells (non-Tfh effector cells). Non-Tfh effector cells were further divided into effector subsets on the basis of CXCR3, CCR4, and CCR6 expression: Th1 (CXCR3+ CCR6−), Th2 (CXCR3− CCR6− CCR4+), Th17 (CXCR3− CCR6+), and Th17/Th1 (CXCR3+ CCR6+) cells (11–13). CD8+ T cells were examined by CD45RA and CCR7 staining to detect naive, central memory (Tcm), effector memory (Tem), and terminally differentiated effector memory (Tem) cells (14). Within the CD3− CD56− population, CD19-expressing B cells were gated. Gating strategies are shown in \nSupplementary Figures 1\n and \n2A\n. In parallel, we analyzed IFNγ- and/or IL-17A-producing T cells in BAL fluid and PB samples.\n\nCytokine Measurement\nIFNγ, IL-6, and IL-17A in BAL fluid were measured by multiplex ELISA, using commercially available kits (U-Plex Th17 Combo 2, Meso Scale Discovery).\n\nStatistical Analysis\nSignificant differences in means between groups were determined by the two-tailed Mann-Whitney U test, two-tailed Wilcoxon paired rank test, or one-way ANOVA. P < 0.05 was considered statistically significant. All statistical analyses were done using Prism software.\n\nResults\nPatient Demographic Features\nThe clinical characteristics of the patients are summarized in \nTable 1\n. Ten of the 11 patients had AML, and most (10/11) had intermediate or advanced cytogenetic characteristics. Most patients (5/7 in the ICI group; 4/4 in the control group) also had leukopenia, with a median white blood cell count of 0.4 × 103/ml. Most patients in the ICI group (6/7) were receiving azacytidine in addition to the ICIs. Four patients were receiving a PD-1 inhibitor and three patients were receiving a combination of CTLA-4 and PD-1 inhibitors; two patients were receiving avelumab (3 mg/kg every 2 weeks), two patients were receiving nivolumab (3 mg/kg every 2 weeks), two patients were receiving ipilimumab (1 mg/kg every 12 weeks) plus nivolumab (3 mg/kg every 2 weeks), and one patient was receiving ipilimumab (3 mg/kg every 4 weeks) plus nivolumab (3 mg/kg every 2 weeks). All patients were on prophylactic regimen including quinolone, azol-antifungal agent, and antiviral nucleoside analogue. Patients in the ICI group developed respiratory symptoms at a median of 2.5 weeks after the initiation of ICIs; however, the range was broad (0.5 to 27.5 weeks). Three patients in the ICI group were receiving steroids at the time of bronchoscopy, at a median dose of 125 mg prednisone (or equivalent), and four patients were receiving steroids at the time of PB collection, at a median dose of 62.5 mg. Four patients in the ICI group had a positive BAL culture result, indicating extracellular bacteria with or without a virus.\n\nTable 1 Basic characteristics of study patients.\n\nCharacteristic\tICI group (n=7)\tICI-pneumonia (n=4)\tICI-pneumonitis (n=3)\tControls (n=4)\t\nAge, years, median (range)\t69 (25–81)\t63 (25–81)\t77 (52–79)\t62.5 (55–79)\t\nSex (male/female)\t2/5\t0/4\t2/1\t3/1\t\nPrimary tumor\t\t\t\t\t\n AML\t6\t3\t3\t4\t\n MDS\t1\t1\t0\t0\t\nECOG performance status, median (range)\t1.5 (1–2)\t1.5 (1–2)\t1.5 (1–2)\t1.5 (1–2)\t\nPatients with antecedent hematologic disorder\t1\t1\t0\t2\t\nCytogenetic group\tAdverse\t5\t4\t1\t1\t\nIntermediate\t2\t0\t2\t2\t\nFavorable\t0\t0\t0\t1\t\nMolecular mutations (minimum ≥ 2 cases)\tTP53\t3\t2\t1\t0\t\nFLT3\t2\t1\t1\t0\t\nDNMT3A\t0\t0\t0\t2\t\nPeripheral blood WBC count at bronchoscopy, ×103/ml, median (range)\t0.4 (0.2–17.5)\t0.5 (0.2–6.2)\t0.4 (0.4–17.5)\t0.4 (0.1–3.2)\t\nPeripheral blood blasts at bronchoscopy, %, median (range)\t25 (0–68) (n=5)\t16 (7–25) (n=2)\t40 (0–68) (n=3)\t2.5 (0–5) (n=2)\t\nBM blasts on most recent BM biopsy prior to bronchoscopy, %, median (range)\t44 (10–90)\t23.5 (10–90)\t58 (44–84)\t34 (1–87)\t\nICI treatment status (frontline/salvage)\t3/4\t3/1\t0/3\tn/a\t\nTreatment regimen\t\t\t\t\t\n Azacytidine + ICI-based\t6\t3\t3\t0\t\n Non-azacytidine + ICI-based\t1\t1\t0\t0\t\n Fludarabine + cytarabine + idarubicin + sorafenib\t0\t0\t0\t1\t\n Cytarabine + idarubicin\t0\t0\t0\t1\t\n Non-immune investigational small molecule(s)\t0\t0\t0\t2\t\nBest response to treatment regimen (CR or CRp)\t1\t0\t1\t1\t\nPatients actively on ICI treatment at bronchoscopy\t7\t4\t3\tn/a\t\nDiscontinuation of ICI protocol prior to bronchoscopy\t0\t0\t0\tn/a\t\nICI regimen\t\t\t\t\t\n PD-1 inhibitor\t4\t2\t2\tn/a\t\n CTLA-4 inhibitor\t0\t0\t0\tn/a\t\n Combined PD-1 and CTLA-4 inhibitors\t3\t2\t1\tn/a\t\nAdmission status at bronchoscopy, routine floor/ICU\t7\t4/0\t3/0\t4/0\t\nPatients receiving steroid at time of bronchoscopy\t\t\t\t\t\nDose of prednisone (or equivalent) at time of bronchoscopy, mg, median (range)\t125 (50–300) (n=3)\t50 (n=1)\t212.5 (125–300) (n=2)\tn/a (n=0)\t\nPatients receiving steroid at time of blood draw\t\t\t\t\t\nDose of prednisone (or equivalent) at time of blood draw, mg, median (range)\t62.5 (30,150) (n=4)\t35 (20–50) (n=2)\t112.5 (75–150) (n=2)\tn/a (n=0)\t\nDuration, weeks, median (range)\t\t\t\t\t\n From first ICI infusion to respiratory symptoms\t2.5 (0.5–27.5)\t1.5 (0.5–3.5)\t3.5 (0.5–27.5)\tn/a\t\n From first ICI infusion to bronchoscopy\t4 (0.5–28)\t3.5 (0.5–6.5)\t4 (2–28)\tn/a\t\n From last ICI infusion to respiratory symptoms\t0.5 (0.5–2)\t0.5 (0.5–1.5)\t2 (0.5–2)\tn/a\t\n From last ICI infusion to bronchoscopy\t2 (0.5–5.5)\t1.5 (0.5–5.5)\t2 (1.5–2)\tn/a\t\nPatients receiving prophylactic antibiotic at time of bronchoscopy\t7\t4\t3\t4\t\nAntibacterial agent\t\t\t\t\t\n Levofloxacin\t7\t4\t3\t2\t\n Ciprofloxacin\t0\t0\t0\t2\t\nAntifungal agent\t\t\t\t\t\n Fluconazole\t2\t1\t1\t2\t\n Voriconazole\t3\t2\t1\t0\t\n Posaconazole\t1\t1\t0\t1\t\n Isavuconazole\t1\t0\t1\t0\t\n Esavuconazole\t0\t0\t0\t1\t\nAntiviral agent\t\t\t\t\t\n Valaciclovir\t6\t3\t3\t4\t\n Acyclovir\t1\t1\t0\t0\t\nPatients admitted ≤6 weeks prior to bronchoscopy\t3\t2\t1\t2\t\nBAL fluid culture results\t\t\t\t\t\n Negative\t3\t2\t1\t0\t\n Virus\t0\t0\t0\t0\t\n Extracellular bacteria\t3\t1\t2\t2\t\n Fungi\t0\t0\t0\t2\t\n Extracellular bacteria and virus\t1\t1\t0\t0\t\nFindings on chest CT\t\t\t\t\t\n Infectious pneumonia\t4\t4\t0\t4\t\n Hypersensitivity pneumonitis\t2\t0\t2\t0\t\n Organizing pneumonia\t1\t0\t1\t0\t\nICI, immune checkpoint inhibitor; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cells; BM, bone marrow; n/a, not applicable; CR, complete remission; CRp, complete remission without platelet recovery; ICU, intensive care unit; BAL, bronchoalveolar lavage; CT, computed tomography.\n\nManual Differentials of Bronchoalveolar Lavage and Peripheral Blood\nFor all patients, manual leukocyte differentials of BAL and PB cells were counted as standard of care (\nTable 2\n). The differentiation tests of PB from four patients, two in the ICI group and two in the control group, could not be performed owing to severe leukopenia. The frequency of BAL lymphocytes was significantly higher in the ICI group than in the control group (mean ± SD; ICI vs. control; 26.4 ± 15.0 vs. 3.8 ± 3.6; P = 0.01), whereas the mean frequency of BAL macrophages was significantly lower in the ICI group than in the control group (mean ± SD; ICI vs. control; 64.7 ± 15.0 vs. 86.5 ± 7.1; P = 0.03). This trend was more prominent in the ICI-pneumonia group than in the ICI-pneumonitis group (\nFigure 2\n). Consistently, the mean frequency of PB lymphocytes in the ICI group was higher than in the control group; however, the differences did not reach statistical significance (mean ± SD; ICI vs. control; 44.8 ± 15.0 vs. 19.0± 11.3; P = 0.09).\n\nTable 2 Manual differentiations of bronchoalveolar lavage (BAL) and peripheral blood (PB) samples.\n\nBAL\tICI group (n=7)\tICI-pneumonia (n=4)\tICI-pneumonitis (n=3)\tControl (n=4)\t\nCell subsets, %, median (range)\t\t\t\t\t\nLymphocyte\t32 (8–46)\t36 (32–46)\t13 (8–14)\t2.5 (1–9)\t\nMacrophage\t65 (41–84)\t56.5 (41–65)\t81 (69–84)\t84 (81–97)\t\nNeutrophil\t0 (0–1)\t0.5 (0–1)\t0 (0–0)\t0 (0–0)\t\nEosinophil\t0 (0–0)\t0 (0–0)\t0 (0–0)\t0 (0–0)\t\nBasophil\t0 (0–0)\t0 (0–0)\t0 (0–0)\t0 (0–0)\t\nOthers\t9 (1–17)\t7 (1–12)\t11 (2–17)\t11.5 (1–13)\t\n\nPB*\n\t\nICI group (n=5)\n\t\nICI-pneumonia (n=2)\n\t\nICI-pneumonitis (n=3)\n\t\nControl (n=2)\n\t\nCell subsets, %, median (range)\t\t\t\t\t\nLymphocyte\t39 (32–67)\t46 (39–53)\t33 (32–67)\t19 (11–27)\t\nMacrophage\t5 (0–20)\t7 (1–13)\t5 (0–20)\t47.5 (12–83)\t\nNeutrophil\t16 (0–33)\t25.5 (18–33)\t13 (0–16)\t28 (0–56)\t\nEosinophil\t1 (0–1)\t1 (1–1)\t0 (0–1)\t2.5 (0–5)\t\nBasophil\t1 (0–4)\t1 (1–1)\t0 (0–4)\t0 (0–0)\t\nOthers†\n\t28 (0–68)\t19.5 (11–28)\t44 (0–68)\t3 (0–6)\t\nICI, immune checkpoint inhibitor; BAL, bronchoalveolar lavage; PB, peripheral blood.\n\n*PB differentiation tests could not be performed in two patients in the ICI-pneumonia group and two patients in the control group owing to severe leukopenia.\n\n\n†Blasts are included.\n\nFigure 2 Proportion of major bronchoalveolar lavage (BAL) cell subsets with manual differential tests. Bars indicate the mean and the SEM. One-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, n.s., not significant. ICI, immune checkpoint inhibitor.\n\nDistinct Immune Landscape of Bronchoalveolar Lavage T Cells in the Immune Checkpoint Inhibitor Group\nGiven the enrichment of lymphocytes in BAL fluid and PB, we focused on characterizing lymphocytes and enumerating major lymphocytic subsets in both BAL fluid and PB (\nFigure 3\n; \nSupplementary Table 2\n). The absolute number of lymphocytes per 1 ml BAL fluid was higher in the ICI group than in the control group (mean ± SD; ICI vs. control: 23,791 ± 41,142 cells vs. 1,285 ± 1,051 cells; P = 0.01; \nSupplementary Table 2\n). The proportions of NK cells (CD3− CD56+), NK T cells (CD3+ CD56+), B cells (CD3− CD56− CD19+), and CD4+ T cells (CD3+ CD4+ CD8−) were similar between the ICI and control groups (\nFigure 3A\n; \nSupplementary Figure 1\n). BAL CD8+ T cells (CD3+ CD4− CD8+) were significantly expanded in the ICI group compared with the control group in terms of frequencies and numbers (frequency: mean ± SD; ICI vs. control; 28.4 ± 13.0% vs. 5.8 ± 1.2%; P = 0.006) (absolute cell numbers: mean ± SD; ICI vs. control; 28.4 ± 13.0% vs. 5.8 ± 1.2%). Most of these CD8+ T cells were CD45RA− CCR7− effector memory cells (64.2 ± 30.7%; \nFigure 3B\n), suggesting that these cells play a role in ICI-related pulmonary complications. The frequencies and absolute number of cells for lymphocytic immune subsets in the PB samples were similar between the ICI and control groups (\nFigure 3C\n).\n\nFigure 3 Characterization of lymphoid immune cell subsets in bronchoalveolar lavage (BAL) fluid and peripheral blood (PB). (A) Proportions of major BAL immune cell subsets within live lymphocytes and absolute cell numbers in 1 ml BAL fluid. NK, natural killer cells; NK T, natural killer T cells; B, B cells. Bars indicate the mean and the SEM. Mann-Whitney U test. *P<0.05, **P<0.01. (B) Proportions of CD8+ T cell subsets within BAL CD8+ T cells. Tn, naïve T cells; Tcm, central memory T cells; Tem, effector memory T cells; Temra, terminally differentiated T cells. Bars indicate the mean and the SEM. One-way ANOVA. *P<0.05, **P<0.01, ***P<0.001. (C) Proportions of major PB immune cell subsets within live lymphocytes and absolute cell numbers in 1 ml PB. Bars indicate the mean and the SEM. (D) Proportions of CD4+ T cell subsets within CD4+ T cells and absolute cell numbers in 1 ml BAL fluid. Treg, regulatory T cells; Tfh, follicular helper T cells. Bars indicate the mean and the SEM. Mann-Whitney U test. *P<0.05. (E) Proportion of BAL CD4+ T cells expressing indicated transcription factors (left), transcription factors and surface molecules (middle and right). Bars indicate the mean and the SEM. Mann-Whitney U test. *P<0.05. (F) PD-1 on BAL naïve CD4+ T cells and BAL CXCR3+ CCR6+ Th17/Th1 cells. Left panel shows one of the most representative plots and right panel shows quantification. Wilcoxon paired rank test. *P<0.05. (G) Proportions and absolute numbers of IFNγ- and/or IL-17-producing CD4+ and CD8+ T cells in BAL fluid. Bars indicate the mean and the SEM. Mann-Whitney U test. *P<0.05. (H) Levels of IFNγ, IL-6, and IL-17A in BAL fluid measured by multiplex ELISA. Bars indicate the mean and the SEM.\n\nNext, we delineated CD4+ T cell subsets on the basis of chemokine/cytokine receptor expression, including regulatory T cells, naïve T cells, follicular helper T cells, Th1, Th2, Th17, and Th17/Th1 cells (9–13) (\nFigure 3D\n; \nSupplementary Figure 2\n). Although the proportions of PB CD4+ T cell subsets were similar between the ICI and control groups (\nSupplementary Figure 3\n), BAL Th17/Th1 cells were significantly expanded in the ICI group compared with the control group (mean ± SD; ICI vs. control; 43.8 ± 20.5% vs. 13.3 ± 8.8%; P = 0.04; \nFigure 3D\n). For selected patients (n=3 in control; n=3 in ICI-pneumonia; n=2 in ICI-pneumonitis), along with chemokine/cytokine receptors, we also investigated expression of key transcription factors including T-bet (Th1), GATA3 (Th2), RoRγT (Th17), and FoxP3 (Treg) (\nFigure 3E\n; \nSupplementary Figure 3\n) (10). Consistent with data in \nFigure 3D\n, we observed enrichment of T-bet+ RORγt+ (Th1) and CXCR3+ T-bet+ CCR6+ RORγt+ (Th1/Th17) cells in BAL CD4+ T cells in the ICI group. Most (48.0 ± 22.5%) BAL Th17/Th1 cells expressed PD-1 (\nFigure 3F\n), suggesting that these cells had persistent antigen exposure (15).\n\nTo evaluate the functionality of the T cells, we performed intracellular staining to assess IFNγ- and/or IL-17-producing T cells (\nFigure 3G\n; \nSupplementary Figure 4\n). In BAL fluid, the absolute number of IFNγ- and/or IL-17-producing CD4+ T cells was higher in the ICI group than in the control group. In addition to the number of cells, the frequency of IFNγ+ IL-17+ CD4+ T cells in BAL fluid was significantly higher in the ICI group than in the control group (mean ± SD; ICI vs. control; 4.1 ± 2.4% vs. 0.7 ± 1.3%; P = 0.03; \nFigure 3G\n). Consistently, although proportions of IFNγ+ IL-17− CD8+ cells in BAL fluid were similar between the two groups, the absolute number of these cells was higher in the ICI group than in the control group (mean ± SD; ICI vs. control; 2135.0 ± 2203.0 cells vs. 30.0 ± 44.0 cells; P = 0.01; \nFigure 3G\n). Although not statistically significant, the levels of soluble IFNγ, as well as IL-6 and IL-17A, key cytokines for Th17 cell differentiation, plasticity, and function (10, 16), in the BAL fluid were higher in the ICI group than in the control group (\nFigure 3H\n). IFNγ- and/or IL-17-producing CD4+ and CD8+ T cells in PB were comparable between the ICI and control groups (\nSupplementary Figure 4\n).\n\nClonally Expanded Bronchoalveolar Lavage T Cells in the Immune Checkpoint Inhibitor Group\nWe analyzed the TCR repertoire in 11 matched BAL fluid and PB samples (\nFigure 4\n). T cells in the ICI group, especially the BAL T cells, were significantly clonally expanded compared with the control group (mean ± SD; ICI vs. control; 0.077 ± 0.011 vs. 0.014 ± 0.002; P = 0.006). Clonality and diversity of PB T cells was higher in the ICI-pneumonitis group than in the ICI-pneumonia and control groups (clonality: mean ± SD; ICI-pneumonitis vs. ICI-pneumonia vs. control; 0.16 ± 0.02 vs. 0.03 ± 0.03 vs. 0.03 ± 0.03, P = 0.001) (diversity: mean ± SD; ICI-pneumonitis vs. ICI-pneumonia vs. control; 0.02 ± 0.01 vs. 0.0004 ± 0.0003 vs. 0.0004 ± 0.0006; P = 0.001) (\nFigure 4A\n). We investigated the overlapped T cell clones in BAL and PB (\nFigure 4B\n; \nSupplementary Figure 6\n). Although not reached statistical significance, a greater degree of overlap was observed in the ICI-pneumonitis, compared with ICI-pneumonia and controls (\nFigure 4B\n), suggesting that ICI-pneumonitis might be a systemic inflammation.\n\nFigure 4 \n(A) Clonality and diversity of T cells in the bronchoalveolar lavage (BAL) fluid and peripheral blood (PB). Bars indicate the mean and the SEM. One-way ANOVA. *P<0.05, **P<0.01, n.s., not significant. (B) Quantification of overlapped T-cell receptor sequences between BAL and PB. Bars indicate the mean and the SEM. One-way ANOVA.\n\nSubgroup analysis of the ICI group based on ICI regimen [PD-1 inhibitor (n=4) compared with combined CTLA-4 and PD-1 inhibitors (n=3)] and concurrent steroid treatment at the time of biospecimen collection [steroid (n=3) compared with no steroid (n=4)] revealed no differences in immunophenotypes or TCR repertoire (data not shown).\n\nDiscussion\nAML/MDS patients receiving ICIs can develop pneumonia due to their diseases and leukopenia and pneumonitis as an immune-related adverse event. As the first step to investigate mechanisms underlying these ICI-related pulmonary complications, we immunoprofiled BAL fluid and PB samples from AML/MDS patients with pulmonary complications after ICI therapy. Compared with control patients (ICI-naïve AML/MDS patients with bacterial/fungal pneumonia), patients with ICI-related pulmonary complications had enriched lymphocytes, especially Th17/Th1 cells and IFNγ+ CD8+ T cells, in BAL fluid, as well as clonally expanded BAL T cells. Subgroup analysis of the ICI group revealed that patients with ICI-pneumonia had predominant BAL lymphocytes and patients with ICI-pneumonitis had enhanced T cell clonality and diversity in PB. Combined, our data suggest that distinct T cell responses occur in patients with ICI-related pulmonary complications.\n\nTh17 cells are highly plastic and can be differentiated into CXCR3+ CCR6+ IFNγ+ IL-17+ Th17/Th1 cells. Studies have shown that Th17/Th1 cells play an important role in the pathogenesis of autoimmune diseases (17). Indeed, Th17/Th1 cells were shown to be enriched in inflammatory sites of autoimmune diseases including the colon in Crohn’s disease, cerebrospinal fluid in multiple sclerosis, and synovial fluid in rheumatoid arthritis and juvenile idiopathic arthritis (13, 18–21). Recent studies revealed that these cells are also enriched in the BAL fluid from patients with sarcoidosis (22–24). Based on the studies, we speculate that enrichment of BAL Th17/Th1 cells in our study is not a non-specific finding secondary from inflammation; rather we hypothesize that these BAL Th17/Th1 cells play a key role in the pathogenesis of ICI-related pulmonary complications. Our hypothesis is partially supported by the in vivo and in vitro observations that genetic or pharmacologic depletion of PD-1 enhanced Th17 responses in a mouse model of allergic asthma (25). Further studies are warranted to investigate the generation and function of Th17/Th1 cells in ICI-related pulmonary complications.\n\nAbout 3–5% of patients with solid tumors develop pneumonitis after ICI therapy (6). The pneumonitis with solid tumors is one of early immune-related adverse events with onset at a median of 2.8 months, with a wide range (9 days to 19.2 months) (6). Suresh et al. recently characterized BAL fluid from patients with solid tumors who developed ICI-induced pneumonitis, and that analysis revealed prominent lymphocytes, especially IFNγ+ CD8+ T cells (26). Patients in our cohort also developed respiratory symptoms early after the initiation of ICIs (median: 2.5 weeks), and BAL analyses revealed prominent lymphocytes in the ICI group (\nTable 2\n). Importantly, we observed enrichment of IFNγ+ CD8+ T cells, but we also observed enrichment of Th17/Th1 cells, suggesting that there are shared and distinct mechanisms underlying ICI-induced pneumonitis depending on the tumor type. Dissection of immune profiles of ICI-induced pneumonitis between patients with solid tumors and those with leukemia would be of future interest.\n\nThe difference in immunophenotypes between ICI-pneumonia and ICI-pneumonitis is unclear. Although the difference was not statistically significant, we found that the median onset of respiratory symptoms was shorter in the ICI-pneumonia group than in the ICI-pneumonitis group (ICI-pneumonia vs. ICI-pneumonitis; 1.5 vs. 3.5 weeks), and proportions of BAL lymphocytes were higher in the ICI-pneumonia group, suggesting that BAL lymphocytes, most likely T cells, of the ICI-pneumonia actively proliferate and/or survive longer compared with BAL T cells of the ICI-pneumonitis. Considering these findings, we speculate that patients with ICI-pneumonia might have more enhanced T cell memory responses than patients with ICI-pneumonitis. Not mutually exclusive, it is also possible that antigens in ICI-pneumonia have heightened antigenicity compared with those in ICI-pneumonitis. In contrast, we found that clonality and diversity of circulating T cells were higher in the ICI-pneumonitis group than in the ICI-pneumonia group. Collectively, we hypothesis that exogenous antigens (bacteria and/or fungus) in the ICI-pneumonia might provide strong TCR and toll-like receptor signal, which induce global and indirect T cell activation/reactivation with prolonged T cell survival. In contrast, endogenous antigens (self-antigens or tumor antigens) might specifically activate T cells recognizing these endogenous antigens, resulting in enhanced TCR clonality. Our hypothesis is supported by the study, showing enhanced TCR clonality in inflamed joints (synovial fluid) and blood of patients with psoriatic arthritis, one of the most common autoimmune diseases (27). In addition, previous studies showed an increase of clonality and diversity of T cells in patients with immune-related adverse events (28–31). However, given our small sample size and the unstable PB cells in AML/MDS, we could not make any conclusions at present. Future studies investigating cell proliferation (Ki67), apoptosis (annexin V, DAPI), exhaustion (LAG3, TIM3, PD-1, TIGIT), and anti-apoptosis gene expression (Bcl2, Bcl-xL) in BAL/PB cells between ICI-pneumonia and ICI-pneumonitis will enable us to dissect mechanisms of ICI-pneumonia and ICI-pneumonitis. Nevertheless, BAL differentiation counts and/or TCR repertoires in PB might be a potential biomarker to differentiate ICI-pneumonia from ICI-pneumonitis.\n\nOur study has a few limitations. First, because of the small number of patients analyzed, these data are inconclusive. Second, this study does not have a control group comprising patients with solid tumors who developed ICI-induced pneumonitis. In addition, some patients in the ICI group were on azacitidine in addition to ICI and azacitidine can alter immune profiles (32, 33). Indeed, studies revealed increased numbers of Tregs and decreased numbers of CD8+ T cells and Th1 cells after azacitidine therapy (32, 33). Our study showed enrichment of BAL Th17/Th1 cells and IFNγ+ IL-17− CD8+ T cells in the ICI group while studies showed that stable and decreased numbers of Th17 and CD8+ T cells with azacitidine. Together, we speculated that azacitidine might not have influenced our main observations; however, given that epigenetic mechanisms are critical in regulating T cell lineage commitment (34), ICI-naïve AML/MDS patients with azacitidine monotherapy should also be served as a control group. Third, three participants in the ICI group were receiving steroids at the time of BAL fluid collection and four at the time of PB sample collection, which might have altered the immune profiles.\n\nIn this study, the samples were mainly obtained from the pilot phase IB trials initiated in 2017-2018 at the University of Texas MD Anderson Cancer Center, comparing efficacy and safety of ICI-based therapies in patients with AML/MDS. With the initial encouraging results, we have recently opened a number of additional ICI-based trials for AML and MDS including clinical trials of azacitidine + nivolumab + ipilimumab (NCT02397720), azacitidine+venetoclax+nivolumab (NCT02397720), azacitidine + venetoclax +avelumab (NCT03390296), azacitidine + venetoclax + TIM3 antibody (NCT04150029), with larger numbers of participants (150–180) expected to be enrolled at the MD Anderson across these phase IB/II larger trials. In this manuscript, we aimed to generate hypothesis rather test the hypothesis. Since 10–12% of the AML/MDS patients develops pneumonitis (1, 6), from these upcoming trials, we expect to collect 15–22 BAL and matching PB samples from AML/MDS patients with ICI-pneumonitis (and similar numbers of the samples from AML/MDS patients with ICI-pneumonia as well). Detailed investigation of cell survivals, proliferation, and exhaustion are warranted in future studies to dissect underlying mechanisms between ICI-pneumonia and ICI-pneumonitis. Based on distinct TCR repertoires between ICI-pneumonia and ICI-pneumonitis, analysis of both TCR α and β chains are also needed in the future studies. ICI-naïve AML/MDS patients who develops pulmonary complications after azacitidine monotherapy will be served as a control group in future studies. Additionally, the standard therapy for frontline older AML has now transitioned to azacitidine+venetoclax, and it is possible this will emerge as a more effective therapy in frontline MDS as well. We have a large number of patients treated with azacitidine and venetoclax for both AML and MDS and plan to assess BAL samples on these patients as well to serve as an additional future control. Finally, although we did not see differences of immune profiles of concurrent steroid treatment, the analysis might be underpowered. Future studies should carefully model the use of steroids and standardize BAL collection before steroids are administered. In some cases of life-threatening pneumonitis, steroid therapy is empirically initiated prior to the diagnostic bronchoscopy. Nevertheless, larger numbers of the samples in the future studies will enable us to perform subgroup analysis (steroid vs. no steroid) with adequate power. In conclusion, our study showed distinct immunophenotypes of T cells in BAL fluid in AML/MDS patients with ICI-related pulmonary complications. Detailed molecular and cellular characterization of immune cells in a larger number of patients, with appropriate controls, may provide insights into the mechanisms of pneumonitis in AML/MDS treated with ICIs-based therapy, as well as provide diagnostic biomarkers to differentiate pneumonitis from pneumonia and potentially predict the severity of the pneumonitis.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by The IRB at the University of Texas MD Anderson Cancer Center. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nSK performed experiments, analyzed the data, and wrote the manuscript. AS, VS, HK, GG-M, FR, LB, DB, SE, SF, and ND provided samples. JI, WR-V, MD, SN, RM, LW, ST, CG, and AF performed experiments and discussed results. AD and PB analyzed the data and discussed results. AN discussed the results. SK, AS, VS, DK, and ND were responsible for adjudication of the patients. RN and ND oversaw the study and discussed results. All authors reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\nThis work was supported by The University of Texas MD Anderson Cancer Center Division of Internal Medicine Developmental Funds (SK), the NIH RO1 grants (RN: R01HL141966 and R01HL143520) and CPRIT grant (RN: RP190326).\n\nConflict of Interest\nSN has received research support from Kite/Gilead, Cellectis, Poseida, Merck, Acerta, Karus, BMS, Unum Therapeutics, Allogene, and Precision Biosciences; served as consultant and advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, Merck, Precision Biosciences, Cell Medica, Incyte, Allogene, Calibr, and Legend Biotech; and has patents related to cell therapy. ND has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Karyopharm, Sevier, Genentech, and ImmunoGen and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, and Agios.\n\nThe 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\nAcknowledgments\nThe authors thank Jairo Matthews and Wilmer Flores for their support in obtaining human samples. We also thank Jordan Kramer for analyzing the data and reading the manuscript critically. Finally, the authors also thank Editing Services, Research Medical Library at The University of Texas MD Anderson Cancer Center for editing the manuscript.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.590494/full#supplementary-material\n\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nDaver N Basu S Garcia-Manero G Cortes J Ravandi F Jabbour E \nPhase IB/II study of nivolumab in combination with azacytidine in patients with relapsed acute myeloid leukemia . Madrid, Spain : EHA Learning Center (2017 ). p. S474 .\n2 \nAlatrash G Daver N Mittendorf EA \nTargeting Immune Checkpoints in Hematologic Malignancies\n. Pharmacol Rev (2016 ) 68 (4 ):1014–25. 10.1124/pr.116.012682 \n\n3 \nBoddu P Kantarjian H Garcia-Manero G Allison J Sharma P Daver N \nThe emerging role of immune checkpoint based approaches in AML and MDS\n. 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"keywords": "Th17/Th1 cells; acute myeloid leukemia; checkpoint inhibitor; immune-related adverse event; pneumonitis",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011014:Pneumonia; D013601:T-Lymphocytes",
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{
"abstract": "Solid organ transplant (SOT) recipients may be more vulnerable to coronavirus disease 2019 (COVID-19). Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the optimal management strategy for these patients is yet unclear.\n\n\n\nWe present 53 SOT recipients (31 kidney transplant recipients, 8 liver transplant recipients, 5 heart transplant recipients, 5 lung transplant recipients, 3 liver-kidney transplant recipients, and 1 kidney-after-heart transplant recipient), transplanted at a Swedish high-volume transplant center and each diagnosed with COVID-19 between February 21, 2020 and June 22, 2020. Demographic, clinical, and treatment data were extracted from the electronic patient files.\n\n\n\nPatients reported fever (61%), cough (43%), diarrhea (31%), and upper respiratory symptoms (29%). The median age was 56 years, and 57% were male. According to severity, 55% had mild, 13% had moderate, 19% had severe, and 13% had critical disease. Thirty-seven patients (70%) were hospitalized, with 8 requiring intensive care. Thirteen of the 37 patients were initially managed as outpatients but later hospitalized. One patient received hydroxychloroquine, and no patients received antivirals. Antimetabolites and calcineurin inhibitors were held or reduced in two-thirds. Twenty-seven of 37 hospitalized patients (73%) received low-molecular-weight heparin. Five (13.5%) hospitalized patients died. Overall survival for the entire cohort was 90.5%. No rejection episodes were noted.\n\n\n\nHospitalization, lowering of immunosuppression, and prophylactic anticoagulation were the most common therapeutic interventions for SOT recipients with COVID-19. A significant proportion of patients could be managed on an outpatient basis, while keeping a low threshold for admission. Mild and moderate disease forms seem to have a good outcome.",
"affiliations": "Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Division of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden.;Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.;Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.",
"authors": "Felldin|Marie|M|;Søfteland|John Mackay|JM|;Magnusson|Jesper|J|;Ekberg|Jana|J|;Karason|Kristjan|K|;Schult|Andreas|A|;Larsson|Hillevi|H|;Oltean|Mihai|M|;Friman|Vanda|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000003436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "105(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000328:Adult; D000368:Aged; D000086382:COVID-19; D005260:Female; D061847:Hospitals, High-Volume; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D000086402:SARS-CoV-2; D013548:Sweden",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "108-114",
"pmc": null,
"pmid": "32826796",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Initial Report From a Swedish High-volume Transplant Center After the First Wave of the COVID-19 Pandemic.",
"title_normalized": "initial report from a swedish high volume transplant center after the first wave of the covid 19 pandemic"
} | [
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"abstract": "Turner syndrome (TS) affects 1 in 2500 females. Monosomy X is the most common etiology, classically presenting with hypoestrogenemia and short stature. We present two cases of partial X chromosome deletions that do not reflect the typical phenotype of TS. Patient 1 presented at age 17 with primary amenorrhea, cognitive delay and tall stature. Patient 2 presented at age 16 with primary amenorrhea, normal intelligence and average stature. Patient 1's karyotype revealed isodicentric X chromosome [46 X, idic(X)(q21)]. Patient 2's karyotype revealed [46 X,del(X)(q13.3)]. The stature of these patients was not affected. Estrogen therapy was required to provide secondary sexual changes promote bone health. Advances in technology and reproductive health provide an opportunity to make more specific recommendations for patients previously mistakenly diagnosed with TS.",
"affiliations": "Department of Obstetrics and Gynecology, Rochester Regional Health, USA.;Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.;Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.;Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.",
"authors": "Dawkins|Josette C|JC|;Carpinello|Olivia|O|;Hill|Micah|M|;DeCherney|Alan H|AH|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2018.e00084",
"fulltext": "\n==== Front\nCase Rep Womens HealthCase Rep Womens HealthCase Reports in Women's Health2214-9112Elsevier S2214-9112(18)30118-810.1016/j.crwh.2018.e00084e00084ArticlePhenotypic variations in X chromosome mutations: Two case reports Dawkins Josette C. Josette.Dawkins@rochesterregional.orga⁎Carpinello Olivia bHill Micah bDeCherney Alan H. ba Department of Obstetrics and Gynecology, Rochester Regional Health, USAb Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA⁎ Corresponding author at: 1425 Portland Avenue, Rochester, NY 14621, USA. Josette.Dawkins@rochesterregional.org07 11 2018 1 2019 07 11 2018 21 e000841 10 2018 17 10 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Turner syndrome (TS) affects 1 in 2500 females. Monosomy X is the most common etiology, classically presenting with hypoestrogenemia and short stature. We present two cases of partial X chromosome deletions that do not reflect the typical phenotype of TS.\n\nPatient 1 presented at age 17 with primary amenorrhea, cognitive delay and tall stature. Patient 2 presented at age 16 with primary amenorrhea, normal intelligence and average stature.\n\nPatient 1's karyotype revealed isodicentric X chromosome [46 X, idic(X)(q21)]. Patient 2's karyotype revealed [46 X,del(X)(q13.3)]. The stature of these patients was not affected. Estrogen therapy was required to provide secondary sexual changes promote bone health.\n\nAdvances in technology and reproductive health provide an opportunity to make more specific recommendations for patients previously mistakenly diagnosed with TS.\n\nHighlights\n• Patients with X chromosome mutations should not be classified as Turner Variants.\n\n• The exact karyotype is useful to explain the clinical and phenotypic findings.\n\n• Advances in technology and reproductive health allow for specific recommendations.\n\n\n\nKeywords\nTurner variantX chromosome mutation\n==== Body\n1 Introduction\nThere is wide variation in the phenotypic presentation of patients with X chromosome mutations and deletions. Turner syndrome, first described in 1938 and explicated by cytogenetic chromosomal analysis in 1959, is one of the most common sex chromosome disorders [1,2]. The most common etiology is monosomy X, which accounts for 50–60% of cases. Mosaicism with aberrant X chromosomes, primarily isochromosomes, has also been described. Although the reported incidence of Turner syndrome has been quoted as 1:2500, the true incidence in the developed world is likely now significantly lower (1: 4000) due to ultrasound screening and elective terminations [3]. The syndrome may be identified through the characteristic finding of cystic hygroma on ultrasound or with non-invasive prenatal testing (NIPT). However, in cases of X chromosome mosaicism, cystic hygroma and other soft-tissue ultrasound markers may not be reliably identified [4]. Evaluation for fetal aneuploidy by examining maternal plasma derived cell free fetal DNA (cf DNA) has now become the most sensitive screening method for the detection of Turner syndrome. Abnormal findings are confirmed either by chorionic villus sampling or amniocentesis [5].\n\nPrior to NIPT and ultrasound, the stereotypical patient with Turner syndrome was diagnosed clinically. Classically, the affected newborn has increased nuchal skin, edema of the distal extremities, a shield-shaped thorax with widely spaced nipples and facial dysmorphia such as low-set ears and a low hairline [6]. Cardiac defects such as coarctation of the aorta and hypoplastic left heart may present with cyanosis in the newborn, while musculoskeletal abnormalities such as cubitus valgus, short stature, and shortened 4th metacarpal with abnormal finger nails become more evident in childhood and adolescence. Other clinical findings, including hypothyroidism, urological abnormalities, and metabolic dysfunction may also become apparent later in life. Sybert and McCauley reported that approximately two-thirds of patients with Turner syndrome are diagnosed after birth or during childhood. Only one-third of patients were diagnosed in adolescence or in young adulthood after failing to undergo puberty [7]. The classic presentation is with low estrogen, short stature, and cardiac anomalies [6,7].\n\nPatients with one or more of the above findings may have a karyotype determination as part of their evaluation. If they are found to have an abnormal X chromosome, they are often labeled as “Turner variants” or “atypical Turner syndrome”. However, many of them do not meet the classical picture of Turner syndrome and may even violate the putative phenotype. We present two patients with X chromosome partial deletions that do not reflect Turner syndrome. With newer technologies, the phenotype and exact karyotype can be better correlated. Given the genetic diagnosis, we purport that these patients should no longer be classified as “Turner variants” but should instead be separately classified as having X chromosome mutations and partial deletions.\n\n2 Cases\n2.1 Patient 1\nPatient 1 presented to an outside provider at age 17 with primary amenorrhea, failure to undergo puberty, cognitive delay and low-set ears. Karyotype determination revealed isodicentric X chromosome [46 X, idic(X)(q21)] with deletion of most of the long arm (q), and with duplication of the centromere, proximal long arm and short arm (p) (Fig. 1). She was labeled as a Turner variant and was placed on combined oral contraceptive pills for hormone replacement therapy. Her medical history included depression, migraines, left hydronephrosis and reconstructive mammoplasty. Her physical examination was otherwise unremarkable, and she was noted to be six feet three inches tall, which was appropriate given the height of her parents. Oral contraceptive pills controlled her vasomotor symptoms for 15 years, but subsequently these worsened. Evaluation at this time revealed low serum estradiol of <5 mIU/mL and decreased bone mineral density on dual energy x-ray absorptiometry (DEXA) with a Z score of −2.0 at the distal forearm and −0.4 to −0.8 in the spine, femoral neck and hip. An estrogen patch was added to her regimen to improve her vasomotor symptoms and bone mineral density.Fig. 1 Karyotype for patient 1 and 2.\n\nFig. 1\n\nThe patient then took a long air flight and developed a significant pulmonary embolism with right heart strain, which required thrombolytics and management in the intensive care unit. Hormonal therapy was discontinued and she was placed on rivaroxaban (Xarelto®) for anticoagulation. She subsequently developed disordered sleep patterns and mood changes, and her vasomotor symptoms worsened. It was at this time that she was referred to our clinic, at the age of 32. Sertraline hydrochloride (Zoloft ®) was started in an attempt to treat her vasomotor symptoms and mood symptoms. However, no improvement was seen. Her estradiol level was <5 pg/mL, FSH 28 mIU/mL, LH 21 mIU/mL and an antimullerian hormone (AMH) < 0.015 ng/mL. She was referred to hematology, where her thrombophilia workup was negative. At the suggestion of hematology, her Xarelto was continued and she was restarted on an estradiol 0.1 mg patch twice weekly. Since restarting HRT, the patient's vasomotor symptoms have been controlled and her mood disturbances have significantly improved.\n\n2.2 Patient 2\nPatient 2 was referred at age 16 for primary amenorrhea, delayed breast development and disordered sleep. She denied hot flashes and had no other complaints. Physical examination revealed normal height (five feet three inches) and weight, with a BMI of 23.6 (kg/m2), mild acne, normal external female genitalia, vaginal atrophy of the introitus, Tanner stage I-II breasts and Tanner stage IV pubic hair. Her FSH level was 97mIU/mL, LH 29 mIU/mL, AMH 0.054 ng/mL, prolactin 17 ng/dL, free T4 1.35 ng/dL, and TSH 5.32 mU/L. Thyroid peroxidase antibodies and thyroglobulin antibodies were both positive and 21 hydroxylase antibodies were negative. Her DEXA scan showed decreased bone mineral density with a T score of −2.2 at the lumbar spine and femoral neck. Pelvic MRI demonstrated absent ovaries and small uterus (4.0 × 1.3 × 1.7 cm) without an identifiable endometrium. An echocardiogram was normal and her fragile X testing was normal. Karyotype determination revealed partial deletion of the long arm [46 X,del(X)(q13.3)] (Fig. 1). She was started on Synthroid and hormone replacement with estradiol tablets (Estrace®) 2 mg daily. Six months later, she reported breast development. She was counseled on future fertility with use of donor eggs and continues to do well.\n\n3 Discussion\nThese two cases demonstrate the variations in genetic and phenotypic presentations of patients with X chromosome mutations. While they have some phenotypic similarities to those with Turner syndrome, these patients do not fit the classic presentation and do not have the same medical considerations.\n\nThe diagnosis of X chromosome mutations is critical in patients with short stature and ovarian insufficiency so that recombinant growth hormone and hormonal replacement may be initiated in a timely manner. Patients who do not receive growth hormone therapy are shorter than their adult counterparts due to failure of the growth spurt with puberty as well as deletion of the Xp [8]. The SHOX homeobox gene located on Xp22.23 is involved in skeletal growth and development. Additionally, short stature resulting from disordered growth occurs in various parts of the life cycle, including in utero, during childhood and at puberty [9]. Maximal height is achieved when recombinant growth hormone is combined with estrogen therapy, which is usually initiated at 12–14 years of age. Neither of our patients required growth hormone therapy. Both patients had preservation of the Xp, which likely played a role in their tall and average heights [10].\n\nBone mineral density was affected in both patients due to estrogen deficiency. Although the normal range of T scores has not been clearly delineated for adolescents, a Z score of less than - 2.0 is considered low bone density for chronological age [11]. Estrogen therapy, calcium and vitamin D are paramount for establishment of normal bone mineralization.\n\nBoth patients presented with delayed puberty and were found to have ovarian insufficiency in mid-adolescence. Ovarian failure is associated with deletion of the q arm, and there was at least partial deletion in both of our patients [12]. Our patients required exogenous estrogen to provide secondary sexual development, promote bone health and cardiovascular protection. Patient 1 was able to achieve normal breasts using augmentation mammoplasty while patient 2 utilized pharmacologic therapy for breast development. Estrogen is also useful for the maturation of the infantile uterus, which may be useful to support a pregnancy later in life. The use of exogenous estrogens, however, is not without consequences. Venous thromboembolism (VTE) is a serious complication in any patient on exogenous estrogen and may increase the risk 2–4 times above baseline, particularly in those with additional risk factors. Patient 1 developed a provoked VTE after prolonged air travel. Although her estrogen therapy was paused during the period of critical health and shortly afterwards, hormonal replacement therapy was subsequently restarted with anticoagulation treatment. Based on current evidence, it is appropriate to continue much-needed hormonal replacement therapy in patients after a provoked VTE who are appropriately anticoagulated [13].\n\nCardiac defects such as aortic coarctation, hypoplastic left heart, bicuspid valves, and vasculopathy affect up to 30% of patients with Turner syndrome [14]. However, both our patients were without cardiac abnormalities. This is important information for future reproductive counseling. Cardiovascular risks associated with Turner syndrome increase in pregnancy and some infertility centers choose not to allow such patients to conceive, even with donor egg [15]. Evidence is lacking that partial X chromosome deletions are associated with the same cardiovascular risk profile.\n\nIn addition to correctly identifying the specific X chromosome mutations, determination of the karyotype is also useful to exclude an abnormal Y chromosome. Findings of a partial Y chromosome would necessitate the removal of the non-functional streak gonads due to risk of malignancy [16].\n\nFinally, it is important to appropriately classify patients with X chromosome mutations and deletions, for both medical and psychosocial reasons. For instance, both patients would likely have felt out of place in a support group for patients with Turner syndrome given their normal to tall stature. Additionally, the majority of patients and their carers now seek information online. An improper search term may leave parents confused and frustrated if the available information is not pertinent to their own child.\n\nWith technological advances, the wide genetic variations in patients with X chromosome mutations and partial deletions can now be correlated to their clinical presentation. Such patients should no longer be classified as “Turner variants” but should instead be separately classified as having X chromosome mutations and deletions.\n\nContributors\nAll authors contributed to the preparation of this case report and saw and approved the final manuscript.\n\nConflict of Interest\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n\nFunding\nPublication of this case report was supported, in part, by the Program in Reproductive Endocrinology and Gynecology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.\n\nPatient Consent\nObtained.\n\nProvenance and Peer Review\nThis case report was peer reviewed.\n==== Refs\nReferences\n1 Turner H. A syndrome of infantilism, congenital webbed neck and cubitus valgus Endocrinology 23 1938 566 574 \n2 Ford C.E. Jones K.W. Polani P.E. de Almeida J.C. Briggs J.H. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome) Lancet (London, England) 1 7075 1959 711 713 \n3 Iyer N.P. Tucker D.F. Roberts S.H. Moselhi M. Morgan M. Matthes J.W. Outcome of fetuses with Turner syndrome: a 10-year congenital anomaly register based study J. Matern. Fetal Neonatal Med. 25 1 2012 68 73 \n4 Alpman A. Cogulu O. Akgul M. Arikan E.A. Durmaz B. Karaca E. Sagol S. Ozkinay C. Ozkinay F. Prenatally diagnosed Turner syndrome and cystic hygroma: incidence and reasons for referrals Fetal Diagn. Ther. 25 1 2009 58 61 19202339 \n5 Salomon L.J. Alfirevic Z. Audibert F. Kagan K.O. Paladini D. Yeo G. Raine-Fenning N. ISUOG Clinical Standards Committee ISUOG updated consensus statement on the impact of cfDNA aneuploidy testing on screening policies and prenatal ultrasound practice Ultrasound Obstet. Gynecol. 49 6 2017 815 816 28573775 \n6 Savendahl L. Davenport M.L. Delayed diagnoses of Turner's syndrome: proposed guidelines for change J. Pediatr. 137 4 2000 455 459 11035820 \n7 Sybert V.P. McCauley E. Turner's syndrome N. Engl. J. Med. 351 12 2004 1227 1238 15371580 \n8 Nguyen H.H. Wong P. Strauss B.J. Jones G. Ebeling P.R. Milat F. Vincent A. Delay in estrogen commencement is associated with lower bone mineral density in Turner syndrome Climacteric 20 5 2017 436 441 28523940 \n9 Ranke M.B. Pfluger H. Rosendahl W. Stubbe P. Enders H. Bierich J.R. Majewski F. Turner syndrome: spontaneous growth in 150 cases and review of the literature Eur. J. Pediatr. 141 2 1983 81 88 6662146 \n10 Fiot E. Zenaty D. Boizeau P. Haignere J. Dos Santos S. Leger J. French Turner Syndrome Study Group X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome Eur. J. Endocrinol. 174 3 2016 281 288 26744895 \n11 Baroncelli G.I. Bertelloni S. Sodini F. Saggese G. Osteoporosis in children and adolescents: etiology and management Paediatric Drugs 7 5 2005 295 323 16220996 \n12 Ebrahimi M. Akbari Asbagh F. Pathogenesis and causes of premature ovarian failure: an update Int. J. Fertil. Steril. 5 2 2011 54 65 24963360 \n13 Martinelli I. Lensing A.W. Middeldorp S. Levi M. Beyer-Westendorf J. van Bellen B. Bounameaux H. Brighton T.A. Cohen A.T. Trajanovic M. Gebel M. Lam P. Wells P.S. Prins M.H. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use Blood 127 11 2016 1417 1425 26696010 \n14 Eckhauser A. South S.T. Meyers L. Bleyl S.B. Botto L.D. Turner syndrome in girls presenting with coarctation of the aorta J. Pediatr. 167 5 2015 1062 1066 26323199 \n15 Practice Committee of American Society For Reproductive Medicine Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome Fertil. Steril. 97 2 2012 282 284 22192347 \n16 Binder G. Koch A. Wajs E. Ranke M.B. Nested polymerase chain reaction study of 53 cases with Turner's syndrome: is cytogenetically undetected Y mosaicism common? J. Clin. Endocrinol. Metab. 80 12 1995 3532 3536 8530595\n\n",
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"abstract": "Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia. However, there is only one case report of letrozole induced hypercalcemia. A 52-year-old female patient was referred to our clinic because of the recent discovery of hypercalcemia (11.0 mg/dL). The patient had a history of left breast carcinoma. She had started a course of letrozole (aromatase inhibitor; 2.5 mg dose/day) ten months earlier. Patient's parathyroid hormone-related protein levels were normal and a bone scintigram revealed no evidence of skeletal metastasis. Other potential causes of high calcium levels were ruled out. We recognized that, when letrozole was taken at one dose daily (2.5 mg), she had recurrent hypercalcemia. Our experience suggests that letrozole may precipitate hypercalcemia in a patient with breast cancer.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.;Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.;Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.;Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey.",
"authors": "Ipekci|Suleyman Hilmi|SH|;Baldane|Suleyman|S|;Ozturk|Ercument|E|;Araz|Murat|M|;Korkmaz|Huseyin|H|;Colkesen|Fatih|F|;Kebapcilar|Levent|L|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2014/608585Case ReportLetrozole Induced Hypercalcemia in a Patient with Breast Cancer Ipekci Suleyman Hilmi \n1\n*Baldane Suleyman \n1\nOzturk Ercument \n2\nAraz Murat \n3\nKorkmaz Huseyin \n2\nColkesen Fatih \n2\nKebapcilar Levent \n1\n1Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey2Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey3Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Selcuk University, 42131 Konya, Turkey*Suleyman Hilmi Ipekci: sipekci@gmail.comAcademic Editor: Katsuhiro Tanaka\n\n2014 15 5 2014 2014 60858527 2 2014 30 4 2014 Copyright © 2014 Suleyman Hilmi Ipekci et al.2014This 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.Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia. However, there is only one case report of letrozole induced hypercalcemia. A 52-year-old female patient was referred to our clinic because of the recent discovery of hypercalcemia (11.0 mg/dL). The patient had a history of left breast carcinoma. She had started a course of letrozole (aromatase inhibitor; 2.5 mg dose/day) ten months earlier. Patient's parathyroid hormone-related protein levels were normal and a bone scintigram revealed no evidence of skeletal metastasis. Other potential causes of high calcium levels were ruled out. We recognized that, when letrozole was taken at one dose daily (2.5 mg), she had recurrent hypercalcemia. Our experience suggests that letrozole may precipitate hypercalcemia in a patient with breast cancer.\n==== Body\n1. Introduction\n\nHypersecretion of PTH related peptide is a relatively common cause of malignancy-related hypercalcemia. However, there is only one case report of letrozole induced hypercalcemia. We report a case of hypercalcemia that appeared with letrozole treatment in a patient with breast cancer.\n\n2. Case\nA 52-year-old female patient was referred to our clinic because of the recent discovery of hypercalcemia in a routine oncological control. Her oncologist, assuming that the diagnosis was most likely to be tumor-induced hypercalcemia, referred her to an endocrinologist, who undertook further tests to reveal the etiology of hypercalcemia. The physical examination revealed her to be eupneic, blood pressure of 120/80 mmHg with 84 beats per second. The patient had a history of left breast carcinoma. Our patient had undergone a left mastectomy one year previously (estrogen-receptor positive, progesterone-receptor positive, Her2 negative) and received letrozole without any complications until hospitalization. She remained well and achieved a complete response without an increase of carcinoembryonic antigen (CEA, (normal value <5 ng/mL)) or carbohydrate antigen 15-3 (CA 15-3, normal value: 0.5–29 IU/mL) since ten months.\n\nCurrently she is 1.62 m tall, weighting 62 kg, with a body mass index (BMI) of 23 kg/m2 and using letrozole only for the indication prescribed. She had started a course of letrozole ten months earlier. Her family history was unremarkable. As her hypercalcemia was mild and did not elicit any symptoms, she did not require immediate measures to correct this.\n\nInvestigations to determine the cause of the hypercalcemia were performed. Initial laboratory evaluation showed hypercalcemia at 11 mg/dL, iPTH as 15 pg/mL normal albumin 4.3 g/dL, and phosphorus level 3.5 mg/dL (Normal: 2.5–4.8) and creatinine 0.57 mg/dL. 24 h urinary calcium excretion was found to be 247 mg/day (normal: 100–300 mg/day). Further blood tests demonstrated that alkaline phosphatase level was 64 U/L (35–104) and 25-hydroxy vitamin D level was 22 ng/mL (normal: 20–30) within normal limits. A dual energy X-ray absorptiometry (DEXA) scan was performed, which revealed mild osteopenia at the left femoral neck (T score: −1.6). No previous bone mineral density (BMD) measurement had been taken prior to this.\n\nOn other days, our patient's serum calcium and iPTH level returned to within normal range without any medications. When we analyzed the sequence of laboratory tests, there were episodes of calcium and iPTH levels with fluctuating on repeat analyses over a period of ten months between 9.5–11 mg/dL (Figure 1, normal: 8.5–10.2 mg/dL) and 11–17 pg/mL (Figure 2, normal: 12–65), respectively.\n\nA workup investigation to exclude other causes of hypercalcemia was done. She underwent an extensive evaluation including careful history, family history, physical examination, and lab work to exclude possible other causes of hypercalcemia. Parathyroid hormone related peptide was 0.28 pmol/L (normal: 0–1.3) and bone scan was normal, thus making malignancy-related hypercalcemia unlikely. Computed tomography of thorax, neck and abdomen, and PET-BT did not reveal any malignancy.\n\nAlthough serum phosphorus was normal and iPTH was not increased, in order to rule out hyperparathyroidism, evaluation of the parathyroid glands was performed using ultrasound and MIBI scan, which were normal. Clinically, patients with FHH (familial hypocalciuric hypercalcemia) have relative hypocalciuria and inappropriately normal or elevated iPTH in the face of persistent mild hypercalcemia, none of which our patient had.\n\nIn addition to malignancy-related hypercalcemia, the differential diagnosis of hypercalcemia includes calcium supplements hypervitaminosis D, milk-alkali syndrome, granulomatous diseases, medications, inflammatory and rheumatic diseases, and other endocrine disorders.\n\n25-hydroxy vitamin D level was not elevated ruling out hypervitaminosis D. Tuberculin test, computed tomography of thorax, and bone survey were normal, thus ruling out a granulomatous process (tuberculosis or sarcoidosis). Erythrocyte sedimentation rate and ANA level were normal, ruling out inflammatory and rheumatic diseases. Thyroid-stimulating hormone and free thyroid hormones should be checked to help rule out hyperthyroidism. Free T4, Free T3, and TSH were normal, ruling out hyperthyroidism, and there were no signs or symptoms suggestive of Cushing disease, adrenal insufficiency, acromegaly, or pheochromocytoma. Normal prolactin level and IGF-I in the age- and gender-matched normal range excluded the diagnosis of prolactinoma and acromegaly in our patient, respectively. Basal cortisol level was 19 μg/dL, and therefore we could rule out adrenal insufficiency. An overnight dexamethasone suppression test (DST) was done. After a 1-mg dose DST, the plasma cortisol level was 0.8 μg/dL. Hence, we could rule out Cushing syndrome. A 24-hour total urinary metanephrines and fractionated catecholamines were within normal range. She had no evidence of leukemia and lymphoma and a normal complete blood count. Serum electrophoresis was negative for monoclonal proteins. She indicated no symptoms of peptic ulcer, and there was neither exogenous vitamin D intake nor family history of endocrinopathy. She had no history of taking vitamin A, calcium supplements, and thiazide medication and no recent history of immobilization. Assessment of bone metabolism using markers of bone turnover could yield useful information and guide management decisions in our case. Urinary hydroxyproline level was significantly increased (35 mg/24 h/m2; normal: 22–55 years—8.5–23.5 mg/24 h/m2).\n\nBecause of sufficient vitamin D level, oral bisphosphonate was administered and letrozole was restarted at one-half dose (1.25 mg). She was discharged and we closely follow up patient's serum calcium, CEA, CA 15-3, and for distant metastasis.\n\n3. Discussion\nIntensive investigations did not lead to any underlying cause for elevated serum calcium and urinary hydroxyproline level, and hypercalcemia may be explained by using letrozole treatment in our patient.\n\nMalignancy-related hypercalcemia is due to increased osteoclast activities and bone resorption caused by the increased release of various mediators from the tumor or nontumoral host cells [1–4].\n\nAromatase inhibitors (AIs) are an important component of adjuvant therapy in postmenopausal women with estrogen receptor positive breast cancer. Letrozole works by blocking aromatase that converts androgens to estrogen [5]. While the main source of estrogen in premenopausal women is the ovaries, the main source in postmenopausal women is the adrenals. Adrenal androgens are converted to estrogens by aromatase enzymes. Aromatase inhibitors prevent this conversion. In postmenopausal women, AIs cause relatively rapid decreases in circulating estrogen. Treatment with AIs, therefore, results in bone loss due to estrogen deficiency [6]. Estrogens exert a major effect in women on bone remodeling by inhibiting interleukin-6 (IL-6) productions that reduces bone resorption and also controls the timing of osteoclast apoptosis. Estrogens deficiency, therefore, results in a longer life span of osteoclasts [6]. Urinary hydroxyproline level was significantly increased in our patient. Hydroxyproline is the major breakdown product of collagen, the primary protein of the bone matrix. It is considered as clinical index of bone resorption and a major determinant of bone status. During bone loss, collagen fibrils are broken down and hydroxyproline is excreted in the urine [7].\n\nSerum intact PTH and phosphor were not low in our patient but they were lower limits of the reference ranges. We considered they might be mild hypercalcemia and mild deficiency of vitamin D. Changes in circulating calcium concentrations alter PTH secretion via a negative feedback system. An increase in calcium binding stimulates phospholipase C and inhibits adenylate cyclase and the resultant rise in phosphatidylinositol trisphosphate and reduction in cAMP concentrations reduces PTH release [8]. As a result, PTH secretion is inversely proportional to serum calcium concentration [8]. In addition to this negative feedback control of PTH secretion, a normal in vitamin D concentration reduces PTH level. A serum 25-hydroxy vitamin D of 40 nmol/L (40 nmol/L = 16 ng/mL) appears to represent a critical point in vitamin D metabolism at which vitamin D deficiency begins to unduly stress normal calcium homeostasis. We showed that serum 25-hydroxy vitamin D concentrations <40 nmol/L (25-hydroxy vitamin D level was 22 ng/mL in our case) are associated with significantly higher serum PTH [9]. However, the secretion of PTH is never fully suppressed like in our case.\n\nOn the other hand, the most common cancers associated with hypercalcemia are breast and lung cancer and multiple myeloma. There are three major mechanisms [10–12] by which hypercalcemia of malignancy can occur: osteolytic metastases with local release of cytokines (including osteoclast activating factors); tumor secretion of parathyroid hormone-related protein (PTHrP); and tumor production of 1,25-dihydroxyvitamin D (calcitriol). Patient's parathyroid hormone-related protein levels were normal, thus making PTHrP related hypercalcemia unlikely. One of the limitations of this report is that cytokines such as IL-6, IL-8, IL-1, and VEGF which are secreted by breast cancer cells were not determined and may contribute to the effects of PTHrP on bone resorption [13]. Increased production of 1,25-dihydroxyvitamin D (calcitriol) is the cause of almost all cases of hypercalcemia in Hodgkin lymphoma and approximately one-third of cases in non-Hodgkin lymphoma [11]. Although 1,25-dihydroxyvitamin D-induced hypercalcemia has not been described in patients with breast cancer, we should have measured the 1,25-dihydroxyvitamin D level which was the second limitation of our report.\n\nClinical trials have found that the AIs, unlike the hormone therapy tamoxifen, increase bone fracture risk [14]. Moreover, flare hypercalcemia has a rapid onset that characteristically occurs within several days of starting therapy; symptoms are usually short-lived and serum calcium levels return to normal when the offering agent is withdrawn [4]. However, the temporal relation of the onset of hypercalcemia and administration of letrozole may suggest a possible role for the drug.\n\nWomen receiving adjuvant AIs therapy for breast cancer are at increased risk for fractures [14], which has been shown to result in increased morbidity and mortality in women with postmenopausal osteoporosis [15]. We recommended that patients should be initiated on bisphosphonate therapy for the prevention and treatment of osteopenia and flare hypercalcemia. For women who have osteoporosis and are on aromatase inhibitors, bisphosphonates should help reduce fracture risk [16]. The therapy contains a potent nitrogen containing drug, that is, alendronate, which binds hydroxyapatite crystals of bone with high affinity and inhibit bone resorption by decreasing osteoclastic activity and its growth. After the inhibition of resorption, these agents become affixed to the bone matrix, where they reside until the remodeling begins again [17]. Reduction in bone loss during antiresorptive treatment is demonstrated by decreased excretion of hydroxyproline after antiresorptive therapy [18].\n\nWe report a case of hypercalcemia that occurred after initiation of letrozole in a patient with breast cancer. To our knowledge, the association of hypercalcemia and letrozole has been previously reported one time [4]. If this occurs, letrozole might be restarted cautiously with therapeutic benefit.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Serum calcium concentrations showing temporary remission of hypercalcemia.\n\nFigure 2 Course of serum parathyroid hormone concentrations.\n==== Refs\n1 Santarpia L Koch CA Sarlis NJ Hypercalcemia in cancer patients: pathobiology and management Hormone and Metabolic Research 2010 42 3 153 164 2-s2.0-77949279840 19960404 \n2 Arumugam GP Sundravel S Shanthi P Sachdanandam P Tamoxifen flare hypercalcemia: an additional support for gallium nitrate usage Journal of Bone and Mineral Metabolism 2006 24 3 243 247 2-s2.0-33645848503 16622738 \n3 Nikolić-Tomǎević Z Jelic S Popov I Radosavljeví D Mitroví L Tumor “flare” hypercalcemia—an additional indication for bisphosphonates? Oncology 2001 60 2 123 126 2-s2.0-0035082362 11244326 \n4 Kuroi K Yamashita T Aruga T Flare hypercalcemia after letrozole in a patient with liver metastasis from breast cancer: a case report Journal of Medical Case Reports 2011 5, article 495 2-s2.0-80053536070 \n5 Smith IE Dowsett M Aromatase inhibitors in breast cancer The New England Journal of Medicine 2003 348 24 2431 2442 2-s2.0-0038210242 12802030 \n6 Confavreux CB Fontana A Guastalla JP Munoz F Brun J Delmas PD Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Prevention with bisphosphonates Bone 2007 41 3 346 352 2-s2.0-34547569748 17618847 \n7 Delmas PD Biochemical markers of bone turnover for the clinical investigation of osteoporosis Osteoporosis International 1993 3 1 81 86 2-s2.0-0027457859 8461587 \n8 Nussey S Whitehead S The parathyroid glands and vitamin D Endocrinology: An Integrated Approach 2001 Chapter 5 Oxford, UK BIOS Scientific Publishers http://www.ncbi.nlm.nih.gov/books/NBK24/ \n9 Need AG Horowitz M Morris HA Nordin BEC Vitamin D status: effects on parathyroid hormone and 1,25- dihydroxyvitamin D in postmenopausal women The American Journal of Clinical Nutrition 2000 71 6 1577 1581 2-s2.0-0034049909 10837301 \n10 Stewart AF Clinical practice. Hypercalcemia associated with cancer The New England Journal of Medicine 2005 352 4 373 379 2-s2.0-13744250353 15673803 \n11 Seymour JF Gagel RF Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas Blood 1993 82 5 1383 1394 2-s2.0-0027181234 8364192 \n12 Clines GA Guise TA Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone Endocrine-Related Cancer 2005 12 3 549 583 2-s2.0-26944459975 16172192 \n13 Bendre MS Margulies AG Walser B Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-κ B ligand pathway Cancer Research 2005 65 23 11001 11009 2-s2.0-28244452125 16322249 \n14 Rabaglio M Sun Z Price KN Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial Annals of Oncology 2009 20 9 1489 1498 2-s2.0-69849115729 19474112 \n15 Morin S Lix LM Azimaee M Metge C Caetano P Leslie WD Mortality rates after incident non-traumatic fractures in older men and women Osteoporosis International 2011 22 9 2439 2448 2-s2.0-79959634329 21161507 \n16 Rusz O Kahán Z Bone homeostasis and breast cancer: implications for complex therapy and the maintenance of bone integrity Pathology & Oncology Research 2013 19 1 1 10 23212591 \n17 Xu XL Gou WL Wang AY Basic research and clinical applications of bisphosphonates in bone disease: what have we learned over the last 40 years? Journal of Translational Medicine 2013 11, article 303 \n18 Jagtap VR Ganu JV Effect of antiresorptive therapy on urinary hydroxyproline in postmenopausal osteoporosis Indian Journal of Clinical Biochemistry 2012 27 1 90 93 2-s2.0-84857709885 23277718\n\n",
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"title": "Letrozole induced hypercalcemia in a patient with breast cancer.",
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"abstract": "Nivolumab has been associated with immune-related adverse events, including nephritis, with acute interstitial nephritis being the most commonly reported renal manifestation.\n\n\n\nWe describe the first case to our knowledge of minimal change disease with nephrotic syndrome associated with the PD-1 checkpoint inhibitor, Nivolumab. Minimal change disease has been reported with other immune checkpoint inhibitors; however, this is the first reported case with Nivolumab. We report development of nephrotic syndrome with acute kidney injury in a 57-year-old man, 1 month after commencement of Nivolumab for metastatic squamous cell carcinoma of the tongue. Minimal change disease was confirmed by renal biopsy. Management with corticosteroids and cessation of Nivolumab failed to improve kidney function or nephrosis.\n\n\n\nThis case adds to current literature identifying minimal change as an additional complication of immune checkpoint inhibitor-associated acute kidney injury. Given the increasing use of immune checkpoint inhibitors for a range of malignancies, nephrologists, oncologist and generalists should be aware of the spectrum of kidney pathologies associated with their use.",
"affiliations": "Renal Department, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia.;Medical Oncology Department, Chris O Brien Lifehouse, University of Sydney, Sydney, New South Wales, Australia.;Medical Oncology Department, Chris O Brien Lifehouse, University of Sydney, Sydney, New South Wales, Australia.;Renal Department, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia.",
"authors": "Vaughan|Erin|E|;Connolly|Elizabeth|E|0000-0002-5579-3728;Hui|Mun|M|;Chadban|Steven|S|",
"chemical_list": "D000077594:Nivolumab",
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"keywords": "Nivolumab; immune related adverse event; immune-mediated nephritis; nephrotic syndrome; onconephrology",
"medline_ta": "Cancer Rep (Hoboken)",
"mesh_terms": "D015551:Autoimmunity; D017024:Chemotherapy, Adjuvant; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D009402:Nephrosis, Lipoid; D000077594:Nivolumab; D010166:Palliative Care; D000077195:Squamous Cell Carcinoma of Head and Neck; D014062:Tongue Neoplasms",
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"title": "Minimal change disease in a patient receiving checkpoint inhibition: Another possible manifestation of kidney autoimmunity?",
"title_normalized": "minimal change disease in a patient receiving checkpoint inhibition another possible manifestation of kidney autoimmunity"
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"reactionmeddrapt": "Febrile neutropenia",
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},
{
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"literaturereference": "VAUGHAN, E.. MINIMAL CHANGE DISEASE IN A PATIENT RECEIVING CHECKPOINT INHIBITION: ANOTHER POSSIBLE MANIFESTATION OF KIDNEY AUTOIMMUNITY?. CANCER REPORTS. 2020?3 (5):E1250",
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"abstract": "Priapism, a rare but well-known adverse reaction of first and second generation anti-psychotics, has been hypothesized to be associated with blockade of alpha 1 receptors. However, genetic abnormalities or heritability of affected cytochrome P450 alleles has not been ruled out as a causal mechanism. A case is presented with three episodes of priapism within 17 days while taking standard FDA (Food and Drug Administration) approved doses of quetiapine. Cytochrome P450 3A4 genotype testing was performed and resulted with normal enzymatic activity. This case further eliminates enzymatic metabolism as a possible cause of priapism, thus strengthening the alpha one receptor blockade hypothesis.",
"affiliations": "University of Mississippi Medical Center, Department of Psychiatry and Human Behavior, 2500 North State Street, Jackson, MS 39216, USA.;University of Mississippi Medical Center, Department of Psychiatry and Human Behavior, 2500 North State Street, Jackson, MS 39216, USA.",
"authors": "Jackson|Jon C|JC|;Torrence|Chasity L|CL|",
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"country": "United States",
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"doi": "10.1016/j.eucr.2014.09.003",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(14)00138-710.1016/j.eucr.2014.09.003AndrologyQuetiapine-induced Priapism Requiring Frequent Emergency Admissions: A Case Report Jackson Jon C. JCJackson@umc.edu∗Torrence Chasity L. University of Mississippi Medical Center, Department of Psychiatry and Human Behavior, 2500 North State Street, Jackson, MS 39216, USA∗ Corresponding author. Tel.: +1 601 984 5826; fax: +1 601 984 5885. JCJackson@umc.edu18 10 2014 1 2015 18 10 2014 3 1 1 2 15 8 2014 25 9 2014 29 9 2014 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Priapism, a rare but well-known adverse reaction of first and second generation anti-psychotics, has been hypothesized to be associated with blockade of alpha 1 receptors. However, genetic abnormalities or heritability of affected cytochrome P450 alleles has not been ruled out as a causal mechanism. A case is presented with three episodes of priapism within 17 days while taking standard FDA (Food and Drug Administration) approved doses of quetiapine. Cytochrome P450 3A4 genotype testing was performed and resulted with normal enzymatic activity. This case further eliminates enzymatic metabolism as a possible cause of priapism, thus strengthening the alpha one receptor blockade hypothesis.\n\nKeywords\nPriapismQuetiapineAntipsychotic agents\n==== Body\nCase report\nA divorced 48 year old Caucasian male presented to the emergency department with a painful erection of nine hours duration which woke him from sleep. He denied recent sexual activity or arousal, use of phosphodiesterase inhibitors, sickle cell trait or anemia, malignancy history, perineal trauma, or illicit drug use which was confirmed by negative toxicology screening. He admitted use of smokeless tobacco. Medical and psychiatric history included hypertension, hypercholesterolemia, and schizoaffective disorder. He was maintained on quetiapine 800 mg nightly for the past 10 years with brief periods of non-compliance and medication changes. The most recent period of non-compliance was eight months prior to presentation at which time he was admitted to an inpatient psychiatric unit. Since discharge, he reported full compliance with quetiapine 800 mg nightly, clonazepam 1 mg three times daily, atenolol 100 mg daily, hydrochlorothiazide 12.5 mg daily, and pravastatin 40 mg nightly. Over-the-counter medications taken include aspirin 81 mg daily and aspirin-caffeine powder packets for occasional headaches. Compliance was confirmed by pharmacy records and pill count. Physical examination revealed a fully erect penis, circumcised phallus, and moderate tenderness throughout. No erythema or induration was present, and bilateral testicles were soft. The remaining genitourinary examination was unremarkable. He appeared fully awake and alert. No signs of quetiapine overdose including somnolence, tachycardia, respiratory depression, or hypotension were present. Laboratory data confirmed normal complete blood counts, electrolytes, and hepatic function. Urine gas chromatography-mass spectroscopy (GCMS) was positive for nicotine, cotinine, lidocaine, and quetiapine metabolite. Given cytochrome P450 3A4 is primarily responsible for quetiapine's metabolism, genotype testing was obtained. The cytochrome P450 study was done to rule out any enzymatic or genetic abnormality interfering with metabolism of the above medications.1, 2 Urology was consulted and aspirated 15 cc of dark, red blood from the bilateral corpora after local anesthesia with 1% lidocaine. The patient was given 1000 mcg of phenylephrine and 750 mg of levofloxacin orally. Aspiration of the corporal bodies resulted in gradual detumescence and relief of the patient's pain. After a three hour observation, he was medically cleared for discharge from the emergency room. As this was the patient's third episode of priapism within 17 days, psychiatry was consulted for recommendations as his priapism was speculated to be related to his psychotropic medications. The previous two episodes had similar presentations to the one described and resolved with improvement in pain after the procedure by urology. Further history revealed two episodes of priapism within one month approximately one year ago while taking chlorpromazine. The patient was unaware of other medications taken in addition to chlorpromazine. Following these occurrences, his primary psychiatrist promptly stopped chlorpromazine, and symptoms did not recur until 17 days ago. During these episodes, the patient denied recent sexual activity or arousal, use of phosphodiesterase inhibitors, perineal trauma, or illicit drug use. Taking this history into consideration, psychiatric consultation recommended not exceeding the recommended daily dose of quetiapine, reducing clonazepam 1 mg to twice daily, and following up promptly with his primary psychiatrist within 1 week for directions on discontinuing quetiapine and cross-titrating to another anti-psychotic medication. He was instructed to return to the emergency department if another episode occurred.\n\nComments\nWe report this case linking quetiapine, a second generation anti-psychotic medication to priapism as there is limited data on anti-psychotics and their link with priapism in the literature. Previous cases involved a single ingestion or overdose of quetiapine outside the therapeutic range or stable daily dosage within the therapeutic range lacking further laboratory data or genetic testing linking hepatic functioning or other medication interactions to the possibility of causing priapism.3, 4, 5 In contrast to other cases, cytochrome P450 3A4 genetic testing was performed as our patient clearly has a propensity for priapism with use of daily dosed anti-psychotics including his prior history one year ago.1, 2 Furthermore, the patient denied taking more than the recommended daily dose of quetiapine and the absence of other side effects that have been previously linked to quetiapine overdose including somnolence, tachycardia, respiratory depression, and hypotension.3 Any use of illicit substances or other medications were ruled out by GCMS. As quetiapine and clonazepam are significant cytochrome P450 3A4 substrates, cytochrome genetic testing allowed a closer examination of the patient's enzymatic functioning.1 We hypothesized there were likely malfunctioning hepatic cytochrome enzymes with a major role in the medications' metabolism either inherited or acquired (Table 1). Upon review of his cytochrome lab results, the patient had CYP 3A4 CC genotype, which predicts normal enzyme activity. Direct polymorphism analysis of the CYP 3A4 allele was performed by a polymerase chain reaction (PCR) based on 5′-nuclease assay using fluorescently labeled detection probes, which does not detect all CYP 3A4 genetic variants. As a result of CYP testing, enzymatic and metabolizing abnormalities are less likely the mechanism of the patient's frequent emergency department visits. These results do not exclude hepatic enzyme genetic abnormalities or confounding medication interactions as the cause, only less likely in this patient. This suggests quetiapine's alpha 1 adrenergic antagonist properties are the most likely cause of this patient's priapism.5\n\nConflict of interest\nThe authors declare no conflicts of interest.\n\nSupplementary data\nSupplementary Material\n \n\nTable 1 Pharmacokinetic metabolism profiles\n\nMedication\tCYP substrate\tInducer of CYP\tInhibitor of CYP\t\nAspirin\t2C9 (minor)\t2C19 (weak)\tNone\t\nAtenolol\tNone\tNone\tNone\t\nChlorpromazine\t1A2 (minor)\n2D6 (major)\tNone\t2D6 (moderate)\t\nClonazepam\t3A4 (major)\tNone\tNone\t\nHydrochlorothiazide\tNone\tNone\tNone\t\nPravastatin\t3A4 (minor)\tNone\tNone\t\nQuetiapine\t3A4 (major)\n2D6 (minor)\tNone\tNone\n==== Refs\nReferences\n1 Geraci M.J. McCoy S.L. Crum P.M. Anti-psychotic-induced priapism in an HIV patient: a cytochrome P450-mediated drug interaction Int J Emerg Med 3 2010 81 84 20606815 \n2 Hosseini S.H. Bajoghli H. Ghaeli P. Effects of cigarette smoking on priapism induced by quetiapine: a case report DARU J Pharm Sci 20 2012 55 \n3 Pais V.M. Ayvazian P.J. Priapism from quetiapine overdose: first report and proposal of mechanism Urology 58 2001 462vii–462viii \n4 Davol P. Rukstalis D. Priapism associated with routine use of quetiapine: case report and review of the literature Urology 66 2005 880.e13 880.e14 16230163 \n5 Penaskovic K.M. Hag F. Raza S. Priapism during treatment with olanzapine, quetiapine, and risperidone in a patient with schizophrenia: a case report Prim Care Companion J Clin Psychiatry 12 5 2010 PCC 09I00939\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "3(1)",
"journal": "Urology case reports",
"keywords": "Antipsychotic agents; Priapism; Quetiapine",
"medline_ta": "Urol Case Rep",
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"pmid": "26793482",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports",
"references": "20606815;11549503;21274367;16230163;23352178",
"title": "Quetiapine-induced Priapism Requiring Frequent Emergency Admissions: A Case Report.",
"title_normalized": "quetiapine induced priapism requiring frequent emergency admissions a case report"
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{
"abstract": "To evaluate “papillary thyroid carcinoma-pregnancy” interaction among cancer survivors.\n\n\n\nThe clinical records of 8 pregnant women who received treatment for papillary thyroid cancer before their pregnancy were evaluated. Clinical features, pregnancy/perinatal outcomes and high-risk factors were compared with 45 controls who were randomly assigned from the institutional perinatal medicine database.\n\n\n\nPatients in the cancer group were older than the control group (34.3 vs 29.8 years). The cesarean section rate was higher (62.5% vs 33.3%) and the APGAR scores at the 1st and 5th minutes were lower in the cancer group.\n\n\n\nManagement of pregnancies with papillary thyroid cancer treatment and follow-up requires a multidisciplinary approach with careful antenatal care and perinatal surveillance. Patients who have received papillary thyroid cancer treatment can safely undergo pregnancy.",
"affiliations": "Clinic of General Surgery, University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey;Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey;Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey;Division of Neonatology, Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey;Deparment of Reproductive Endocrinology, University of Health Sciences, Dr. Zekai Tahir Burak Zekai Tahir Burak Women Health Health Practice and Research Center, Ankara, Turkey;Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey",
"authors": "Beksaç|Kemal|K|;Aktoz|Fatih|F|;Örgül|Gökçen|G|;Çelik|Hasan Tolga|HT|;Özgü-Erdinç|A Seval|AS|;Beksaç|M Sinan|MS|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/jtgga.2017.0057",
"fulltext": "\n==== Front\nJ Turk Ger Gynecol AssocJ Turk Ger Gynecol AssocJTGGAJournal of the Turkish German Gynecological Association1309-03991309-0380Galenos Publishing 2946903210.4274/jtgga.2017.005716719Original InvestigationPregnancy in papillary thyroid cancer survivors Beksaç Kemal 1*http://orcid.org/0000-0002-6339-505XAktoz Fatih 2http://orcid.org/0000-0003-3210-849XÖrgül Gökçen 2http://orcid.org/0000-0003-0578-4230Çelik Hasan Tolga 3http://orcid.org/0000-0002-1725-0722Özgü-Erdinç A. Seval 4http://orcid.org/0000-0002-6132-5779Beksaç M. Sinan 2http://orcid.org/0000-0001-6362-787X\n1 Clinic of General Surgery, University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey\n2 Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey\n3 Division of Neonatology, Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey\n4 Deparment of Reproductive Endocrinology, University of Health Sciences, Dr. Zekai Tahir Burak Zekai Tahir Burak Women Health Health Practice and Research Center, Ankara, Turkey\n5 Division of Neonatology, Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey\n6 Deparment of Reproductive Endocrinology, University of Health Sciences, Dr. Zekai Tahir Burak Zekai Tahir Burak Women Health Health Practice and Research Center, Ankara, Turkey* Address for Correspondence: E-mail:kemalbeksac@yahoo.com6 2018 4 6 2018 19 2 94 97 20 10 2017 16 2 2018 ©Copyright 2018 by the Turkish-German Gynecological Education and Research Foundation2018Journal of the Turkish-German Gynecological AssociationObjective:\nTo evaluate “papillary thyroid carcinoma-pregnancy” interaction among cancer survivors.\n\nMaterial and Methods:\nThe clinical records of 8 pregnant women who received treatment for papillary thyroid cancer before their pregnancy were evaluated. Clinical features, pregnancy/perinatal outcomes and high-risk factors were compared with 45 controls who were randomly assigned from the institutional perinatal medicine database.\n\nResults:\nPatients in the cancer group were older than the control group (34.3 vs 29.8 years). The cesarean section rate was higher (62.5% vs 33.3%) and the APGAR scores at the 1st and 5th minutes were lower in the cancer group.\n\nConclusion:\nManagement of pregnancies with papillary thyroid cancer treatment and follow-up requires a multidisciplinary approach with careful antenatal care and perinatal surveillance. Patients who have received papillary thyroid cancer treatment can safely undergo pregnancy.\n\nPregnancy papillary thyroid cancer thyroid cancer survivor thyroid\n==== Body\nIntroduction\nIt has been reported that the incidence of papillary thyroid carcinoma (PTC) has been increasing over the last decades (1,2,3). It has also been reported that differentiated thyroid cancer is more common in women and is the second most common cancer diagnosed during pregnancy and the postpartum period with a prevalence of 14 per 100.000 live births (4,5,6). However, there are conflicting results and opinions in the literature related to PTC-pregnancy interaction and optimal timing of surgical and medical intervention (7,8,9,10,11,12,13). \n\nAnother critical issue of the “PTC-pregnancy interaction” is the management of pre- and post-operative thyroid gland problems (14,15,16). Treatment of hyperthyroidism is important in order to avoid fetal hypothyroidism (14,15). However, drug selection is also important because there is an increased risk of birth defects among methimazole users (14,16). Propylthiouracil, which is relatively hepatotoxic, is preferred in early pregnancy because of the possible teratogenicity of methimazole (14). On the other hand, management of hypothyroidism is critical in order to reduce the incidence rate of miscarriage and to maintain normal fetal brain development (14). The effects of radioactive iodine (RAI or I-131) therapy on gonads and pregnancy outcomes must also be carefully considered in patients with PTC (12,13). \n\nRecently, it has been reported that high levels of pro- and anti-angiogenic factors may be a risk factor for adverse outcomes via their effect on maternal thyroid function (17). Ectopic production of β human chorionic gonadotrophin (hCG) by PTC cells must also be considered in clinical practice (18). Thus, PTC and PTC-related changes may be critical both from the maternal and the perinatal morbidity/mortality rate point of view. In this clinical report, we analyzed medical/obstetric histories and the clinical features of 8 pregnancies with PTC.\n\nMaterial and Methods\nOur institution’s pregnancy-associated cancer database, which consisted of 110 patients whose cancer was diagnosed between 2002 and 2015, was retrospectively evaluated (19). Eight PTC survivors were found to be eligible for the study. All of the patients received bilateral total thyroidectomy and were given RAI therapy after surgery as indicated (20). \n\nClinical features, treatment modalities and pregnancy/perinatal outcomes were evaluated and compared with 45 patients as a control group who were randomly assigned from the institutional perinatal medicine database, which included all pregnancies followed in the clinic. The evaluated parameters included patients’ age, obstetric history, mode of delivery, gestational week (day) at delivery, birthweight, APGAR scores at the 1st, 5th, and 10th minute, and the Beksaç et al. (21,22) obstetrics index (BOI). The BOI is an index for the assessment of risk levels of high-risk pregnancy groups, which is (number of living children + π/10)/Gravida. BOIp is the calculation of the index during the course of the last pregnancy (the perinatal outcome of the last pregnancy is not considered during the calculation).\n\nStatistical analysis\nThe Statistical Package for Social Sciences version 17 (IBM SPSS Statistics, USA) was used for data analysis. Pearson’s chi-square and Fisher’s exact tests were used for categorical variables, and the Mann-Whitney U and t-test was used for continuous variables. The last pregnancy of each patient was considered for evaluation. Sample size calculations were performed using G*Power v3.15 general power analysis program. We used 0.5 effect size, 0.8 power, and 5% level of significance (alpha) for calculations (23).\n\nResults\nDemographics and clinical features of each group are given in Table 1. Table 2 shows obstetric history, BOI, gestational day of delivery, pregnancy outcome, birthweight of the fetus, and obstetric complications of the last pregnancy of each patient. All patients received thyroid hormone replacement therapy after their respective surgery/management (gestational and teratologic risks of the drugs were considered in all cases with necessary precautions). All patients were alive and disease free at the time of retrospective evaluation. All patients became pregnant within the first year after RAI therapy. \n\nThe mean age in the thyroid cancer group was 34.3 years, which was statistically significantly higher than the control group, which was 29.8 years (p=0.013). We found that the cesarean section rate was higher in the thyroid cancer group (p=0.054,) which was 62.5% of the cases. We also found that the 1-minute and 5-minute APGAR scores were statistically significantly lower in the cancer group (p=0.022 and p=0.03, respectively). The mean interval between cancer treatment and pregnancy was 4.5±3.11 years (range, 1-11 years).\n\nIn this clinical series, 7 of 8 patients delivered (five by cesarean section and two by vaginal delivery), and one pregnancy ended with spontaneous abortion. One neonate had corpus callosum agenesis (the family refused to have induced abortion) and was delivered vaginally. Neonates of a twin pregnancy were delivered by cesarean section at the 37th gestational week (in vitro fertilization twin; 2060 and 2060 g male neonates) with no complications. One patient was preeclamptic and delivered a 1900 g female neonate at the 36th gestational week (this neonate was discharged from the intensive neonatal care unit with no complications). \n\nThere was no statistically significant difference between the control and study groups in terms of birthweight (3195±566 g and 3051±886 g, respectively), and the gestational week at delivery was lower in patients with cancer (266 days vs 271 days; p=0.016). We believe that this finding is not critical in clinical practice. The obstetric history and perinatal outcomes of previous pregnancies of both groups were evaluated using BOIp and no statistical differences were observed.\n\nDiscussion\nThyroid cancer, with an incidence of 9 per 100.000 persons per year (24), has seriously increased over the last two decades, mainly due to the papillary type (1,2). It has also been reported that differentiated thyroid cancer is more common in women and is the second most common cancer diagnosed during pregnancy and the postpartum period with a prevalence of 14 per 100,000 live births (4,5,6). Several studies have suggested an association between PTC and reproductive variables such as estrogen and hCG (2,6). \n\nThe “Pregnancy-PTC” interaction is full of controversies. hCG, which is a weak thyroid-stimulating hormone agonist, may sometimes be secreted by PTC cells (18,25). On the other hand, various growth factors and pro- and anti-angiogenic factors may influence perinatal outcome via thyroid (dys) function (17). Some authors reported that pregnancy had no effect on PTC, whereas others suggested that PTC may progress during pregnancy (9,10). However, there is a consensus about the timing of surgery when PTC is diagnosed during pregnancy (7,8,26). Surgery can be delayed until after delivery in appropriate patients. It has been reported that I-131 therapy may result in transient ovarian dysfunction, but subsequent pregnancies are safe without any significant consequence to perinatal outcome (12,13). In our study, we have shown that pregnant women with thyroid cancer history are older than the general population. Actually, this finding is not surprising because most women should be in remission or disease free before getting pregnant for better maternal and fetal outcomes. The long treatment period and awareness the fetal teratogenic effect of medication seems to force women to delay their pregnancies. We believe that pregnancy planning should be postponed until after having proper PTC treatment due to these uncertainties.\n\nCancer-related worry is very important for patients with PTC who want to become pregnant (27). On the other hand, stress is an important determinant for patients whose PTC diagnosis was made during pregnancy (28). Waiting for surgery is another problem to be managed during pregnancy due to long wait times (29). Our findings demonstrate that PTC survivors might be encouraged to become pregnant if they are willing to do so even when considering the facts mentioned above.\n\nThe effect of PTC on pregnancy needs to be studied. There are no case-control prospective studies on the effect of PTC on obstetrics/perinatal complications. In our case series, we demonstrated that 1-minute and 5-minute APGAR scores were lower in PTC survivors and the cesarean section rate is higher in this group of patients compared with the control group. PTC-related immune and metabolic changes may be responsible for the inflammatory changes at the materno-fetal interface (injury of the cellular components of the intervillous space) and this might be the reason of impaired fetal perfusion going together with stress-intolerant babies, increased cesarean section rates, and low APGAR scores.\n\nAll these factors and patient-specific surgical/medical treatment modalities necessitate a patient-specific antenatal care program and careful perinatal surveillance.\n\nEthics Committee Approval: Ethic aproval number: GO16/217.\n\nInformed Consent: It was taken.\n\nPeer-review: Externally peer-reviewed.\n\nAuthor Contributions: Concept - K.B., F.A., G.Ö., H.T.Ç., A.S.Ö.E., M.S.B.; Design - K.B., F.A., G.Ö., H.T.Ç., A.S.Ö.E., M.S.B.; Supervision - M.S.B.; Materials - K.B., F.A., G.Ö., H.T.Ç., A.S.Ö.E., M.S.B.; Writer - K.B., M.S.B.\n\nConflict of Interest: No conflict of interest is declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nTable 1 Demographic and clinical features of patients\nTable 2 Pregnancy outcome variables of patients with thyroid cancer\n==== Refs\nReferences\n1 Leenhardt L Grosclaude P Cherie-Challine L Thyroid Cancer Committee Increased incidence of thyroid carcinoma in france: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee Thyroid 2004 14 1056 60 15650358 \n2 Sungwalee W Vatanasapt P Kamsa-Ard S Suwanrungruang K Promthet S Reproductive risk factors for thyroid cancer: a prospective cohort study in Khon Kaen, Thailand Asian Pac J Cancer Prev 2013 14 5153 5 24175792 \n3 Xhaard C Rubino C Clero E Maillard S Ren Y Borson-Chazot F et al Menstrual and reproductive factors in the risk of differentiated thyroid carcinoma in young women in France: a population-based case-control study Am J Epidemiol 2014 180 1007 17 25269571 \n4 Smith LH Danielsen B Allen ME Cress R Cancer associated with obstetric delivery: results of linkage with the California cancer registry Am J Obstet Gynecol 2003 189 1128 35 14586366 \n5 Siegel RL Miller KD Jemal A Cancer statistics, 2015 CA Cancer J Clin 2015 65 5 29 25559415 \n6 Imran SA Rajaraman M Management of differentiated thyroid cancer in pregnancy J Thyroid Res 2011 2011 549609 21687597 \n7 Uruno T Shibuya H Kitagawa W Nagahama M Sugino K Ito K Optimal timing of surgery for differentiated thyroid cancer in pregnant women World J Surg 2014 38 704 8 24248429 \n8 Cabezon CA Carrizo LC Costanzo PR Evolution of differentiated thyroid cancer during pregnancy in a community University Hospital in Buenos Aires, Argentina Arq Bras Endocrinol Metabol 2013 57 307 11 23828435 \n9 Budak A Gulhan I Aldemir OS Ileri A Tekin E Ozeren M Lack of influence of pregnancy on the prognosis of survivors of thyroid cancer Asian Pac J Cancer Prev 2013 14 6941 3 24377629 \n10 Shindo H Amino N Ito Y Kihara M Kobayashi K Miya A et al Papillary thyroid microcarcinoma might progress during pregnancy Thyroid 2014 24 840 4 24397849 \n11 Lee JC Zhao JT Clifton-Bligh RJ Gill AJ Gundara JS Ip J et al Papillary thyroid carcinoma in pregnancy: a variant of the disease? Ann Surg Oncol 2012 19 4210 6 22875646 \n12 Sioka C Fotopoulos A Effects of I-131 therapy on gonads and pregnancy outcome in patients with thyroid cancer Fertil Steril 2011 95 1552 9 21300333 \n13 Grammatikakis I Trakakis E Evangelinakis N Hintipas E Salamalekis G Kassanos D Successful pregnancy after radiotherapy with 131I for differentiated thyroid cancer. A case report and review of the literature Clin Exp Obstet Gynecol 2010 37 328 30 21355471 \n14 Momotani N Iwama S [Management of Graves' disease and hypothyroidism in pregnancy] Nihon Rinsho 2012 70 1971 5 23214070 \n15 Ma L Qi H Chai X Jiang F Mao S Liu J et al The effects of screening and intervention of subclinical hypothyroidism on pregnancy outcomes: a prospective multicenter single-blind, randomized, controlled study of thyroid function screening test during pregnancy J Matern Fetal Neonatal Med 2016 29 1391 4 26181769 \n16 Li X Liu GY Ma JL Zhou L Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis Clinics (Sao Pulo) 2015 70 453 9 \n17 Korevaar TI Steegers EA de Rijke YB Visser WE Jaddoe VW Visser TJ et al Placental Angiogenic Factors Are Associated With Maternal Thyroid Function and Modify hCG-Mediated FT4 Stimulation J Clin Endocrinol Metab 2015 100 1328 34 \n18 Alikhan M Koshy A Hyjek E Stenson K Cohen RN Yeo KT Discrepant serum and urine beta-hCG results due to production of beta-hCG by a cribriform-morular variant of thyroid papillary carcinoma Clin Chim Acta 2015 438 181 5 25181612 \n19 Turgal M Beksac K Basaran D Yazicioglu A Ozyuncu O Aran O et al Pregnancy after Cancer Treatment and Pregnancy Associated Cancer: A Single Center Experience with 96 Cases Gynecology Obstetrics & Reproductive Medicine 2015 21 91 6 \n20 Bohinc BN Perkins JM Appropriate dosing of adjuvant radioactive iodine for differentiated thyroid cancer Curr Opin Oncol 2014 26 31 5 24225414 \n21 Beksaç MS Aydin E Turgal M Karaagaoglu E An Obstetrics Index for the Assessment of Risk Levels of “High Risk Pregnancy” Groups Gynecology Obstetrics & Reproductive Medicine 2015 21 10 3 \n22 Beksaç K Örgül G Çağan M Karaağaoğlu E Arslan S Beksaç MS Retrospective evaluation of pregnant women with celiac disease J Turk Ger Gynecol Assoc 2017 18 56 59 28506952 \n23 Faul F Erdfelder E Lang AG Buchner A G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences Behav Res Methods 2007 39 175 91 17695343 \n24 Yasmeen S Cress R Romano PS Xing G Berger-Chen S Danielsen B et al Thyroid cancer in pregnancy Int J Gynaecol Obstet 2005 91 15 20 16085061 \n25 Hershman JM Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors Thyroid 1999 9 653 7 10447009 \n26 Guerrero-Vazquez R Moreno Reina E Gros Herguido N Martinez Brocca MA Navarro Gonzalez E Advanced thyroid carcinoma in pregnancy: case report of two pregnancies Gynecol Endocrinol 2015 31 852 5 26416790 \n27 Bresner L Banach R Rodin G Thabane L Ezzat S Sawka AM Cancer-related worry in Canadian thyroid cancer survivors J Clin Endocrinol Metab 2015 100 977 85 25393643 \n28 Buchmann L Ashby S Cannon RB Hunt JP Psychosocial distress in patients with thyroid cancer Otolaryngology Head Neck Surg 2015 152 644 9 \n29 Eskander A Devins GM Freeman J Wei AC Rotstein L Chauhan N et al Waiting for thyroid surgery: a study of psychological morbidity and determinants of health associated with long wait times for thyroid surgery Laryngoscope 2013 123 541 7 22865699\n\n",
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"abstract": "Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still's disease (AOSD). Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medecine Specialties, Geneva University Hospital, Rue Gabrielle Perret Gentil 4, 1211 Geneva 14, Switzerland.;Division of Clinical Pathology, Geneva University Hospital and Geneva Faculty of Medicine, Rue Gabrielle Perret Gentil 4, 1211 Geneva 14, Switzerland.;Division of Gastroenterology and Hepatology, Department of Internal Medecine Specialties, Geneva University Hospital, Rue Gabrielle Perret Gentil 4, 1211 Geneva 14, Switzerland.",
"authors": "Drepper|Michael|M|0000-0002-3963-3396;Rubbia-Brandt|Laura|L|;Spahr|Laurent|L|",
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"doi": "10.1155/2013/964828",
"fulltext": "\n==== Front\nCase Reports HepatolCase Reports HepatolCRIHEPCase Reports in Hepatology2090-65872090-6595Hindawi Publishing Corporation 10.1155/2013/964828Case ReportTocilizumab-Induced Acute Liver Injury in Adult Onset Still's Disease http://orcid.org/0000-0002-3963-3396Drepper Michael \n1\n*Rubbia-Brandt Laura \n2\nSpahr Laurent \n1\n1Division of Gastroenterology and Hepatology, Department of Internal Medecine Specialties, Geneva University Hospital, Rue Gabrielle Perret Gentil 4, 1211 Geneva 14, Switzerland2Division of Clinical Pathology, Geneva University Hospital and Geneva Faculty of Medicine, Rue Gabrielle Perret Gentil 4, 1211 Geneva 14, Switzerland*Michael Drepper: michael.drepper@hcuge.chAcademic Editors: F. Imazeki, J. Kaneko, G. H. Koek, F. Pérez Roldán, Y. Sugawara, and M. Vigano\n\n2013 15 7 2013 2013 96482830 4 2013 6 6 2013 Copyright © 2013 Michael Drepper et al.2013This 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.\nBackground. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still's disease (AOSD). Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.\n==== Body\n1. Introduction\nAdult onset Still's disease (AOSD) is a systemic inflammatory disease clinically characterized by remittent fever, polyarthritis, stain rash, and lymphadenopathy in association with deregulated proinflammatory cytokines (interleukin-1, -6 and -18, tumor necrosis factor α, and interferon γ) production [1, 2]. Of interest, a correlation of IL-6 serum levels with AOSD's activity has been described [1, 3].\n\nTocilizumab is a neutralizing humanized monoclonal antibody against the human interleukin-6 (IL-6) receptor that is able to block soluble and membrane-bound receptors [4]. It is licensed over the world as second-line treatment for rheumatoid arthritis (RA) and in Japan and Europe for juvenile idiopathic arthritis [5, 6]. Disease improvement or remission has been reported following tocilizumab treatment in refractory AOSD [2, 7].\n\n2. Case Report\nAn 18-year-old female from Angola was diagnosed with AOSD in September 2010 following recurrent fever, polyarthritis, abdominal lymphadenopathy, liver and spleen enlargement, and hyperferritinemia. She was initially treated with oral corticoids with early methotrexate adjunction due to incomplete control of symptoms. Despite this treatment, corticoids could not be tapered under the dose of 15 mg/day, motivating introduction of tocilizumab (8 mg/kg) in June 2011, permitting interruption of corticoids and methotrexate in December 2011. In 2012, she had no symptoms and liver function tests were normal under tocilizumab once every 3 weeks.\n\nOn January 21, 2013, she complained of nausea, abdominal discomfort, and pruritus that persisted for two days in spite of a daily dose of 1 gram of paracetamol. On January 24, biological tests showed the following: white blood cells: 3500/μL (N 4000–11000), platelets: 52000/μL (N 150000–350000), aspartate aminotransferase (AST): 2622 U/L (N 11–42), alanine aminotransferase (ALT): 2628 U/L (N 9–42), alkaline phosphatase (ALP): 110 U/L (N 30–125), gamma glutamyltranspeptidase (GGT): 272 U/L (N 9–35), and total bilirubin: 61 μmol/L (N 7–25). Prothrombin time was 66% (N > 70) with an International Normalized Ratio of 1.21, but dosage of factor V activity was normal as well as kidney function. Blood paracetamol concentration was not measured at admission due to minor exposure. At hospital admission, she was alert with a slightly tender liver and no signs of chronic liver disease. Abdominal imaging was normal except for mild liver and spleen enlargement (Figure 1). Viral hepatitis (A, B, C, and E) as well as HIV, CMV, EBV, and herpes simplex virus tested negative. Autoimmune testing (total IgG, antinuclear, antiactin, and anti-LKM1 antibodies) was negative and ceruloplasmin was normal. Transaminase levels remained elevated and bilirubin levels increased to 335 μmol/L. On January 28 a transjugular liver biopsy was performed with a portosushepatic venous pressure gradient of 8 mmHg. Histology showed extensive centrilobular hepatocyte necrosis with collapse. Hepatocytes were ballooned with clear cytoplasm. Mild inflammatory periportal cell infiltrations as well as rare areas of micro- and macrovesicular steatosis were also observed (Figure 2). These histological alterations were consistent with acute drug-induced liver injury (DILI). She received a 3-day course of intravenous N-acetylcysteine according to the recent literature reporting transplant-free survival in acute severe nonacetaminophen liver injury [8, 9], and liver function tests were monitored until normalization 6 weeks later (Figure 3).\n\nCausality assessment by the Naranjo score and the Liverpool Adverse Drug Reaction Causality Assessment Tool [10] both indicated tocilizumab as a probable cause of our patient's acute liver failure. The patient and her rheumatologist were instructed not to be reexposed to tocilizumab.\n\n3. Discussion \nThe liver has an important ability to regenerate after injury or resection with IL-6 playing a key role in its regulation. Secreted by Kupffer cells, this cytokine primes hepatocytes for mitosis, which are then stimulated by mitogenic factors like hepatic growth factor (HGF) until achieving the original liver mass again. Accordingly, IL-6 deficient mice were more vulnerable to carbon tetrachloride (CCl4), a molecule used to simulate drug-induced liver toxicity, with a protective effect of IL-6 injection [4, 11].\n\nSevere liver injury is a rare complication of tocilizumab therapy. Published trials on tocilizumab in rheumatoid arthritis (RA) reported mild to moderate AST and ALT elevations in a maximum of 40 and 2.7%, respectively [12, 13], with only 3 cases of severe liver injury [14–16]. We report here a detailed case of acute DILI caused by tocilizumab with a complete resolution of liver function tests. Our observation differs from the other three cases of severe tocilizumab-induced liver injury already published. \n\nMahamid et al. and Hiura et al. reported each a case with rather sub acute evolution over months leading in the first case to histological focal pericentral vein hepatocellular necrosis and steatosis [14]. In the second one, of note a lethal case, marked liver atrophy and ascites were observed with no focal necrosis but mild inflammatory cell infiltration and little periportal fibrosis at histology [15]. Interestingly, liver enzymes were normal or only slightly elevated, and supplementary immunohistochemical analysis in the second case revealed a high amount of cleaved caspase 3 antigen positive hepatocytes, suggesting rather apoptosis than necrosis at the origin of liver injury [15]. The authors hypothesized that the poor outcome could be due to IL-6 inhibition, a cytokine involved with liver regeneration [4].\n\nOn the contrary, Alfreijat et al. described one case of severe acute hepatitis similar to ours, with important liver enzyme elevation (AST 1455 U/L and ALT 2296 U/L) and hyperbilirubinemia (178.5 μmol/L). Liver biopsy showed focal hepatocellular necrosis with ballooning degeneration of hepatocytes and focal bile stasis. Biological tests returned to normal after tocilizumab discontinuation and 10 weeks under steroids [16]. However, concomitant use of potentive hepatotoxic drugs rendered the causal relationship between tocilizumab and DILI more difficult in this case. Rather quick recovery in both cases favors acute tocilizumab toxicity rather than IL-6-blockage-induced impaired liver regeneration at the origin of the liver damage.\n\nOur patient developed liver injury 19 months after initial tocilizumab exposure, a longer period compared to 1 and 3 months in previously reported cases. Nevertheless, the period from drug intake to DILI manifestation can vary considerably and is only one item among other criteria in the causality assessment scales [17, 18]. Moreover, no other relevant drug exposure has been identified, and liver biopsy showed clear signs of drug-induced liver injury.\n\nFinally, liver enzyme elevation or liver damage may be associated with AOSD itself [19]. In our case, AOSD-related liver damage seems very unlikely as the patient did not present any clinical sign of disease activity, and biological inflammation markers were low at admission.\n\nAcute and severe hepatitis may complicate the course of tocilizumab treatment, although this is a rare event. Pathogenic mechanisms are incompletely elucidated, but interference of tocilizumab with IL-6-mediated liver regeneration may participate. Careful monitoring of liver function tests should be applied to patients receiving tocilizumab.\n\nConflict of Interests\nThe authors declare no conflict of interests.\n\nFigure 1 Abdominal CT showing mild liver and spleen enlargement.\n\nFigure 2 Histological view (haematoxylin-eosin stain, original magnification ×200) demonstrating extensive areas of hepatocytes with necrosis, ballooning degeneration, macro- and microvesicular steatosis (MS), and acidophil bodies (A). Insert: centrilobular vein (CV) showing endotheliitis (arrow) (original magnification ×400).\n\nFigure 3 Liver function test evolution: day 1: January 24, 2013 and ULN: upper limit of normal.\n==== Refs\n1 Sakai R Nagasawa H Nishi E Successful treatment of adult-onset Still’s disease with tocilizumab monotherapy: two case reports and literature review Clinical Rheumatology 2012 31 3 569 574 2-s2.0-84859780892 22215118 \n2 Suematsu R Ohta A Matsuura E Therapeutic response of patients with adult Still’s disease to biologic agents: multicenter results in Japan Modern Rheumatology 2012 22 712 719 2-s2.0-82655183454 22160845 \n3 Chen D-Y Lan J-L Lin F-J Hsieh T-Y Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset still’s disease Journal of Rheumatology 2004 31 11 2189 2198 2-s2.0-7544248841 15517632 \n4 Drucker C Gewiese J Malchow S Scheller J Rose-John S Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration Journal of Autoimmunity 2010 34 1 29 37 2-s2.0-75249083288 19717281 \n5 Smolen JS Schoels MM Nishimoto N Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions Annals of the Rheumatic Diseases 2013 72 482 492 23172750 \n6 de Benedetti F Brunner HI Ruperto N Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis The New England Journal of Medicine 2012 367 2385 2395 23252525 \n7 de Boysson H Fevrier J Nicolle A Auzary C Geffray L Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence Clinical Rheumatology 2013 32 141 147 23108887 \n8 Lee WM Hynan LS Rossaro L Intravenous N-acetylcysteine improves transplant-free survival in early stage non acetaminophen acute liver failure Gastroenterology 2009 137 3 856.e1 864.e1 2-s2.0-66149098373 19524577 \n9 Singh S Hynan LS Lee WM Improvements in hepatic serological biomarkers are associated with clinical benefit of intravenous N-acetylcysteine in early stage non- acetaminophen acute liver failure Digestive Diseases and Sciences 2013 58 1397 1402 23325162 \n10 Gallagher RM Kirkham JJ Mason JR Development and inter-rater reliability of the liverpool adverse drug reaction causality assessment tool PLoS ONE 2011 6 12 2-s2.0-83355170778 e28096 \n11 Kovalovich K Deangelis RA Li W Furth EE Ciliberto G Taub R Increased toxin-induced liver injury and fibrosis in interleukin-6- deficient mice Hepatology 2000 31 1 149 159 2-s2.0-0033970969 10613740 \n12 Nishimoto N Ito K Takagi N Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions Modern Rheumatology 2010 20 3 222 232 2-s2.0-77956646068 20221663 \n13 Jones G Ding C Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis Clinical Medicine Insights 2010 3 81 89 2-s2.0-79751520384 21234291 \n14 Mahamid M Paz K Reuven M Safadi R Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports International Journal of General Medicine 2011 4 657 660 21941451 \n15 Hiura M Abe S Tabaru A Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis Hepatology Research 2011 41 5 492 496 2-s2.0-79955138896 21435128 \n16 Alfreijat M Habibi M Bhatia P Bhatia A Severe hepatitis associated with tocilizumab in a patient with rheumatoid arthritis Rheumatology 2013 52 1340 1341 23315786 \n17 García-Cortés M Stephens C Lucena MI Fernández-Castañer A Andrade RJ Causality assessment methods in drug induced liver injury: strengths and weaknesses Journal of Hepatology 2011 55 3 683 691 2-s2.0-84860389774 21349301 \n18 Suk KT Kim DJ Kim CH A prospective nationwide study of drug-induced liver injury in Korea The American Journal of Gastroenterology 2012 107 1380 1387 22733303 \n19 Kong X-D Xu D Zhang W Zhao Y Zeng X Zhang F Clinical features and prognosis in adult-onset still’s disease: a study of 104 cases Clinical Rheumatology 2010 29 9 1015 1019 2-s2.0-77956189225 20549276\n\n",
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"title": "Tocilizumab-Induced Acute Liver Injury in Adult Onset Still's Disease.",
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"abstract": "Investigate the otopathology of angiosarcoma of the temporal bone, which has not been previously described in the literature.\n\n\n\nPostmortem evaluation and literature review.\n\n\n\nPostmortem histological evaluation of the temporal bones and review of the literature for the treatment and prognosis of this rare disease were performed.\n\n\n\nA 50-year-old male with right chronic otitis media presented with progressive hearing loss, disequilibrium, otalgia, and acute facial paresis. Biopsy of the external auditory canal was unrevealing, but specimens from a canal wall down tympanomastoidectomy later showed high-grade angiosarcoma. Magnetic resonance imaging demonstrated an unresectable middle ear and mastoid mass extending superiorly into the temporal lobe. The patient received induction chemotherapy followed by proton beam radiation therapy and concurrent paclitaxel and bevacizumab. His course was complicated by a cerebrospinal fluid leak and cauda equina syndrome from leptomeningeal sarcomatosis. The patient died after developing meningitis and a temporal lobe abscess. Postmortem otopathology revealed persistent angiosarcoma in the internal auditory canal, although none was found in the middle ear or mastoid. There was inflammatory infiltrate throughout the mastoid, with direct extension of neutrophils and bacteria into the cochlea and through the tegmen into the middle cranial fossa.\n\n\n\nAngiosarcoma of the temporal bone can arise in the setting of chronic otitis media. In this case, postmortem temporal bone sections demonstrated viable cancer despite chemoradiation. Inflammatory infiltrates crossing from the middle ear/mastoid into the labyrinth and central nervous system illustrate pathways for the development of otogenic meningitis.\n\n\n\n4 Laryngoscope, 129:737-742, 2019.",
"affiliations": "Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts.;Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts.;Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts.;Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts.",
"authors": "Chen|Jenny X|JX|0000-0002-2992-4771;Kozin|Elliott D|ED|0000-0002-0305-0682;O'Malley|Jennifer|J|;Chebib|Ivan|I|;Hedley-Whyte|E Tessa|ET|;Faquin|William|W|;Nadol|Joseph|J|;Quesnel|Alicia M|AM|",
"chemical_list": null,
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"issue": "129(3)",
"journal": "The Laryngoscope",
"keywords": "Otopathology; chronic otitis media; intracranial abscess; meningitis",
"medline_ta": "Laryngoscope",
"mesh_terms": "D017809:Fatal Outcome; D006394:Hemangiosarcoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D010033:Otitis Media; D012888:Skull Neoplasms; D013701:Temporal Bone",
"nlm_unique_id": "8607378",
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"pages": "737-742",
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"pubdate": "2019-03",
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"references": null,
"title": "Otopathology in Angiosarcoma of the Temporal Bone.",
"title_normalized": "otopathology in angiosarcoma of the temporal bone"
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{
"abstract": "Asparaginase-induced hypertriglyceridemia can have a spectrum of clinical presentations, from being asymptomatic to having life-threatening thrombosis or hyperviscosity syndrome. At present, there is no recommendation on routine lipid monitoring during asparaginase-containing treatment phase, nor a standardized guideline on its management. Two cases are presented here to illustrate the effects of concurrent infection on asparaginase-induced hypertriglyceridemia in patients with high-risk ALL and the use of SMOFlipid infusion as a treatment option in an acute situation.",
"affiliations": "Pediatric Hematology and Oncology Unit, Department of Pediatrics, UKM Medical Centre, Faculty of Medicine, The National University of Malaysia, Kuala Lumpur, Malaysia.;Pediatric Hematology and Oncology Unit, Department of Pediatrics, UKM Medical Centre, Faculty of Medicine, The National University of Malaysia, Kuala Lumpur, Malaysia.;Pediatric Hematology and Oncology Unit, Department of Pediatrics, UKM Medical Centre, Faculty of Medicine, The National University of Malaysia, Kuala Lumpur, Malaysia.",
"authors": "Lau|Sie Chong Doris|SCD|;Loh|C-Khai|CK|;Alias|Hamidah|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2021.660627",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.660627\nPediatrics\nCase Report\nCase Report: The Use of Intravenous SMOFlipid Infusion to Treat Severe Asparaginase-Induced Hypertriglyceridemia in Two Pediatric Acute Lymphoblastic Leukemia Patients\nLau Sie Chong Doris\n\nLoh C-Khai\n\nAlias Hamidah *\n\nPediatric Hematology and Oncology Unit, Department of Pediatrics, UKM Medical Centre, Faculty of Medicine, The National University of Malaysia, Kuala Lumpur, Malaysia\nEdited by: Peter Michael Gordon, University of Minnesota Twin Cities, United States\n\nReviewed by: Robin Williams, University of Minnesota Twin Cities, United States; Barbara Buldini, Università degli Studi di Padova, Italy\n\n*Correspondence: Hamidah Alias midalias@ppukm.ukm.edu.my\nThis article was submitted to Pediatric Hematology and Hematological Malignancies, a section of the journal Frontiers in Pediatrics\n\n22 4 2021\n2021\n9 66062729 1 2021\n30 3 2021\nCopyright © 2021 Lau, Loh and Alias.\n2021\nLau, Loh and Alias\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.\nAsparaginase-induced hypertriglyceridemia can have a spectrum of clinical presentations, from being asymptomatic to having life-threatening thrombosis or hyperviscosity syndrome. At present, there is no recommendation on routine lipid monitoring during asparaginase-containing treatment phase, nor a standardized guideline on its management. Two cases are presented here to illustrate the effects of concurrent infection on asparaginase-induced hypertriglyceridemia in patients with high-risk ALL and the use of SMOFlipid infusion as a treatment option in an acute situation.\n\nacute lymphoblastic leukemia\nasparaginase\nhypertriglyceridemia\nomega-3\nSMOFlipid\npediatric\ncase report\n==== Body\nIntroduction\n\nAsparaginase is an important chemotherapeutic agent used in remission induction protocols for childhood acute lymphoblastic leukemia (ALL) (1, 2). However, its use has been associated with abnormalities in lipid metabolism, such as hypertriglycerides (3–5). Although, this is usually transient, it may also cause transaminitis, pancreatitis, life-threatening thrombosis, or hyperviscosity syndrome (6–11). Currently there is no standard guideline for the management of asparaginase-induced hypertriglyceridemia. Here, we report the beneficial use of SMOFlipid infusion (containing 3% fish oil which is high in eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) to bring down the triglyceride (TG) levels in two teenagers with severe hypertriglyceridemia following induction chemotherapy for high-risk ALL.\n\nCase 1\n\nA 12-year-old boy with no family history of dyslipidaemia presented with 1-week history of fever and bilateral lower limb petechiae. Clinically, he was pale and had multiple cervical lymphadenopathy and hepatomegaly. Bone marrow aspiration and trephine biopsy (BMAT) confirmed the diagnosis of pre-B ALL and he was stratified as high risk ALL due to hyperleukocytosis (white cell count of 65.1 × 109/L) at initial presentation. He was started on induction chemotherapy (UKALL 2003 Regimen B) consisting of intrathecal methotrexate (MTX), oral dexamethasone (6 mg/m2/day for 28 days), intramuscular (IM) E. coli L-asparaginase (6000 IU/m2 every other day for 12 doses), intravenous (IV) vincristine (1.5 mg/m2/dose weekly for 5 weeks) and IV daunorubicin (25 mg/m2/dose weekly × 4 weeks). At Day 15 induction, he developed recurrent epigastric pain; serum amylase, and ultrasound abdomen revealed no evidence of pancreatitis. His serial liver function test however showed mild elevation of alanine transaminase (ALT) ranging between 59 and 169 U/L (N:0–55 U/L). He was managed symptomatically as dexamethasone-induced gastritis with close monitoring of his liver function. Subsequently he was admitted at Day 20 induction for febrile neutropenia secondary to periungual abscess and was started on broad spectrum antibiotics. At this juncture, he also had grade IV oral mucositis and was unable to tolerate orally. Prior to commencement of total parenteral nutrition (TPN), blood investigations were performed and revealed elevated serum triglyceride (TG) at 8.86 mmol/L as well as elevated liver transaminases - ALT of 219 U/L; aspartate transaminase (AST) of 103 U/L (N: <45 U/L); gamma-glutamyl transferase (GGT) of 370 U/L (N: 13–64 U/L). Apart from the intermittent epigastric pain, he had no other complaint hence the hypertriglyceridemia was managed conservatively with low fat diet; lipid was omitted from the TPN. By this time, he had already received 10 doses of native E. coli L-asparaginase (Figure 1).\n\nFigure 1 Triglyceride and alanine transaminase (ALT) trends during treatment with L-asparaginase and following infusion of SMOFlipid.\n\nWhile in the ward, he became delirious and had incoherent speech. Clinical examination did not reveal any focal neurological deficit and his blood pressure was normal. Magnetic resonance imaging (MRI) of the brain showed no evidence of posterior reversible encephalopathy syndrome (PRES), MTX neurotoxicity, or leptomeningeal enhancement. Magnetic resonance angiography (MRA) was also performed and revealed normal cerebral vessels with no thrombosis. The cerebrospinal fluid (CSF) sent for cytology, culture, microscopy examination, and biochemistry results were all normal. However, at this point of time, his serum TG had increased further to 14.97 mmol/L. Due to unavailability of plasmapheresis service at that critical time, a decision was made to give him IV infusion of SMOFlipid at 0.5 g/kg/day. His conscious level improved within 24 h and the serum TG level reduced rapidly over the next 2 days. Lipid infusion was ceased after 5 days. His liver function normalized after 2 weeks. Subsequent chemotherapy was changed to EsPhALL protocol (Version 5) as his BCR-ABL was positive. Although, each cycle of L-asparaginase administration was associated with transient increase in the serum TG, he remained asymptomatic. Unfortunately, 6 months after diagnosis, he developed Plesiomonas shigelloides and Klebsiella pneumoniae septicaemic shock and succumbed.\n\nCase 2\n\nA 13-year-old boy with late relapse B-ALL (isolated marrow relapse with BCR-ABL positive at relapse) was commenced on chemotherapy – EsPhALL protocol (Version 5)(induction phase as per UKALL 2003 Regimen B protocol, and concurrent oral Imatinib 300 mg/m2 daily). He had no history of severe adverse reaction toward chemotherapy during his initial treatment for standard risk pre-B ALL at 4 years old (UKALL 97(99) Regimen A). There was no family history of dyslipidaemia. The day 15 induction bone marrow and cytogenetic examination were in remission. At Day 28 induction chemotherapy, he developed severe vincristine-induced peripheral neuropathy and was admitted for supportive care. Blood investigation on admission revealed elevated liver transaminase (ALT 402 U/L); serum TG was not performed. He had received a total of 12 doses of native E. coli L-asparaginase as per treatment protocol. Retrospectively, his serial ALT and AST during the induction phase chemotherapy was elevated, ranging between 57–345 U/L and 91–92 U/L, respectively, while his serum TG was 1.77–3.07 mmol/L.\n\nOn day 3 of admission, he developed febrile neutropenia and Pseudomonas aeruginosa septicaemic shock. Broad-spectrum antibiotic was commenced and he was transferred to Pediatric Intensive Care Unit (PICU) for inotrope support. His condition stabilized and the inotrope was weaned off after 72 h. Blood culture taken after 48 h of antibiotic initiation was negative. However, while in PICU, he became delirious and started talking inappropriately. His pupils were equal and reactive bilaterally and neurological examination did not reveal any focal abnormality. Brain imaging and lumbar puncture were not performed as he was not stable at that time. The serial liver function test (LFT) showed worsening transaminitis (ALT 592 U/L) at this juncture, and fasting TG was markedly elevated (15.49 mmol/L). SMOFlipid infusion was initiated at 0.5 g/kg/day and the serum TG declined to 5.77 mmol/L in 2 days. Unfortunately, he developed Candida tropicalis septicaemia with multiorgan failure 3 weeks later and succumbed. Post-mortem lumbar puncture showed no evidence of meningitis.\n\nDiscussion\n\nAsparaginase-induced hypertriglyceridemia has been reported to occur in 10–67% of children treated for ALL (4, 6, 8). As routine lipid monitoring is not incorporated into most of the treatment protocol worldwide, this condition could be underdiagnosed. In patients with unexplained transaminitis, a high index of suspicion would allow prompt investigations for hypertriglyceridemia as illustrated in the cases above. Both our patients most likely had asparaginase-induced hypertriglyceridemia during the early phase of induction chemotherapy but were clinically asymptomatic. We postulate that the acute febrile illness exacerbate the existing problem of hypertriglyceridemia, leading to rapid increase in the TG levels and this could cause hyperviscosity. Comprehensive investigations are required for any patient who presents with neurological impairment in order to exclude other differential diagnoses including meningitis, encephalitis, and intracranial bleed. In oncology patients, MRI brain, whenever possible, should be performed to look for changes suggestive of MTX neurotoxicity, or PRES which may also present with altered mental status before attributing it to hypertriglyceridemia.\n\nAs hypertriglyceridemia is transient and majority of the patients are asymptomatic, no omission, or modification of the asparaginase dosage are required (5, 6, 8). However, symptomatic patients or those with markedly elevated TG level may benefit from medical treatment. There are currently no standard treatment guidelines for asparaginase-induced hypertriglyceridemia in pediatric patients with ALL. Isolated case reports and small reviews have suggested several approaches, namely short-term fasting or low-fat diet, oral fibrates, oral omega-3 fatty acids, and insulin infusion (7, 10, 12, 13). Plasmapheresis has been shown to be effective in reducing TG levels rapidly after 2 h of apheresis (9); clinical improvement was seen as early as 8 h and normalization of the TG levels was achieved after 72 h of plasmapheresis (3). However, the availability of plasmapheresis may be limited due to the cost and requirement for technical expertise. The use of SMOFlipid infusion to treat severe or symptomatic hypertriglyceridemia has not been reported before.\n\nSMOFlipid is a lipid emulsion formulation which has been used as a source of parenteral nutrition for pediatric patients with critical illness, following major gastrointestinal tract surgery or preterm babies who were unable to tolerate enteral feeding (14, 15). Small number of studies has shown that it was safe and well-tolerated among the pediatric population (16–18). A further study on the safety and efficacy of SMOFlipid in pediatric patients aged 3 months to 16 years old is currently ongoing (www.clinicaltrials.gov Identifier: NCT03563222). The constituents of SMOFlipid are soybean oil (6%), medium chain triglycerides (6%), olive oil (5%), and fish oil (3%). The fish oil here is characterized by a high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which are long-chain, polyunsaturated, omega-3 fatty acids. Although the exact mechanisms of action are not well-understood, it was proposed that omega-3 fatty acids can reduce hepatic very-low-density lipoprotein (VLDL)-TG synthesis/secretion and enhances TG clearance from circulating VLDL and chylomicron particles (19, 20). The use of oral omega-3 fatty acids in addition to dietary modification in a relatively well patient allows reduction of TG levels over a slower course (6, 12). As both our patients were unwell and had severe hypertriglyceridemia, an alternative approach was considered in the absence of plasmapheresis. The idea of using SMOFlipid came from the afore-mentioned principle that the omega-3 (fish oil) in the SMOFlipid can also theoretically be used to reduce triglyceride level. Precaution must be taken as SMOFlipid is contraindicated in severe hyperlipidaemia or severe disorders of lipid metabolism with serum TG >1,000 mg/dL. However, our patients did not have these comorbidities prior to the illness hence, SMOFlipid infusion was initiated at the lowest infusion rate of 0.5g/kg/day with close monitoring to ensure no further increment of the TG level. Clinical improvement was seen within 24–48 h concurrent with the reduction of TG level although biochemical markers abnormalities (liver transaminases) may persist for several weeks. Subsequent asparaginase doses may be given safely with close monitoring of the TG levels as in our first patient (21).\n\nThe two cases here highlighted the importance of early recognition of clinical and biochemical indicators of hypertriglyceridemia in patients with high-risk ALL during induction chemotherapy, especially in the setting of acute infection. We also reported our observation on the effect of SMOFlipid infusion in lowering the TG level rapidly in acute situation when plasmapheresis is not available at the treating centre. However, further study regarding feasibility and safety of SMOFlipid would be required before it can be recommended as one of the treatment option for hypertriglyceridemia.\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\nWritten informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nSL, C-KL, and HA were responsible for the clinical management of the patients. SL acquired the clinical data and drafted the initial manuscript. HA reviewed the intellectual contents of the manuscript and made substantial modification during revision. All authors reviewed and approved final manuscript as submitted and agree to be accountable for all aspects of the work.\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==== Refs\nReferences\n\n1. Pession A Valsecchi MG Masera G Kamps WA Magyarosy E Rizzari C . Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol. (2005) 23 :7161–7. 10.1200/JCO.2005.11.411 16192600\n2. Egler RA Ahuja SP Matloub Y . L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. (2016) 7 :62–71. 10.4103/0976-500X.184769 27440950\n3. Solano-Paez P Villegas JA Colomer I Gutierrez MD Fernandez-Teijeiro A . L-asparaginase and steroids-associated hypertriglyceridemia successfully treated with plasmapheresis in a child with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. (2011) 33 :e122–4. 10.1097/MPH.0b013e3181faf7a1 21399528\n4. Hijiya N van der Sluis IM . Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma. (2016) 57 :748–57. 10.3109/10428194.2015.1101098 26457414\n5. Tong WH Pieters R de Groot-Kruseman HA Hop WCJ Boos J Tissing WJE . Toxicity of very prolonged PEG asparaginase and Erwinia asparaginase courses in relation to asparaginase activity levels with a special focus on dyslipidemia. Haematologica. (2014) 99 :1716–21. 10.3324/haematol.2014.109413 25150254\n6. Bhojwani D Darbandi R Pei D Ramsey LB Chemaitilly W Sandlund JT . Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. Eur J Cancer. (2014) 50 :2685–94. 10.1016/j.ejca.2014.06.023 25087182\n7. Athanassiadou F Kourti M Papageorgiou T Stamou M Makedou A Boufidou A . Severe hyperlipidemia in a child with acute lymphoblastic leukemia treated with L-asparaginase and prednisone. Pediatr Int. (2004) 46 :743–4. 10.1111/j.1442-200x.2004.01991.x 15660880\n8. Cohen H Bielorai B Harats D Toren A Pinhas-Hamiel O . Conservative treatment of L-asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. (2010) 54 :703–6. 10.1002/pbc.22305 20063421\n9. Ridola V Buonuomo PS Maurizi P Putzulu R Annunziata ML Pietrini D . Severe acute hypertriglyceridemia during acute lymphoblastic leukemia induction successfully treated with plasmapheresis. Pediatr Blood Cancer. (2008) 50 :378–80. 10.1002/pbc.20986 16883590\n10. Dietel V Buhrdel P Hirsch W Korholz D Kiess W . Cerebral sinus occlusion in a boy presenting with asparaginase-induced hypertriglyceridemia. Klin Padiatr. (2007) 219 :95–6. 10.1055/s-2007-921455 17405075\n11. Rosenson RS Shott S Tangney CC . Hypertriglyceridemia is associated with an elevated blood viscosity: Triglycerides and blood viscosity. Atherosclerosis. (2002) 161 :433–9. 10.1016/S0021-9150(01)00656-6 11888528\n12. Bostrom B . Successful management of extreme hypertriglyceridemia from pegaspargase with omega-3. Pediatr Blood Cancer. (2012) 59 :350. 10.1002/pbc.24108 22392609\n13. Lawson EB Gottschalk M Schiff DE . Insulin infusion to treat severe hypertriglyceridemia associated with pegaspargase therapy: a case report. J Pediatr Hematol Oncol. (2011) 33 :e83–6. 10.1097/MPH.0b013e3181f46c22 21343748\n14. Choudhary N Tan K Malhotra A . Inpatient outcomes of preterm infants receiving ω-3 enriched lipid emulsion (SMOFlipid): an observational study. Eur J Pediatr. (2018) 177 :723–31. 10.1007/s00431-018-3112-3 29445923\n15. Casson C Nguyen V Nayak P Channabasappa N Berris K Panczuk J . A comparison of smoflipid® and intralipid® in the early management of infants with intestinal failure. J Pediatr Surg. (2020) 55 :153–7. 10.1016/j.jpedsurg.2019.09.073 31672409\n16. Goulet O Antebi H Wolf C Talbotec C Alcindor LG Corriol O . A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. J Parenter Enteral Nutr. (2010) 34 :485–95. 10.1177/0148607110363614 20852176\n17. Tomsits E Pataki M Tolgyesi A Fekete G Rischak K Szollar L . Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil: A randomised, double-blind clinical trial in premature infants requiring parenteral nutrition. J Pediatr Gastroenterol Nutr. (2010) 51 :514–21. 10.1097/MPG.0b013e3181de210c 20531018\n18. Rayyan M Devlieger H Jochum F Allegaert K . Short-term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain triglycerides, and fish oil: A randomized, double-blind study in preterm infants. J Parenter Enteral Nutr. (2012) 36 :81S–94S. 10.1177/0148607111424411 22237883\n19. Shearer GC Savinova OV Harris WS . Fish oil – how does it reduce plasma triglycerides? Biochim Biophys Acta. (2012) 1821 :843–51. 10.1016/j.bbalip.2011.10.011 22041134\n20. Bays HE Tighe AP Sadovsky R Davidson MH . Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther. (2008) 6 :391–409. 10.1586/14779072.6.3.391 18327998\n21. Lashkari HP Lancaster D Atra A Champion MP Taj MM . Symptomatic severe hypertriglyceridaemia with asparaginase therapy in acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma: is rechallenging safe? Int J Hematol. (2011) 94 :571–5. 10.1007/s12185-011-0966-9 22057510\n\n",
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"abstract": "This study aimed to explain the dynamics of prostate-specific antigen (PSA) levels in patients with prostate cancer who were treated with carbon ion radiotherapy (CIRT) and neoadjuvant androgen-deprivation therapy (ADT).\n\n\n\nEighty-five patients with intermediate-risk prostate cancer who received CIRT and neoadjuvant ADT from December 2015 to December 2017 were analyzed in the present study. The total dose of CIRT was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. The PSA bounce was defined as a ≥0.4 ng/ml increase of PSA levels from the nadir, followed by any decrease. PSA failure was defined using the Phoenix criteria.\n\n\n\nThe median patient age was 68 (range, 48-81) years. The median follow-up duration was 33 (range, 20-48) months. The clinical T stage was T1c, T2a, and T2b in 27, 44, and 14 patients, respectively. The Gleason score was 6 in 3 patients and 7 in 82 patients. The median pretreatment PSA level was 7.37 (range, 3.33-19.0) ng/ml. All patients received neoadjuvant ADT for a median of 6 (range, 2-117) months. PSA bounces were observed in 39 patients (45.9%), occurring a median of 12 (range, 6-30) months after CIRT. PSA failure was observed in eight patients (9.4%), occurring a median of 21 (range, 15-33) months after CIRT. The 3-year PSA failure-free survival rate was 88.5%. No clinical recurrence was observed during the follow-up period. Younger age and lower T stage were significant predictors of PSA bounce. Younger age was a significant predictor of PSA failure.\n\n\n\nIn this study, we identified the significant predictors of the occurrence of PSA bounce and failure. Further follow-up is needed to reveal the clinical significance of PSA dynamics.",
"affiliations": "Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.",
"authors": "Takakusagi|Yosuke|Y|0000-0001-5218-0806;Oike|Takahiro|T|;Kano|Kio|K|;Anno|Wataru|W|;Tsuchida|Keisuke|K|;Mizoguchi|Nobutaka|N|;Serizawa|Itsuko|I|;Yoshida|Daisaku|D|;Katoh|Hiroyuki|H|;Kamada|Tadashi|T|",
"chemical_list": "D000726:Androgen Antagonists; D017430:Prostate-Specific Antigen",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0241636",
"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0241636\nPONE-D-20-18791\nResearch Article\nMedicine and Health Sciences\nOncology\nCancer Treatment\nMedicine and Health Sciences\nOncology\nCancers and Neoplasms\nGenitourinary Tract Tumors\nProstate Cancer\nMedicine and Health Sciences\nUrology\nProstate Diseases\nProstate Cancer\nMedicine and Health Sciences\nOncology\nCancer Treatment\nRadiation Therapy\nMedicine and Health Sciences\nClinical Medicine\nClinical Oncology\nRadiation Therapy\nMedicine and Health Sciences\nOncology\nClinical Oncology\nRadiation Therapy\nBiology and Life Sciences\nAnatomy\nExocrine Glands\nProstate Gland\nMedicine and Health Sciences\nAnatomy\nExocrine Glands\nProstate Gland\nBiology and Life Sciences\nBiochemistry\nHormones\nAndrogens\nResearch and Analysis Methods\nImaging Techniques\nNeuroimaging\nComputed Axial Tomography\nBiology and Life Sciences\nNeuroscience\nNeuroimaging\nComputed Axial Tomography\nMedicine and Health Sciences\nDiagnostic Medicine\nDiagnostic Radiology\nTomography\nComputed Axial Tomography\nResearch and Analysis Methods\nImaging Techniques\nDiagnostic Radiology\nTomography\nComputed Axial Tomography\nMedicine and Health Sciences\nRadiology and Imaging\nDiagnostic Radiology\nTomography\nComputed Axial Tomography\nMedicine and Health Sciences\nOncology\nBiology and Life Sciences\nAnatomy\nDigestive System\nGastrointestinal Tract\nRectum\nMedicine and Health Sciences\nAnatomy\nDigestive System\nGastrointestinal Tract\nRectum\nProstate-specific antigen dynamics after neoadjuvant androgen-deprivation therapy and carbon ion radiotherapy for prostate cancer\nPSA dynamics after carbon ion radiotherapyhttps://orcid.org/0000-0001-5218-0806Takakusagi Yosuke ConceptualizationData curationInvestigationMethodologyProject administrationWriting – original draft1* Oike Takahiro ConceptualizationSupervisionValidationWriting – review & editing2 Kano Kio Data curationFormal analysisInvestigation1 Anno Wataru Data curationInvestigation1 Tsuchida Keisuke Data curationFormal analysisInvestigation1 Mizoguchi Nobutaka Formal analysisMethodologyValidation1 Serizawa Itsuko SupervisionValidation1 Yoshida Daisaku SupervisionValidationWriting – review & editing1 Katoh Hiroyuki ConceptualizationSupervisionWriting – review & editing1 Kamada Tadashi SupervisionWriting – review & editing1 1 \nDepartment of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan\n2 \nDepartment of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan\nChun Stephen Editor MD Anderson Cancer Center, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: y-takakusagi@kcch.jp\n6 11 2020 \n2020 \n15 11 e024163618 6 2020 16 10 2020 © 2020 Takakusagi et al2020Takakusagi 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\nThis study aimed to explain the dynamics of prostate-specific antigen (PSA) levels in patients with prostate cancer who were treated with carbon ion radiotherapy (CIRT) and neoadjuvant androgen-deprivation therapy (ADT).\n\nMethods\nEighty-five patients with intermediate-risk prostate cancer who received CIRT and neoadjuvant ADT from December 2015 to December 2017 were analyzed in the present study. The total dose of CIRT was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. The PSA bounce was defined as a ≥0.4 ng/ml increase of PSA levels from the nadir, followed by any decrease. PSA failure was defined using the Phoenix criteria.\n\nResults\nThe median patient age was 68 (range, 48–81) years. The median follow-up duration was 33 (range, 20–48) months. The clinical T stage was T1c, T2a, and T2b in 27, 44, and 14 patients, respectively. The Gleason score was 6 in 3 patients and 7 in 82 patients. The median pretreatment PSA level was 7.37 (range, 3.33–19.0) ng/ml. All patients received neoadjuvant ADT for a median of 6 (range, 2–117) months. PSA bounces were observed in 39 patients (45.9%), occurring a median of 12 (range, 6–30) months after CIRT. PSA failure was observed in eight patients (9.4%), occurring a median of 21 (range, 15–33) months after CIRT. The 3-year PSA failure-free survival rate was 88.5%. No clinical recurrence was observed during the follow-up period. Younger age and lower T stage were significant predictors of PSA bounce. Younger age was a significant predictor of PSA failure.\n\nConclusions\nIn this study, we identified the significant predictors of the occurrence of PSA bounce and failure. Further follow-up is needed to reveal the clinical significance of PSA dynamics.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nBackground\nAmong cancers, prostate cancer ranks second globally in morbidity and fifth in mortality [1]. Radiotherapy is one of the definitive treatments for localized or locally advanced prostate cancer. The number of patients treated with radiotherapy for prostate cancer has been increasing in Japan according to a structural survey conducted by the Japanese Society for Therapeutic Radiology and Oncology [2]. Brachytherapy, intensity-modulated radiotherapy (IMRT), and particle beam radiotherapy are the radiotherapy modalities used for patients with prostate cancer [3–6].\n\nThe first carbon ion radiotherapy (CIRT) clinical trial for prostate cancer was initiated in 1995 at the National Institute of Radiological Sciences (Chiba, Japan) [7]. CIRT offers biological and physical advantages over conventional photon radiotherapy with X-rays. Regarding the biological aspect, carbon ion beams have an estimated 2–3-fold higher relative biological effectiveness (RBE) than X-rays [8, 9]. In terms of the physical aspect, a more conformal dose distribution can be delivered via CIRT based on the ability of accelerated carbon ions to release a maximal amount of energy at the end of their track, resulting in a Bragg peak [10]. These features have led to favorable clinical outcomes for CIRT in prostate cancer [6, 11]. In the ion-beam Radiation Oncology Center in Kanagawa (i-ROCK), similar to previous studies of CIRT for prostate cancer, favorable clinical outcomes were achieved for prostate cancers treated with CIRT [12].\n\nSerum prostate-specific antigen (PSA) is a sensitive marker of treatment outcomes for prostate cancer [13]. Fluctuation of PSA levels is often observed after radiotherapy without any clinical recurrence [14–16]. Such benign PSA fluctuation, which was first reported in 1997, is known as the PSA bounce [17]. PSA bounces can be disconcerting for patients and physicians [18], and they may lead to unnecessary salvage treatment for cases that meet the definition of PSA failure. Therefore, accurate clinical interpretation of PSA dynamics after radiotherapy for prostate cancer is necessary to avoid patient anxiety or a false-positive diagnosis of relapse, which can instigate unnecessary treatment [19].\n\nPSA bounces have been observed after various radiotherapy modalities for prostate cancer, such as low-dose-rate brachytherapy (LDR-BT), high-dose-rate brachytherapy (HDR-BT), IMRT, and stereotactic radiotherapy (SRT). However, only one study has reported PSA dynamics after CIRT [20]. In that study, although PSA dynamics after CIRT alone was revealed, that after CIRT using androgen-deprivation therapy (ADT) was not investigated. Thus, the present study aimed to explain the dynamics of PSA in patients with prostate cancer who were treated with CIRT and ADT.\n\nMaterials and methods\nThe study was approved by the institutional review board of Kanagawa Cancer Center (approval number: 2019–171). Written informed consent was obtained from all patients. Clinical data obtained between December 2015 and December 2019 was accessed in this study. The source of medical records used in this work was Kanagawa Cancer Center.\n\nPatients\nIn total, the cases of 85 consecutive patients with intermediate-risk prostate cancer who received CIRT at i-ROCK between December 2015 and December 2017 were analyzed in the present study. The patients were classified using the D’Amico risk group classification [21]. The clinical stage was determined using computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, and other diagnostic images. The eligibility criteria for this study were as follows: (i) histological diagnosis of prostate adenocarcinoma, (ii) cT1cN0M0 to T2bN0M0 according to the 7th UICC classification, (iii) performance status of 0–2, (iv) age of 20 years or older, (v) no previous treatment for prostate cancer excluding ADT, and (vi) followed up at least 1 year post-CIRT.\n\nCIRT\nAll patients were treated at i-ROCK in Japan. The first clinical treatment for prostate cancer at the i-ROCK was performed in 2015 [22].\n\nPatients were placed in the supine position on a vacuum mattress (BlueBAG: Elekta AB, Stockholm, Sweden) and immobilized using thermoplastic shells (Shellfitter: Kuraray, Tokyo, Japan). Enema was used before CT for CIRT planning. The rectum was emptied as much as possible using a laxative and an antiflatulent before each session, and enema was performed if the patient did not defecate within 24 h of treatment. The patients urinated and drank water 60 min before CT. A set of CT images with 2-mm-thick slices was taken for treatment planning.\n\nContouring of the target volumes and normal tissues was performed using MIM maestro software version 5.6 (MIM Software Inc., Cleveland, OH, USA). Dose calculation and optimization were performed using the Monaco version 5.20 system (Elekta AB).\n\nThe prostate volume was measured via CT imaging. The gross tumor volume was not defined. The clinical target volume (CTV) included the entire prostate and proximal seminal vesicles. Planning target volume (PTV) 1 was created by adding anterior and lateral margins of 10 mm and a posterior margin of 5 mm to the CTV. Boost therapy was performed using PTV2, in which the posterior edge was set in front of the anterior wall of the rectum to reduce the rectal dose in the ninth course of treatment [23, 24]. The rectum was delineated as the organ at risk from 10 mm above the upper margin of the PTV to 10 mm below the lower margin of the PTV.\n\nThe total dose was set at 51.6 Gy (RBE). After the first eight fractions were delivered using PTV1, boost therapy was performed using PTV2 in the latter four fractions. The PTV was covered by ≥95% of the prescribed dose, and the maximum PTV dose was limited to <105% of the prescribed dose. The dose constraint for the rectum aimed at V80% < 10 ml.\n\nCIRT was administered once daily for 4 days a week for 3 weeks. All patients were treated using the spot scanning method. CIRT was performed from both the right and left sides of the patient. One port was used for each treatment session. Verification of the patient position was performed using in-room CT during the first, fifth, and ninth treatment sessions. In each treatment session, a computer-aided online positioning system was employed to verify the positioning accuracy to less than 1 mm.\n\nADT\nUrologists administered ADT. Neoadjuvant ADT was administered for 4–8 months through the end of CIRT [6]. ADT was performed via combined androgen blockade with an antiandrogen plus medical castration in principle. We performed a representative ADT using a combination of bicalutamide and leuprorelin acetate.\n\nFollow-up\nA urologist and a radiation oncologist conducted patient follow-up at 3-month intervals for the first 3 years after CIRT and at 6-month intervals thereafter. PSA was measured at each follow-up visit. In the present study, the PSA bounce was defined as a PSA increase of at least 0.4 ng/ml from the nadir PSA level, followed by any decrease [25, 26]. PSA failure was defined using the Phoenix definition, namely, the nadir PSA level plus 2 ng/ml [27]. The follow-up period and the time to the event were calculated from the start of CIRT to the date of the event.\n\nStatistical analysis\nStatistical analysis was performed using STATA software (version 13.1, TX, USA). The correlation of clinical variables with PSA dynamics was assessed via the Cox regression analyses. Prognostic factors, for which p value was calculated as <0.10, were evaluated using the multivariate stepwise Cox regression model [28]. Comparative analyses for continuous variables, such as PSA level and age of the two groups, were examined using the Mann–Whitney U test. Non-parametric receiver operating characteristic (ROC) curves were generated and Youden index (J = max [sensitivity + specificity– 1]) was used to determine the optimal cut-off values [29]. Comparative analyses for categorical variables of the two groups were examined using the chi-squared test. A p value of <0.05 was considered significant. The PSA failure-free survival rate was estimated using the Kaplan–Meier method.\n\nResults\nPatient characteristics\nPatient characteristics are summarized in Table 1. The median patient age was 68 (range, 48–81) years. The median follow-up duration was 33.1 (range, 20.1–48.3) months. All patients completed CIRT on schedule. Neoadjuvant ADT was administered to all patients, and the median duration of ADT was 6.2 (range, 2.3–116.9) months. The patient who received ADT for 116.9 months, which is an outlier, was treated via combined androgen blockade in the first year. PSA elevation was observed 4 years after initial ADT, and the patient was treated by antiandrogen alone irregularly when PSA elevation was observed. Four months of combined androgen blockage was performed in this patient before CIRT. Pre-CIRT PSA levels were measured a median of 15 (range, 0–40) days before the start of CIRT.\n\n10.1371/journal.pone.0241636.t001Table 1 Patient characteristics (n = 85).\nCharacteristics\tn (%)\t\nFollow-up duration, months, median (range)\t33.1 (20.1–48.3)\t\nAge, years, median (range)\t68 (48–81)\t\nT stage\t\t\n 1c\t27 (31.8%)\t\n 2a\t44 (51.8%)\t\n 2b\t14 (16.5%)\t\nPretreatment PSA, ng/ml, median (range)\t7.37 (3.33–19.0)\t\n < 10\t62 72.9%)\t\n 10 ≤ 20\t23 (27.1%)\t\nGleason score\t\t\n 6\t3 (3.5%)\t\n 7\t82 (96.5%)\t\nD’Amico classification\t\t\n intermediate\t85 (100.0%)\t\nADT\t\t\n neoadjuvant\t85 (100.0%)\t\n duration, month, median (range)\t6.2 (2.3–116.9)\t\nProstate volume, cc, median (range)\t26.9 (11.9–88.2)\t\npre-CIRT PSA, ng/ml, median (range)\t0.31 (0.01–3.28)\t\nTime to nadir PSA, month, median (range)\t3 (3–24)\t\nPSA: Prostate specific antigen, ADT: Androgen deprivation therapy.\n\nPSA dynamics\nPSA dynamics for all patients is presented in Fig 1(a). The average PSA dynamics based on the presence or absence of the PSA bounce is presented in Fig 1(b). The average PSA level in the PSA bounce group was significantly higher than that in the PSA bounce-free group beyond 3 months after CIRT (p < 0.05). The average PSA dynamics for the presence or absence of PSA failure is presented in Fig 1(c). The average PSA level in the PSA failure group was significantly higher than that in the PSA failure-free group before CIRT and at all time points between 6 and 36 months after CIRT, excluding 30 months (p < 0.05).\n\n10.1371/journal.pone.0241636.g001Fig 1 (a). Prostate-specific antigen (PSA) dynamics after carbon ion radiotherapy (CIRT) for all patients. The PSA dynamics in patients with biochemical relapse is indicated by the red line. No clinical recurrence was observed. (b). The average PSA dynamics in patients with or without PSA bounces. (c). The average PSA dynamics in patients with or without PSA failure.\n\nPSA bounces were observed in 39 patients (45.9%) a median of 12 (range, 6–30) months after CIRT. Predictive significance of clinical variables for the occurrence of PSA bounces was assessed via Cox regression analysis (Table 2). In the univariate analysis, younger age, lower T stage, and higher PSA nadir were significantly associated with the occurrence of a PSA bounce (p < 0.001, 0.015, and 0.029, respectively). The median ages of patients with and without PSA bounces were 68 (range, 48–79) and 70 (range, 55–81) years, respectively (p = 0.001). The T stage in the PSA bounce group was T1c, T2a, and T2b in 16 (41.0%), 20 (51.3%), and 3 (7.7%) patients, respectively, versus 11 (23.9%), 24 (52.2%), and 11 (23.9%) patients, respectively, in the PSA bounce-free group (p = 0.027). The median PSA nadir of patients with and without PSA bounces were 0.014 ng/ml (range, 0–2.183 ng/ml) and 0 ng/ml (range, 0–0.201 ng/ml), respectively (p = 0.002). ADT duration was not correlated with the occurrence of PSA bounce (p = 0.731). In the multivariate analyses, younger age and lower T stage were significantly associated with the occurrence of a PSA bounce (p < 0.001 and 0.049, respectively). The ROC curve analysis calculated the area under the ROC curve (AUC) as 0.705 and determined a cut-off value of 68 years, at which the sensitivity and specificity were measured to be 76.1 and 61.5%, respectively (Fig 2a).\n\n10.1371/journal.pone.0241636.g002Fig 2 (a). ROC curve for the correlation between PSA bounce and age. The area under the ROC curve was 0.705. The cut-off value was 68 years, at which the sensitivity and specificity were 76.1 and 61.5%, respectively. (b). ROC curve for the correlation between PSA bounce and age. The area under the ROC curve was 0.844. The cut-off value was 65 years, at which the sensitivity and specificity were 77.9 and 87.5%, respectively.\n\n10.1371/journal.pone.0241636.t002Table 2 Predictive significance of clinical factors for the occurrence of PSA bounce.\n\tUnivariate\t\tMultivariate\t\t\nHR\t(95% CI)\tp-value\tHR\t(95% CI)\tp-value\t\nAge\t0.92\t(0.88–0.96)\t< 0.001\t0.92\t(0.88–0.96)\t< 0.001\t\nT stage\t0.55\t(0.34–0.89)\t0.015\t0.60\t(0.37–0.99)\t0.049\t\nGleason score\t0.69\t(0.17–2.86)\t0.605\t-\t\t\t\ninitial PSA\t0.97\t(0.88–1.07)\t0.587\t-\t\t\t\nProstate volume\t1.02\t(0.99–1.04)\t0.088\t1.01\t(0.99–1.03)\t0.159\t\nADT duration\t1.00\t(0.98–1.02)\t0.731\t-\t\t\t\npre-CIRT PSA\t1.28\t(0.89–1.84)\t0.181\t-\t\t\t\nPSA nadir\t2.55\t(1.10–5.88)\t0.029\t2.00\t(0.87–4.64)\t0.104\t\nTime to PSA nadir\t0.93\t(0.81–1.06)\t0.284\t-\t\t\t\nPSA: Prostate specific antigen, ADT: Androgen deprivation therapy, CIRT: Carbon ion radiotherapy, HR: Hazard ratios, CI: Confidence interval.\n\nPrognostic factors, for which p value was calculated as < 0.10, were evaluated by multivariate analysis.\n\nPSA failure was observed in eight patients (9.4%). The characteristics of eight patients with PSA failure are summarized in Table 3. Of these eight patients with PSA failure, the PSA level decreased in seven patients without any treatment such as ADT in a median of 3 (range, 3–15) months after PSA failure. No salvage treatments were performed in these seven patients in the follow-up period. The remaining patient received ADT immediately after the occurrence of PSA failure without radiological confirmation of clinical recurrence. As shown in Fig 3, the 3-year PSA failure-free rate was 88.5%. PSA failure occurred in a median of 21 (range, 15–33) months after CIRT. Clinical recurrence was not detected by CT, MRI, and bone scintigraphy.\n\n10.1371/journal.pone.0241636.g003Fig 3 Prostate-specific antigen (PSA) failure-free rate.\nThe 3-year PSA failure-free rate was 88.5%.\n\n10.1371/journal.pone.0241636.t003Table 3 Characteristics of patients with PSA failure.\nAge\tT stage\tPSA (ng/ml)\tGleason score\tTime to failure (month)\tPSA dynamics after PSA failure\tTime to decreasing PSA after PSA failure (month)\t\n61\tT2b\t17.09\t7\t33\tdecreased spontaneously\t3\t\n61\tT2a\t9.2\t7\t21\tdecreased spontaneously\t3\t\n64\tT1c\t11.21\t7\t21\tdecreased spontaneously\t15\t\n58\tT2a\t8.43\t7\t15\tdecreased spontaneously\t3\t\n54\tT1c\t4.83\t7\t15\tdecreased spontaneously\t6\t\n63\tT2a\t14.79\t7\t30\tdecreased spontaneously\t3\t\n50\tT2a\t6.27\t7\t21\tdecreased spontaneously\t3\t\n68\tT2a\t8.35\t7\t24\tdecreased by ADT\t3\t\nPSA: Prostate specific antigen, ADT: Androgen deprivation therapy.\n\nThe predictive significance of clinical variables for the occurrence of PSA failure was assessed via the Cox regression analyses (Table 4). In the univariate analysis, younger age, higher pre-CIRT PSA levels, and higher PSA nadir were significantly associated with the occurrence of PSA failure (p = 0.002, 0.007, and 0.003, respectively). The median ages of patients with and without PSA failure were 61 (range, 50–68) and 69 (range, 48–81) years, respectively (p = 0.001). The median pre-CIRT PSA levels of patients with and without PSA failure were 1.24 (range, 0.30–3.97) and 0.25 (range, 0.01–3.28) ng/ml, respectively (p = 0.009). The median PSA nadir of patients with and without PSA bounces were 0.014 ng/ml (range, 0–2.183 ng/ml) and 0 ng/ml (range, 0–0.201 ng/ml), respectively (p = 0.002). ADT duration was not correlated with the occurrence of PSA failure (p = 0.614). In the multivariate analysis, only younger age was statistically significantly associated with the occurrence of PSA failure (p = 0.008). The ROC curve analysis calculated the area under the ROC curve (AUC) as 0.844 and determined a cut-off value of 65 years, at which the sensitivity and specificity were calculated as 77.9 and 87.5%, respectively (Fig 2b).\n\n10.1371/journal.pone.0241636.t004Table 4 Predictive significance of clinical factors for the occurrence of PSA failure.\n\tUnivariate\t\tMultivariate\t\t\nHR\t(95% CI)\tp-value\tOR\t(95% CI)\tp-value\t\nAge\t0.86\t(0.79–0.95)\t0.002\t0.85\t(0.75–0.96)\t0.008\t\nT stage\t1.02\t(0.37–2.82)\t0.962\t-\t\t\t\nGleason score\tNA\t-\t-\t-\t\t\t\ninitial PSA\t1.12\t(0.95–1.31)\t0.166\t-\t\t\t\nProstate volume\t1.03\t(0.99–1.07)\t0.093\t1,04\t(0.97–1.09)\t0.153\t\nADT duration\t0.93\t(0.71–1.22)\t0.614\t-\t\t\t\npre-CIRT PSA\t2.45\t(1.28–4.70)\t0.007\t1.61\t(0.72–3.57)\t0.244\t\nPSA nadir\t6.67\t(1.88–23.64)\t0.003\t3.34\t(0.92–12.08)\t0.066\t\nTime to PSA nadir\t0.84\t(0.54–1.31)\t0.443\t-\t\t\t\nPSA bounce\t7.84\t(0.96–63.85)\t0.054\t2.52\t(0.28–22.93)\t0.411\t\nPSA: Prostate specific antigen, ADT: Androgen deprivation therapy, CIRT: Carbon ion radiotherapy, HR: Hazard ratios, CI: Confidence interval, NA: Not available.\n\nPrognostic factors, for which p value was calculated as < 0.10, were evaluated by multivariate analysis.\n\nDiscussion\nWe investigated the dynamics of PSA in patients with prostate cancer who were treated with CIRT and neoadjuvant ADT in the present study. The occurrence of PSA bounce and failure was correlated with younger age. To the best of our knowledge, this is the first report of PSA dynamics after CIRT with neoadjuvant ADT.\n\nMultiple definitions of the PSA bounce have been reported, and no consensus has been established. Several studies used the definition of an increase of >0.2 ng/ml in PSA levels followed by a spontaneous decrease to the pre-bounce level or lower [13, 16, 20, 30, 31]. In the present study, no patient met this definition, as the nadir PSA level was extremely low because of the use of neoadjuvant ADT. Thus, we defined the PSA bounce as an increase of at least 0.4 ng/ml followed by any decrease, in line with previous studies [25, 26]. In a study of PSA bounces in patients treated with conventional external radiotherapy, the bounce was defined as an increase of 0.5 ng/ml [32]. Conversely, the PSA bounce was defined as an increase of 0.1 ng/ml followed by two consecutive decreases after IMRT [33].\n\nPSA bounces have been mainly reported after brachytherapy. PSA bounces were observed in 28%–49% of patients after LDR-BT [14]. In two other studies, PSA bounces were observed in 43 and 48% of patients treated with HDR-BT, respectively [34, 35]. In a study of PSA dynamics after HDR-BT combined with conventional external beam radiotherapy, PSA bounces were detected in 31% patients [36].\n\nPSA bounces have also been observed in patients treated with external beam radiotherapy alone. After IMRT, the occurrence rate of PSA bounces ranged 11%–32% [25, 33, 37, 38]. Recently, SRT has been performed for the definitive treatment of prostate cancer, and PSA bounces were also observed after SRT. In a multi-institutional analysis of PSA dynamics, PSA bounces were noted in 26% of patients [18]. Only one study of PSA dynamics after particle beam radiotherapy has been reported [20]. In that study, PSA bounces were observed in 55.7% of patients treated with CIRT alone for prostate cancer.\n\nAge was one of the first and most frequently described predictive factors for PSA bounces after brachytherapy [14]. Age was a significant consistent predictor of PSA bounces after IMRT [25, 33]. Regarding other treatment modalities, namely, SRT or HDR-BT combined with external beam radiotherapy, younger age was a significant predictor for PSA bounces [18, 36]. In addition, age was detected as a predictive factor for PSA bounces after CIRT [20]. Similar results were observed in the present study, as younger age was a predictive factor for PSA bounces and PSA failure. Therefore, it is suggested that age is a predictor for PSA bounce regardless of the radiotherapy modality.\n\nIn the present study, lower T stage was significantly correlated with PSA bounce. In a study of the PSA bounce after LDR-BT, lower T stage was one of the predictive factors for PSA bounce [39]. Sengoz et al. reported that PSA bounce was more frequent in patients with T1–2 stage cancers after external body radiation therapy [40]. The mechanism by which lower T stage tended to correlate with PSA bounces was unclear. Several previous studies have suggested that T stage has no correlation with PSA bounces [14, 19, 36]. Further investigation is warranted to reveal the correlation between T stage and PSA bounces.\n\nDespite the accumulation of data on post-radiotherapy PSA dynamics, its relevance to clinical outcomes remains unclear. One study suggested that PSA bounces did not predict biochemical recurrence or clinical disease recurrence [33]. Another study reported that PSA bounces after external beam radiotherapy were correlated with PSA failure [26]. By contrast, some reports stated that the PSA bounce was a good predictive factor for PSA failure [19]. Hinnen et al. found that PSA bounces after LDR-BT were predictive of better outcomes [41]. A long-term analysis suggested that the PSA bounce was a significant factor for better overall survival [42]. In CIRT, PSA bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival [20]. In the present study, a significant correlation between PSA bounces and PSA failure was not observed; however, PSA bounces tended to correlate with PSA failure. Longer follow-up is warranted to further explain this issue.\n\nSome patients who exhibited PSA bounces experienced increases in PSA levels of 2 ng/ml or more, which met the Phoenix criteria. The PSA bounce exceeds the 2 ng/ml limit in approximately 10% of patients after brachytherapy [13]. Approximately 1% of patients treated with SRT experienced a PSA increase of >2 ng/ml above the nadir [18]. However, PSA levels spontaneously decreased without any treatment in those patients. A similar clinical course was observed in the present study, as most patients experienced spontaneous decreases of PSA levels. Therefore, even among patients with PSA increases exceeding 2 ng/ml, which met the PSA failure criteria, continuous close PSA surveillance should be considered to confirm the PSA bounce without immediate treatment such as ADT. These findings may provide important information for both patients and physicians to understand PSA dynamics after CIRT.\n\nThe present study had several limitations, such as its single-institutional nature, small number of patients, short observation period, and lack of cases of clinical recurrence. In particular, the small number of PSA failure cases could reduce the power of the statistical analysis. Although the correlation between PSA bounces and androgen production in younger age patients was suggested [43], serum androgen levels were not measured in the present study.\n\nConclusions\nWe observed the dynamics of PSA in patients with prostate cancer who were treated with CIRT and neoadjuvant ADT in the present study. PSA levels should be examined after treatment to survey for clinical recurrence. Further follow-up is needed to reveal the clinical significance of PSA dynamics.\n\nAbbreviations\nADTandrogen-deprivation therapy\n\nAUCarea under the curve\n\nCIRTcarbon ion radiotherapy\n\nCTcomputed tomography\n\nCTVclinical target volume\n\nHDR-BThigh-dose-rate brachytherapy\n\nIMRTintensity-modulated radiotherapy\n\ni-ROCKion-beam Radiation Oncology Center in Kanagawa\n\nLDR-BTlow-dose-rate brachytherapy\n\nMRImagnetic resonance imaging\n\nPSAprostate-specific antigen\n\nPTVplanning target volume\n\nRBErelative biological effectiveness\n\nROCreceiver operating characteristic\n\nSRTstereotactic radiation therapy\n\n10.1371/journal.pone.0241636.r001\nDecision Letter 0\nChun Stephen Academic Editor © 2020 Stephen Chun2020Stephen ChunThis 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.Submission Version0\n14 Jul 2020\n\n\nPONE-D-20-18791\n\nProstate-Specific Antigen Dynamics After Carbon Ion Radiotherapy for Prostate Cancer\n\nPLOS ONE\n\nDear Dr. Takakusagi,\n\nThank you for submitting your manuscript to PLOS ONE. 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The conclusions must be drawn appropriately based on the data presented. \n\nReviewer #1: No\n\nReviewer #2: Yes\n\nReviewer #3: Partly\n\n**********\n\n2. Has the statistical analysis been performed appropriately and rigorously? \n\nReviewer #1: No\n\nReviewer #2: Yes\n\nReviewer #3: No\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\nReviewer #3: No\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\nReviewer #3: No\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: Dear authors, thank you for submitting this manuscript, which I read with great interest. Please find my comments below, which I hope will be a positive contribution.\n\nSummary:\n\nThis manuscript reviews the retrospective analysis of PSA failure and bounce for the patients with intermediate-risk prostate cancer treated with CIRT combined with neoadjuvant hormonal therapy at a single institution. There is limited information about PSA kinetics about CIRT combined with hormonal therapy.\n\nThis reviewer has some significant concerns that need to be addressed by the authors:\n\nComments:\n\nAbstraction\n\nLine 53, 54:\n\nIt would be helpful to have a more specific conclusion based on the findings of the data reported in the paper. Statements with \"investigated\" are not conclusions.\n\nBackground\n\nLine 74-77:The facility's description is considered to be not directly relevant in the background. I recommend that you consider moving it to the methods paragraph.\n\nMaterials and Methods\n\nLine 134-135: Describe the details of dose constraints other than the rectum.\n\nLine 156: Statistical Analysis Paragraph\n\n\"The correlation of clinical variables with PSA dynamics was assessed via logistic regression.\" In Table 2 and 4, was logistic regression analysis performed for both univariate and multivariate analyses? If not, please add a different test method used for univariate analysis.\n\nPSA failure and PSA bounce are both time series data and it is not appropriate to use logistic regression in the test method\n\nIn the multivariable analysis, the number of independent variables greatly exceeds the number of occurrence events, which lead to inappropriate results. Describe the process of selecting explanatory variables.\n\nClarify the detail about the statistical methods for differences between groups in the PSA time series used in Figures 1b and 1c.\n\nResults\n\nTables:\n\nRemove unnecessary gray lines in each table.\n\nTable1: The sum of pretreatment PSA is not 85. Correct the number of patient numbers in each category.\n\nTable2: The results of PSA nadir is not correctly displayed.\n\nReviewer #2: Given the fact that the clinical significance of PSA bounce is unclear and its definition is various, I think such a prospective observational study is valuable. This manuscript is very important as the first report of PSA dynamics after CIRT with neoadjuvant ADT.\n\nI have one question that there were 8 patients with PSA failure, 7 were followed up, and only 1 was treated immediately. What is the reason for this difference?\n\nReviewer #3: General comments\n\nCarbon ion radiotherapy requires advanced technique and the patient number is limited compared with those who receive photon radiotherapy. The current study analyzed intermediate risk prostate cancer patients who received CIRT and ADT to illustrate the dynamics of PSA after treatment.\n\nIt is essential to further describe the intention to investigate PSA dynamics for prostate cancer after CIRT and ADT and potential clinical impact to emphasize the value of this study.\n\nSpecific comments\n\nMaterials and methods section\n\n1. How many patients were in the favorable intermediate risk group among the 85 patients? If any, please describe the indication of neoadjuvant ADT use.\n\n2. Please describe the ADT regimen (drug name and dosage) specifically and clarify the last dose of ADT and its active duration.\n\n3. Please explain why patients received neoadjuvant ADT of various duration (4 to 8 months) in this study. Did the authors investigate whether the duration of ADT administration was associated with the time interval of subsequent incidents of PSA bounce/PSA failure?\n\nStatistical analysis section\n\n4. Please describe the starting date to calculate the follow-up time.\n\n5. The current study investigated the correlation between different continuous variables and PSA bounce/PSA failure. ROC curve analysis should be adopted to survey the potential cutoff value of these continuous variables.\n\n6. Cox regression should be considered in multivariate analysis to investigate the effect of these variables on the time it takes for PSA bounce or PSA failure to happen.\n\nResults section\n\n7. The median follow-up time was 33.1 (range, 20.1–48.3) months, which is relatively short for intermediate risk group prostate cancer patients.\n\n8. Compared with conventional fractionated RT for prostate (about 7 to 8 weeks), the treatment course of 3 weeks using CIRT was relatively short. Usually, the decline of PSA after RT is gradual and it usually take several months to reach the PSA nadir. Most patients in the current study reached nadir rapidly within 3 to 4 months after CIRT. How can the authors confirm that the nadir is due to the effect of CIRT (unique RBE?) rather than effect of ADT?\n\n9. Only eight patients developed biochemical failure during follow-up of this cohort. The small number could reduce the power of statistical analysis.\n\n10. Seven of eight patients developed PSA failure and five of them had PSA level decrease spontaneously. Please explain the findings.\n\n11. Only one out of eight patients with PSA failure received salvage ADT. What about the other patients? Did those patients receive any other salvage therapy? Otherwise, the authors should provide the subsequent management and clinical course of those patients.\n\nDiscussion section\n\n12. The authors could try to review the published literature to compare the PSA dynamics of intermediate risk prostate cancer patients receiving CIRT, CIRT with ADT, IMRT, and IMRT with ADT.\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\nReviewer #3: 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\n10.1371/journal.pone.0241636.r002\nAuthor response to Decision Letter 0\nSubmission Version1\n10 Aug 2020\n\n\nReviewer #1: \n\nThank you for your review and precise suggestions. We have revised our manuscript according to your suggestions as follows: \n\n“Dear authors, thank you for submitting this manuscript, which I read with great interest. Please find my comments below, which I hope will be a positive contribution.\n\nSummary:\n\nThis manuscript reviews the retrospective analysis of PSA failure and bounce for the patients with intermediate-risk prostate cancer treated with CIRT combined with neoadjuvant hormonal therapy at a single institution. There is limited information about PSA kinetics about CIRT combined with hormonal therapy.\n\nThis reviewer has some significant concerns that need to be addressed by the authors:”\n\nComments:\n\nAbstraction\n\n“Line 53, 54:\n\nIt would be helpful to have a more specific conclusion based on the findings of the data reported in the paper. Statements with \"investigated\" are not conclusions.”\n\n We have revised the Conclusion of the Abstract. A new sentence has been added to explain our study in the Conclusion. (Page 4, lines 54 to 55).\n\n “This study revealed the significant predictors of PSA bounce and PSA failure.”\n\n“Background\n\nLine 74-77:The facility's description is considered to be not directly relevant in the background. I recommend that you consider moving it to the methods paragraph.”\n\n The sentence describing our facility has been moved to the Materials and Methods section. (pages 7–8, lines 112–113). \n\n“Materials and Methods\n\nLine 134-135: Describe the details of dose constraints other than the rectum.”\n\n V80% < 10ml for the rectum was the only dose constraint in this study. Other DVH parameters for the rectum were not used for dose constraints. We did not use dose constraints for other normal tissues, such as bladder, urethra, penile bulb, and femoral head. \n\n“Line 156: Statistical Analysis Paragraph\n\n\"The correlation of clinical variables with PSA dynamics was assessed via logistic regression.\" In Table 2 and 4, was logistic regression analysis performed for both univariate and multivariate analyses? If not, please add a different test method used for univariate analysis.\n\nPSA failure and PSA bounce are both time series data and it is not appropriate to use logistic regression in the test method\n\nIn the multivariable analysis, the number of independent variables greatly exceeds the number of occurrence events, which lead to inappropriate results. Describe the process of selecting explanatory variables.”\n\nWe have revised the statistical analysis according to the comments. The Cox regression model was newly adopted for both univariate and multivariate analyses. Another reviewer suggested that we analyze the ROC curve. We have revised the manuscript to explain the statistical methods in the Materials and Methods section. (Page 10, lines 161–167).\n\n “The correlation of clinical variables with PSA dynamics was assessed via Cox regression model. Prognostic factors of which p value was calculated as < 0.10 were evaluated by multivariate stepwise Cox regression model [28]. Comparative analyses for continuous variables such as PSA level and age of the two groups were examined using the Mann–Whitney U test. Receiver operating characteristic (ROC) curves were generated and used to determine the optimal cut-off value.”\n\nThe results were modified using the Cox regression model. We have revised Tables 2 and 4 to reflect these changes and have revised the text to explain the new results. (Page 15, lines 203–205; page 16, lines 210–214; page 19, lines 238–240; and pages 19–20, lines 244–246).\n\n“In the univariate analysis, younger age, lower T stage and higher PSA nadir were statistically significantly associated with the occurrence of a PSA bounce (p = 0.000, 0.015 and 0.029, respectively).”\n\n“The median PSA nadir of patients with and without PSA bounces were 0.014 (range, 0-2.183) and 0 (range, 0-0.201) ng/ml, respectively (p = 0.002). In the multivariate analysis, younger age and lower T stage were significantly associated with the occurrence of a PSA bounce (p = 0.000 and 0.049, respectively).”\n\n“In the univariate analysis, younger age, higher pre-CIRT PSA levels, and higher PSA nadir were significantly associated with the occurrence of PSA failure (p = 0.002, 0.007, and 0.003, respectively).”\n\n“The median PSA nadir of patients with and without PSA bounces were 0.014 (range, 0-2.183) and 0 (range, 0-0.201) ng/ml, respectively (p = 0.002).”\n\nThe Cox regression model revealed that T stage was also correlated with PSA bounces, so we have added explanations of these results to the Results section. (Page 20, lines 212 to 214) We have also added a discussion about the relationship between T stage and PSA bounces to the Discussion section. (Page 24, lines 294 to 301).\n\n“In the multivariate analysis, younger age and lower T stage were significantly associated with the occurrence of a PSA bounce (p = 0.000 and 0.049, respectively).”\n\n“In the present study, lower T stage was significantly correlated with PSA bounce. In a study of the PSA bounce after LDR-BT, lower T stage was one of the predictive factors for PSA bounce [38]. Sengoz et al. reported that PSA bounce was more frequent in patients with T1-2 stage after external body radiation therapy [39]. The mechanism which lower T stage tended to correlate with PSA bounces was unclear. On the other hand, there were several studies suggested that T stage had no correlation with PSA bounces [14, 19, 35]. Further investigation is warranted to reveal the correlation between T stage and PSA bounces.”\n\nWe have added a new figure to show the ROC curves (Fig. 2a and 2b).\n\n“Clarify the detail about the statistical methods for differences between groups in the PSA time series used in Figures 1b and 1c.”\n\nWe have revised the manuscript to clarify the statistical methods for PSA in each of the two groups. (Page 11, lines 164 to 166).\n\n “Comparative analyses for continuous variables such as PSA level and age of the two groups were examined using the Mann–Whitney U test.”\n\n“Results\n\nTables:\n\nRemove unnecessary gray lines in each table.”\n\nThe gray lines are not shown in the PDF file. We have attached the PDF file for the tables.\n\n“Table1: The sum of pretreatment PSA is not 85. Correct the number of patient numbers in each category.\n\nTable2: The results of PSA nadir is not correctly displayed.”\n\nWe have revised Tables 1 and 2 accordingly.\n\n \n\nReviewer #2: \n\nThank you for your review and precise suggestions. We have revised our manuscript according to your suggestions as follows: \n\n“Given the fact that the clinical significance of PSA bounce is unclear and its definition is various, I think such a prospective observational study is valuable. This manuscript is very important as the first report of PSA dynamics after CIRT with neoadjuvant ADT.\n\nI have one question that there were 8 patients with PSA failure, 7 were followed up, and only 1 was treated immediately. What is the reason for this difference?” \n\nWe had not decided the treatment protocol after PSA failure, and each urologist determined the treatment policy for each case. We have to consider the treatment policy for the patient with PSA failure. As the results of the present study showed that PSA level decreased without treatment in many PSA failure cases, we believe that careful follow-up is important.\n\n \n\nReviewer #3: \n\nThank you for your review and precise suggestions. We have revised our manuscript according to your suggestions. \n\n“General comments\n\nCarbon ion radiotherapy requires advanced technique and the patient number is limited compared with those who receive photon radiotherapy. The current study analyzed intermediate risk prostate cancer patients who received CIRT and ADT to illustrate the dynamics of PSA after treatment.”\n\n“It is essential to further describe the intention to investigate PSA dynamics for prostate cancer after CIRT and ADT and potential clinical impact to emphasize the value of this study.”\n\nSpecific comments\n\nMaterials and methods section\n\n“1. How many patients were in the favorable intermediate risk group among the 85 patients? If any, please describe the indication of neoadjuvant ADT use.”\n\nThirty patients were found to be in the favorable intermediate risk group after NCCN classification. Because we used the D’Amico classification in this study, intermediate risk was not divided into favorable and unfavorable groups. It is still unclear whether ADT is necessary for patients with favorable intermediate risk of prostate cancer treated by CIRT. This is a subject for future analysis.\n\n“2. Please describe the ADT regimen (drug name and dosage) specifically and clarify the last dose of ADT and its active duration.”\n\nWe have explained the ADT regimen in the Materials and Methods section. (Page 10, lines 148–149).\n\n “We performed a representative ADT using a combination of bicaltamide and leuprorelin acetate.”\n\n“3. Please explain why patients received neoadjuvant ADT of various duration (4 to 8 months) in this study. Did the authors investigate whether the duration of ADT administration was associated with the time interval of subsequent incidents of PSA bounce/PSA failure?”\n\nThe ADT duration was determined by the results of previous research. We have added a reference to clarify the previous research. (Page 10, line 147).\n\nThe ADT duration was not associated with either PSA bounce or PSA failure (Tables 2 and 4).\n\nStatistical analysis section\n\n“4. Please describe the starting date to calculate the follow-up time.”\n\nWe have modified the Materials and Methods section to clarify the starting date in order to calculate the follow-up time. (Page 10, lines 157 to 158).\n\n“5. The current study investigated the correlation between different continuous variables and PSA bounce/PSA failure. ROC curve analysis should be adopted to survey the potential cutoff value of these continuous variables.”\n\nWe performed a ROC curve analysis. We have added new sentences to the Materials and Methods section to explain the statistical analysis. (Page 11, lines 166–167).\n\n “Receiver operating characteristic (ROC) curves were generated and used to determine the optimal cut-off value.”\n\nWe have added new figures (Fig. 2a and 2b) and sentences to explain the results of the ROC analyses. (Page 16, lines 214–217 and page 20, lines 247–250).\n\n“The ROC curve analysis calculated the area under the ROC curve (AUC) as 0.705 and determined a cut-off value of 68 years, at which the sensitivity and specificity were measured to be 76.1 and 61.5 %, respectively. (Fig 2(a))” \n\n“The ROC curve analysis calculated the area under the ROC curve (AUC) as 0.844 and determined a cut-off value of 65 years, at which the sensitivity and specificity were calculated as 77.9 and 87.5 %, respectively. (Fig 2(b))”\n\n“6. Cox regression should be considered in multivariate analysis to investigate the effect of these variables on the time it takes for PSA bounce or PSA failure to happen.”\n\nWe have revised the statistical analysis section. Cox regression model was newly adopted for both univariate and multivariate analyses. We have revised the Materials and Methods section to explain the statistical methods. (Page 10, lines 161–167). \n\n “The correlation of clinical variables with PSA dynamics was assessed via the Cox regression analyses. Prognostic factors, for which p value was calculated as <0.10, were evaluated using the multivariate stepwise Cox regression model [28]. Comparative analyses for continuous variables, such as PSA level and age of the two groups, were examined using the Mann–Whitney U test. Receiver operating characteristic (ROC) curves were generated and used to determine the optimal cut-off values.”\n\nThe results were changed by the Cox regression model. We have revised Tables 2 and 4 and have added sentences to explain these results. (Page 15, lines 203 to 205; page 16, lines 210–214; page 19, lines 238–240; pages 19–20, lines 244–246).\n\n“In the univariate analysis, younger age, lower T stage and higher PSA nadir were statistically significantly associated with the occurrence of a PSA bounce (p = 0.000, 0.015 and 0.029, respectively).”\n\n“The median PSA nadir of patients with and without PSA bounces were 0.014 (range, 0-2.183) and 0 (range, 0-0.201) ng/ml, respectively (p = 0.002). In the multivariate analysis, younger age and lower T stage were significantly associated with the occurrence of a PSA bounce (p = 0.000 and 0.049, respectively).”\n\n“In the univariate analysis, younger age, higher pre-CIRT PSA levels, and higher PSA nadir were significantly associated with the occurrence of PSA failure (p = 0.002, 0.007, and 0.003, respectively).”\n\n“The median PSA nadir of patients with and without PSA bounces were 0.014 (range, 0-2.183) and 0 (range, 0-0.201) ng/ml, respectively (p = 0.002).”\n\nThe Cox regression model revealed that T stage was also correlated with PSA bounces, so we have added sentences to explain these results in Results section. (Page 20, lines 212 to 213) and have added a discussion regarding the relationship between T stage and PSA bounces in the Discussion section. (Page 24, lines 293 to 300).\n\n“In the multivariate analysis, younger age and lower T stage were significantly associated with the occurrence of a PSA bounce (p = 0.000 and 0.049, respectively).”\n\n“In the present study, lower T stage was significantly correlated with PSA bounce. In a study of the PSA bounce after LDR-BT, lower T stage was one of the predictive factor for PSA bounce [38]. Sengoz et al. reported that PSA bounce was more frequent in patients with T1-2 stage after external body radiation therapy [39]. The mechanism which lower T stage tended to correlate with PSA bounces was unclear. On the other hand, there were several studies suggested that T stage had no correlation with PSA bounces [14, 19, 35]. Further investigation is warranted to reveal the correlation between T stage and PSA bounces.”\n\nResults section\n\n“7. The median follow-up time was 33.1 (range, 20.1–48.3) months, which is relatively short for intermediate risk group prostate cancer patients.”\n\nWe also believe that the short follow-up duration is a limitation in this study. A longer follow-up is warranted to reveal the clinical significance of PSA dynamics.\n\n“8. Compared with conventional fractionated RT for prostate (about 7 to 8 weeks), the treatment course of 3 weeks using CIRT was relatively short. Usually, the decline of PSA after RT is gradual and it usually take several months to reach the PSA nadir. Most patients in the current study reached nadir rapidly within 3 to 4 months after CIRT. How can the authors confirm that the nadir is due to the effect of CIRT (unique RBE?) rather than effect of ADT?”\n\nDarivis et al. reported the relationship between ADT and CIRT alone (ref 20). They did not mention the duration for PSA nadir, but a figure in that study demonstrated that it takes several months or more to reach PSA nadir by CIRT alone. Therefore, it is suggested that the short time to PSA nadir in the present study may be affected ADT.\n\n9. Only eight patients developed biochemical failure during follow-up of this cohort. The small number could reduce the power of statistical analysis.\n\nWe also believe that the small number of patients with PSA failure is a limitation of the present study. Further investigation is warranted in the future.\n\n10. Seven of eight patients developed PSA failure and five of them had PSA level decrease spontaneously. Please explain the findings.\n\nBecause clinical recurrence was not observed in any of the seven patients, careful surveillance of PSA was selected and PSA level was decreased without any salvage treatment. Several cases that met the PSA failure criteria among patients with PSA bounce have been reported in previous studies (13, 18). A similar clinical course was observed in these seven patients in this study.\n\n11. Only one out of eight patients with PSA failure received salvage ADT. What about the other patients? Did those patients receive any other salvage therapy? Otherwise, the authors should provide the subsequent management and clinical course of those patients.\n\nThe seven patients with PSA failure did not receive any salvage therapy. We have added the following sentence to clarify this point: \n\n“No salvage treatments were performed in these seven patients in the follow-up period.” (Page 18, line 226 to 227).\n\nDiscussion section\n\n12. The authors could try to review the published literature to compare the PSA dynamics of intermediate risk prostate cancer patients receiving CIRT, CIRT with ADT, IMRT, and IMRT with ADT.\n\nWe could not find any previous literature that investigated PSA dynamics limited to intermediate risk groups. Especially for CIRT, there has been only one study into PSA dynamics (Darwis et al.) (20). Therefore, we believe that the present study has novelty and may provide important information for both patients and physicians to understand PSA dynamics after CIRT.\n\nAttachment Submitted filename: Responce to Reviewers.docx\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0241636.r003\nDecision Letter 1\nChun Stephen Academic Editor © 2020 Stephen Chun2020Stephen ChunThis 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.Submission Version1\n26 Aug 2020\n\n\nPONE-D-20-18791R1\n\nProstate-Specific Antigen Dynamics After Carbon Ion Radiotherapy for Prostate Cancer\n\nPLOS ONE\n\nDear Dr. Takakusagi,\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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.\n\nPlease submit your revised manuscript by Oct 10 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.\n\nPlease include the following items when submitting your revised manuscript:\n\nA rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.\n\nA marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.\n\nAn unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.\n\n\n\nIf you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.\n\nIf applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols\n\nWe look forward to receiving your revised manuscript.\n\nKind regards,\n\nStephen Chun\n\nAcademic Editor\n\nPLOS ONE\n\n[Note: HTML markup is below. Please do not edit.]\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\nReviewer #3: (No Response)\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\nReviewer #3: Partly\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously? \n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\nReviewer #3: No\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\nReviewer #3: No\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\nReviewer #3: No\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: The revised version is well re-written replying the comments of the reviewers. I feel that the revised manuscript is suitable for publication.\n\nReviewer #2: Given the fact that the clinical significance of PSA bounce is unclear and its definition is various, I think such a prospective observational study is valuable. This manuscript is very important as the first report of PSA dynamics after CIRT with neoadjuvant ADT. I think this paper is worthy for publication.\n\nReviewer #3: Thank the authors for revising the manuscript; however, some problems remain in the revised manuscript.\n\n1. The topic of the manuscript is “Prostate-Specific Antigen Dynamics After Carbon Ion Radiotherapy for Prostate Cancer.” If the authors were not able to confirm whether the PSA dynamics was due to the effect of CIRT, ADT or both, the issue of this investigation should be “Prostate-Specific Antigen Dynamics After Neoadjuvant ADT and CIRT for Prostate Cancer.” Precisely, the study demonstrated the prostate-specific antigen dynamics after neoadjuvant androgen-deprivation therapy combined with carbon ion radiotherapy for intermediate risk prostate cancer patients.\n\n2. Table 1 demonstrated that the duration of ADT were enormously diverse with median of 6.2 months (ranging from 2.3 to 116.9 months). Essentially, this arises the concern of its potential effects on the time period for PSA bounce or PSA failure. This issue stayed unexplained in the revised manuscript.\n\n3. Only eight patients developed biochemical failure during follow-up of this cohort. The small number could reduce the power of statistical analysis, which should be estimated in the manuscript.\n\n4. Importantly, the statistical analyses have some fundamental problems even after revision. The results of the univariate analysis and Cox regression model of multivariate analysis provided in Table 2 and Table 3 were insufficient to demonstrate how those parameters were correlated with the time period for PSA bounce or PSA failure to happen. For example, if younger age and lower T stage were not clearly defined in the investigation, how did authors conclude that younger age and lower T stage were associated with the time period for PSA bounce or PSA failure to occur after CIRT?\n\nBecause CIRT requires advanced techniques and the patient number is limited compared with those who receive photon radiotherapy, this requires careful statistical analysis to investigate PSA dynamics to confirm its clinical impact.\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\nReviewer #3: 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\n10.1371/journal.pone.0241636.r004\nAuthor response to Decision Letter 1\nSubmission Version2\n9 Sep 2020\n\n\nReviewer #1: The revised version is well re-written replying the comments of the reviewers. I feel that the revised manuscript is suitable for publication.\n\n We thank the reviewer for evaluating our manuscript and for their encouraging comments.\n\nReviewer #2: Given the fact that the clinical significance of PSA bounce is unclear and its definition is various, I think such a prospective observational study is valuable. This manuscript is very important as the first report of PSA dynamics after CIRT with neoadjuvant ADT. I think this paper is worthy for publication.\n\n We appreciate the reviewer’s feedback and are elated to hear this news.\n\nReviewer #3: Thank the authors for revising the manuscript; however, some problems remain in the revised manuscript.\n\nWe thank the reviewer for evaluating our manuscript. According to the suggestions, we have revised the manuscript as follows.\n\n1. The topic of the manuscript is “Prostate-Specific Antigen Dynamics After Carbon Ion Radiotherapy for Prostate Cancer.” If the authors were not able to confirm whether the PSA dynamics was due to the effect of CIRT, ADT or both, the issue of this investigation should be “Prostate-Specific Antigen Dynamics After Neoadjuvant ADT and CIRT for Prostate Cancer.” Precisely, the study demonstrated the prostate-specific antigen dynamics after neoadjuvant androgen-deprivation therapy combined with carbon ion radiotherapy for intermediate risk prostate cancer patients.\n\nWe have revised the title to “Prostate-Specific Antigen Dynamics After Neoadjuvant Androgen-Deprivation Therapy and Carbon Ion Radiotherapy for Prostate Cancer,” as per their insight (page 1, lines 2–3).\n\n2. Table 1 demonstrated that the duration of ADT were enormously diverse with median of 6.2 months (ranging from 2.3 to 116.9 months). Essentially, this arises the concern of its potential effects on the time period for PSA bounce or PSA failure. This issue stayed unexplained in the revised manuscript.\n\nTables 2 and 3 demonstrate that the ADT duration was not associated with the occurrence of PSA bounce and failure. This has been delineated in the Results section as follows: \n\nADT duration was not correlated with the occurrence of PSA bounce (p = 0.731) (page 16, lines 219–220).\n\nADT duration was not correlated with the occurrence of PSA failure (p = 0.614) (page 20, lines 258–259).\n\n3. Only eight patients developed biochemical failure during follow-up of this cohort. The small number could reduce the power of statistical analysis, which should be estimated in the manuscript.\n\nWe agree with the reviewer’s comment that this small number of patients has contributed to a reduction of statistical power. We have acknowledged this as a limitation of our study, which is as follows:\n\nIn particular, the small number of PSA failure cases could reduce the power of the statistical analysis (page 26, lines 341–342). \n\n4. Importantly, the statistical analyses have some fundamental problems even after revision. The results of the univariate analysis and Cox regression model of multivariate analysis provided in Table 2 and Table 3 were insufficient to demonstrate how those parameters were correlated with the time period for PSA bounce or PSA failure to happen. For example, if younger age and lower T stage were not clearly defined in the investigation, how did authors conclude that younger age and lower T stage were associated with the time period for PSA bounce or PSA failure to occur after CIRT?\n\nBecause CIRT requires advanced techniques and the patient number is limited compared with those who receive photon radiotherapy, this requires careful statistical analysis to investigate PSA dynamics to confirm its clinical impact.\n\nIn the present study, we solely aimed to determine the occurrence of PSA bounce, PSA failure, and related clinical factors; elucidation of the time period for PSA bounce or failure to occur was beyond the scope of this study. This has been stated in the manuscript as follows: \n\nIn this study, we identified the significant predictors of the occurrence of PSA bounce and failure. (page 4, lines 55–56).\n\nThe occurrence of PSA bounce and failure was correlated with younger age. (page 22, lines 273–274).\n\nAttachment Submitted filename: Responce to reviwers.docx\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0241636.r005\nDecision Letter 2\nChun Stephen Academic Editor © 2020 Stephen Chun2020Stephen ChunThis 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.Submission Version2\n12 Oct 2020\n\n\nPONE-D-20-18791R2\n\nProstate-Specific Antigen Dynamics After Neoadjuvant Androgen-Deprivation Therapy and Carbon Ion Radiotherapy for Prostate Cancer\n\nPLOS ONE\n\nDear Dr. Takakusagi,\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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.\n\nPlease submit your revised manuscript by Nov 26 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.\n\nPlease include the following items when submitting your revised manuscript:\n\nA rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.\n\nA marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.\n\nAn unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.\n\n\n\nIf you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.\n\nIf applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols\n\nWe look forward to receiving your revised manuscript.\n\nKind regards,\n\nStephen Chun\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (if provided):\n\nAfter additional statistical review, with minor revisions as suggested by Reviewer #4 to clarify methodology, this manuscript will be acceptable for publication.\n\n[Note: HTML markup is below. Please do not edit.]\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 #4: 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 #4: Yes\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously? \n\nReviewer #4: 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 #4: 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 #4: 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 #4: In the statistical analysis section, authors should give details on how the ROC curves were used to generate the optimal cutoffs (was it from univariable model? Or multivariable model?) or list any appropriate reference articles.\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 #4: 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\n10.1371/journal.pone.0241636.r006\nAuthor response to Decision Letter 2\nSubmission Version3\n16 Oct 2020\n\n\nReviewer #4: \n\nWe thank the reviewer for evaluating our manuscript. According to the suggestions, we have revised the manuscript as follows.\n\n“In the statistical analysis section, authors should give details on how the ROC curves were used to generate the optimal cutoffs (was it from univariable model? Or multivariable model?) or list any appropriate reference articles.”\n\nWe used Youden index to determine the optimal cut-off value. We have revised the statistical analysis section to clarify how the cut off value was generated (Page 11, lines 172-174) and a new reference have been added (ref number 29)\n\n“Non-parametric receiver operating characteristic (ROC) curves were generated and Youden index (J = max [sensitivity + specificity – 1]) was used to determine the optimal cut-off values [29].”\n\n“29) Conroy AL, Liles WC, Molyneux ME, Rogerson SJ, Kain KC. Performance characteristics of combinations of host biomarkers to identify women with occult placental malaria: a case-control study from Malawi. PLoS One. 2011;6(12)”\n\nAttachment Submitted filename: Responce to reviwer.docx\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0241636.r007\nDecision Letter 3\nChun Stephen Academic Editor © 2020 Stephen Chun2020Stephen ChunThis 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.Submission Version3\n19 Oct 2020\n\n\nProstate-Specific Antigen Dynamics After Neoadjuvant Androgen-Deprivation Therapy and Carbon Ion Radiotherapy for Prostate Cancer\n\nPONE-D-20-18791R3\n\nDear Dr. Takakusagi,\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\nStephen Chun\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (optional):\n\nReviewers' comments:\n\n10.1371/journal.pone.0241636.r008\nAcceptance letter\nChun Stephen Academic Editor © 2020 Stephen Chun2020Stephen ChunThis 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.\n28 Oct 2020\n\n\nPONE-D-20-18791R3 \n\nProstate-Specific Antigen Dynamics After Neoadjuvant Androgen-Deprivation Therapy and Carbon Ion Radiotherapy for Prostate Cancer \n\nDear Dr. Takakusagi:\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. Stephen Chun \n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n1 Ferlay J , Soerjomataram I , Dikshit R , Eser S , Mathers C , Rebelo M \net al\nCancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012\n. Int J Cancer . 2015 ;136 :E359 –86\n. 10.1002/ijc.29210 \n25220842 \n2 Shibuya H , Tsujii H . The structural characteristics of radiation oncology in Japan in 2003\n. Int. J. Radiat. Oncol. Biol. Phys . 2005 ;62 :1472 –6\n. 10.1016/j.ijrobp.2004.12.082 \n16029809 \n3 Smith GD , Pickles T , Crook J , Martin AG , Vigneault E , Cury FL , et al\nBrachytherapy improves biochemical failurefree survival in low- and intermediate-risk prostate cancer compared with conventionally fractionated external beam radiation therapy: a propensity score matched analysis\n. Int J Radiat Oncol Biol Phys \n2015 ;91 :505 –16\n. 10.1016/j.ijrobp.2014.11.018 \n25596107 \n4 Deutsch I , Zelefsky MJ , Zhang Z , Mo Q , Zaider M , Cohen G , et al\nComparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT\n. Brachytherapy \n2010 ;9 :313 –8\n. 10.1016/j.brachy.2010.02.196 \n20685176 \n5 Bryant C , Smith TL , Henderson RH , Hoppe BS , Mendenhall WM , Nichols RC , et al\nFive-Year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer\n. Int J Radiat Oncol Biol Phys \n2016 ;95 :422 –34\n. 10.1016/j.ijrobp.2016.02.038 \n27084658 \n6 Nomiya T , Tsuji H , Kawamura H , Ohno T , Toyama S , Shioyama Y , et al\nA multi-institutional analysis of prospective studies of carbon ion radiotherapy for prostate cancer: A report from the Japan Carbon ion Radiation Oncology Study Group (J-CROS)\n. Radiother Oncol . 2016 ;121 :288 –93\n. 10.1016/j.radonc.2016.10.009 \n27836119 \n7 Akakura K , Tsujii H , Morita S , Tsuji H , Yagishita T , Isaka S , et al\nPhase I/II clinical trials of carbon ion therapy for prostate cancer\n. Prostate \n2004 ;58 :252 –8\n. 10.1002/pros.10328 \n14743464 \n8 Kanai T , Endo M , Minohara S , Miyahara N , Koyama-ito H , Tomura H , et al\nBiophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy\n. Int J Radiat Oncol Biol Phys . 1999 ;44 :201 –10\n. 10.1016/s0360-3016(98)00544-6 \n10219815 \n9 Kanai T , Matsufuji N , Miyamoto T , Mizoe J , Kamada T , Tsuji H , et al\nExamination of GyE system for HIMAC carbon therapy\n. Int J Radiat Oncol Biol Phys . 2006 ;64 :650 –6\n. 10.1016/j.ijrobp.2005.09.043 \n16414376 \n10 Schulz-Ertner D , Tsujii H . Particle radiation therapy using proton and heavier ion beams\n. J Clin Oncol . 2007 ;25 :953 –64\n. 10.1200/JCO.2006.09.7816 \n17350944 \n11 Ishikawa H , Tsuji H , Kamada T , Akakura K , Suzuki H , Shimazaki J \net al\nCarbon-ion radiation therapy for prostate cancer\n. Int J Urol . 2012 ;19 :296 –305\n. 10.1111/j.1442-2042.2012.02961.x \n22320843 \n12 Takakusagi Y , Katoh H , Kano K , Anno W , Tsuchida K , Mizoguchi N , et al\nPreliminary result of carbon-ion radiotherapy using the spot scanning method for prostate cancer\n. Radiat Oncol . 2020 ;15 :127 \n10.1186/s13014-020-01575-7 \n32460889 \n13 Caloglu M , Ciezki J . Prostate-specific antigen bounce after prostate brachytherapy: review of a confusing phenomenon\n. Urology \n2009 ;74 :1183e90 \n10.1016/j.urology.2009.01.043 \n19428077 \n14 Burchardt W , Skowronek J . Time to PSA rise differentiates the PSA bounce after HDR and LDR brachytherapy of prostate cancer\n. J Contemp Brachytherapy . 2018 ;10 :1 –9\n. 10.5114/jcb.2018.73786 \n29619050 \n15 Crook J , Gillan C , Yeung I , Austen L , McLean M , Lockwood G . PSA kinetics and PSA bounce following permanent seed prostate brachytherapy\n. Int J Radiat Oncol Biol Phys \n2007 ;69 :426 –33\n. 10.1016/j.ijrobp.2007.03.031 \n17869662 \n16 Patel C , Elshaikh MA , Angermeier K , Ulchaker J , Klein EA , Chehade N , et al\nPSA bounce predicts early success in patients with permanent iodine-125 prostate implant\n. Urology \n2004 ;63 :110 –13\n\n10.1016/j.urology.2003.08.025 \n14751360 \n17 Wallner KE , Blasko J , Dattoli MJ . Evaluating cancer status\nProstate brachytherapy made complicated . Smart Medicine Press ; Seattle \n1997 \n18 Jiang NY , Dang AT , Yuan Y , Chu FI , Shabsovich D , King CR \net al\nMulti-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy\n. Int J Radiat Oncol Biol Phys . 2019 ;105 :628 –36\n. 10.1016/j.ijrobp.2019.06.2539 \n31276777 \n19 Åström L , Sandin F , Holmberg L . Good prognosis following a PSA bounce after high dose rate brachytherapy and external radiotherapy in prostate cancer\n. Radiother Oncol . 2018 ;129 :561 –6\n. 10.1016/j.radonc.2018.08.011 \n30193693 \n20 Darwis NDM , Oike T , Kawamura H , Kawahara M , Kubo N , Sato H \net al\nKinetics of prostate-specific antigen after carbon ion radiotherapy for prostate cancer\n. Cancers (Basel) . 2020 \n3 \n4 ;12 (3 ). 10.3390/cancers12030589 \n32143495 \n21 D’Amico AV , Whittington R , Malkowicz SB , Schultz D , Blank K , Broderick GA , et al\nBiochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer\n. JAMA . 1998 ;280 :969 –74\n. 10.1001/jama.280.11.969 \n9749478 \n22 Nakayama Y , Minohara S , Nonaka T , Nomiya T , Kusano Y , Takeshita E \net al\nThe Ion-Beam Radiation Oncology Center in Kanagawa (i-ROCK) Carbon Ion Facility at the Kanagawa Cancer Center\n. Int J Part Ther . 2016 ;2 :478 –80\n. 10.14338/IJPT-15-00024.1 \n31772959 \n23 Tsuji H , Yanagi T , Ishikawa H , Kamada T , Mizoe JE , Kanai T , et al\nHypofractionated radiotherapy with carbon ion beams for prostate cancer\n. Int J Radiat Oncol Biol Phys . 2005 ;63 :1153 –60\n. 10.1016/j.ijrobp.2005.04.022 \n15990247 \n24 Ishikawa H , Tsuji H , Kamada T , Yanagi T , Mizoe J.E , Kanai T , et al\nCarbon ion radiation therapy for prostate cancer: results of a prospective phase II study\n. Radiother Oncol . 2006 ;81 :57 –64\n. 10.1016/j.radonc.2006.08.015 \n16971008 \n25 Sheinbein C , Teh BS , Mai WY , Grant W , Paulino A , Butler EB . Prostate-specific antigen bounce after intensity-modulated radiotherapy for prostate cancer\n. Urology . 2010 ;76 :728 –33\n. 10.1016/j.urology.2009.04.074 \n19616279 \n26 Horwitz EM , Levy LB , Thames HD , Kupelian PA , Martinez AA , Michalski JM , et al\nBiochemical and clinical significance of the posttreatment prostate-specific antigen bounce for prostate cancer patients treated with external beam radiation therapy alone: a multiinstitutional pooled analysis\n. Cancer . 2006 ;107 :1496 –1502\n. 10.1002/cncr.22183 \n16944536 \n27 Roach M 3rd, Hanks G , Thames H Jr, Schellhammer P , Shipley WU , Sokol GH , et al\nDefining biochemical failure following radio therapy with clinically localized prostate cancer: recommendations of the RTOG- ASTRO Phoenix Consensus Conference\n. Int J Radiation Oncol Biol Phys . 2006 ;65 :965 –74\n.\n28 Hung IF , Wong DK , Poon RT , Fong DY , Chui AH , Seto WK , et al\nRisk factors and post-resection independent predictive score for the recurrence of hepatitis B-related hepatocellular carcinoma\n. PLoS One . 2016 \n2 \n22 ;11 (2 ):e0148493 \n10.1371/journal.pone.0148493 \n26901762 \n29 Conroy AL , Liles WC , Molyneux ME , Rogerson SJ , Kain KC . Performance characteristics of combinations of host biomarkers to identify women with occult placental malaria: a case-control study from Malawi\n. PLoS One . 2011 ;6 (12 ) 10.1371/journal.pone.0028540 \n22174834 \n30 Mazeron R , Bajard A , Montbarbon X , Gassa F , Malet C , Rocher F , et al\nPermanent 125I-seed prostate brachytherapy: early prostate specific antigen value as a predictor of PSA bounce occurrence\n. Radiat Oncol \n2012 ;7 :46 \n10.1186/1748-717X-7-46 \n22449081 \n31 Zwahlen DR , Smith R , Andrianopoulos N , Matheson B , Royce P , Millar JL . Prostate-specific antigen bounce after permanent iodine-125 prostate brachytherapy—an Australian analysis\n. Int J Radiat Oncol Biol Phys \n2011 ;79 :179 –87\n. 10.1016/j.ijrobp.2009.10.016 \n20378267 \n32 Rosser CJ , Kamat AM , Wang X , Do KA , Sanchez-Ortiz RF , Kuban DA \net al\nIs patient age a factor in the occurrence of prostate-specific antigen bounce phenomenon after external beam radiotherapy for prostate cancer?\n\nUrology \n2005 ;66 :327 –31\n. 10.1016/j.urology.2005.02.026 \n16040084 \n33 Tan YG , Lau Kam On W , Huang HH , Tan Wee Kiat T . Prostate specific antigen bounce after intensity-modulated radiation therapy in an Asian population\n. Asian J Urol . 2016 ;3 :59 –63\n. 10.1016/j.ajur.2015.12.001 \n29264166 \n34 McGrath SD , Antonucci JV , Fitch DL , Ghilezan M , Gustafson GS , Vicini FA , et al\nPSA bounce after prostate brachytherapy with or without neoadjuvant androgen deprivation\n. Brachytherapy \n2010 ;9 :137 –44\n. 10.1016/j.brachy.2009.07.005 \n19850537 \n35 Mehta NH , Kamrava M , Wang PC , Steinberg M , Demanes J . Prostate-specific antigen bounce after high-dose-rate monotherapy for prostate cancer\n. Int J Radiat Oncol Biol Phys \n2013 ; 86 : 729 –33\n.23582852 \n36 Makarewicz R , Lebioda A , Terlikiewicz J , Biedka M , Wiśniewski T . PSA bouncing after brachytherapy HDR and external beam radiation therapy: a study of 121 patients with minimum 5-years follow-up\n. J Contemp Brachytherapy . 2009 ;1 :92 –6\n. 27795718 \n37 Cuccia F , Mazzola R , Arcangeli S , Mortellaro G , Figlia V , Caminiti G , et al\nModerate hypofractionated helical tomotherapy for localized prostate cancer: preliminary report of an observational prospective study\n. Tumori . 2019 \n12 ;105 (6 ):516 –23\n. 10.1177/0300891619867846 \n31432765 \n38 Nicosia L , Mazzola R , Rigo M , Figlia V , Giaj-Levra N , Napoli G , et al\nModerate versus extreme hypofractionated radiotherapy: A toxicity comparative analysis in low- and favorable intermediate-risk prostate cancer patients\n. J Cancer Res Clin Oncol . 2019 \n10 ;145 (10 ):2547 –54\n. 10.1007/s00432-019-02983-3 \n31324979 \n39 Sheinbein C , Teh BS , Mai WY , Grant W , Paulino A , Butler EB . Prostate-specific antigen bounce after intensity-modulated radiotherapy for prostate cancer\n. Urology . 2010 \n9 ;76 (3 ):728 –33\n. 10.1016/j.urology.2009.04.074 \n19616279 \n40 Sengoz M , Abacioglu U , Cetin I , Turkeri L . PSA bouncing after external beam radiation for prostate cancer with or without hormonal treatment\n. Eur Urol . 2003 \n5 ;43 (5 ):473 –7\n. 10.1016/s0302-2838(03)00138-6 \n12705989 \n41 Hinnen KA , Monninkhof EM , Battermann JJ , van Roermund JG , Frank SJ , van Vulpen M . Prostate specific antigen bounce is related to overall survival in prostate brachytherapy\n. Int J Radiat Oncol Biol Phys \n2012 ;82 :883 –8\n. 10.1016/j.ijrobp.2010.11.049 \n21300477 \n42 Freiberger C , Berneking V , Vögeli TA , Kirschner-Hermanns R , Eble MJ , Pinkawa M . Long-term prognostic significance of rising PSA levels following radiotherapy for localized prostate cancer—focus on overall survival\n. Radiat Oncol . 2017 \n6 \n14 ;12 :98 \n10.1186/s13014-017-0837-5 \n28615058 \n43 Stock RG , Stone NN , Cesaretti JA . Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: descriptions and implications\n. Int J Radiat Oncol Biol Phys \n2003 ;56 :448e53 \n10.1016/s0360-3016(02)04470-x \n12738319\n\n",
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"abstract": "Bladder cancer is the most common urinary tract malignancy. Platinum-based chemotherapy is the first line of treatment in locally advanced or metastatic bladder cancer. Immunotherapy has become a novel therapy option in a broad variety of malignancies including bladder cancer. Immunotherapy is approved as first line of treatment in patients who are ineligible for platinum-based chemotherapy and second-line treatment for metastatic urothelial cancer who progressed after platinum-based treatments. We present the case of an 83-year-old female with metastatic bladder cancer who was chemotherapy ineligible and had complete response with immune checkpoint inhibitor pembrolizumab.",
"affiliations": "Saint Joseph's University Medical Center, Paterson, NJ, USA.;Saint Joseph's University Medical Center, Paterson, NJ, USA.;Reading Hospital, West Reading, PA, USA.;Saint Joseph's University Medical Center, Paterson, NJ, USA.;Saint Joseph's University Medical Center, Paterson, NJ, USA.",
"authors": "Singh|Balraj|B|0000-0001-7986-6031;Kaur|Parminder|P|;Gupta|Sachin|S|;Guragai|Nirmal|N|;Maroules|Michael|M|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34308703\n10.1177/23247096211035603\n10.1177_23247096211035603\nCase Report\nComplete Response With Immunotherapy: A Case of Metastatic Bladder Cancer\nhttps://orcid.org/0000-0001-7986-6031\nSingh Balraj MD 1\nKaur Parminder MD 1\nGupta Sachin MD 2\nGuragai Nirmal MD 1\nMaroules Michael MD 1\n1 Saint Joseph’s University Medical Center, Paterson, NJ, USA\n2 Reading Hospital, West Reading, PA, USA\nBalraj Singh, MD, Saint Joseph’s University Medical Center, Paterson, 703 Main Street, NJ 07503, USA. Email: bsriar9@gmail.com\n26 7 2021\nJan-Dec 2021\n9 2324709621103560311 6 2021\n3 7 2021\n7 7 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\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).\nBladder cancer is the most common urinary tract malignancy. Platinum-based chemotherapy is the first line of treatment in locally advanced or metastatic bladder cancer. Immunotherapy has become a novel therapy option in a broad variety of malignancies including bladder cancer. Immunotherapy is approved as first line of treatment in patients who are ineligible for platinum-based chemotherapy and second-line treatment for metastatic urothelial cancer who progressed after platinum-based treatments. We present the case of an 83-year-old female with metastatic bladder cancer who was chemotherapy ineligible and had complete response with immune checkpoint inhibitor pembrolizumab.\n\nbladder cancer\nimmunotherapy\ncomplete response\npneumonitis\npembrolizumab\nurothelial cancer\nchemotherapy\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nBladder cancer is the most common urinary tract neoplasm. In the United States, approximately 80 000 new cases and 17 000 deaths occur each year due to bladder cancer. 1 In Western Europe and the United States, urothelial carcinoma is the common histologic type. 2 Muscle-invasive bladder cancer is defined when malignancy involves the detrusor muscle and have a higher metastatic potential. The most common presenting symptom in patients with bladder cancer is painless hematuria (grossly visible or microscopic), although irritative voiding symptoms (frequency, urgency, dysuria) can also be the presenting manifestation. 3 Depending on the age, comorbidities, functional status of the patient, and stage of the malignancy, treatment options include surgery, radiation, chemotherapy, and most recently immunotherapy and targeted therapies.\n\nCase Presentation\n\nWe report the case of an 83-year-old female who presented to the emergency department for lower abdominal pain. The pain started 1 month prior to the presentation and progressively got worse. A computed tomography (CT) scan of the abdomen and pelvis showed significant left-sided hydronephrosis, hydroureter, mass in left side of the base of the bladder (Figure 1), and 4.6 × 4.7 cm mass medial to the left common femoral artery (Figure 2). The patient underwent transurethral resection of the bladder tumor, which showed large necrotic mass involving left posterior bladder/trigone and left side of bladder wall (likely cause of left-sided hydronephrosis, hydroureter), and pathology was consistent with high-grade urothelial carcinoma with invasion of muscularis propria. The patient was diagnosed with metastatic bladder cancer. The patient was not a chemotherapy candidate based on the age and performance status and immunotherapy was started with pembrolizumab. The patient got 7 cycles of pembrolizumab (every 3 weeks) and then presented to hospital for breathing difficulty and CT scan of the chest showed pneumonitis. The patient was initiated on steroids, pembrolizumab permanently stopped, and eventually discharged home. The patient continued to follow-up as outpatient off therapy and repeat CT chest, abdomen, and pelvis 6 month post last treatment showed no evidence of metastatic disease in chest, abdomen, and pelvis–complete response (Figure 3).\n\nFigure 1. Computed tomography scan of the abdomen and pelvis showing significant left-sided hydronephrosis, hydroureter, and mass in left side of the base of the bladder.\n\nFigure 2. Computed tomography scan of the abdomen and pelvis showing 4.6 × 4.7 cm mass medial to the left common femoral artery.\n\nFigure 3. Computed tomography scan of the chest, abdomen, and pelvis showing no evidence of metastatic disease–complete response.\n\nDiscussion\n\nPlatinum-based chemotherapy regimen remains the first-line treatment standard for locally advanced or metastatic bladder cancer. Immunotherapy is approved as first line of treatment in patients who are ineligible for platinum-based chemotherapy and second-line treatment for metastatic urothelial cancer who progressed after platinum-based treatments. 4 The programmed cell death 1 (PD-1) receptor is expressed predominantly by T-cells. Binding of PD-1 to its ligands (PD-L1/PD-L2) leads to inhibition of proliferation and immune response of T-cells. Tumors cells can avoid the immune system through the PD-1 mechanism. Pembrolizumab blocks the PD-1 receptor and inhibits both ligands (PD-L1/PD-L2) from interacting with PD-1 receptor resulting in revamping of the T-cell response and immune response. 5 The Food and Drug Administration has approved the PD-1 inhibitors nivolumab and pembrolizumab as well as the PD-L1 inhibitors atezolizumab and avelumab for patients with urothelial carcinoma.\n\nImmunotherapy drugs can cause immune-related adverse events. The most commonly reported side effects are colitis, hepatitis, pneumonitis, endocrinopathies (hyperthyroidism, thyroiditis, primary adrenal insufficiency, hypothyroidism, diabetes), dermatologic events, acute kidney injury, rheumatologic events, and myocarditis. 6 Cessation of the immune checkpoint inhibitor and initiation of steroids is the most common treatment used for the adverse events.\n\nIn the KEYNOTE-052 study, 370 patients with advanced urothelial cancer who were cisplatin-ineligible and treatment naive were enrolled, 6% of patient’s achieved a complete response. 7 Abdelhakam et al reported a case of 53-year-old male with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy with metastasis to the bone and achieved a durable complete response with checkpoint inhibitor—atezolizumab. 8 The patient in the report got 2 years of treatment with atezolizumab, and imaging with magnetic resonance and bone scan showed no evidence of disease. In our case, the patient received only 7-month treatment due to immunotherapy-induced pneumonitis, and CT chest, abdomen, and pelvis 6 month post last treatment showed no evidence of metastatic disease. Our case adds to the literature regarding complete response of a metastatic bladder cancer in an otherwise chemotherapy ineligible patient and side effect profile of immunotherapy.\n\nRecently pembrolizumab was approved by the Food and Drug Administration for the treatment of patients with non-muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors. The patients were ineligible for or have elected not to undergo cystectomy and the tumor was bacillus Calmette-Guérin unresponsive. A total of 148 patients were enrolled in the study. In this study, complete response rate of 41% and median response duration of 16.2 months was achieved in the 96 patients with carcinoma in situ that was bacillus Calmette-Guérin unresponsive. Complete response lasting at least 12 months was achieved in 46% of responding patients. 9 Complete response has been observed in other types of malignancies. Based on analysis of data from 5 clinical trials of pembrolizumab, a total of 149 patients with microsatellite instability-high/mismatch repair deficient tumors (15 different tumor types—60% of patients having metastatic colorectal cancer), an overall response rate of 39.6% and complete response rate of 7% was achieved. 10\n\nConclusion\n\nWe present the case of an elderly female with metastatic bladder cancer who was chemotherapy ineligible and hence was given immune checkpoint inhibitor pembrolizumab and complete response was achieved.\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\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our hospital does not require ethics committee approval for case reports.\n\nInformed Consent: Verbal informed consent was obtained from the patient for the publication.\n\nORCID iD: Balraj Singh https://orcid.org/0000-0001-7986-6031\n==== Refs\nReferences\n\n1 Siegel RL Miller KD Fuchs HE Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71 :7-33. doi:10.3322/caac.21654 33433946\n2 Wong MCS Fung FDH Leung C Cheung WWL Goggins WB Ng CF . The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection. Sci Rep. 2018;8 :1129. doi:10.1038/s41598-018-19199-z 29348548\n3 Sexton WJ Wiegand LR Correa JJ Politis C Dickinson SI Kang LC. Bladder cancer: a review of non-muscle invasive disease. Cancer Control. 2010;17 :256-268. doi:10.1177/107327481001700406 20861813\n4 Patel VG Oh WK Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70 :404-423. doi:10.3322/caac.21631 32767764\n5 Gong J Chehrazi-Raffle A Reddi S Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018;6 :8. doi:10.1186/s40425-018-0316-z 29357948\n6 Bajwa R Cheema A Khan T , et al . Adverse effects of immune checkpoint inhibitors (programmed death-1 inhibitors and cytotoxic T-lymphocyte-associated protein-4 inhibitors): results of a retrospective study. J Clin Med Res. 2019;11 :225-236. doi:10.14740/jocmr3750 30937112\n7 Balar AV Castellano DE O’Donnell PH , et al . Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population. J Clin Oncol. 2017;35 (6 suppl ):284. doi:10.1200/JCO.2017.35.6_suppl.284\n8 Abdelhakam D Young PR Jain MK Nassar A Copland JA Tan W. Complete remission with immunotherapy: case report of a patient with metastatic bladder cancer to the humerus. Urol Case Rep. 2020;30 :101130. doi:10.1016/j.eucr.2020.101130 32123665\n9 Balar AV Kamat AM Kulkarni GS , et al . Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22 :919-930. doi:10.1016/S1470-2045(21)00147-9 34051177\n10 Marcus L Lemery SJ Keegan P , et al . FDA Approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25 :3753-3758. doi:10.1158/1078-0432.Ccr-18-4070 30787022\n\n",
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"keywords": "bladder cancer; chemotherapy; complete response; immunotherapy; pembrolizumab; pneumonitis; urothelial cancer",
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"mesh_terms": "D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell; D005260:Female; D006801:Humans; D007167:Immunotherapy; D001749:Urinary Bladder Neoplasms; D014571:Urologic Neoplasms",
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"title": "Complete Response With Immunotherapy: A Case of Metastatic Bladder Cancer.",
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{
"abstract": "BACKGROUND\nDisseminated nocardiosis is a rare disease mostly occurring in immunocompromised patients.\n\n\nMETHODS\nWe report a case of disseminated nocardiosis in a diabetic patient with both pulmonary and cutaneous involvement. Nocardia elegans was isolated and identified using the 16s ribosomal RNA gene sequence data.\n\n\nRESULTS\nClinical improvement was observed within 3 months after initiation of antimicrobial treatment with oral doxycycline, trimethoprim-sulfamethoxazole and intravenous penicillin, but the patient died 5 months later after arbitrary discontinuation of the treatment.\n\n\nCONCLUSIONS\nThis is the first case report of disseminated nocardiosis caused by Nocardia elegans in China.",
"affiliations": "Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China. youyi_cq@163.com.;Department of Dermatology and Allergy, Technische Universitaet Muenchen, Munich, Germany.;Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.;Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.;Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.",
"authors": "You|Yi|Y|;Chen|Wenchief|W|;Zhong|Baiyu|B|;Song|Ziqiang|Z|;Yang|Xichuan|X|",
"chemical_list": "D000900:Anti-Bacterial Agents; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-018-1144-2",
"fulltext": null,
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"issn_linking": "0300-8126",
"issue": "46(5)",
"journal": "Infection",
"keywords": "16s ribosomal RNA; Gene sequencing; Nocardia elegans; Nocardiosis",
"medline_ta": "Infection",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009615:Nocardia; D009617:Nocardia Infections; D010802:Phylogeny; D018410:Pneumonia, Bacterial; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S; D017422:Sequence Analysis, DNA; D017192:Skin Diseases, Bacterial",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "705-710",
"pmc": null,
"pmid": "29737456",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "3447015;27826114;19593231;16699488;16014473;19578288;26637381;21461846;20110385;21968966;18361877;16582679;17374898;25224198;24974451;18335548;11321080;16614249;17108276;18473100",
"title": "Disseminated nocardiosis caused by Nocardia elegans: a case report and review of the literature.",
"title_normalized": "disseminated nocardiosis caused by nocardia elegans a case report and review of the literature"
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{
"abstract": "We present a patient with anti-MDA5 negative, anti-Ku positive clinically amyopathic dermatomyositis (CADM). A 61-year-old woman presented with a chief complaint of a 20-year history of a pruritic rash that was active on her face, chest, hands, legs, and back. A mildly scaly, erythematous, photo-distributed eruption along with slightly violaceous, scaly papules accentuated on the wrist, metacarpophalangeal joints, proximal interphalangeal and distal interphalangeal joints. Antibody profile was significant for positive ANA and anti-dsDNA, elevated anti-TIF-1gamma (RDL)/p155, and weakly positive anti Ku. Biopsy was consistent with dermatomyositis. Melanoma differentiation-associated gene 5 antibody (anti-MDA-5) has been identified as the most commonly associated autoantibody found in CADM and is associated with poor prognosis and a biomarker for the diagnosis of rapidly progressive interstitial lung disease. To our knowledge, our patient is the first case of negative anti-MDA-5 and anti-Ku positive CADM.",
"affiliations": "Department of Dermatology, University of California Davis, Sacramento, CA Zen Dermatology, Sacramento, CA. rksivamani@ucdavis.edu.",
"authors": "Carrington|Alexis E|AE|;Tartar|Danielle M|DM|;Sivamani|Raja K|RK|",
"chemical_list": "D001323:Autoantibodies; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1; D000072200:Ku Autoantigen; D008727:Methotrexate",
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"issn_linking": "1087-2108",
"issue": "27(4)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D001323:Autoantibodies; D001327:Autoimmune Diseases; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D000072200:Ku Autoantigen; D008727:Methotrexate; D008875:Middle Aged",
"nlm_unique_id": "9610776",
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"pages": null,
"pmc": null,
"pmid": "33999578",
"pubdate": "2021-04-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anti-MDA-5 negative, anti-Ku positive clinically amyopathic dermatomyositis.",
"title_normalized": "anti mda 5 negative anti ku positive clinically amyopathic dermatomyositis"
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"medicinalproduct": "METFORMIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
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"drugindication": "Major depression",
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"medicinalproduct": "SERTRALINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Hyperlipidaemia",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "SIMVASTATIN"
},
{
"actiondrug": "5",
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"drugindication": "Product used for unknown indication",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "Alendronate calcium"
}
],
"patientagegroup": null,
"patientonsetage": "61",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Carrington AE, Tartar DM, Sivamani RK. Anti-mda-5 negative, anti-ku positive clinically amyopathic dermatomyositis. Dermatol-Online-J 2021;27(4):A6.",
"literaturereference_normalized": "anti mda 5 negative anti ku positive clinically amyopathic dermatomyositis",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211214",
"receivedate": "20211214",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20182365,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Rurioctocog alfa (recombinant factor VIII: Advate®) is available for the control of bleeding in patients with hemophilia A in Japan. To evaluate the inhibitor development, safety, and efficacy of rurioctocog alfa, a non-interventional and observational postmarketing surveillance was conducted on 352 previously treated Japanese patients aged 1-76 years with ≥ 4 exposure days under the conditions of routine clinical practice. A post-hoc comparison of the mean annualized bleeding rates which required treatment with rurioctocog alfa detected a statistically significant difference (P < 0.0001) between patients treated on regular prophylaxis (8.5 bleeds/year) and patients treated on an on-demand basis (36.6 bleeds/year). Favorable prophylactic and on-demand hemostatic efficacy (\"excellent\" or \"good\") were shown in 88.5-100% of patients across all treatment regimens. A total of 22 events of adverse drug reactions were reported in 13 male patients. Of the 352 patients, 3 (0.9%) patients, all of whom had ≤ 50 exposure days before enrollment, developed de novo FVIII inhibitor. No deaths or allergic reactions were reported. Rurioctocog alfa was found to be well-tolerated and effective among patients with hemophilia A in a postmarketing routine clinical practice.",
"affiliations": "Department of Laboratory Medicine, Tokyo Medical University Hospital, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. k-fukuta@qa2.so-net.ne.jp.;Department of Pediatrics, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan.;Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pediatrics, Nara Medical University, Kashihara, Japan.;Department of Pediatrics, Nara Medical University, Kashihara, Japan.;Department of Pediatrics, Nara Medical University, Kashihara, Japan.;The Japanese Red Cross Tokai Hokuriku Block Blood Center, Seto, Japan.;Department of Clinical Scientific Writing, Shire, Tokyo, Japan.;Department of Medical Affairs, Shire, Tokyo, Japan.;Department of Medical Affairs, Shire, Tokyo, Japan.;Department of Biostatistics, Shire, Vienna, Austria.;Kitakyushu Yahata-Higashi Hospital, Kitakyusyu, Japan.",
"authors": "Fukutake|Katsuyuki|K|;Taki|Masashi|M|;Matsushita|Tadashi|T|;Nogami|Keiji|K|;Shima|Midori|M|;Yoshioka|Akira|A|;Takamatsu|Junki|J|;Uchikawa|Haruhiko|H|;Takagi|Hiroshi|H|;Arai|Morio|M|;Engl|Werner|W|;Shirahata|Akira|A|",
"chemical_list": "D019774:Blood Coagulation Factor Inhibitors; D006490:Hemostatics; C078147:F8 protein, human; D005169:Factor VIII",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-018-02574-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "109(3)",
"journal": "International journal of hematology",
"keywords": "Advate; Hemophilia A; Postmarketing surveillance; Previously treated patients; Recombinant factor VIII",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D019774:Blood Coagulation Factor Inhibitors; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII; D005260:Female; D006467:Hemophilia A; D006470:Hemorrhage; D006490:Hemostatics; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D011446:Prospective Studies",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "336-345",
"pmc": null,
"pmid": "30604312",
"pubdate": "2019-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "11012701;11307831;15357767;17083507;17687129;18540895;19817995;20579113;20825504;21204915;22456059;22564135;22776238;23802542;25000469;25039809;25074524;29044825;3122859",
"title": "Inhibitor development, safety and efficacy of Advate® among previously treated patients with hemophilia A in a postmarketing surveillance in Japan.",
"title_normalized": "inhibitor development safety and efficacy of advate among previously treated patients with hemophilia a in a postmarketing surveillance in japan"
} | [
{
"companynumb": "JP-SHIRE-JP201901017",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125063",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FACTOR VIII DEFICIENCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "ADVATE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Factor VIII inhibition",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KATSUYUKI, F? MASASHI, T? TADASHI, M? KEIJI, N? MIDORI, S, ET AL. INHIBITOR DEVELOPMENT, SAFETY AND EFFICACY OF ADVATE AMONG PREVIOUSLY TREATED PATIENTS WITH HEMOPHILIA A IN A POSTMARKETING SURVEILLANCE IN JAPAN. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2019?1-10",
"literaturereference_normalized": "inhibitor development safety and efficacy of advate among previously treated patients with hemophilia a in a postmarketing surveillance in japan",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190114",
"receivedate": "20190114",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15822887,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "JP-SHIRE-JP201901016",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
"drugadditional": "3",
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"drugauthorizationnumb": "125063",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION",
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"drugindication": "PROPHYLAXIS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ADVATE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
"drugadditional": "3",
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"drugauthorizationnumb": "125063",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION",
"drugdosagetext": "UNK UNK, 3X A WEEK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FACTOR VIII DEFICIENCY",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "3",
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"drugstartdateformat": null,
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"medicinalproduct": "ADVATE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FUKUTAKE, K.? TAKI, M.? MATSUSHITA, T.? NOGAMI, K.? SHIMA, M.? ET AL.. INHIBITOR DEVELOPMENT, SAFETY AND EFFICACY OF ADVATE AMONG PREVIOUSLY TREATED PATIENTS WITH HEMOPHILIA A IN A POSTMARKETING SURVEILLANCE IN JAPAN. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2019",
"literaturereference_normalized": "inhibitor development safety and efficacy of advate among previously treated patients with hemophilia a in a postmarketing surveillance in japan",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190114",
"receivedate": "20190114",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15822880,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "JP-SHIRE-JP201901015",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
"drugadditional": "3",
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"drugauthorizationnumb": "125063",
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"drugcharacterization": "1",
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"drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION",
"drugdosagetext": null,
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"drugindication": "FACTOR VIII DEFICIENCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "ADVATE"
},
{
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},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "RECOMBINATE"
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "4"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FUKUTAKE, K.? TAKI, M.? MATSUSHITA, T.? NOGAMI, K.? SHIMA, M.? ET AL.. INHIBITOR DEVELOPMENT, SAFETY AND EFFICACY OF ADVATE AMONG PREVIOUSLY TREATED PATIENTS WITH HEMOPHILIA A IN A POSTMARKETING SURVEILLANCE IN JAPAN. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2019",
"literaturereference_normalized": "inhibitor development safety and efficacy of advate among previously treated patients with hemophilia a in a postmarketing surveillance in japan",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190114",
"receivedate": "20190114",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15822885,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "JP-SHIRE-JP201901021",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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},
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"drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION",
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"drugindication": "PROPHYLAXIS",
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"medicinalproduct": "ADVATE"
},
{
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},
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"drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION",
"drugdosagetext": "UNK UNK, 3X A WEEK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FACTOR VIII DEFICIENCY",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ADVATE"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haemorrhage",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KATSUYUKI, F.? MASASHI, T.? TADASHI, M.? KEIJI, N.? MIDORI, S.? ET AL.. INHIBITOR DEVELOPMENT, SAFETY AND EFFICACY OF ADVATE AMONG PREVIOUSLY TREATED PATIENTS WITH HEMOPHILIA A IN A POSTMARKETING SURVEILLANCE IN JAPAN. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2019",
"literaturereference_normalized": "inhibitor development safety and efficacy of advate among previously treated patients with hemophilia a in a postmarketing surveillance in japan",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190115",
"receivedate": "20190115",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15830093,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "Klinefelter syndrome (KS) is a chromosome abnormality characterized by a 47, XXY karyotype associated with hypogonadism and infertility. We present two cases of leukemia in patients with KS. The first patient presented with acute promyelocytic leukemia. He relapsed after the end of treatment. The second patient was diagnosed with chronic myeloid leukemia. Treatment with imatinib failed and the patient presented with myeloid blast crisis.",
"affiliations": "Department of Hematology, Aziza Othmana University Hospital, Place du gouvernement, la Kasbbah, 1008 Tunis, Tunisia.;Laboratory of Histology and Cytogenetics, Department of Histology and Cytogenetics, Faculty of Medicine of Tunis, Institut Pasteur de Tunis, El Manar Tunis University, 13, Place Pasteur, BP74, 1002 Tunis, Tunisia.;Department of Hematology, Aziza Othmana University Hospital, Place du gouvernement, la Kasbbah, 1008 Tunis, Tunisia.;Laboratory of Histology and Cytogenetics, Department of Histology and Cytogenetics, Faculty of Medicine of Tunis, Institut Pasteur de Tunis, El Manar Tunis University, 13, Place Pasteur, BP74, 1002 Tunis, Tunisia.;Department of Hematology, Aziza Othmana University Hospital, Place du gouvernement, la Kasbbah, 1008 Tunis, Tunisia.;Department of Hematology, Aziza Othmana University Hospital, Place du gouvernement, la Kasbbah, 1008 Tunis, Tunisia.;Laboratory of Histology and Cytogenetics, Department of Histology and Cytogenetics, Faculty of Medicine of Tunis, Institut Pasteur de Tunis, El Manar Tunis University, 13, Place Pasteur, BP74, 1002 Tunis, Tunisia.;Laboratory of Histology and Cytogenetics, Department of Histology and Cytogenetics, Faculty of Medicine of Tunis, Institut Pasteur de Tunis, El Manar Tunis University, 13, Place Pasteur, BP74, 1002 Tunis, Tunisia.;Laboratory of Histology and Cytogenetics, Department of Histology and Cytogenetics, Faculty of Medicine of Tunis, Institut Pasteur de Tunis, El Manar Tunis University, 13, Place Pasteur, BP74, 1002 Tunis, Tunisia.;Department of Hematology, Aziza Othmana University Hospital, Place du gouvernement, la Kasbbah, 1008 Tunis, Tunisia.",
"authors": "Bchir|M|M|;Ayed|W|W|;Neji|H Ben|HB|;Kilani|O|O|;Kefi|S|S|;Zarrouk|M|M|;Guermani|H|H|;Hentati|S|S|;Amouri|A|A|;Meddeb|B|B|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-015-0590-6",
"fulltext": null,
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"issn_linking": "0971-4502",
"issue": "32(Suppl 1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Acute promyelocytic leukemia; Chronic myelogenous leukemia; Karyotype; Klinefelter syndrome",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "66-8",
"pmc": null,
"pmid": "27408358",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "16106025;15160966;7841064;15798142;24959017;25378984;3567882;22184514;8616797",
"title": "Leukemia in Patients with Klinefelter Syndrome: A Report of Two Cases.",
"title_normalized": "leukemia in patients with klinefelter syndrome a report of two cases"
} | [
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"drugindication": "CHRONIC MYELOID LEUKAEMIA",
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"drugdosagetext": "140 MG, QD",
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"drugindication": "CHRONIC MYELOID LEUKAEMIA",
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],
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"reaction": [
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blast crisis in myelogenous leukaemia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BCHIR M, AYED W, NEJI HB, KILANI O, KEFI S, ZARROUK M ET AL.. LEUKEMIA IN PATIENTS WITH KLINEFELTER SYNDROME: A REPORT OF TWO CASES. INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION. 2016;32(SUPPL. 1):S66-S68",
"literaturereference_normalized": "leukemia in patients with klinefelter syndrome a report of two cases",
"qualification": "3",
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},
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},
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}
] |
{
"abstract": "OBJECTIVE\nThe treatment modality for desmoid-type fibromatosis has shifted from surgery to conservative treatment. The guideline committee for clinical care of extra-abdominal desmoid-type fibromatosis in Japan conducted a systematic review of treatment with doxorubicin-based chemotherapy for desmoid-type fibromatosis.\n\n\nMETHODS\nWe searched the pertinent literature. Two reviewers evaluated and screened it independently for eligibility and extracted data. They rated each report according to the grading of recommendations development and evaluation methodology. Based on the 'body of evidence', which the reviewers created, the clinical guideline committee decided a recommendation for the clinical question, 'Is doxorubicin-based chemotherapy effective for patients with extra-abdominal desmoid-type fibromatosis?'\n\n\nRESULTS\nFifty-three articles were extracted by the literature search, and one from hand search. After the first and second screenings, five articles were subjected to the final evaluation. There were no randomized controlled trials. According to response evaluation criteria in solid tumors criteria, the response rates of doxorubicin-based regimens and liposomal doxorubicin were 44% (28.6-54) and 33.3% (0-75) on average, respectively. In two reports, the response rates of doxorubicin-based regimens were higher than those of non-doxorubicin-based ones; 54% vs 12%, 40% vs 11%, respectively. The rates of G3 or G4 complications according to common terminology criteria for adverse events were 28% and 13% with doxorubicin-based and liposomal doxorubicin chemotherapy, respectively, including neutropenia or cardiac dysfunction. None of the reports addressed the issue of QOL.\n\n\nCONCLUSIONS\nAlthough the evidence level was low in the evaluated studies, doxorubicin-based and liposomal doxorubicin chemotherapy was observed to be effective. However, doxorubicin-based chemotherapy is associated with non-ignorable adverse events, and is not covered by insurance in Japan. We weakly recommend doxorubicin-based chemotherapy for patients with extra-abdominal desmoid-type fibromatosis in cases resistant to other treatments.",
"affiliations": "Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Hemodialysis and Surgery, Ichikawa Hospital, International University of Health and Welfare, Otawara, Japan.;Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Shimizu|Koki|K|;Kawashima|Hiroyuki|H|;Kawai|Akira|A|;Yoshida|Masahiro|M|;Nishida|Yoshihiro|Y|",
"chemical_list": "D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyaa125",
"fulltext": null,
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"issn_linking": "0368-2811",
"issue": "50(11)",
"journal": "Japanese journal of clinical oncology",
"keywords": "chemotherapy; desmoid; doxorubicin; guideline; systematic review",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000005:Abdomen; D000970:Antineoplastic Agents; D004317:Doxorubicin; D018222:Fibromatosis, Aggressive; D006801:Humans; D007564:Japan; D011092:Polyethylene Glycols; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "1274-1281",
"pmc": null,
"pmid": "32700733",
"pubdate": "2020-10-22",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Effectiveness of doxorubicin-based and liposomal doxorubicin chemotherapies for patients with extra-abdominal desmoid-type fibromatosis: a systematic review.",
"title_normalized": "effectiveness of doxorubicin based and liposomal doxorubicin chemotherapies for patients with extra abdominal desmoid type fibromatosis a systematic review"
} | [
{
"companynumb": "JP-JNJFOC-20190711635",
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"actiondrug": "5",
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
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"drugdosagetext": "UNKNOWN",
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"drugindication": "FIBROMATOSIS",
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"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Adverse event",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac dysfunction",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
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],
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"literaturereference": "SHIMIZU K, KAWASHIMA H, KAWAI A, YOSHIDA M, NISHIDA Y. EFFECTIVENESS OF DOXORUBICIN?BASED AND LIPOSOMAL DOXORUBICIN CHEMOTHERAPIES FOR PATIENTS WITH EXTRA?ABDOMINAL DESMOID?TYPE FIBROMATOSIS: A SYSTEMATIC REVIEW. JAPANESE JOURNAL OF CLINICAL ONCOLOGY. 2020?1?9.",
"literaturereference_normalized": "effectiveness of doxorubicin based and liposomal doxorubicin chemotherapies for patients with extra abdominal desmoid type fibromatosis a systematic review",
"qualification": "3",
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},
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"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Microscopic colitis (MC) is an inflammatory condition of the large bowel that is associated with chronic, nonbloody diarrhea. Colonoscopy usually demonstrates normal mucosa, while tissue biopsy reveals intraepithelial lymphocytes or a subepithelial collagen band. Although no specific antibody has been discovered, MC is associated with several autoimmune disorders such as celiac disease, Hashimoto's thyroiditis, and rheumatoid arthritis. There are only a small number of case reports documenting possible hereditary MC cases, but up to 12% of patients with MC have a family history of inflammatory bowel disease. Other associations include proton pump inhibitor use, cigarette smoking, HLA-DQ2/86, and possibly some gastrointestinal infections.",
"affiliations": "Department of Medicine, University of Massachusetts Medical Center, Worcester, MA.;Department of Gastroenterology, University of Massachusetts Medical Center, Worcester, MA.;Department of Gastroenterology, Staten Island University Hospital, Staten Island, NY.",
"authors": "Fasullo|Matthew J|MJ|;Al-Azzawi|Yasir|Y|;Abergel|Jeffrey|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2017.87",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.8710.14309/crj.2017.87Case ReportColonMicroscopic Colitis After Fecal Microbiota Transplant Fasullo et alMicroscopic Colitis after FMTFasullo Matthew J. DO1Al-Azzawi Yasir MD2Abergel Jeffrey MD31 Department of Medicine, University of Massachusetts Medical Center, Worcester, MA2 Department of Gastroenterology, University of Massachusetts Medical Center, Worcester, MA3 Department of Gastroenterology, Staten Island University Hospital, Staten Island, NYCorrespondence: Matthew Fasullo, Department of Medicine, University of Massachusetts Medical Center, 55 Lake Ave, North Worcester, MA 01605 (matthew.fasullo@umassmemorial.org)2017 19 7 2017 4 e8727 2 2017 25 5 2017 Copyright © Fasullo et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Microscopic colitis (MC) is an inflammatory condition of the large bowel that is associated with chronic, nonbloody diarrhea. Colonoscopy usually demonstrates normal mucosa, while tissue biopsy reveals intraepithelial lymphocytes or a subepithelial collagen band. Although no specific antibody has been discovered, MC is associated with several autoimmune disorders such as celiac disease, Hashimoto’s thyroiditis, and rheumatoid arthritis. There are only a small number of case reports documenting possible hereditary MC cases, but up to 12% of patients with MC have a family history of inflammatory bowel disease. Other associations include proton pump inhibitor use, cigarette smoking, HLA-DQ2/86, and possibly some gastrointestinal infections.\n==== Body\nIntroduction\nMicroscopic colitis (MC) causes chronic diarrhea, abdominal cramping, nausea, anxiety, and weight loss. Epidemiologic studies demonstrate that MC is a more common cause of diarrhea than previously shown, affecting approximately 5 of every 100,000 people per year, with a mean age at diagnosis of 65 years and a female preponderance.1,2 Several medications, autoimmune diseases, infections, and toxins have been associated with MC. Physical examination and colonoscopy are typically unremarkable.3 The diagnosis of MC can only be made on the basis of abnormalities seen on colonic biopsies. Fecal microbiota transplant (FMT), on the other hand, is the reconstitution of normal colonic flora by a stool transplant from a healthy donor to an individual infected with Clostridium difficile.\n\nCase Report\nA 39-year-old woman with a past medical history significant for depression and recurrent Clostridium difficile infection presented with 2 weeks of profuse, watery diarrhea. She presented with similar symptoms 6 months prior, at which time she was found to have a positive stool C. difficile antigen. Over the next 10 weeks she was started on a succession of treatments (ie, metronidazole, followed by oral vancomycin, and then fidaxomicin) without symptom resolution. Biopsies from a colonoscopy were unremarkable (Figure 1). She underwent a FMT 4 weeks later and experienced complete symptom resolution during the initial 6 weeks after FMT. Her symptoms then returned, and she was again hospitalized.\n\nFigure 1 Normal colonic mucosa prior to FMT.\n\nThe patient described a gradual onset of profuse, watery diarrhea over 2 weeks that peaked at 10 bowel movements per day. She denied nausea, vomiting, fever, myalgias, dizziness, hematochezia, changes to her diet, recent travel, drug or tobacco use, and sick contacts. Physical exam was significant for an anxious-appearing, thin woman with mild left and right lower abdominal tenderness. Initial laboratory data, including basic metabolic profile, complete blood count, liver function test, thyroid-stimulating hormone, C-reactive protein, and fecal calprotectin were all within normal limits. Additional tests, including anti-Saccharomices cerevisiae and a celiac disease panel, were negative. Infectious workup for C. difficile, human immunodeficiency virus, Escherichia coli, salmonella, shigella, campylobacter, hepatitis panel, and fecal leukocytes was negative. Abdominal imaging, including ultrasound and computed tomography scan, was negative. Biopsies from a repeat colonoscopy revealed increased intraepithelial lymphocytes in the colonic epithelial layer and increased numbers of subepithelial chronic inflammatory cells consistent with lymphocytic colitis (LC) (Figure 2). The patient was promptly started on budesonide therapy, which resulted in a significant reduction in symptoms. She was subsequently discharged 2 days later and was able to return to work the next week.\n\nFigure 2 Abnormal colonic mucosa consistent with lymphocytic colitis showing >20 intraepithelial lymphocytes per 100 surface epithelial cells.\n\nDiscussion\nMC is an inflammatory condition of the large bowel that is associated with chronic, nonbloody diarrhea with a grossly normal-appearing colonoscopy, and it is diagnosed by tissue biopsy. MC can be further classified into 2 distinct classes: LC and collagenous colitis (CC). The histopathological criteria for CC include a thickened subepithelial collagen layer of at least 10 µm, inflammation in the lamina propria with lymphocytes and plasma cells, and epithelial damage. The criteria for LC is a density of at least 20 intraepithelial lymphocytes per 100 surface epithelial cells, epithelial damage, and a subepithelial collagen layer of less than 10 µm.4 While the etiology remains obscure, the most common theories suggest that MC results from immune system activation in the colonic mucosa after exposure to antigenic factors, including toxins, infections, and medications. Commonly reported associations include autoimmune-based disorders such as celiac disease, thyroid disease, and rheumatoid arthritis, although no specific antibody has yet been associated with MC. There are a small number of case reports documenting cases of hereditary MC, but up to 12% of patients with MC have a family history of inflammatory bowel disease.5 Other potential associations include the use of proton pump inhibitors, cigarette smoking, and HLA-DQ2/8, and some case reports document newly diagnosed MC after gastrointestinal infection with C. difficile, Yersinia species, and Campylobacter species.6-8 The diagnosis of MC often occurs after an extensive workup for alternative causes of diarrhea. Withdrawal of toxic agents and drugs is required when MC began as a consequence of its use. While antidiarrheal agents are typically used, budesonide is the only drug proven to be effective in randomized, placebo-controlled trials, and it is currently the standard treatment for MC.\n\nWe describe a previously healthy 39-year-old woman presenting with new microscopic colitis after FMT for recurrent C. difficile colitis. We postulate that gut dysbiosis caused by the incorporation of a foreign microbiome resulted in a dysregulated immune response. We postulate that this caused chemotaxis of lymphocytes to the affected area as well as a spike in bacterial metabolite production.9 While FMT is rapidly being incorporated into clinical practice, much is still unknown regarding the stool donor protocol as well as complications of the therapy. The literature for reported complications of FMT include bloating, diarrhea, constipation, perforation, and bacteremia, as well as a few reports documenting adverse reactions including cancers.10 Other studies have described histologic findings consistent with MC on colonoscopic biopsies taken at the time of FMT, suggesting its pathogenesis may be associated with C. difficile rather than FMT.11 Biopsies from our patient, however, were negative for MC prior to initiation of FMT. We hope to bring attention to a potential gap in knowledge regarding adverse effects of FMT, and to suggest pre-FMT screening for MC during donor analysis.\n\nDisclosures\nAuthor contributions: MJ Fasullo wrote the manuscript and is the article guarantor. Y. Al-Azzawi and J. Abergel wrote and edited the manuscript.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1 Bohr J , Tysk C , Eriksson S , Abrahamsson H , Järnerot G \nCollagenous colitis: A retrospective study of clinical presentation and treatment in 163 patients . Gut . 1996 ;39 (6 ):846. 9038667 \n2 Tangri V , Chande N \nMicroscopic colitis: An update . J Clin Gastroenterol . 2009 ;43 :293 –6 .19169149 \n3 Bohr J , Tysk C , Eriksson S , Järnerot G \nCollagenous colitis in Orebro, Sweden: An epidemiological study 1984–1993 . Gut . 1995 ;37 (3 ):394. 7590436 \n4 Lazenby AJ , Yardley JH , Giardiello FM , Jessurun J , Bayless TM \nLymphocytic (\"microscopic\") colitis: A comparative histopathologic study with particular reference to collagenous colitis . Hum Pathol . 1989 ;20 (1 ):18 –28 .2912870 \n5 Järnerot G , Hertervig E , Grännö C , et al. \nFamilial occurrence of microscopic colitis: A report on five families . Scand J Gastroenterol . 2001 ;36 (9 ):959 –62 .11521987 \n6 Wilcox GM , Mattia AR \nMicroscopic colitis associated with omeprazole and esomeprazole exposure . J Clin Gastroenterol . 2009 ;43 :551 –3 .19142168 \n7 Fernández-Bañares F , Esteve M , Farré C , et al. \nPredisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis . Eur J Gastroenterol Hepatol . 2005 ;17 (12 ):1333 –8 .16292086 \n8 Ingle SB , Adgaonkar BD , Hinge CR \nMicroscopic colitis: Common cause of unexplained nonbloody diarrhea . World J Gastrointest Pathophysiol . 2014 ;5 :48 –53 .24891975 \n9 Tariq R , Smyrk T , Pardi DS , Tremaine WJ , Khanna S \nNew-onset microscopic colitis in an ulcerative colitis patient after fecal microbiota transplantation . Am J Gastroenterol . 2016 ;111 (5 ):751 –2 .27151129 \n10 Rao K , Safdar N \nFecal microbiota transplantation for the treatment of Clostridium difficile infection . J Hosp Med . 2016 ;11 (1 ):56 –61 .26344412 \n11 Agrawal M , Aroniadis OC , Brandt LJ , et al. \nThe long-term efficacy and safety of fecal microbiota transplant for recurrent, severe, and complicated clostridium difficile infection in 146 elderly individuals . J Clin Gastroenterol . 2016 ;50 (5 ):403 –7 .26352106\n\n",
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"medline_ta": "ACG Case Rep J",
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"nlm_unique_id": "101638398",
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"pages": "e87",
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"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24891975;26352106;27151129;9038667;26344412;2912870;11521987;19142168;7590436;19169149;16292086",
"title": "Microscopic Colitis After Fecal Microbiota Transplant.",
"title_normalized": "microscopic colitis after fecal microbiota transplant"
} | [
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"abstract": "BACKGROUND\nRefeeding syndrome (RFS) is an important and well-known complication in malnourished patients, but the incidence of RFS after obesity surgery is unknown and the awareness of RFS in obese patients as a postsurgical complication must be raised. We present a case of RFS subsequent to biliopancreatic diversion in a morbidly obese patient.\n\n\nMETHODS\nA 48-year-old female patient with a BMI of 41.5 kg/m2 was transferred to our hospital due to Wernicke's Encephalopathy in a global malabsorptive syndrome after biliopancreatic diversion. Parenteral nutrition, vitamin supplementation and high-dosed intravenous thiamine supplementation were initiated. After 14 days, the patient started to develop acute respiratory failure, and neurological functions were impaired. Blood values showed significant electrolyte disturbances. RFS was diagnosed and managed according to the NICE guidelines. After 14 days, phosphate levels had returned to normal range, and neurological symptoms were improved.\n\n\nCONCLUSIONS\nExtreme weight loss following obesity surgery has been shown to be associated with undernutrition. These patients are at high risk for evolving RFS, even though they may still be obese. Awareness of RFS as a postsurgical complication, the identification of patients at risk as well as prevention and correct management should be routinely performed at every bariatric center.",
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"fulltext": "\n==== Front\nObes FactsObes FactsOFAObesity Facts1662-40251662-4033S. Karger GmbH Wilhelmstrasse 20A, P.O. Box · Postfach · Case postale, D–79095, Freiburg, Germany · Deutschland · Allemagne, Phone: +49 761 45 20 70, Fax: +49 761 4 52 07 14, information@karger.de 2674562410.1159/000442534ofa-0009-0012Case ReportRefeeding Syndrome: An Important Complication Following Obesity Surgery Chiappetta Sonja \na\n*Stein Jürgen \nb\n\nc\n\naDepartment of Obesity and Metabolic Surgery, Sana Klinikum Offenbach, Offenbach, Germany\nbClinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/M., Germany\ncICCC Rhein-Main, Frankfurt/M., Germany*Dr. Sonja Chiappetta, Department of Obesity and Metabolic Surgery, Sana Klinikum Offenbach, Starkenburgring 66, 63069 Offenbach, Germany, sonja1002@gmx.de3 2016 9 1 2016 9 1 2016 9 1 12 16 27 7 2015 28 10 2015 Copyright © 2016 by The Author(s) Published by S. Karger GmbH, Freiburg2016This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.Background\nRefeeding syndrome (RFS) is an important and well-known complication in malnourished patients, but the incidence of RFS after obesity surgery is unknown and the awareness of RFS in obese patients as a postsurgical complication must be raised. We present a case of RFS subsequent to biliopancreatic diversion in a morbidly obese patient.\n\nCase Report\nA 48-year-old female patient with a BMI of 41.5 kg/m2 was transferred to our hospital due to Wernicke‘s Encephalopathy in a global malabsorptive syndrome after biliopancreatic diversion. Parenteral nutrition, vitamin supplementation and high-dosed intravenous thiamine supplementation were initiated. After 14 days, the patient started to develop acute respiratory failure, and neurological functions were impaired. Blood values showed significant electrolyte disturbances. RFS was diagnosed and managed according to the NICE guidelines. After 14 days, phosphate levels had returned to normal range, and neurological symptoms were improved.\n\nConclusion\nExtreme weight loss following obesity surgery has been shown to be associated with undernutrition. These patients are at high risk for evolving RFS, even though they may still be obese. Awareness of RFS as a postsurgical complication, the identification of patients at risk as well as prevention and correct management should be routinely performed at every bariatric center.\n\nKey Words\nRefeeding syndromeBiliopancreatic diversionObesity surgery\n==== Body\nIntroduction\nDue to the worldwide epidemic of obesity, bariatric procedures are increasing in frequency and are among the most commonly performed gastrointestinal operations today. In 2011, Roux-en-Y gastric bypass (RYGB) was the most common bariatric procedure (46.6%), followed by sleeve gastrectomy (SG; 27.8%), adjustable gastric banding (AGB; 17.8%), and biliopancreatic diversion/duodenal switch (BPD/DS; 2.2%) [1]. Early and late postoperative morbidity is associated with both surgical and nutritional complications. Macro- and micronutrient deficiencies are common in obese patients even before surgery and are frequent complications following obesity surgery, dependent on the bariatric procedure used [2]. While patients with BPD as a malabsorptive procedure achieve the best results in terms of excess weight loss (EWL) - up to 70% during a 15-year follow-up period [3] -, nutritional deficiencies are common after malabsorptive procedures [4], with protein malnutrition occurring in 7%. As a result, 1.7% of these patients require surgical revision in the form of common limb elongation or restoration [3].\n\nRefeeding syndrome (RFS) is an important complication known to occur in malnourished patients with a subnormal BMI after oral, parenteral and enteral resumption of nutrition. RFS reflects the change from catabolic to anabolic metabolism. During refeeding, glycemia leads to increased insulin and decreased secretion of glucagon. Insulin stimulates glycogen, fat, and protein synthesis, a process requiring minerals such as phosphate and magnesium, and cofactors such as thiamine. The consequence is a fall in serum levels of phosphate, potassium, and magnesium. This severe electrolyte disturbance can cause a life-threatening condition [5], and early recognition is vital in order to reduce morbidity and mortality [6]. Major risk factors for the development of RFS, according to NICE guidelines, are a BMI < 16 kg/m2, unintentional weight loss of >15% over the last 3-6 months, little or no nutritional intake for more than 10 days, and low levels of phosphate, potassium, or magnesium prior to feeding. Minor risk factors are specified as a BMI < 18.5 kg/m2, unintentional weight loss of 10-15% over the last 3-6 months, little or no nutritional intake for more than 5 days, and a history of alcohol abuse or chronic use of diuretics, antacids, chemotherapy or insulin [7]. Thus, refeeding syndrome primarily occurs in patients with anorexia. A recently published multicenter study from France reported an incidence of 10% in these patients [8].\n\nAlthough at first glance obese patients may not appear to be undernourished but quite the opposite, a significant risk of RFS can arise due to chronic weight loss after obesity surgery, with an EWL of approximately 60-80% not uncommon in the postoperative course. The true incidence of RFS after obesity surgery is unknown, and current literature describes only three isolated cases of RFS after obesity surgery. One late death due to malnutrition and RFS after BPD/DS was reported in 1997 [9] while Silk et al. described two further cases in 2011 [10]. The first of these case reports describes RFS in a patient with slippage after gastric banding, with long-lasting dysphagia before diagnosis and a BMI of 17.4 kg/m2. The patient underwent laparoscopic removal of the gastric banding and developed RFS postoperatively after receiving 450 kcal in the first 24 h and 1500 kcal/day over the following 2 days. The second report describes a patient who underwent RYGB at a BMI of 50 kg/m2 and presented with peptic ulceration of the gastrojejunal anastomosis 8 weeks after surgery. Four months after surgery, the patient had an EWL of 52% (BMI 37 kg/m2) and a disabling fear of taking anything orally owing to pain experienced when swallowing. In accordance with NICE guidelines, enteral nutrition was reintroduced at a rate of 5 kcal/kg daily. However, despite adherence to recommendations, the patient developed RFS within 24 h.\n\nIn this clinical case report, we describe the fourth case of RFS in a patient after BPD. In this case, RFS occurred after enteral nutrition, with typical neurological and pulmonal symptoms resolving after exact diagnosis and treatment.\n\nCase Report\nA 48-year-old female patient with a BMI of 41.5 kg/m2 (height 1.68 m, weight 117 kg) was transferred to our bariatric center due to protracted diarrhea and vomiting associated with progressive apathy and weakness due to lithium overdose. The patient was known to be taking lithium-containing medication on the basis of her known depression. The diagnosis was made by colleagues from the neurological hospital from which she had been transferred. The patient's bariatric history started in 2003, when she had undergone laparoscopic gastric banding at an initial weight of 174 kg (BMI 61.6 kg/m2). Gastric banding was removed in 2005 due to slippage, and in 2009 the patient presented again at the initial weight of 174 kg. Indication for BPD was given, and BPD-Scopinaro was performed laparoscopically. Three years after surgery, the patient showed an EWL of 83.96%, but was additionally suffering from manifest hypoproteinemia associated with edema and chronic dermatoses. Initial nutritional monitoring and supplementation brought no improvement, and indication for laparoscopic conversion in BPD-Larrad was given, aiming to reduce protein malabsorption. Surgery was performed in 2012 at a weight of 85 kg (BMI 30.1 kg/m2). The postoperative course was uneventful, and follow-up in 2013 showed normal values of total serum protein and a weight of 98 kg. Due to her known depression and noncompliance the patient did not present from 2013 to 2014 for follow-up consultation, as a result of which no supplementation was performed during this year. The patient reported that her diet was scarce of protein.\n\nOn admission to our bariatric center in 2014, the patient presented with a global malabsorptive syndrome, with deficiencies of vitamin B1, B12, B6, D, K, zinc, selenium, and iron, and with severe hypoproteinemia. The patient was in a state of mental confusion and was found to have gait disorders and acute ophthalmoplegia with diplopia. MRI scan of the brain showed no pathological findings of hemorrhagic or ischemic stroke. The classic triad of ophthalmoplegia, gait and stance disorder, together with mental confusion associated with vitamin B1 deficiency, led to the diagnosis of Wernicke‘s encephalopathy. Parenteral nutrition, vitamin supplementation, and high dose intravenous thiamine supplementation (300 mg/day) were initiated.\n\nDue to protracted vomiting and diarrhea, an upper gastrointestinal endoscopy was performed. This was negative for stenosis. A stool culture showed no abnormal bacteria or parasites in the sample. Treatment with parenteral, and then enteral, nutrition via a nasogastric tube at a rate of 1,200 kcal/day (10 kcal/kg) was initiated according to the NICE guidelines for patients at high risk for RFS.\n\nDuring the course of the next 10 days, the patient started to develop acute respiratory failure due to pulmonary edema, necessitating non-invasive ventilation. Neurological functions were impaired. Blood values showed significant electrolyte disturbances, including hypopotassemia, hypomagnesemia and severe hypophosphatemia of 0.9 mg/dl (0.05 mmol/l) (range 2.5-4.5 mg/dl).\n\nRFS was managed in accordance with NICE guidelines, with appropriate fluid balance and micronutrient replacement aimed at the correction of potassium, phosphate, calcium and magnesium, with intravenous supplementation of 18 mmol phosphate over 12 h [7]. Diuretic therapy was started in order to treat the pulmonary edema.\n\nAfter 14 days, phosphate levels had returned to the normal range (3.8 mg/dl) and neurological symptoms had improved. The patient showed no further mental confusion and was able to begin self-mobilization. At this point, she began a progressive oral diet with nutritional supplements, which was well tolerated. All pulmonary and neurological symptoms resolved following treatment.\n\nIndication for revisional surgery was given, and 1 month after RFS, the patient underwent open revision from BPD-Larrad to RYGB with an alimentary limb of 150 cm, a biliopancreatic limb of 50 cm, and a common channel of 280 cm. RYGB was chosen as a less malabsorptive procedure which would allow maintenance of EWL achieved with weight loss surgery.\n\nDiscussion\nThe true incidence of RFS after bariatric surgery remains unknown, and only three cases of RFS after obesity surgery are described in current literature [9,10]. The present case underlines that obese patients with extreme weight loss following obesity surgery associated with undernutrition are at high risk for evolving RFS upon recommencement of increased nutritional intake. Thus, BMI does not play a role as an indicator for patients at risk.\n\nIt is therefore vital that measures are taken at bariatric centers to identify patients at risk and to effect early diagnosis and prevention. Regular follow-up, constant supplementation, regular monitoring of micronutrient concentrations, and early intervention when weight loss is excessive are of paramount importance. Specific additional risk factors for the development of RFS after obesity surgery include dysphagia and vomiting as well as protracted diarrhea [9,10]. Macro- and micronutrient deficiencies are common after obesity surgery [2], and chronic thiamine deficiency can aggravate the risk of evolving RFS.\n\nMetabolic changes due to RFS can cause serious clinical complications since micronutrient and mineral deficiencies impact important physiological functions of the cardiac, respiratory, renal, neurological, hematological, musculoskeletal, and gastrointestinal systems. Possible consequences may include cardiac decompensation, pre-renal failure with metabolic acidosis, and even sudden death [6].\n\nIn patients with RFS, use of a feeding jejunostomy in the acute setting is a useful means of promoting protein absorption, especially because it prevents regurgitation of feeding formula. We used a nasogastric tube, placed via upper endoscopy in order to avoid a surgical procedure. While RFS may occur after parenteral or enteral feeding, the risk of RFS is higher after enteral nutrition, probably due to the incretin effect caused by absorption of glucose [11].\n\nThe patient described here was in a life-threatening condition, and missed diagnosis would probably have led to the patient's death. Notably, not the BMI itself but the history of weight loss is the major determinant for the identification of patients at risk following obesity surgery. Further research is needed to determine the true incidence of RFS after obesity surgery and to ascertain the best management protocols.\n\nPrevention of RFS through regular follow-up and sufficient supplementation after bariatric surgery is mandatory in all patients.\n\nConclusion\nDue to chronic weight loss after surgery, obese patients are at high risk for evolving RFS when resuming increased food intake after achieving sufficient weight loss. This applies especially to patients with postoperative complications. RFS is concomitant to any patient suffering from severe malnutrition and requiring feeding, independent of BMI and the bariatric procedure performed. The possibility of RFS as a serious complication must therefore be considered in the long-term postoperative treatment of obese patients.\n\nThe identification of patients at risk as well as the prevention and the correct management of this condition should be matters of priority at every bariatric center.\n\nAuthorship\nBoth authors performed substantial contributions to conception and design of the article and to acquisition, analysis and interpretation of data. Both authors reviewed the manuscript for important intellectual content and approved the final version for publication.\n\nClinical work was performed at Krankenhaus Sachsenhausen, Department of General and Bariatric Surgery (Prof. R. Weiner) and Department of Gastroenterology and Clinical Nutrition, Schulstraße 31, 60594 Frankfurt, Germany.\n\nDisclosure Statement\nDr. Sonja Chiappetta and Prof. Jürgen Stein have no conflicts of interest or financial ties to disclose.\n\nAcknowledgement\nThe authors thank Janet Collins (ICCC Rhein-Main, Frankfurt/M., Germany) for language support and proofreading.\n==== Refs\nReferences\n1 Buchwald H Oien DM Metabolic/bariatric surgery worldwide 2011 Obes Surg 2013 23 427 436 23338049 \n2 Stein J Stier C Raab H Weiner R The nutritional and pharmacological consequences of obesity surgery Aliment Pharmacol Ther 2014 40 582 609 25078533 \n3 Scopinaro N Gianetta E Adami GF Friedman D Traverso E Marinari GM Cuneo S Vitale B Ballari F Colombini M Baschieri G Bachi V Biliopancreatic diversion for obesity at eighteen years Surgery 1996 119 261 268 8619180 \n4 Santarpia L Grandone I Alfonsi L Sodo M Contaldo F Pasanisi F Long-term medical complications after malabsorptive procedures: effects of a late clinical nutritional intervention Nutrition 2014 30 1301 1305 24986553 \n5 Mehanna HM Moledina J Travis J Refeeding syndrome: what it is, and how to prevent and treat it. BMJ 2008 336 1495 1498 18583681 \n6 Crook MA Refeeding syndrome: problems with definition and management. Nutrition. 2014 30 1448 1455 25280426 \n7 \nNational Institute for Health and Care Excellence \nNutrition support for adults: oral nutrition support, enteral tube feeding and parenteral nutrition. NICE guidelines CG32. 2006. www.nice.org.uk/guidance/cg32 (last accessed Novemeber 19, 2015).\n8 Vignaud M Constantin JM Ruivard M Villemeyre-Plane M Futier E Bazin JE Annane D AZUREA group (AnorexieRea Study Group) Refeeding syndrome influences outcome of anorexia nervosa patients in intensive care unit: an observational study Crit Care 2010 14 R172 20920160 \n9 Baltasar A del Rio J Escrivá C Arlandis F Martínez R Serra C Preliminary results of the duodenal switch Obes Surg 1997 7 500 504 9730508 \n10 Silk Z Jones L Heath D Refeeding syndrome: an important complication after bariatric surgery Surg Obes Relat Dis 2011 7 e21 23 20627710 \n11 Zeki S Culkin A Gabe SM Nightingale JM Refeeding hypophosphataemia is more common in enteral than parenteral feeding in adult in patients. Clin Nutr 2011 30 365 368 21256638\n\n",
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"abstract": "BACKGROUND\nThe autologous arteriovenous fistula (AVF) is considered the best vascular access for haemodialysis in patients with chronic kidney disease but in time can lead to several complications.\nHerein we describe a case of a large cephalic vein aneurysm causing heart failure in a renal transplant patient being treated with radio-cephalic AVF for haemodialysis. The patient was judged to be at very high risk for potential catastrophic rupture of the aneurysm and his cardiac function was deteriorating so a surgical resection was offered. Under general anesthesia, a longitudinal incision was performed on the volar side of the forearm and the anastomotic junction was ligated. The cephalic vein aneurysm was isolated and a total resection of the vein, up to the joint of the elbow, was carried out. A specimen was also submitted for histological and immunohistochemical analysis.\n\n\nCONCLUSIONS\nAt present no clear indications pertaining to the need to close an AVF after kidney transplantation exist. Some authors recommend a closing of the fistula in patients with stable renal function to prevent the onset of complications, while others advise never to close the asymptomatic fistula in order to preserve vascular access for haemodialysis in case of graft failure.\n\n\nCONCLUSIONS\nBased on our clinical experience, we suggest not ligating vascular access during the first year following transplantation with the exception of patients needing emergent closure. Otherwise, surgical closure to prevent the onset of complications could be considered a viable option in the following subset of patients: those who are 3 or more years from transplantation with good and stable renal function, those with a significant growth of venous aneurysms or have a high AVF flow rate or are young patients.",
"affiliations": "Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Naples, Italy.;Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Naples, Italy. Electronic address: umbertomarcello.bracale@unina.it.;Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Naples, Italy.;Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Naples, Italy.;Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Naples, Italy.;Department of Surgical, Oncological and Oral Sciences, Vascular Surgery Unit, University of Palermo, Palermo, Italy.",
"authors": "Panagrosso|Marco|M|;Bracale|Umberto Marcello|UM|;Del Guercio|Luca|L|;Viscardi|Alessia|A|;Peluso|Antonio|A|;Dinoto|Ettore|E|",
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"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)30566-6\n10.1016/j.ijscr.2020.07.055\nCase Report\nCase report of a large cephalic vein aneurysm inducing heart failure in a renal transplant patient with radio-cephalic fistula for haemodialysis\nPanagrosso Marco a Bracale Umberto Marcello umbertomarcello.bracale@unina.ita⁎ del Guercio Luca a Viscardi Alessia a Peluso Antonio a Dinoto Ettore b a Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Naples, Italy\nb Department of Surgical, Oncological and Oral Sciences, Vascular Surgery Unit, University of Palermo, Palermo, Italy\n⁎ Corresponding author at: Department of Public Health, Vascular Surgery Unit, University Federico II of Naples, Via Sergio Pansini 5, 80131, Naples, Italy. umbertomarcello.bracale@unina.it\n27 8 2020 \n2020 \n27 8 2020 \n77 Suppl S162 S165\n6 6 2020 16 7 2020 17 7 2020 © 2020 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• The venous aneurysm is one of the most common complications of autologous AVF.\n\n• The vein aneurysm should be treat by surgical resection and anastomotic ligature.\n\n• AVF shouldn’t be ligated from 1-year kidney transplantation except in some cases.\n\n• Surgical ligation to prevent complications could be considered an option.\n\n\n\nIntroduction\nThe autologous arteriovenous fistula (AVF) is considered the best vascular access for haemodialysis in patients with chronic kidney disease but in time can lead to several complications.\n\nPresentation of a case\nHerein we describe a case of a large cephalic vein aneurysm causing heart failure in a renal transplant patient being treated with radio-cephalic AVF for haemodialysis. The patient was judged to be at very high risk for potential catastrophic rupture of the aneurysm and his cardiac function was deteriorating so a surgical resection was offered. Under general anesthesia, a longitudinal incision was performed on the volar side of the forearm and the anastomotic junction was ligated. The cephalic vein aneurysm was isolated and a total resection of the vein, up to the joint of the elbow, was carried out. A specimen was also submitted for histological and immunohistochemical analysis.\n\nDiscussion\nAt present no clear indications pertaining to the need to close an AVF after kidney transplantation exist. Some authors recommend a closing of the fistula in patients with stable renal function to prevent the onset of complications, while others advise never to close the asymptomatic fistula in order to preserve vascular access for haemodialysis in case of graft failure.\n\nConclusion\nBased on our clinical experience, we suggest not ligating vascular access during the first year following transplantation with the exception of patients needing emergent closure. Otherwise, surgical closure to prevent the onset of complications could be considered a viable option in the following subset of patients: those who are 3 or more years from transplantation with good and stable renal function, those with a significant growth of venous aneurysms or have a high AVF flow rate or are young patients.\n\nKeywords\nArteriovenous fistulaRenal transplantationHeart failureSurgical repair\n==== Body\n1 Introduction\nChronic kidney disease is increasingly recognized as a global health issue affecting 10%–15% of the world population. Despite an increase in the number of kidney transplants - the best treatment for end-stage renal disease patients - chronic haemodialysis still remains the most common therapy. The autologous arteriovenous fistula (AVF) provides the best access to circulation because of low complication rates, long-term use and lower costs compared to an arteriovenous graft and central venous catheter. Current guidelines in postoperative care of kidney transplant recipients do not give clear recommendations about management of AVF for stable kidney transplant patients [1], [2].\n\nHerein we describe the management of a large cephalic vein aneurysm causing heart failure in a renal transplant patient with a radio-cephalic AVF for haemodialisys. This research work has been reported in line with the SCARE checklist [3].\n\n2 Case presentation\nA 53-year-old male patient was admitted to our Nephrology Unit with a 3-month history of gradually progressive dyspnea and bilateral leg swelling. The patient noted an increasing volume in his left radio-cephalic AVF for haemodialysis access that had significantly grown in size over the past few years although he did not experience any discomfort. On examination, multiple pulsatile masses were noted along the entire forearm the largest of which was localized at the wrist and measured a maximum transverse diameter of more than 10 cm (102 mm) (Fig. 1A).Fig. 1 A) Multiple giant venous aneurysms along the course of the left cephalic vein: the largest is easily observable on the wrist, where radio-cephalic fistula is located; 1B) Surgical incision and aneurysm exposure.\n\nFig. 1\n\nThe patient had a history of hypertension and end-stage renal disease secondary to nephrotic syndrome. He required haemodialysis treatment through his left-sided radio-cephalic AVF for 14 consecutive years prior to his successful kidney transplantation from a deceased donor 16 years ago. At the time of admission, the patient was still under immunosuppressive therapy with cyclosporine (400 mg/die) and corticosteroids (5 mg/die) and presented a decreased ejection fraction of approximately 30 % with a dilated left ventricle and global hypokinesis on transthoracic echocardiography. The reduction of cardiac output had also caused a renal function decrement of the graft. He denied having had any recent trauma.\n\nA duplex scan showed an arterio-venous anastomosis between the radial artery and cephalic vein and confirmed the presence of multiple giant aneurysms of the cephalic vein. The brachial artery also appeared to be increased in size with a maximum diameter of about 24 mm with indices of resistance (0.46−0.55) which, however, can still be considered within the normal limits but the flow rate of the AVF was very high at around 11 L/min. The radial artery in the post-anastomotic tract showed a reverse flow estimated at about 210 mL/min. The post-anastomotic side of the vein appeared to be characterized by the presence of large aneurysms of the cephalic vein with considerable variations in size and the presence of parietal calcifications without intraluminal thrombotic material. The patient was judged to be at very high risk for catastrophic rupture of the large cephalic aneurysm and his cardiac function was deteriorating and so a surgical resection was offered.\n\nA longitudinal incision was performed under general anesthesia on the volar side of the forearm and the anastomotic junction was ligated (Fig. 1B). The cephalic vein aneurysms were isolated and a total resection of the vein, up to the joint of the elbow, was carried out. The surgical procedure lasted about two and half hours with 150−200 ml of total blood loss. The histological specimen was sent to pathological anatomy laboratory and subjected to hematoxylin and eosin staining, Weigert Von Gieson and immunohistochemical analysis for CD4+ and CD8+ lymphocytes. The histological evaluation showed large calcification of the vein wall (Fig. 2A), while the Weigert van Gieson for elastic and connective fibers highlighted the slipping of the wall and loss of collagen fibers (Fig. 2B). Finally, the immunohistochemical analysis for CD4+ and CD8+ lymphocytes showed intense inflammatory infiltration of the intimate, medium and adventitia of the degenerated vessel (Fig. 2C) No bleeding or ischemia nor nerve injury of the hand resulted in the post-operative period. After one month a duplex scan and blood tests were performed, respectively showing radial artery patency and normalization of serum creatinine levels (1.1 mg/dl). The patient was doing well 6 months after the procedure.Fig. 2 Histological and immunoistochemical analysis: 2A) Hematoxylin and Eosin; 2B) Weigert Van Gieson; 2C) CD8+ perivasal.\n\nFig. 2\n\n3 Discussion\nThe maturation of an AVF involves some histopathological changes in the arterial and venous system which are influenced by hemodynamic aspects. Usually the normal caliber of the cephalic vein is about 2.3–2.6 mm however the creation of an AVF for hemodialysis determines a process of \"arterialization\" of the vein resulting in a significant increase in its caliber. The role that immunosuppressive drugs and corticosteroids play in the evolution of aneurysmal disease is still controversial and often debated [2], [4]. Corticosteroids have often been shown to cause arterial wall damage although no report has yet directly proven an aneurysmatogenic effect. Conversely, the hypertensive effect of corticosteroids is widely recognized as producing stress on the arterial wall and might have been the key factor in this case since our patient was hypertensive [5], [6]. There are, however, other studies linking the adverse evolution of the disease to chronic therapy with these drugs due to potential damage of the arteries’ muscular layers which leads to a significant increase in the incidence of aneurysms [7], [8]. All of this could be explained by the multiple and different functions and link receptors that corticosteroids play in our body. Conflicting studies also exist on the need to close the AVF after kidney transplantation. In fact, we found that some authors recommend the closure of the fistula [9] on account of the reduction in cardiac mass (left ventricle) with a percentage around 15.8 % at 21 months that could be linked to a reduction in heart disease [10], [11]. In their meta-analysis Zheng et al. demonstrated that AVF closure improves cardiac morphology and kidney graft function, resulting in improved renal perfusion [12]. A recent clinical trial showed that AVF ligation was associated with a significant reduction in the left ventricle myocardial mass (verified with cardiac-MRI) and NT-proBNP levels [13]. Instead other authors argue that there is no real benefit to fistula closure in renal transplant recipients who might benefit from hemodialysis treatment in cases of graft failure and that its closure should be performed only for symptomatic patients with severe venous hypertension, risk of rupture from pseudoaneurysm, significant high-output cardiac failure or ischemic hand [14]. In line with this assertion Weekers et al. described a significant acceleration of eGFR decline over the 12 months following the closure of a functioning AVF in kidney transplant recipients (KTRs) [15]. A recent study has also shown that even in cases of closure of the AVF in renal transplant patients undergoing chronic therapy with corticosteroids and/or immunosuppressive drugs, an increased risk of developing arterial aneurysms may be associated [16].\n\n4 Conclusion\nNowadays current guidelines on postoperative care of KTRs do not give clear recommendations on management of AVF for stable kidney transplant recipients. Based on our clinical experience, the decision to surgically close an AVF should be highly personalized in every patient. Even if the rate of graft failure can also occur after 10- or more years from transplantation, the risk of AVF-linked complications is high. Furthermore, the surgical correction of those complications is not always easy to perform, as in our reported patient’s case. Although many authors determine long-term graft survival using short-term graft function as a predictor, the serum creatinine level at one year is in fact closely predictive of graft survival [17]. Another parameter to consider is the fistula blood flow. Patients with a fistula blood flow >2 L/min are traditionally at increased risk for the development of cardiac failure and renal allograft dysfunction through high venous pressure and therefore would perhaps benefit more from fistula closure [18], [19].\n\nFor these reasons and based upon our experience in this case report, we suggest not ligating the vascular access the first year following transplantation except in cases of patients needing emergent closure such as for severe venous hypertension, risk of rupture from pseudoaneurysm, or significant high output cardiac failure or ischemic hand. Asides from these, surgical closing to prevent the onset of complications could be considered a viable option in subsets of patients who are 3 or more years from transplantation with good and stable renal function, or have a significant growth of venous aneurysms, have a high AVF flow rate or are young in age.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nNone.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nM. Panagrosso, A. Peluso and A. Viscardi wrote the manuscript. U. M. Bracale, L. Del Guercio and E. Dinoto supervised the writing of the manuscript.\n\nRegistration of research studies\nN/A.\n\nGuarantor\nU.M. Bracale.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nAcknowledgements\nThis article is part of a supplement entitled Case reports from Italian young surgeons, published with support from the Department of Surgical, Oncological and Oral Sciences – University of Palermo.\n==== Refs\nReferences\n1 Sequeira A. Naljayan M. Vachharajani T.J. Vascular access guidelines: summary, rationale, and controversies Tech. Vasc. Interv. Radiol. 20 1 2017 2 8 10.1053/j.tvir.2016.11.001 28279405 \n2 Santangelo M.L. Bracale U.M. Carlomagno N. Kidney transplantation and large anastomotic pseudoaneurysm. Transplant management considerations Ann. Ital. Chir. 84 3 2013 275 279 23135415 \n3 Agha R.A. Borrelli M.R. Farwana R. For the SCARE GroupThe SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n4 Sirico M.L. Guida B. Procino A. Human mature adipocytes express albumin and this expression is not regulated by inflammation Mediators Inflamm. 2012 2012 236796 10.1155/2012/236796 \n5 Wooditch A.C. Aronoff S.C. Effect of initial corticosteroid therapy on coronary artery aneurysm formation in Kawasaki disease: a meta-analysis of 862 children Pediatrics 116 2005 989 995 16199713 \n6 Englesbe M.J. Wu A.H. Clowes A.W. Zierler R.E. The prevalence and natural history of aortic aneurysms in heart and abdominal organ transplant recipients J. Vasc. Surg. 37 2003 27 31 12514574 \n7 Reilly J.M. Savage E.B. Brophy C.M. Hydrocortisone rapidly induces aortic rupture in a genetically susceptible mouse Arch. Surg. 125 1990 707 709 2346371 \n8 Ferrara D. Di Filippo M. Spalla F. Giant true brachial artery aneurysm after hemodialysis fistula closure in a renal transplant patient Case Rep. Nephrol. Dial. 6 2016 128 132 27904865 \n9 Lam W. Betal D. Morsy M. Enormous brachio-cephalic arteriovenous fistula aneurysm after renal transplantation: case report and review of the literature Nephrol. Dial. Transplant. 24 2009 3542 3544 19592597 \n10 Unger P. Wissing K.M. Arteriovenous fistula after renal transplantation: utility, futility or threat? Nephrol. Dial. Transplant. 21 2006 254 257 16293634 \n11 Faull R. Rao N. Worthley M. Do arteriovenous fistulas increase cardiac risk? Semin. Dial. 31 2018 357 361 29513901 \n12 Zheng H. Bu S. Song Y. To ligate or not to ligate: a meta-analysis of cardiac effects and allograft function following arteriovenous fistula closure in renal transplant recipients Ann. Vasc. Surg. 63 2020 287 292 31536798 \n13 Rao N. Stokes M.B. Rajwani A. Effects of arteriovenous fistula ligation on cardiac structure and function in kidney transplant recipients Circulation 139 2019 2809 2818 31045455 \n14 Yaffe H.C. Greenstein S.M. Should functioning AV fistulas be ligated after renal transplantation? J. Vasc. Access 13 2012 405 408 22865530 \n15 Weekers L. Vanderweckene P. Pottel H. The closure of arteriovenous fistula in kidney transplant recipients is associated with an acceleration of kidney function decline Nephrol. Dial. Transplant. 32 2017 196 200 27798197 \n16 Dinoto E. Bracale U.M. Vitale G. Late, giant brachial artery aneurysm following hemodialysis fistula ligation in a renal transplant patient: case report and literature review Gen. Thorac. Cardiovasc. Surg. 60 2012 768 770 22627962 \n17 Karcz M. Kusztal M. Boratyńska M. Very long survival of transplanted kidney -characteristics of recipients Transplant. Proc. 50 2018 1730 1732 30056890 \n18 Stoumpos S. Mark P. Should we ligate arteriovenous fistulas in asymptomatic patients after kidney transplantation? Circulation 139 2019 2819 2821 31206325 \n19 Samarendra P. Ramkumar M. Sharma V. Cardiorenal syndrome in renal transplant recipients – it’s the fistula at fault: a case series Clin. Transplant. 32 2018 e13417\n\n",
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"abstract": "A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course. C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly.",
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"authors": "Hagiya|Hideharu|H|;Kokeguchi|Susumu|S|;Ogawa|Hiroko|H|;Terasaka|Tomohiro|T|;Kimura|Kosuke|K|;Waseda|Koichi|K|;Hanayama|Yoshihisa|Y|;Oda|Kaori|K|;Mori|Hisatoshi|H|;Miyoshi|Toru|T|;Otsuka|Fumio|F|",
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{
"abstract": "BACKGROUND\nPolyneuropathy, organomegaly, endocrinopathy, monoclonal syndrome (POEMS) is a rare paraneoplastic syndrome associated with plasma cell dyscrasia.\n\n\nMETHODS\nA 48-year-old man presented with a 1-year history of paresthesia and progressive weakness of extremities. Diagnosis of POEMS syndrome was made for him on the basis of clinical presentation, additional physical findings, typical sclerotic bone lesion, and bone marrow findings. In last admission, he explained episodes of dyspnea and chest pain that associated with frequent premature ventricular contraction in his electrocardiograph. Patient heart monitoring showed some episodes of complete heart block. Infra-His atrioventricular block in electro-physiologic study was detected. He had no history of ischemic heart disease. His cardiopulmonary findings on examination were normal. All results of cardiac biomarkers and serum electrolytes and repeated echocardiography were within normal range. Cong red staining of rectal fat pad biopsy was negative. After pacemaker insertion radiation of sclerotic bone, lesion started for him, but radiotherapy was ineffective, and he expired with respiratory failure. Complete heart block in POEMS syndrome has not been reported previously, and it is the first POEMS case with complete heart block.\n\n\nCONCLUSIONS\nComplete heart block is a cardiac manifestation of POEMS syndrome.",
"affiliations": "Assistant Professor, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Resident, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Pathologist, Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Associate Professor, Interventional Cardiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.",
"authors": "Ashrafi|Farzaneh|F|;Darakhshandeh|Ali|A|;Nematolahy|Pardis|P|;Khosravi|Alireza|A|",
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"fulltext": "\n==== Front\nARYA AtherosclerARYA AtherosclerARYAARYA Atherosclerosis1735-39552251-6638Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences ARYA-10-276Case ReportComplete heart block in a patient with POEMS syndrome: A case report Ashrafi Farzaneh 1Darakhshandeh Ali 2Nematolahy Pardis 3Khosravi Alireza 41 Assistant Professor, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran2 Resident, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran3 Pathologist, Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran4 Associate Professor, Interventional Cardiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, IranCorrespondence to: Ali Darakhshandeh, Email: alidarakhshandeh@yahoo.com9 2014 10 5 276 279 31 8 2013 16 2 2014 © 2014 Isfahan Cardiovascular Research Center & Isfahan University of Medical Sciences2014This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.BACKGROUND\nPolyneuropathy, organomegaly, endocrinopathy, monoclonal syndrome (POEMS) is a rare paraneoplastic syndrome associated with plasma cell dyscrasia.\n\nCASE REPORT\nA 48-year-old man presented with a 1-year history of paresthesia and progressive weakness of extremities. Diagnosis of POEMS syndrome was made for him on the basis of clinical presentation, additional physical findings, typical sclerotic bone lesion, and bone marrow findings. In last admission, he explained episodes of dyspnea and chest pain that associated with frequent premature ventricular contraction in his electrocardiograph. Patient heart monitoring showed some episodes of complete heart block. Infra-His atrioventricular block in electro-physiologic study was detected. He had no history of ischemic heart disease. His cardiopulmonary findings on examination were normal. All results of cardiac biomarkers and serum electrolytes and repeated echocardiography were within normal range. Cong red staining of rectal fat pad biopsy was negative. After pacemaker insertion radiation of sclerotic bone, lesion started for him, but radiotherapy was ineffective, and he expired with respiratory failure. Complete heart block in POEMS syndrome has not been reported previously, and it is the first POEMS case with complete heart block.\n\nCONCLUSION\nComplete heart block is a cardiac manifestation of POEMS syndrome.\n\nComplete Heart BlockPOEM SyndromeMultiple Meloma\n==== Body\nIntroduction\nPOEMS syndrome is a rare paraneoplastic syndrome associated with plasma cell dyscrasia. The acronym POEMS refers to several, but not all, of the features of the syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.1 There are two points related to this acronym. First, all of the features within the acronym are not required to make the diagnosis.2 Second, there are some other features such as sclerotic bone lesion, thrombocytosis, erythrocytosis, papilledema, and extravascular volume overload that are not included in the acronym POEMS.2,3 The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria (polyneuropathy and plasma cell gammopathy), and at least one of the minor criteria (sclerotic bone lesions, Castleman disease, organomegaly, edema, endocrinopathy, skin changes, and papilledema) are present.3 Polyneuropathy and plasma cell dyscrasia are the most common features in patients and seen in all of them.4 Cardiopulmonary manifestation of POEMS syndrome consist of pulmonary hypertension,5 cardiomyopathy,3,6 heart failure,3 pericarditis,3 and myocardial infarction.3,7 Kanda et al. reported five patients with POEMS syndrome and cardiomyopathy. In all patients, diffuse hypokinesia of left ventricular wall motion was seen on echocardiograms. In one case cardiac amyloidosis was diagnosed by Congo red staining of the myocardium biopsy, but the etiology of the cardiomyopathy was not determined in the other four cases.6 Myocardial infarction in POEMS syndrome has rarely been reported. Manning et al. reported a 27-year-old man with POEMS syndrome and extensive myocardial infarction and ulcerative proctitis. The patient had no significant risk factor for coronary arterial disease.7 Manning et al. hypothesized that an abnormal immunoglobulin (or fragment) is responsible for these findings.7\n\nDespite variable manifestation of cardiac disease in POEMS syndrome, complete heart block has not been reported previously. Herein, we present a case of POEMS syndrome with cardiac involvement, characterized by complete heart block.\n\nCase Report\nA 48-year-old man presented with numbness and weakness in lower extremities 1 year before admission in our center. Progressive proximal weakness had been developed in 3 weeks, and he was not able to walk and became wheelchair dependent. No abnormalities in urination and bowel habit were detected. In history he has had a history of low back pain since last year that had been diagnosed as a discopathy and medical treatment had been advised. In the physical examination, his muscle strength was 2/5 in proximal lower extremities and 3/5 in proximal of upper extremities. Deep tendon reflexes were decreased. Touch and pain sensation were also impaired, but anal sphincter tone and cranial nerves were normal.\n\nIn lab data except elevated cerebrospinal fluid protein (90 mg/dl), there were no other abnormalities. Due to ascending and distal sensory motor polyneuropathy, Guillain-Barre syndrome was diagnosed, and plasmapheresis and intravenous immunoglobulin (IVIG) were administered. About 2 weeks after hospitalization thrombocytosis (1,120,000/µl) was detected in lab data, which was associated with splenomegaly and para aortic lymphadenopathy in abdominopelvic computed tomography (CT) scan. Peripheral adenopathy was not detected. Bone marrow aspiration and biopsy reported normal. Splenectomy was performed, but patient had no symptom relief. Finally, after 2 weeks, he discharged with chronic inflammatory demyelinating polyneuropathy diagnosis and advised receiving IVIG monthly. Despite receiving IVIG monthly, his neurological symptoms were aggravated, and he became bedridden. Plasmapheresis was administered, but it had no effect. About 10 months after symptoms onset he was referred to hematology the ward for evaluation of thrombocytosis. He complained of overt weight loss, low back pain, nasal speech and pedal, and hand edema. He had no cardiac or respiratory symptoms. In physical examination, the patient was quadriplegic and deep tendon reflexes were absent. In ophthalmoscopy bilateral papilledema were present. Other abnormal physical examination findings were clubbing and whitening of nails, pedal and hand edema, bilateral gynecomastia and hypertrichosis. Peripheral lymph nodes were not palpable. The cranial nerves were normal. Table 1 shows the patient lab data. Serum protein electrophoresis was normal, but in serum immunofixation immunoglobulin G (IgG) lambda and IgA lambda biclonal gammaglobuline were seen.\n\nIn urine immunofixation, free kappa and lambda light chain were detected. In bone marrow aspiration large clumps of platelets suggestive of severe thrombocytosis and up to 3% highly atypical plasma cells was seen. In bone marrow biopsy, although osteosclerosis was not seen, but infiltrated sheets of poorly differentiated cells were seen (Figure 1). Rectal biopsy was performed. Congo red stain of rectal biopsy was negative. Electromyography and nerve conduction velocity studies revealed axonal and demyelinating polyneuropathy. Multislice CT scan of full spine revealed a sclerotic bone lesion in the body of T5; measuring about 10 mm (Figure 2).\n\nAs the patients had most criteria, diagnosis of POEMS syndrome was considered. In last admission, he had explained episodes of chest pain and dyspnea. Results of cardiovascular and pulmonary examination were normal, evaluation of pulmonary thromboembolism was negative, his electrocardiograph (ECG) showed normal sinus rhythm, frequents premature ventricular contractions (PVC) (three geminal PVC), PR interval 160 ms, QRS interval 100 ms, and QTC interval 163 ms. To reduce PVC diltiazem 30 mg twice daily started. After 2 days heart monitoring in cardiac care unit the patient had frequent episodes of transient complete heart block in cardiac rhythm. On echocardiography, normal cardiac function whit no structural abnormality was detected. After discontinuation of diltiazem, electro-physiologic study was done that showed infra-His atrioventricular (AV) block and patient candidate for permanent pace maker. After pace maker insertion, he referred to the radiotherapy ward for irradiation of sclerotic bone lesion. Unfortunately, radiotherapy was ineffective, and his neuropathy progressed and he passed away with respiratory failure.\n\nDiscussion\nComplete AV block has a variety of causes. Ischemic heart disease is responsible for about 40% of cases of AV block.8 Infiltrative disease such as amyloidosis9 and sarcoidosis10 are other common causes of AV block. Some drugs such as digitalis, amiodarone, calcium channel blockers (especially diltiazem and verapamil), β-blockers and adenosine can impair AV conduction, leading to AV block.11 Most patients with AV block who have no obvious cause except these drugs have underlying conductive disease.11 Drug discontinuation can result in resolution of AV block in some patients but most of them without treatment AV block later recurred. Our patient had no history of coronary and atherosclerotic risk factors for ischemic heart disease; in serial ECG no ST-T changes were seen. An echocardiogram is the most valuable procedure to detecting decreased cardiac function in patients suspected for myocarditis, even when it is subclinical.12,13 On repeated echocardiography, cardiac function was normal, and no evidence of structural disease was seen. Cardiac biomarkers were normal, and patient had no clinical suspicious for myocarditis. To exclude amyloidosis rectal fat biopsy was taken that was negative for Congo red staining. Results of thyroid function test and serum electrolytes were within normal range. Diltiazem was discontinued. However AV block was not resolved. These indicated that underline conducting system abnormality in the patient existed that was related to primary disease.\n\nAcknowledgments\nWe would like to thank the patient for permitting the publication of this article.\n\n\nConflicts of Interest\n\n\nAuthors have no conflict of interests.\n\nFigure 1 Abnormal plasma cell infiltration in bone marrow aspiration\n\nFigure 2 Sclerotic bone lesion in body of T5\n\nTable 1 Laboratory data\n\nVariable\tReference range\tResult\t\nWhite-cell\ncount (/mm3)\t4500-11000\t12500\t\nDifferential\ncount (%)\t\n\t\n\t\n Neutrophils\t55.0-75.0\t45\t\n Lymphocytes\t22.0-44.0\t51.9\t\n Mix\t0.0-10.0\t3.1\t\n Platelet count (/mm3)\t150000-350000\t1019000\t\n Hematocrit (%)\t41.0-53.0 (men)\t48.0\t\n Hemoglobin (g/dl)\t13.5-17.5 (men)\t14.5\t\n Mean corpuscular volume\t80.0-100.0\t89.6\t\n Testosterone (ng/ml)\t3.0-12.0\t0.4\t\n Albumin (mg/dl)\t3.4-5.0\t2.9\t\n Creatinine (mg/dl)\t0.6-1.5\t0.5\t\n BUN (mg/dl)\t8.0-25.0\t13.0\t\n aPTT (s)\t22.1-34.0\t28.0\t\n PT (s)\t10.3-13.2\t14.2\t\n INR\t1.00\t1.16\t\n TSH (μg/dl)\t0.3-50.0\t2.4\t\n T4 (μU/ml)\t4.0-12.0\t5.5\t\n FBS (mg/dl)\t< 100\t78\t\nBUN: Blood urea nitrogen; aPTT: Particle thromboplastin time; PT: Prothrombin time\n\nINR: International normal ratio; TSH: Thyroxin stimulating hormone; T4: Tetraiodo-thyronine\n\nFBS: Fasting blood sugar\n==== Refs\nREFERENCES\n1 Bardwick PA Zvaifler NJ Gill GN Newman D Greenway GD Resnick DL Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Baltimore) 1980 59 4 311 22 6248720 \n2 Dispenzieri A How I treat POEMS syndrome. Blood 2012 119 24 5650 8 22547581 \n3 Dispenzieri A Kyle RA Lacy MQ Rajkumar SV Therneau TM Larson DR POEMS syndrome: definitions and long-term outcome. Blood 2003 101 7 2496 506 12456500 \n4 Soubrier MJ Dubost JJ Sauvezie BJ POEMS syndrome: a study of 25 cases and a review of the literature. French Study Group on POEMS Syndrome. Am J Med 1994 97 6 543 53 7985714 \n5 Li J Tian Z Zheng HY Zhang W Duan MH Liu YT Pulmonary hypertension in POEMS syndrome. Haematologica 2013 98 3 393 8 22983590 \n6 Kanda J Kawabata H Yamaji Y Ichinohe T Ishikawa T Tamura T Reversible cardiomyopathy associated with Multicentric Castleman disease: successful treatment with tocilizumab, an anti-interleukin 6 receptor antibody. Int J Hematol 2007 85 3 207 11 17483056 \n7 Manning WJ Goldberger AL Drews RE Goldstein BJ Matheson JK Rabinowe SL POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature. Semin Arthritis Rheum 1992 22 3 151 61 1295088 \n8 Zoob M Smith KS The aetiology of complete heart-block. Br Med J 1963 2 5366 1149 53 14060910 \n9 Falk RH Diagnosis and management of the cardiac amyloidoses. Circulation 2005 112 13 2047 60 16186440 \n10 Sekhri V Sanal S Delorenzo LJ Aronow WS Maguire GP Cardiac sarcoidosis: a comprehensive review. Arch Med Sci 2011 7 4 546 54 22291785 \n11 Zeltser D Justo D Halkin A Rosso R Ish-Shalom M Hochenberg M Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol 2004 44 1 105 8 15234417 \n12 Nieminen MS Heikkila J Karjalainen J Echocardiography in acute infectious myocarditis: relation to clinical and electrocardiographic findings. Am J Cardiol 1984 53 9 1331 7 6711435 \n13 Pinamonti B Alberti E Cigalotto A Dreas L Salvi A Silvestri F Echocardiographic findings in myocarditis. Am J Cardiol 1988 62 4 285 91 3400607\n\n",
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{
"abstract": "OBJECTIVE\nPatients receiving cisplatin are at high risk of thromboembolic events (TEEs). The objective of this study was to assess the effect of cisplatin-based neoadjuvant chemotherapy (NCT) on the incidence of perioperative TEEs in patients undergoing radical cystectomy.\n\n\nMETHODS\nWe analyzed a consecutive sample of 202 patients with urothelial carcinoma treated with radical cystectomy between 2005 and 2013. Data were collected retrospectively by reviewing medical records. Median follow-up was 16.9 months. Events of interest were defined as venous or arterial TEEs occurring from the date of diagnosis to 30 days after surgery. TEE incidence among patients treated with NCT and cystectomy was compared with that among patients treated with cystectomy alone using Fisher exact test and Cox proportional hazards regression. Proportional hazards regression was also used to assess whether TEE is a predictor of cancer progression and survival.\n\n\nRESULTS\nOf 202 patients, 17 (8.4%) developed a TEE, including 8 of 42 (19.1%) treated with NCT and cystectomy and 9 of 160 (5.6%) treated with cystectomy alone (risk ratio = 3.39, 95% CI: 1.39-8.24). After adjustment for observation time, there remained an association between treatment with NCT and risk of TEE (hazard ratio = 2.40; 95% CI: 0.92-6.27; P = 0.07). Overall, 7 events occurred before cystectomy and 10 occurred postoperatively. Among patients treated with NCT, 6 of 8 events occurred before cystectomy. Detection of TEE was clinically significant as preoperative TEE was found to be an independent predictor of progression and cancer-specific mortality (adjusted hazard ratio = 3.91, 95% CI: 1.34-11.45). The main limitations of our study are its retrospective data collection and small absolute number of events.\n\n\nCONCLUSIONS\nTEE occurs commonly in patients with urothelial carcinoma undergoing NCT. Preoperative TEE is an independent predictor of progression and cancer-specific mortality.",
"affiliations": "Division of Urology, McMaster University, Hamilton, Ontario, Canada.;Division of Urology, McMaster University, Hamilton, Ontario, Canada; Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada.;Division of Urology, McMaster University, Hamilton, Ontario, Canada; Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada.;Division of Uro-oncology, Department of Surgical Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canda.;Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada; Division of Medical Oncology, McMaster University, Hamilton, Ontario, Canada.;Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada; Division of Medical Oncology, McMaster University, Hamilton, Ontario, Canada.;Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.;Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.;Division of Urology, McMaster University, Hamilton, Ontario, Canada; St. Joseph׳s Healthcare Hamilton, Hamilton, Ontario, Canada.;Division of Urology, McMaster University, Hamilton, Ontario, Canada; Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address: jehonathan.pinthus@jcc.hhsc.ca.",
"authors": "Zareba|Piotr|P|;Patterson|Laurel|L|;Pandya|Rishikesh|R|;Margel|David|D|;Hotte|Sebastien J|SJ|;Mukherjee|Som D|SD|;Elavathil|Leelamma|L|;Daya|Dean|D|;Shayegan|Bobby|B|;Pinthus|Jehonathan H|JH|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1439",
"issue": "32(7)",
"journal": "Urologic oncology",
"keywords": "Neoadjuvant chemotherapy; Thromboembolism; Urothelial carcinoma",
"medline_ta": "Urol Oncol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002295:Carcinoma, Transitional Cell; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D003131:Combined Modality Therapy; D015653:Cystectomy; D005260:Female; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013923:Thromboembolism; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "9805460",
"other_id": null,
"pages": "975-80",
"pmc": null,
"pmid": "25027682",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant chemotherapy and radical cystectomy.",
"title_normalized": "thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant chemotherapy and radical cystectomy"
} | [
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"abstract": "A case of PI in a 57-year-old patient with colonic inertia treated with lactulose for PSE secondary to cirrhosis is described. The colonic inertia led to longer transit time. Retained lactulose and a build-up of carbon dioxide and hydrogen gas occurred in the setting of altered bacterial flora deficient in hydrogen metabolism. The increased gas pressure caused extravasation of air into the intestine, causing PI with pneumoperitoneum. They both resolved with discontinuation of lactulose.",
"affiliations": "Department of Medicine, The Hershey Medical Center, Pennsylvania State University, College of Medicine, 17033, USA.",
"authors": "Goodman|R A|RA|;Riley|T R|TR|",
"chemical_list": "D007792:Lactulose",
"country": "United States",
"delete": false,
"doi": "10.1023/a:1012308911096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "46(11)",
"journal": "Digestive diseases and sciences",
"keywords": null,
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D006801:Humans; D007792:Lactulose; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011006:Pneumatosis Cystoides Intestinalis; D011027:Pneumoperitoneum",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "2549-53",
"pmc": null,
"pmid": "11713968",
"pubdate": "2001-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "890284;4050637;8425681;2298358;9179525;3264581;6040871;3551239;1587203;6827705;7572888;685959;4938483;13345634;525221;13580754;3538558;4159616;576710;4929274;8943984;7446522;1479305;4365449;4073766;14031571;1765913;9250851;6758034;2192457;2013193;10455375;292844;14923068;2012947;3375145;3231344;3234693",
"title": "Lactulose-induced pneumatosis intestinalis and pneumoperitoneum.",
"title_normalized": "lactulose induced pneumatosis intestinalis and pneumoperitoneum"
} | [
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"literaturereference": "RILEY III T,GOODMAN R. LACTULOSE-INDUCED PNEUMATOSIS INTESTINALIS AND PNEUMOPERITONEUM. DIG DIS SCI 2001 NOV?46(11):2549-53.",
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{
"abstract": "BACKGROUND\nOral baclofen toxicity is extremely rare, but can affect patients with renal disease due to the drug's predominant renal clearance of approximately 69-85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses.\n\n\nMETHODS\nA 69-year-old woman with a history of hemodialysis-dependent end-stage renal disease presented to the Emergency Department with encephalopathy, ataxia, and dystonia after the addition of a recent baclofen prescription for back pain (10 mg twice daily). She had been taking baclofen as prescribed for approximately 1 week when, the day prior to admission, she had increased her dose to a total of 40 mg. Diagnostic studies demonstrated the patient had chronic, end-stage renal disease and a supratherapeutic concentration of baclofen. Signs and symptoms resolved with hemodialysis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity.",
"affiliations": "Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, Allentown, Pennsylvania.;Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, Allentown, Pennsylvania.;Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, Allentown, Pennsylvania.",
"authors": "Porter|Lauren M|LM|;Merrick|Stephanie S|SS|;Katz|Kenneth D|KD|",
"chemical_list": "D058788:GABA-B Receptor Antagonists; D010276:Parasympatholytics; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2016.09.025",
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"issue": "52(4)",
"journal": "The Journal of emergency medicine",
"keywords": "baclofen; end-stage renal disease; hemodialysis; impaired baclofen clearance; toxicity",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000368:Aged; D001259:Ataxia; D001416:Back Pain; D001418:Baclofen; D001927:Brain Diseases; D003221:Confusion; D004421:Dystonia; D004636:Emergency Service, Hospital; D005260:Female; D058788:GABA-B Receptor Antagonists; D006801:Humans; D007676:Kidney Failure, Chronic; D009127:Muscle Rigidity; D010276:Parasympatholytics; D006435:Renal Dialysis",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e99-e100",
"pmc": null,
"pmid": "27789113",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen Toxicity in a Patient with Hemodialysis-Dependent End-Stage Renal Disease.",
"title_normalized": "baclofen toxicity in a patient with hemodialysis dependent end stage renal disease"
} | [
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}
],
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"reaction": [
{
"reactionmeddrapt": "Muscle rigidity",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "20.1",
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},
{
"reactionmeddrapt": "Ataxia",
"reactionmeddraversionpt": "20.1",
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},
{
"reactionmeddrapt": "Dystonia",
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},
{
"reactionmeddrapt": "Somnolence",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Confusional state",
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "PORTER LM, MERRICK SS, KATZ KD. BACLOFEN TOXICITY IN A PATIENT WITH HEMODIALYSIS-DEPENDENT END-STAGE RENAL DISEASE. J-EMERG-MED 2017;52(4):E99-E100.",
"literaturereference_normalized": "baclofen toxicity in a patient with hemodialysis dependent end stage renal disease",
"qualification": "1",
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},
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},
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},
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"transmissiondate": "20171127"
}
] |
{
"abstract": "We present a case of 63-year-old male with hypertension and hyperlipidaemia, who was an athlete in the \"masters category\". Because of interaction between amlodipine and simvastatin, in combination with physical activity, the patient reported: muscle pain, weakness of the muscles, dizziness, and confusion. After amlodipine and simvastatin discontinuation, all symptoms resolved rapidly.\n\n\nCONCLUSIONS\n(1) Concomitant use of several drugs by elderly individual patients, the risk of drug--physical activity interactions may occur.",
"affiliations": null,
"authors": "Schetz|Daria|D|;Foerster|Jerzy|J|;Sein Anand|Jacek|J|",
"chemical_list": "D017311:Amlodipine; D019821:Simvastatin",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2240",
"issue": "72(9)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D017311:Amlodipine; D003221:Confusion; D004244:Dizziness; D004347:Drug Interactions; D015444:Exercise; D006801:Humans; D006949:Hyperlipidemias; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D063806:Myalgia; D019821:Simvastatin",
"nlm_unique_id": "19840720R",
"other_id": null,
"pages": "488-90",
"pmc": null,
"pmid": "26827575",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Drug interaction in 63-year-old male sportsman--a case report.",
"title_normalized": "drug interaction in 63 year old male sportsman a case report"
} | [
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},
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"medicinalproduct": "TRANDOLAPRIL"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERINDOPRIL ARGININE"
},
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"drugdosageform": "Film-coated tablet",
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},
{
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},
{
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{
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},
{
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{
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{
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},
{
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},
{
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Feeling abnormal",
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20150101"
}
},
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"literaturereference": "Schetz D, Foerster J, Sein Anand J. Drug interaction in 63-year-old male sportsman-a case report. PRZEGLA D LEKARSKI. 2015;72(9):488-90",
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},
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},
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"transmissiondate": "20220423"
},
{
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},
{
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"activesubstancename": "AMLODIPINE BESYLATE"
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},
{
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},
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},
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},
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"narrativeincludeclinical": "CASE EVENT DATE: 2015"
}
},
"primarysource": {
"literaturereference": "SCHETZ D, FOERSTER J, SEIN ANAND J. DRUG INTERACTION IN 63-YEAR-OLD MALE SPORTSMAN-A CASE REPORT.. PRZEGLA?D LEKARSKI. 2015?72 (9):488-90",
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},
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},
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}
] |
{
"abstract": "BACKGROUND\nPembrolizumab is a highly selective IgG4 kappa isotype monoclonal antibody against the programmed cell death-1 (PD-1) molecule. In the treatment of non-small cell lung cancer (NSCLC), pembrolizumab has demonstrated significant efficacy, significant survival outcomes, long-lasting responses, and a good safety profile compared with cytotoxic chemotherapy.\n\n\nMETHODS\nA 79-year-old Korean male presented with a left side palpable neck mass. An ultrasound-guided core-needle biopsy of the largest neck mass was performed, and squamous cell carcinoma was confirmed based on the histological and immunohistochemical findings. He was diagnosed with squamous cell carcinoma of the lung with multiple lymph nodes and rib metastases (T1N3M1b, Stage IVA) using enhanced chest computed tomography and 18F-fluorodeoxyglucose positron emission/computed tomography. After 4 cycles of gemcitabine and carboplatin, we clinically judged the disease as progressive. Owing to the high PD-1 expression demonstrated by the patient, pembrolizumab was initiated (200 mg every 3 wk). After 3 cycles of pembrolizumab, a complete response was achieved. At the 4th cycle of pembrolizumab, the white blood cell count was markedly elevated. Peripheral blood smear analysis and bone marrow biopsy were performed. The patient was diagnosed with acute myelomonocytic leukemia.\n\n\nCONCLUSIONS\nWe present the first report of acute myelomonocytic leukemia during pembrolizumab treatment in an NSCLC patient; the mechanism remains unknown.",
"affiliations": "Department of Premedical Course, Chosun University School of Medicine, Gwangju 61452, South Korea.;Department of Hemato-oncology, Chosun University Hospital, Gwangju 61453, South Korea.;Department of Pathology, Chosun University Hospital, Gwangju 61453, South Korea.;Department of Laboratory Medicine, Chosun University Hospital, Gwangju 61453, South Korea.;Department of Pulmonology and Critical Care Medicine, Chosun University Hospital, Gwangju 61453, South Korea. ebusters@chosun.ac.kr.",
"authors": "Kim|Hong-Beum|HB|;Park|Sang-Gon|SG|;Hong|Ran|R|;Kang|Seong-Ho|SH|;Na|Yong Sub|YS|",
"chemical_list": null,
"country": "United States",
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"issn_linking": "2307-8960",
"issue": "8(13)",
"journal": "World journal of clinical cases",
"keywords": "Acute myeloid leukemia; Adverse events; Case report; Immunotherapy; Non-small cell lung cancer",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "2833-2840",
"pmc": null,
"pmid": "32742992",
"pubdate": "2020-07-06",
"publication_types": "D002363:Case Reports",
"references": "28743264;26712084;31467059;31905428;29768155;27827313;29320654;19357394;25891173;25653205;30193240;25421221;30642824;30286224;30271175",
"title": "Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report.",
"title_normalized": "acute myelomonocytic leukemia during pembrolizumab treatment for non small cell lung cancer a case report"
} | [
{
"companynumb": "KR-ACCORD-196181",
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}
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},
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"literaturereference": "KIM HB, PARK SG, HONG R, KANG SH, NA YS. ACUTE MYELOMONOCYTIC LEUKEMIA DURING PEMBROLIZUMAB TREATMENT FOR NON?SMALL CELL LUNG CANCER: A CASE REPORT. WORLD J CLIN CASES. 2020 JUL 6?8(13):2833?2840",
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"transmissiondate": "20201103"
}
] |
{
"abstract": "We describe the case of a 13-year-old boy who presented with persistent thrombocytopenia during maintenance chemotherapy with mercaptopurine and methotrexate for T cell lymphoblastic lymphoma. He was diagnosed with immune thrombocytopenia (ITP) after thorough investigations for the relapse of lymphoma and was successfully treated with immunoglobulin and steroids. ITP is known to be associated with chronic lymphocytic leukemia, Hodgkin lymphoma, and various types of non-Hodgkin lymphoma but rarely with T cell non-Hodgkin lymphoma or in children. Diagnosis of ITP with lymphoma is challenging due to the many factors affecting platelet counts, and ITP often complicates the diagnosis or treatment course of lymphoma. The underlying mechanism of ITP with NHL is still unclear. Drug-induced immunomodulation with a reduction of regulatory T cells might have contributed to the development of ITP in our case.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan.;Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan.;Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan.;Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan.;Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan.",
"authors": "Tokeji|Kayo|K|0000-0003-2226-7614;Sakaguchi|Sachi|S|0000-0003-0119-1796;Kurimoto|Tomoko|T|;Fujimura|Junya|J|;Shimizu|Toshiaki|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/2897325",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2016/2897325Case ReportImmune Thrombocytopenia in a Child with T Cell Lymphoblastic Lymphoma http://orcid.org/0000-0003-2226-7614Tokeji Kayo http://orcid.org/0000-0003-0119-1796Sakaguchi Sachi \n*\nKurimoto Tomoko Fujimura Junya Shimizu Toshiaki Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan*Sachi Sakaguchi: sachi@juntendo.ac.jpAcademic Editor: Salah Aref\n\n2016 7 9 2016 2016 28973257 6 2016 21 8 2016 Copyright © 2016 Kayo Tokeji 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.We describe the case of a 13-year-old boy who presented with persistent thrombocytopenia during maintenance chemotherapy with mercaptopurine and methotrexate for T cell lymphoblastic lymphoma. He was diagnosed with immune thrombocytopenia (ITP) after thorough investigations for the relapse of lymphoma and was successfully treated with immunoglobulin and steroids. ITP is known to be associated with chronic lymphocytic leukemia, Hodgkin lymphoma, and various types of non-Hodgkin lymphoma but rarely with T cell non-Hodgkin lymphoma or in children. Diagnosis of ITP with lymphoma is challenging due to the many factors affecting platelet counts, and ITP often complicates the diagnosis or treatment course of lymphoma. The underlying mechanism of ITP with NHL is still unclear. Drug-induced immunomodulation with a reduction of regulatory T cells might have contributed to the development of ITP in our case.\n==== Body\n1. Introduction\nImmune thrombocytopenia (ITP) is one of the most common causes of symptomatic thrombocytopenia in children. Secondary ITP attributed to coexisting conditions such as chronic lymphocytic leukemia, Hodgkin lymphoma, and various types of non-Hodgkin lymphoma (NHL) have been reported in adults but rarely in children. Here, we describe a case of a 13-year-old boy who was diagnosed with ITP during maintenance chemotherapy for T cell lymphoblastic lymphoma (T-LBL).\n\n2. Case Presentation\nA 13-year-old Japanese boy was referred to our hospital complaining of a right inguinal mass. Biopsy of the mass confirmed an enlarged inguinal lymph node with monotonous proliferation of medium- to large-sized atypical lymphoid cells positive for CD2, cytoplasmic CD3, CD5, and CD7 but negative for CD10, CD19, CD20, and CD22. Although his initial blood examination revealed normal white blood cells (WBCs, 4,500/μL), hemoglobin (14.7 g/dL), and platelets (456,000/μL), bone marrow examination revealed infiltration of atypical blastic cells, and thus he was diagnosed with T-LBL stage IV. Complete remission was achieved after induction chemotherapy. Subsequent courses of chemotherapy were uneventful, and he started maintenance therapy with daily mercaptopurine (60 mg/m2) and weekly methotrexate (25 mg/m2). The first 8 weeks of maintenance therapy was uneventful. Complete blood cell counts at the clinic visit on the fifth week were within expected ranges for WBCs (2,300/μL), hemoglobin (11.1 g/dL), and platelets (125,000/μL).\n\nFour weeks later, at the ninth week clinic visit, the patient presented with petechiae on his lower limbs. Blood examination revealed low platelet counts (37,000/μL) and normal hemoglobin levels (11.1 g/dL). Also, as expected, WBC counts were low (1,400/μL; neutrophils 32.7%, lymphocytes 40.4%, and blastic cells 0%) due to maintenance therapy. His blood chemistry was normal. His physical examination was unremarkable except for the petechiae. Maintenance therapy was suspended, but thrombocytopenia persisted with low platelet counts (7,000–25,000/μL). Bone marrow aspiration and biopsy revealed normocellular bone marrow, normal megakaryocyte counts (6/μL), and no lymphoma cell infiltration. A whole-body 18F-FDG positron emission tomography-computed tomography scan was negative. Platelet-associated immunoglobulin G (PAIgG) was high (446 ng/107 cells; normal range: 9–25 ng/107 cells). The patient received multiple platelet transfusions. Platelet counts immediately after the transfusions were lower than estimated counts, indicating an increase in platelet destruction rather than a decrease of platelet production.\n\nBased on these findings, the patient was diagnosed with ITP, and intravenous immunoglobulin (IVIG; 1 g/kg) was administered 7 weeks after the discontinuation of maintenance therapy. Five days after IVIG therapy, his platelet count recovered (to 100,000/μL), and he was started on oral prednisolone (1 mg/kg/day). Maintenance chemotherapy was resumed 3 weeks after IVIG therapy. Prednisolone was gradually decreased and discontinued 11 weeks after IVIG therapy. The patient completed the 74-week maintenance chemotherapy and has been off therapy for more than 4 months with normal platelet counts (200,000–300,000/μL).\n\n3. Discussion\nITP can present before, at, or after the diagnosis of NHL and often complicates the disease course of NHL. The reported prevalence of ITP in NHL is 0.76% based on four studies including 1,850 patients [1]. A cohort study using a Swedish nation-wide database showed an increased incidence ratio of 7.5 for NHL after diagnosis of ITP [2]. Among the various types of NHL reported in association with ITP, T cell lymphoma seems to be rare. A literature search using PubMed through December 2015 with the MeSH terms of “lymphoma, non-hodgkin” and “purpura, thrombocytopenic, idiopathic” identified 13 cases of ITP in association with T cell lymphoma, including 12 cases of angioimmunoblastic T cell lymphoma and one case of diffuse large T cell lymphoma. The patients with angioimmunoblastic T cell lymphoma were all Japanese, between 56 and 88 years of age, with increased levels of PAIgG [3]. The patient with diffuse large T cell lymphoma was a 53-year-old woman who was diagnosed with chronic ITP 3 years prior to the diagnosis of lymphoma [4].\n\nThe underlying mechanism of ITP with NHL is still unclear. Increased antiplatelet antibodies were observed in most cases of ITP with NHL. As several studies have shown the role of platelet-specific autoreactive T cells in primary ITP [5], it is possible that T cell origin lymphoma cells activate B cells to produce antiplatelet antibodies. This may explain why ITP with NHL is often resistant to standard therapies such as steroids or IVIG but is resolved by treatment for NHL. However, this is less likely to explain the development of ITP in our patient, as he maintained complete remission of lymphoma at the onset of ITP and showed good responses to IVIG and steroid therapy. Drug-induced immunomodulation may contribute to the development of ITP in patients undergoing chemotherapy. Liu et al. reported that CD4+CD25+ regulatory T cells are reduced in number and function in ITP patients [5]. In our patient, ITP developed during maintenance therapy with mercaptopurine and methotrexate, which causes prolonged depletion of CD4+ cells. Genetic susceptibility predisposing to both ITP and NHL may be another potential mechanism.\n\nIn summary, we describe the case of a 13-year-old boy diagnosed with ITP during maintenance chemotherapy for T-LBL. Diagnosis of ITP with NHL is often challenging due to many factors affecting platelet counts. ITP is associated with various types of NHL in adults but rarely with T cell lymphoma. The underlying mechanisms of the development of ITP with NHL and factors influencing treatment responses remain to be explored.\n\nConsent\nWritten informed consent was obtained from the guardian of the patient and written assent was obtained from the patient for publication of this case report.\n\nCompeting Interests\nNone of the authors have financial relationships or competing interests relevant to this manuscript to disclose.\n==== Refs\n1 Hauswirth A. W. Skrabs C. Schützinger C. Autoimmune thrombocytopenia in non-Hodgkin's lymphomas Haematologica 2008 93 3 447 450 10.3324/haematol.11934 2-s2.0-40849136681 18287133 \n2 Fallah M. Liu X. Ji J. Försti A. Sundquist K. Hemminki K. Autoimmune diseases associated with non-Hodgkin lymphoma: a nationwide cohort study Annals of Oncology 2014 25 10 2025 2030 10.1093/annonc/mdu365 2-s2.0-84921340062 25081899 \n3 Oka K. Nagayama R. Yatabe Y. Iijima S. Mori N. Angioimmunoblastic T-cell lymphoma with autoimmune thrombocytopenia: a report of two cases Pathology Research and Practice 2010 206 4 270 275 10.1016/j.prp.2009.04.002 2-s2.0-77950865868 \n4 Nagasawa T. Hasegawa Y. Shimizu S. Serum thrombopoietin level is mainly regulated by megakaryocyte mass rather than platelet mass in human subjects British Journal of Haematology 1998 101 2 242 244 10.1046/j.1365-2141.1998.00683.x 2-s2.0-7144229346 9609516 \n5 Liu B. Zhao H. Poon M.-C. Abnormality of CD4+ CD25+ regulatory T cells in idiopathic thrombocytopenic purpura European Journal of Haematology 2007 78 2 139 143 10.1111/j.1600-0609.2006.00780.x 2-s2.0-33846059033 17328716\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2016()",
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"nlm_unique_id": "101576456",
"other_id": null,
"pages": "2897325",
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"pmid": "27668103",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "18287133;25081899;9609516;17328716;19442454",
"title": "Immune Thrombocytopenia in a Child with T Cell Lymphoblastic Lymphoma.",
"title_normalized": "immune thrombocytopenia in a child with t cell lymphoblastic lymphoma"
} | [
{
"companynumb": "JP-ACCORD-044731",
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{
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{
"abstract": "Both beta-adrenergic receptor antagonist drugs (beta-blockers) and non-dihydropyridine calcium-channel blockers (non-DHP CCBs), ie, diltiazem and verapamil, can cause sinus arrest or severe sinus bradycardia, and when drugs from the two classes are used together, these effects may be more than additive. We report nine patients in whom a beta-blocker (one patient), a non-DHP CCB (one patient), or the combination (seven patients) caused sinus arrest or severe sinus bradycardia which resulted in hospitalization in six of the nine. Although this combination of drugs always has the potential for causing profound bradycardia, certain aspects of the history, such as age, the presence of renal or hepatic disease, and the number and types of other medications, are further predictors of marked bradycardia with hypotension.",
"affiliations": "Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA.",
"authors": "Mills|Theresa A|TA|;Kawji|Mazen M|MM|;Cataldo|Vinceent D|VD|;Pappas|Nicholas D|ND|;O'Meallie|Lawrence P|LP|;Breaux|Darrin M|DM|;Glancy|D Luke|DL|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D014700:Verapamil; D004110:Diltiazem",
"country": "United States",
"delete": false,
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DILTIAZEM."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DILTIAZEM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "074943",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "120 MG, UNK (6 MONTH AGO)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "120",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DILTIAZEM."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DILTIAZEM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "074943",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "360 MG, Q.AM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HYPERTENSION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "360",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DILTIAZEM."
}
],
"patientagegroup": null,
"patientonsetage": "58",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Potentiating drug interaction",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Syncope",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nodal rhythm",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sinus bradycardia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MILLS TA, KAWJI MM, CATALDO VD, PAPPAS ND, O^MEALLIE LP, BREAUX DM, GLANCY DL.. PROFOUND SINUS BRADYCARDIA DUE TO DILTIAZEM, VERAPAMIL, AND/OR BETA-ADRENERGIC BLOCKING DRUGS. JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY. 2004?156:327-331",
"literaturereference_normalized": "profound sinus bradycardia due to diltiazem verapamil and or beta adrenergic blocking drugs",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20191216",
"receivedate": "20191216",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17156663,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "OBJECTIVE\nTo report reactivation of herpes simplex virus keratitis after the injection of dexamethasone implant (Ozurdex) and to raise the awareness of this potentially vision threatening side effect.\n\n\nMETHODS\nA 90-year-old man presented with ocular pain and tearing in the left eye 3 weeks after receiving a dexamethasone implant (Ozurdex) for the treatment of macular edema associated with branch retinal vein occlusion. The patient had a history of herpes simplex virus keratitis that was quiescent for more than 30 years.\n\n\nRESULTS\nClinical examination of the left eye showed arborizing epithelial ulcer with terminal bulbs consistent with herpes simplex virus keratitis.\n\n\nCONCLUSIONS\nQuiescent herpes simplex virus keratitis can be reactivated after dexamethasone implant (Ozurdex). Prophylactic antiviral therapy might be indicated in individuals who have a high risk of recurrent herpetic disease.",
"affiliations": "*Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky; and †Department of Ophthalmology and Visual Sciences, University of Massachusetts School of Medicine, University of Massachusetts, Worcester, Massachusetts.",
"authors": "Jusufbegovic|Denis|D|;Schaal|Shlomit|S|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D004343:Drug Implants; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000376",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "11(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D004343:Drug Implants; D006561:Herpes Simplex; D006801:Humans; D058449:Intravitreal Injections; D016849:Keratitis, Herpetic; D008297:Male; D014775:Virus Activation",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "296-297",
"pmc": null,
"pmid": "27508424",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "QUIESCENT HERPES SIMPLEX KERATITIS REACTIVATION AFTER INTRAVITREAL INJECTION OF DEXAMETHASONE IMPLANT.",
"title_normalized": "quiescent herpes simplex keratitis reactivation after intravitreal injection of dexamethasone implant"
} | [
{
"companynumb": "US-ALLERGAN-1666159US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"drugadministrationroute": "031",
"drugauthorizationnumb": "022315",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "OPHTHALMIC INSERT",
"drugdosagetext": "0.7 MG, SINGLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MACULAR OEDEMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": ".7",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OZURDEX"
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "022315",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "OPHTHALMIC INSERT",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "VISUAL IMPAIRMENT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OZURDEX"
}
],
"patientagegroup": null,
"patientonsetage": "90",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes simplex",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JUSUFBEGOVIC D, SCHAAL S. QUIESCENT HERPES SIMPLEX KERATITIS REACTIVATION AFTER INTRAVITREAL INJECTION OF DEXAMETHASONE IMPLANT. RETINAL CASES + BRIEF REPORTS. 2017?11(4):296-297",
"literaturereference_normalized": "quiescent herpes simplex keratitis reactivation after intravitreal injection of dexamethasone implant",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180615",
"receivedate": "20160822",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12675153,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Hemolacria is a rare complication of epistaxis treated with nasal compression or tamponade. We report the case of a man, aged 81 years, with end-stage renal disease who developed hemolacria after insertion of a \"Rhino Rocket\" nasal tamponade device to treat persistent epistaxis. The hemolacria resolved after treatment with intranasal oxymetazoline. In the setting of epistaxis with nasal tamponade, hemolacria is thought to be caused by retrograde flow from the inferior nasal turbinates via an anatomic connection with the lacrimal system, with passage through the valves of Hasner and Rosenmüller to the lacrimal ducts. Hemolacria is very rare even in severe cases of epistaxis; we postulate that only patients with either congenital absence or acquired incompetence of the lacrimal valves are predisposed to hemolacria after treatment of epistaxis with a tamponade device. Physicians should be aware that hemolacria in the setting of epistaxis is usually a self-limited condition that can be treated with conservative measures to control nasal hemorrhage.",
"affiliations": "Case Western Reserve University School of Medicine, Cleveland, OH Aed65@case.edu.;Case Western Reserve University School of Medicine, Cleveland, OH.",
"authors": "Drake|Anne E|AE|;Packer|Clifford D|CD|",
"chemical_list": "D010109:Oxymetazoline",
"country": "United States",
"delete": false,
"doi": "10.3121/cmr.2020.1566",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-4182",
"issue": "18(2-3)",
"journal": "Clinical medicine & research",
"keywords": "Anatomy; Hemolacria; Nasolacrimal duct",
"medline_ta": "Clin Med Res",
"mesh_terms": "D000281:Administration, Intranasal; D000369:Aged, 80 and over; D004844:Epistaxis; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D010109:Oxymetazoline; D013630:Tampons, Surgical",
"nlm_unique_id": "101175887",
"other_id": null,
"pages": "99-101",
"pmc": null,
"pmid": "32816989",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31529380;31882188;27879619;20633971;30380382;30754966;13605331;23040961;21617906;8352138;29905639;20224466;21791186;30545679;30068743;12881360;30975366;27768644;22205781;8156326",
"title": "Epistaxis Complicated by Hemolacria: A Case Report.",
"title_normalized": "epistaxis complicated by hemolacria a case report"
} | [
{
"companynumb": "US-BAYER-2020-187296",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "999999",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "GASTRO-RESISTANT COATED TABLET",
"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": "ACETYLSALICYLIC ACID"
}
],
"patientagegroup": "6",
"patientonsetage": "81",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Epistaxis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DRAKE AE, PACKER CD. EPISTAXIS COMPLICATED BY HEMOLACRIA: A CASE REPORT. CLINICAL MEDICINE AND RESEARCH. 2020?18:2?3:99?101",
"literaturereference_normalized": "epistaxis complicated by hemolacria a case report",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200904",
"receivedate": "20200904",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18232301,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20201103"
}
] |
{
"abstract": "We report the case of a 4-month-old girl who developed encephalopathy, seizures, and respiratory compromise as a result of baclofen toxicity. After some investigation, the accidental ingestion of baclofen was caused by an error in compounding the patient's prescribed omeprazole with baclofen rather than sodium bicarbonate at a retail pharmacy. This error occurred because these two drugs, which were available as powders, were located side by side on the pharmacy shelf. The pharmacist further reported that their normal practice was to use injectable sodium bicarbonate rather than powder to compound an omeprazole suspension; however, the injectable form was not available due to a national shortage. This report demonstrates how a drug shortage contributed to severe clinical consequences and intensive care hospitalization of a patient. It also highlights the need for system improvement to minimize drug shortages.",
"affiliations": "Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts ; Department of Pediatric Hematology/Oncology, Johns Hopkins Hospital, Baltimore, Maryland.;Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts.;Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts.;Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts.",
"authors": "Lau|Bonnie|B|;Khazanie|Uma|U|;Rowe|Emily|E|;Fauman|Karen|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-21.6.527",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "21(6)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adverse drug effect; baclofen; drug shortage; encephalopathy; extemporaneous compounding; medication error; omeprazole; sodium bicarbonate",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "527-529",
"pmc": null,
"pmid": "28018156",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "23481445",
"title": "How a Drug Shortage Contributed to a Medication Error Leading to Baclofen Toxicity in an Infant.",
"title_normalized": "how a drug shortage contributed to a medication error leading to baclofen toxicity in an infant"
} | [
{
"companynumb": "US-DEXPHARM-20162498",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": "1",
"drugadministrationroute": null,
"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": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OMEPRAZOLE- NOT DEXCEL^S PRODUCT"
}
],
"patientagegroup": "2",
"patientonsetage": "4",
"patientonsetageunit": "802",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Crying",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Pallor",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hyperkalaemia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hypothermia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Medication error",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Depressed level of consciousness",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Eye movement disorder",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Dyskinesia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Encephalopathy",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Infarction",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Irregular breathing",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Metabolic acidosis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hyporeflexia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Pupillary reflex impaired",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Product deposit",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hypotonia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Product reconstitution issue",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LAU BONNIE; KHAZANIE UMA; ROWE EMILY; FAUMAN KAREN. HOW A DRUG SHORTAGE CONTRIBUTED TO A MEDICATION ERROR LEADING TO?BACLOFEN TOXICITY IN AN INFANT. THE JOURNAL OF PEDIATRIC PHARMACOLOGY AND THERAPEUTICS : JPPT : THE OFFICIAL JOURNAL OF PPAG, (2016 NOV-DEC) VOL. 21, NO. 6, PP. 527-529.",
"literaturereference_normalized": "how a drug shortage contributed to a medication error leading to baclofen toxicity in an infant",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170102",
"receivedate": "20170102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 13078297,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170428"
},
{
"companynumb": "US-SAOL THERAPEUTICS-2017SAO01074",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"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": "OMEPRAZOLE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": "020075",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "480 MG, ONCE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "480",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BACLOFEN."
}
],
"patientagegroup": null,
"patientonsetage": "4",
"patientonsetageunit": "802",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Accidental overdose",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "20.0",
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},
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"literaturereference": "LAU B, KHAZANIE U, ROWE E, FAUMAN K. HOW A DRUG SHORTAGE CONTRIBUTED TO A MEDICATION ERROR LEADING TO BACLOFEN TOXICITY IN AN INFANT. J PEDIATR PHARMACOL THER (DOI: 10.5863/1551-6776-21.6.527). 2016;21(6):527-529",
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{
"abstract": "The primary aim of this study was to estimate the prevalence of lithium associated end-stage renal disease (ESRD) and to compare the relative risk of ESRD in lithium users versus non-lithium users. Second, the role of lithium in the pathogenesis of ESRD was evaluated. We used the Swedish Renal Registry to search for lithium-treated patients with ESRD among 2644 patients with chronic renal replacement therapy (RRT)-either dialysis or transplantation, within two defined geographical areas in Sweden with 2.8 million inhabitants. The prevalence date was December 31, 2010. We found 30 ESRD patients with a history of lithium treatment. ESRD with RRT was significantly more prevalent among lithium users than among non-lithium users (p<0.001). The prevalence of ESRD with RRT in the lithium user population was 15.0‰ (95% CI 9.7-20.3), and close to two percent of the RRT population were lithium users. The relative risk of ESRD with RRT in the lithium user population compared with the general population was 7.8 (95% CI 5.4-11.1). Out of those 30 patients, lithium use was classified, based on chart reviews, as being the sole (n=14) or main (n=10) cause of ESRD in 24 cases. Their mean age at the start of RRT was 66 years (46-82), their mean time on lithium 27 years (12-39), and 22 of them had been on lithium for 15 years or more. We conclude that lithium-associated ESRD is an uncommon but not rare complication of lithium treatment.",
"affiliations": "Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: harald.aiff@vgregion.se.;Department of Nephrology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Nephrology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Clinical Sciences, Psychiatry, Lund University, Lund, Sweden.;Diaverum Renal Services Group, Lund & Swedish Renal Registry, Jönköping, Sweden.;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.",
"authors": "Aiff|Harald|H|;Attman|Per-Ola|PO|;Aurell|Mattias|M|;Bendz|Hans|H|;Schön|Staffan|S|;Svedlund|Jan|J|",
"chemical_list": "D000928:Antidepressive Agents; D018692:Antimanic Agents; D008094:Lithium",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-977X",
"issue": "24(4)",
"journal": "European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology",
"keywords": "Adverse effects; Affective disorders; Chronic; Kidney failure; Lithium",
"medline_ta": "Eur Neuropsychopharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents; D018692:Antimanic Agents; D015984:Causality; D015331:Cohort Studies; D015897:Comorbidity; D003430:Cross-Sectional Studies; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008094:Lithium; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders; D015995:Prevalence; D012042:Registries; D012306:Risk; D055502:Secondary Prevention; D013548:Sweden",
"nlm_unique_id": "9111390",
"other_id": null,
"pages": "540-4",
"pmc": null,
"pmid": "24503277",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "End-stage renal disease associated with prophylactic lithium treatment.",
"title_normalized": "end stage renal disease associated with prophylactic lithium treatment"
} | [
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{
"abstract": "Tuberculoma is one of the manifestations of tuberculosis infection in the central nervous system. Even though its prevalence is only 1%, the mortality rate is high. Clinical presentation in immunocompromised patients with tuberculoma maybe different, thus making the diagnosis difficult. We present the case of a 13-year-old girl who was admitted for routine intravenous administration of cyclophosphamide and steroid therapy for nephritis due to systemic lupus erythematosus. She experienced severe headache and focal seizure on the second day of hospitalization. Neurology examination did not show any abnormalities. The Xpert MTB/RIF from the cerebrospinal fluid and sputum yielded negative results. Computed tomography scan and magnetic resonance imaging showed tuberculoma with caseous necrosisaround the fibrous capsule in the right occipital lobe of the brain. Electroencephalography showed no abnormalities. Clinical improvement was seen after 3weeks of treatment; however, antituberculosis drug-induced hepatotoxicity occurred.",
"affiliations": "Division of Respirology, Department of Child Health, Padjadjaran University School of Medicine, Hasan Sadikin General Hospital, Bandung, Indonesia.;Division of Allergy and Immunology, Padjadjaran University School of Medicine, Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Child Health, Padjadjaran University School of Medicine, Hasan Sadikin General Hospital, Bandung, Indonesia.",
"authors": "Nataprawira|Heda Melinda|HM|http://orcid.org/0000-0001-8079-6544;Sapartini|Gartika|G|;Indriani|Ketut|K|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/TurkThoracJ.2018.17033",
"fulltext": null,
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"issn_linking": "2148-7197",
"issue": "19(3)",
"journal": "Turkish thoracic journal",
"keywords": "Tuberculoma; child; systemic lupus erythematosus",
"medline_ta": "Turk Thorac J",
"mesh_terms": null,
"nlm_unique_id": "101648545",
"other_id": null,
"pages": "153-155",
"pmc": null,
"pmid": "30083408",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": "21748845;22069437;25812968;19590444;18400795",
"title": "Delayed Diagnosis of Tuberculoma in a Child with Nephritis due to Systemic Lupus Erythematosus.",
"title_normalized": "delayed diagnosis of tuberculoma in a child with nephritis due to systemic lupus erythematosus"
} | [
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"reaction": [
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"reactionmeddraversionpt": "21.0",
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{
"reactionmeddrapt": "Scleral discolouration",
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"reaction": [
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"reactionmeddrapt": "Partial seizures",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Proteinuria",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Glycosuria",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tuberculoma of central nervous system",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lymphopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
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},
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},
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] |
{
"abstract": "We present a case of an 80-year-old male who developed skull base osteomyelitis after nasopharyngeal cyst removal. A review of the literature regarding complications after nasopharyngeal cyst removal was performed. We describe the difficulty of diagnosing an osteomyelitis infection and the best approach to recognizing osteomyelitis before complications worsen.",
"affiliations": "22494Cedars Sinai Sinus Center of Excellence, Los Angeles, CA, USA.;22494Cedars Sinai Sinus Center of Excellence, Los Angeles, CA, USA.;22494Cedars Sinai Sinus Center of Excellence, Los Angeles, CA, USA.",
"authors": "Raskin|Jonathan|J|;Borrelli|Michela|M|https://orcid.org/0000-0003-1311-9329;Wu|Arthur W|AW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/01455613211039044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-5613",
"issue": "100(6_suppl)",
"journal": "Ear, nose, & throat journal",
"keywords": "infection; nasopharyngeal cyst; osteomyelitis; skull base",
"medline_ta": "Ear Nose Throat J",
"mesh_terms": null,
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "867S-869S",
"pmc": null,
"pmid": "34420423",
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"literaturereference": "Raskin J, Borrelli M, Wu AW. Skull Base Osteomyelitis After Nasopharyngeal Cyst Excision. Ear-Nose-Throat-J 2021;100 (Suppl.)(6):867S-869S.",
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{
"abstract": "OBJECTIVE\nAlthough pre-operative chemoradiotherapy appears to be a promising treatment for patients with pancreatic ductal adenocarcinoma, there have been no reports of the feasibility of pre-operative chemoradiotherapy in pancreatic ductal adenocarcinoma patients with renal impairment. The aim of this study was to evaluate retrospectively the feasibility of pre-operative chemoradiotherapy in pancreatic ductal adenocarcinoma patients with renal impairment.\n\n\nMETHODS\nTwelve patients with resectable pancreatic ductal adenocarcinoma and a creatinine clearance of <60 ml/min were enrolled in this study. Gemcitabine-based pre-operative chemoradiotherapy was performed, followed by surgery. The feasibility of the treatment was evaluated in terms of clinical outcome and adverse events in the patients.\n\n\nRESULTS\nAll 12 patients completed gemcitabine-based pre-operative chemoradiotherapy without worsening of renal function. Restaging after the therapy revealed radiologically unresectable disease in two patients. Among the remaining 10 patients who underwent laparotomy, curative resection was performed in eight patients. After curative resection, five patients out of the eight completed post-operative adjuvant therapy. The 1- and 3-year survival rates after the start of chemoradiotherapy in the 12 patients were 80.8 and 36.9%, respectively.\n\n\nCONCLUSIONS\nOur findings suggest that gemcitabine-based pre-operative chemoradiotherapy may be a safe and effective treatment for pancreatic ductal adenocarcinoma in patients with renal impairment.",
"affiliations": "Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita.;Department of Surgery, Graduate School of Medicine, Osaka University, Suita hnagano@gesurg.med.osaka-u.ac.jp.",
"authors": "Tomimaru|Yoshito|Y|;Eguchi|Hidetoshi|H|;Satoh|Taroh|T|;Tomokuni|Akira|A|;Asaoka|Tadafumi|T|;Wada|Hiroshi|H|;Marubashi|Shigeru|S|;Ogawa|Kazuhiko|K|;Takehara|Tetsuo|T|;Mori|Masaki|M|;Doki|Yuichiro|Y|;Nagano|Hiroaki|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyu224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "45(4)",
"journal": "Japanese journal of clinical oncology",
"keywords": "gemcitabine; neoadjuvant chemoradiotherapy; pancreatic cancer; pre-operative chemoradiotherapy; renal dysfunction",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D021441:Carcinoma, Pancreatic Ductal; D059248:Chemoradiotherapy; D003841:Deoxycytidine; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011300:Preoperative Care; D051437:Renal Insufficiency; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "343-8",
"pmc": null,
"pmid": "25589454",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Feasibility of pre-operative chemoradiotherapy with gemcitabine to treat pancreatic cancer in patients with impaired renal function.",
"title_normalized": "feasibility of pre operative chemoradiotherapy with gemcitabine to treat pancreatic cancer in patients with impaired renal function"
} | [
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{
"abstract": "BACKGROUND\nMalignant infiltration accounts for 0.5% of acute liver failure cases, with non-Hodgkin's lymphoma the predominant cause. Adult T-cell lymphoma/leukemia (ATLL) is a rarer source of acute hepatitis, with only 3 cases reported and all resulting in immediate deterioration with death. ATLL rises from human T-lymphocytic virus-1 (HTLV-1), commonly found in Japan (southern and northern islands), the Caribbean, Central and South America, intertropical Africa, Romania, and northern Iran. In Micronesia, HTLV-1 infection amongst native-born is absent or exceedingly rare.\nA 77-year-old Marshallese man presented to the emergency department with a 1-week history of generalized weakness, fatigue, and nausea. The physical exam revealed a cervical papulonodular exanthem and scleral icterus.\n\n\nMETHODS\nLaboratory studies were remarkable for aspartate-aminotransferase of 230 IU/L (reference range [RR]: 0-40), alanine-aminotransferase of 227 IU/L (RR: 0-41), alkaline phosphatase of 133 IU/L (RR: 35-129), and total bilirubin of 4.7 mg/dL (RR: 0-1.2), supporting acute liver injury. Platelet count was 11.6x104/μL (RR: 15.1-42.4 × 104), hemoglobin was 13.8 g/dL (RR: 13.7-17.5), and white blood cell count was 7570/μL (RR: 3800-10,800) with 81.8% neutrophils (RR: 34.0-72.0) and 10.4% lymphocytes (RR: 12.0-44.0). The peripheral blood smear demonstrated abnormal lymphocytes with occasional flower cell morphology. HTLV-1/2 antibody tested positive. The skin and liver biopsies confirmed atypical T-cell infiltrate. The diagnosis of ATLL was established.\n\n\nMETHODS\nThe patient elected for palliative chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). He began antiviral treatment with zidovudine 250 mg bis in die (BID) indefinitely. Ursodiol and cholestyramine were added for his hyperbilirubinemia.\n\n\nRESULTS\nFour weeks from admission, the patient returned to near baseline functional status and was discharged home.\n\n\nCONCLUSIONS\nThis case highlights that ATLL can initially present as isolated acute hepatitis, and how careful examination of peripheral blood-smear may elucidate hepatitis etiology. We also present support for utilizing ursodiol with cholestyramine for treating a hyperbilirubinemia. Moreover, unlike prior reports of ATLL presenting as liver dysfunction, combined antiviral and CVP chemotherapy was effective in this case. Lastly, there are seldom demographic reports of HTLV-1 infection from the Micronesian area, and our case represents the first indexed case of HTLV-1-associated-ATLL presenting as acute liver failure in a Marshallese patient.",
"affiliations": "University of California, Davis, School of Medicine, Department of Neurological Surgery Sacramento, CA.;University of Hawai'i at Mānoa, John A. Burns School of Medicine, Department of Medicine Honolulu, Hawaii.;The Queen's Medical Center Honolulu, Hawaii.;University of Hawai'i at Mānoa, John A. Burns School of Medicine, Department of Medicine Honolulu, Hawaii.;University of Hawai'i at Mānoa, John A. Burns School of Medicine, Department of Medicine Honolulu, Hawaii.",
"authors": "Ghaffari-Rafi|Arash|A|;Rho|Young Soo|YS|;Hall|Andrew|A|;Villanueva|Nicolas|N|;Nogi|Masayuki|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000026236",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34260522\nMD-D-20-11197\n10.1097/MD.0000000000026236\n26236\n4800\nResearch Article\nClinical Case Report\nHTLV-1 associated acute adult T-cell lymphoma/leukemia presenting as acute liver failure in Micronesian\nA case report\nGhaffari-Rafi Arash MD, MSc ab∗\nRho Young Soo MD cd\nHall Andrew DO de\nVillanueva Nicolas MD cd\nNogi Masayuki MD cd\nSaranathan. Maya\na University of California, Davis, School of Medicine, Department of Neurological Surgery Sacramento, CA\nb University of Hawai’i at Mānoa, John A. Burns School of Medicine Honolulu, Hawaii\nc University of Hawai’i at Mānoa, John A. Burns School of Medicine, Department of Medicine Honolulu, Hawaii\nd The Queen's Medical Center Honolulu, Hawaii\ne University of Hawai’i at Mānoa, John A. Burns School of Medicine, Department of Pathology Honolulu, Hawaii.\n∗ Correspondence: Arash Ghaffari-Rafi, University of California, Davis, School of Medicine, Department of Neurological Surgery, 4860 Y Street, Suite 3740, Sacramento, California (e-mail: arashgr@hawaii.edu).\n16 7 2021\n16 7 2021\n100 28 e2623611 1 2021\n7 5 2021\n19 5 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nMalignant infiltration accounts for 0.5% of acute liver failure cases, with non-Hodgkin's lymphoma the predominant cause. Adult T-cell lymphoma/leukemia (ATLL) is a rarer source of acute hepatitis, with only 3 cases reported and all resulting in immediate deterioration with death. ATLL rises from human T-lymphocytic virus-1 (HTLV-1), commonly found in Japan (southern and northern islands), the Caribbean, Central and South America, intertropical Africa, Romania, and northern Iran. In Micronesia, HTLV-1 infection amongst native-born is absent or exceedingly rare.\n\nPatient Concerns:\n\nA 77-year-old Marshallese man presented to the emergency department with a 1-week history of generalized weakness, fatigue, and nausea. The physical exam revealed a cervical papulonodular exanthem and scleral icterus.\n\nDiagnosis:\n\nLaboratory studies were remarkable for aspartate-aminotransferase of 230 IU/L (reference range [RR]: 0–40), alanine-aminotransferase of 227 IU/L (RR: 0–41), alkaline phosphatase of 133 IU/L (RR: 35–129), and total bilirubin of 4.7 mg/dL (RR: 0–1.2), supporting acute liver injury. Platelet count was 11.6x104/μL (RR: 15.1–42.4 × 104), hemoglobin was 13.8 g/dL (RR: 13.7–17.5), and white blood cell count was 7570/μL (RR: 3800–10,800) with 81.8% neutrophils (RR: 34.0–72.0) and 10.4% lymphocytes (RR: 12.0–44.0). The peripheral blood smear demonstrated abnormal lymphocytes with occasional flower cell morphology. HTLV-1/2 antibody tested positive. The skin and liver biopsies confirmed atypical T-cell infiltrate. The diagnosis of ATLL was established.\n\nInterventions:\n\nThe patient elected for palliative chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). He began antiviral treatment with zidovudine 250 mg bis in die (BID) indefinitely. Ursodiol and cholestyramine were added for his hyperbilirubinemia.\n\nOutcomes:\n\nFour weeks from admission, the patient returned to near baseline functional status and was discharged home.\n\nLessons:\n\nThis case highlights that ATLL can initially present as isolated acute hepatitis, and how careful examination of peripheral blood-smear may elucidate hepatitis etiology. We also present support for utilizing ursodiol with cholestyramine for treating a hyperbilirubinemia. Moreover, unlike prior reports of ATLL presenting as liver dysfunction, combined antiviral and CVP chemotherapy was effective in this case. Lastly, there are seldom demographic reports of HTLV-1 infection from the Micronesian area, and our case represents the first indexed case of HTLV-1-associated-ATLL presenting as acute liver failure in a Marshallese patient.\n\nKeywords\n\nacute hepatitis\nacute liver failure\nadult T-cell lymphoma/leukemia\nHawaii\nhuman T-cell lymphocytic virus-1\nhyperbilirubinemia\nmarshallese\nmicronesia\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nThe first human retrovirus to be identified, human T-lymphocytic virus (HTLV) was isolated in the United States (1980) and Japan (1982) independently.[1–3] Soon after, HTLV type 1 (HTLV-1) was confirmed as the etiology behind the geographic clustering of a distinct leukemia in southwest Japan, termed adult T-cell leukemia/lymphoma (ATLL).[4] Today, 5 to 10 million people worldwide are estimated to be infected with HTLV-1, with numbers relatively unknown in India, China, and several other densely populated regions.[5] Despite the global distribution, HTLV-1 is found in minute foci of high infection prevalence surrounded by low endemic areas (i.e., Mashhad, Iran; Okinawa, Japan; Alice Springs, Australia; Tumaco, Colombia).[6–9] This unusual geographic spread is theorized to arise from the founder effect.[5]\n\nIrrespective of distribution, HTLV-1 infection is associated with numerous diseases, including: ATLL, HTLV-1-associated myelopathy/tropical spastic paraparesis, HTLV-1-associated uveitis, dermatologic conditions (i.e., infective dermatitis, crusted scabies), opportunistic infections, rheumatic/autoimmune conditions (i.e., Sjogren's syndrome, rheumatoid arthritis), inclusion body myositis and polymyositis, polyneuropathy, and depression.[10–22] ATLL itself is further classified into 4 clinical variants (acute, lymphomatous, chronic, and smoldering), with acute being the most common.[3,23] Typically, acute ATLL is characterized by leukocytosis, skin involvement, and generalized lymphadenomegaly; also often accompanied are hepatosplenomegaly, hypercalcemia, and elevated lactic dehydrogenase (LDH).[3,24]\n\nThis case report emphasizes that acute ATLL can present as isolated acute hepatitis without hepatosplenomegaly or an abnormal white blood cell count. Moreover, we highlight how meticulous peripheral blood-smear examination may decipher the cause behind hepatitis of unknown etiology. Unlike the 3 prior reports of ATLL presenting as liver dysfunction, combined antiviral with chemotherapy (cyclophosphamide, vincristine, and prednisone; [CVP]) was effective in our case.[25–27] Furthermore, HTLV-1 infection in Micronesia is reported as absent or rare (with no data from the Marshall Islands), our case represents the second indexing of HTLV-1-associated-ATLL in a Marshallese patient.[28–31] We hope to increase awareness that this life-threatening condition can not only present solely as acute hepatitis, but also in nontraditional populations (i.e., Marshallese and/or Micronesians).\n\n2 Case report\n\nWe present a 77-year old man who was brought to the emergency department (ED) by his wife. He presented with the chief complaint of slowly progressive fatigue and generalized weakness for the past 7-days. At baseline the patient was fully independent without disability, but the worsening progression of symptoms caused the patient to become bedbound and was the impetus for going to the ED.\n\nThe patient denied any inciting events, including new medications or supplements (including kava), changes to diet, recent travel, sick contacts, or exposure to standing water. Associated symptoms included lightheadedness and mild nausea, but no vomiting.\n\nHis past medical history was notable for benign prostatic hyperplasia, hypothyroidism, right thyroid goiter, hypercholesterolemia, and impaired fasting glucose. Past surgeries included transurethral resection of the prostate and right thyroid biopsy. He denied prior traumas, transfusions, and allergies. Immunizations were up-to-date and he had regular follow-up with his primary care provider. His medications included levothyroxine 75 mcg daily, doxazosin 4 mg daily, finasteride 5 mg daily, and pravastatin 40 mg daily. His mother and father both passed away from unknown cancers, his brother has a gastrointestinal stromal tumor, and his adult children have no known health conditions.\n\nThe patient is of native Marshallese descent, born and raised in the Marshall Islands, and immigrated to Hawaii 50-years prior; his family denies any known Japanese ancestry. He lives at home with his wife. He was a former smoker, with 10 to 25 pack years, quitting 37-years ago. He denies any recent and former alcohol or drug use. He is independent with respect to his instrumental activities of daily living.\n\nPatient was lethargic, weak-appearing, thin, and slow in answering questions, but not in acute distress. His sclera was icteric, while cardiac and lungs exams were unremarkable. Abdomen was soft, non-tender, non-distended, without a palpable liver or spleen. Peripheral pulses were 2+ (0–4 grading; 2+ indicates slightly more diminished then normal) with no extremity edema. Cervical, supraclavicular, axillary, and inguinal lymph nodes were not palpable. Skin was remarkable for a cervical papulonodular rash expanding circumferentially around the neck, in the C2-C4 dermatome distribution (Fig. 1).\n\nFigure 1 Papulonodular exanthem. Patient exhibited a new (appeared within past 1 month) upper trunk and proximal extremity papulonodular rash circumferentially encompassing the neck and C2-C4 dermatomes. After biopsy the rash was identified as leukemia cutis.\n\nOn admission the patient's complete blood count was notable for a white blood cell count of 7570/μL (reference range [RR]: 3800–10800) with 81.8% neutrophils (RR: 34.0–72.0) and 10.4% lymphocytes (RR: 12.0–44.0). His hepatic function profile was remarkable for an aspartate-aminotransferase of 230 IU/L (RR: 0–40), alanine-aminotransferase of 227 IU/L (RR: 0–41), and a total-bilirubin of 4.7 mg/dL (RR: 0–1.2). His basic metabolic panel, magnesium, urinalysis, and influenza type A and B assessments were unremarkable. His transaminitis and hyperbilirubinemia were extensively worked-up.\n\nA battery of tests were conducted in assessing for possible causes of hepatic insult and etiology of chief complaint, however results were inconclusive (Table 1). Subsequently, a peripheral blood smear was obtained, which exhibited occasional abnormal lymphocytes with flower cell morphology (Fig. 2). Immunophenotyping by flow cytometry was consistent with mature T-cell leukemia/lymphoma. Flow cytometric evaluation presented an abnormal CD45 bright lymphoid population (small-moderate in size by light scatter; 33% of all cells, 70% of lymphocytes) which expressed CD2, CD3, CD4, CD5, CD25, CD30 (weak), CD43, HLA-DR (weak), and alpha-beta T-cell receptor. There was no significant expression for CD1a, CD7, CD8, CD34, gamma-delta T-cell receptor or natural killer cell markers (CD16, CD56, and CD57). Also present were B-cells without demonstratable surface light chain restriction, along with a population of CD56+/CD3- natural killer cells (6% of lymphocytes). A distinct population of CD34 positive blasts (<0.1%) was not identified.\n\nTable 1 Diagnostics. A series of tests were conducted to elucidate etiology of the patient's hepatic injury. However, the results were inconclusive.\n\nDiagnostic tests\tResults\t\nAcetaminophen (Tylenol) level\t<5 μg (RR: 10–30)\t\nPlasma/serum ethanol\tNegative\t\nGamma-glutamyl transferase\t51 IU/L (RR: 8–61)\t\nComprehensive urine drug screen\tNegative\t\nBlood mercury\t13 mcg/L (RR: < 11)\t\nSerum copper\t58 mcg/dL (RR: 70–175)\t\nCeruloplasmin\t19 mg/dL (RR: 15–30)\t\nMidnight cortisol\t13.0 μgdL (RR: 3.0–16.0)\t\nHIV-1/2 antigen/antibody\tNegative\t\nVitamin B12\t>2000 pg/mL (RR: 232–1245)\t\nSerum folate\t7.0 ng/mL (RR: > 3.1)\t\nHaptoglobin\t<10 mg/dL (RR: 30–200)\t\nEpstein-Barr virus (EBV) quantitative DNA polymerase chain reaction (PCR)\t<200 copies/mL (RR: <200)\t\nRapid plasma reagin\tNon-reactive\t\nAcute hepatitis panel\tNegative: hepatitis A virus antibody IgM, hepatitis B core antibody IgM, hepatitis B surface antigen, hepatitis C antibody\t\nHepatitis E virus IgM\tNot detected\t\nHepatitis E virus IgG\tNot detected\t\nHepatitis D virus antibody\tNegative\t\nThroat herpes simplex virus (HSV) type 1 and 2 by real-time PCR\tHSV type 1 detected, HSV type 2 not detected\t\nAnti-nuclear antibody titer\t<40, RR: ≤40\t\nActin (smooth muscle) antibody IgG\t<20 U, RR: ≤20\t\nMitochondrial antibody\tNegative\t\nLiver kidney microsome antibody IgG\tNegative at <20.0, RR: ≤20.0\t\nIgM\t25 mg/dL, RR: 40–230\t\nIgG\t773 mg/dL, 700–1600\t\nIgA\t169 mg/dL, RR: 70–400\t\nAlpha-1 antitrypsin\t87 mg/dL, RR: 90–200\t\nAlpha-1 antitrypsin phenotype\tPI∗MM (90% of normal individuals have the MM phenotype)\t\nEBV antibody to early antigen IgG ratio\t<0.2 (negative, RR: ≤0.8)\t\nEBV antibody to nuclear antigen IgG ratio\t>8.0 (positive, RR: ≤0.8; indicating past exposure)\t\nEBV antibody to viral capsid antigen (VCA) IgG ratio\t>8.0 (positive, RR ≤0.8; indicating immunological exposure either as silent primary infection or past exposure)\t\nEBV antibody to VCA IgM ratio\t<0.2 (negative, RR ≤0.8)\t\nTransferrin\t150 mg/dL (RR: 200–360)\t\nFerritin\t1267 ng/mL (RR: 30–400)\t\nTotal iron\t179 μgdL (RR: 45–160)\t\nIron binding capacity\t<196 μgdL (RR: 228-428\t\nPercent saturation (iron studies)\t>91.3% (RR: 20–50)\t\n\nFigure 2 Peripheral blood smear. Abnormal lymphocytes with occasional flower cell morphology is observed in the panels A, B, and C.\n\nFollowing, a liver biopsy (Fig. 3) showed hepatic parenchyma with a sinusoidal and portal infiltrate of atypical lymphocytes, along with a number of neutrophils. The atypical lymphocytes were medium-large in size with significant nuclear pleomorphism. Immunohistochemistry showed the atypical lymphocytes to be positive for CD2, CD3, CD4, CD5, and CD30. Ki67 was significantly increased (>90%) in the atypical cells. PAX-5 and CD20 highlighted rare scatted B-cells, while CD7, CD8, CD56, and CD57 highlighted rare scattered natural killer cells. ALK1 was negative. Liver iron staining was graded as 2+ (mild; RR: 0 to 4+), while reticulin and trichrome stains demonstrating no obvious fibrosis. Meanwhile, skin biopsy (Fig. 4) of the left neck trapezius revealed an atypical T-cell infiltrate consistent with T-cell leukemia/lymphoma. Immunophenotypic studies highlighted a CD4 predominant T-cell infiltrate (CD3, CD4, CD8, CD20), with large cells positive for CD30.\n\nFigure 3 Liver biopsy. (A and B), demonstrate liver parenchyma with a sinusoidal and portal infiltrate composed of atypical lymphocytes along with scattered neutrophils. The atypical lymphocytes stained (not shown) positively for CD2, CD3, CD4, CD5, and CD30, with Ki67 significantly increased (> 90%). ALK1 was negative. C, CD3 (T-cell marker) highlights the atypical lymphocyte infiltrate.\n\nFigure 4 Skin biopsy. (A), low magnification shows an atypical cellular infiltrate in the epidermis and dermis. (B), high power demonstrates the infiltrate to be composed of medium sized, mildly pleomorphic lymphocytes. Immunohistochemical staining exhibited lymphocytes positive for CD3, CD4, CD8, and CD20, with occasional large cells positive for CD30, hence consistent with adult T-cell lymphoma/leukemia.\n\nHTLV I/II antibody Western blot resulted positive for HTLV-1 antibodies, consistent with HTLV-1 infection, with the patient being considered infectious. The patient was started on palliative chemotherapy, involving a 21-day cycle of prednisone 100 mg (for 5 days), vincristine 1 mg (dose reduced for hyperbilirubinemia), and cyclophosphamide 750 mg2m. Due to the patient's deteriorating condition, prednisone was initiated prior to confirmation of ATLL, yet there was no improvement in total bilirubin; upon ATLL confirmation, he was then started on cyclophosphamide and vincristine for cytoreduction. Doxorubicin was held due to hyperbilirubinemia. Zidovudine 250 mg bis in die (BID) was initiated (upon return of HTLV-1 results) to reduce HTLV-1 burden. With initiation of the CVP regimen the patient's total lactate dehydrogenase (LDH) and corrected calcium (Fig. 5A, 5C) declined. However, total bilirubin continued rising to a peak of 27.7 mg/dL and eventually declined after the addition of oral cholestyramine/aspartame 4 g daily and ursodiol 300 mg daily (Fig. 5B). Asterixis and hepatic encephalopathy were managed with lactulose 20 g ter in die and rifaximin 550 mg BID.\n\nFigure 5 Trended Serum LDH, Total Bilirubin, and Corrected Calcium. (A), serum LDH down-trended upon initiation of the CVP chemotherapy regimen. (B), total bilirubin continued rising despite initiating chemotherapy, but began down-trending upon initiation of ursodiol and cholestyramine/aspartame. (C), corrected calcium was not elevated on admission, but spiked briefly with the initiation of prednisone, likely secondary to tumor lysis.\n\nThe treatment course was complicated by severe anemia that was out of proportion of chemotherapy induced pancytopenia. Esophagogastroduodenoscopy demonstrated esophagitis, gastritis, and non-bleeding gastric and duodenal ulcers as the source of hemorrhage. Oral mucosa revealed extensive candida. Stool ova and parasite test were negative for Strongyloides stercoralis infection. Tissue biopsy from oropharyngeal area confirmed involvement of herpes simplex virus and Candida which were treated with acyclovir and anidulafungin. Chemotherapy induced bone marrow suppression was treated with filgrastim-sndz. The patient returned to near baseline and was discharge after 4-weeks from hospitalization. However, within 4-weeks of discharge the patient experienced a cardiac arrest at home and passed away.\n\n3 Discussion\n\n3.1 Epidemiology\n\nDistribution of ATLL parallels the prevalence of HTLV-1 infection.[3] Major endemic regions of HTLV-1 include west and central Africa (i.e., Gabon [25% in some Haut-Ogoué region villages], Democratic Republic of the Congo [0.7%–3.7%], Nigeria [5.5%], Ghana [1%–2.7%], Senegal [0.2%–1.2%], Guinea [0.2%–1.9%], Ivory Coast [1%–2.7%], and Cameroon [0.5%–2%]), South America (i.e., Brazil [1.8% in Salvador, Bahia], Peru [1.3%–3.8%], Chile [0.7%–1.9%]), the Caribbean (i.e., Jamaica [6.1%], Barbados [2%], Martinique [2%], Guadeloupe [2%], Trinidad [2%], and Tobago [2%]), and southern Japan [1%–6%].[5,32,33] Meanwhile, in several nations isolated pockets of endemicity can be found surrounded by near absence of HTLV-1 infection: Urmia, Azerbaijan (Iran) [0.34%]; Mashhad, Khorasan (Iran) [1.97%]; Alice Springs, Australia [0.32%]; Fujian, China [0.001%]; Tumaco, Colombia [2.8%].[7,9,34–36] Although few longitudinal studies have been conducted, one 5-year study identified HTLV-1 seroprevalence to be decreasing in Iran, even in endemic centers.[34]\n\nMoreover, within Europe and North America HTLV-1 infection is found primarily amongst individuals with heritage from endemic regions. In Europe, excluding Romania—the only endemic nation [0.00053%]—studies from the United Kingdom, France, and Spain identified over 80% of infections to originate from citizens with heritage from endemic locations—primarily the West Indies (i.e., Jamaica, Barbados, Martinique, Guadeloupe, Trinidad, and Tobago), Africa (i.e., Ghana, Sierra Leone, Senegal, Mali, Guinea, Ivory Coast, and Cameroon), and South America.[5,37,38] Additionally, another 5% to 10% of infections were accounted for by Caucasian women who acquired HTLV-1 through sexual transmission from a partner who originated from an endemic region.[39] Similarly, in mainland United States, HTLV-1 cases are found predominantly in Florida and New York, with those infected usually having Afro-Caribbean or African-American heritage.[5,40]\n\nIn Hawaii, HTLV-1 infection is found amongst patients of southern Japanese heritage.[41–44] Our case represents the second indexing of ATLL in a Micronesian (i.e., Marshallese).[28] Although our patient denies knowledge of having Japanese ancestry, at the outbreak of World War I (1914) and through World War II (1945), Japan occupied the Marshall Islands, resulting in 5.9% of today's Marshallese having mixed ancestry.[45,46] Currently, studies indicate HTLV-1 infection amongst native Micronesians and Polynesians to be absent or incredibly rare.[29] By genotyping the virus, the origin of our patient's infection may have been imputed via molecular epidemiology.\n\nFour geographically distinct genotypes of HTLV-1 exist: Cosmopolitan subtype A (divided into the Transcontinental, Japanese, West African, and North African subgroups), Central African subtype B, Central African/Pygmies subtype D, and Australo-Melanesian subtype C.[5] If our patient acquired HTLV-1 through Japanese heritage his virus would likely be part of the Japanese or Transcontinental subgroups, genotypes both found in Japan.[5] If he was fully native Marshallese, he may have carried subtype C, which would indicate the migration of the virus across the Pacific from Melanesia to Micronesia.\n\n3.2 Transmission\n\nVertical transmission via breastfeeding constitutes the most common route for HTLV-1 infection, with intrauterine or peripartum transmission exceedingly rare (less than 5% of cases).[47] Duration of breastfeeding (≥ 12 months, 24%–32% transmission rate; < 12 months, 5%–9%), mother's proviral load, and HLA class I type mother-child concordance, all modify transmission efficacy.[48–51] Other sources of transmission include blood contact via transfusions or sharing of needles/syringes.[52] Although efficacy of transmission via needle sharing in intravenous drug users is low, transfusion of infected blood produces yields infection in 50% to 60% of recipients.[53,54] As viable lymphocytes are required for HTLV-1 infection, efficacy of transmission drops after storing blood products for more than 1 week.[55] Lastly, sexual intercourse also provides an important transmission route, as HTLV-1 has been found in both cervical secretions and semen, with male-to-female transmission more efficacious than female-to-male.[56]\n\nNotably, HTLV-1 infection route is associated with specific diseases. HTLV-1-associated myelopathy/tropical spastic paraparesis is linked to blood transfusions, while ATLL is associated with breastfeeding, with post-transfusion ATLL unprecedented.[47,57,58] Amongst HTLV-1 carriers, most remain asymptomatic, with lifetime risk of 3% to 5% for developing ATLL.[59] With a diagnosis of ATLL, along with our patient's history precluding transfusions or intravenous drug use, his HTLV-1 was likely acquired via breastfeeding.\n\n3.3 Clinical presentation of adult T-cell lymphoma/leukemia\n\nDue to the diversity in presentation and prognosis, ATLL has been categorized into 4 subtypes per the Shimoyama classification system: smoldering, chronic (leukemic), acute (leukemic), and lymphomatous.[23] The smoldering subtype is characterized by presence of ≥5% abnormal lymphocytes on peripheral blood smear (or <5% if skin/lung infiltration is involved), a normal leukocyte count, a LDH value ≤1.5 times the upper limit of normal (ULN), no lymphadenopathy, no liver, spleen, central nervous system (CNS), bone, or gastrointestinal involvement, and no ascites or pleural effusion.[23] Meanwhile, chronic ATLL is defined by leukocytosis, absolute lymphocytosis, a LDH ≥2 times the ULN, no hypercalcemia, no bone, gastrointestinal, or CNS involvement, and no ascites or pleural effusion; lymphadenopathy, liver, spleen, and skin involvement, along with ≥5% abnormal lymphocytes on peripheral blood smear may be present.[23] Both chronic and smoldering types exhibit favorable prognoses, with 2- and 4-year survival rates of 52.4% and 26.9% in chronic, and 77.7% and 62.8% in smoldering.[23] The presence of ascites and pleural effusion precluded the diagnosis of smoldering or chronic ATLL in our patient.\n\nLymphomatous and acute subtypes are considered the aggressive forms of ATLL, with respective 2- and 4-year survival rates of 21.3% and 5.7% for lymphomatous, and 16.7% and 5.0% for acute.[23,24] The lymphoma subtype is characterized by no lymphocytosis, ≤1% abnormal lymphocytes, and massive lymphadenopathy (>1.5 cm).[23] Our patient lacked lymphadenopathy, including on computed tomography imaging of his head, neck, chest, and abdomen. Hence, our patient was left with the diagnosis of acute ATLL, the most common type, accounting for 60% to 65% of cases.[24,60] Acute ATLL is reserved for patients who do not meet criteria for the other 3 classifications.[23]\n\nAcute ATLL is generally characterized by extensive lymphadenopathy, hepatosplenomegaly, leukocytosis, systemic symptoms (i.e., fever, night sweats, weight loss, and weakness), lytic bone lesions, and diffuse visceral involvement (skin, gastrointestinal tract, and lung infiltration).[23,24,60] Clinical manifestations of severe hypercalcemia (i.e., renal dysfunction, neuropsychiatric alterations) are present in half of patients and generally the presenting symptoms.[24,60]\n\nOur case was highly unusual in that the patient presented only with acute hepatitis and a new papulonodular rash; he had a normal lymphocyte count, no hepatosplenomegaly, no lymphadenopathy, no electrolyte abnormalities (including calcium), and no leukemic systemic symptoms (other than weakness). In the English literature, only 3 other cases of ATLL presenting with acute hepatitis have been indexed, yet in these cases other symptoms including lymphadenopathy, hepatosplenomegaly, fever, rigors, or hypercalcemia were also present.[25,26,61] Hence, this report is the first to describe ATLL presenting exclusively as acute hepatitis with a papulonodular rash (Fig. 1), as well as the first to describe ATLL presenting with acute hepatitis in a Marshallese patient.\n\nMalignant infiltration accounts for only 0.5% of acute liver failure cases, with most cases secondary to non-Hodgkin's lymphoma.[62] Thus, ATLL induced acute liver failure is exceedingly rare. However, in certain regions of Japan where HTLV-1 is highly endemic, the incidence of ATLL infiltrating the liver is greater than non-Hodgkin's lymphoma.[63] Hepatically, ATLL cells generally localize to the periportal region, resulting in massive hepatic ischemia and eventual widespread necrosis of the hepatocytes (suspected secondary to the Schwartzman phenomena).[64] ATLL (versus non-Hodgkin's lymphoma) liver infiltration portends a poorer prognosis, possibly secondary to the risk of sepsis-induced hepatopathy, disseminated intravascular coagulation, or hemophagocytosis syndrome—complications not present in our patient.[63,65–67]\n\nOverall, our case highlights how in situations where etiology of liver failure remains enigmatic, the clinical team should consider a peripheral blood smear to probe possibility of a hematologic malignancy (Fig. 2).\n\n3.4 Diagnosis\n\nAt the 13th International Conference on Human Retrovirology: HTLV (2008), ATLL researchers drafted a consensus statement on management of the disease.[16] To diagnosis ATLL (excluding lymphomatous subtype), ATLL-cells (extensively polylobulated nuclei containing condensed homogenous chromatin, with absent/small nucleoli and agranular/basophilic cytoplasm) must be detected in the peripheral blood; notably, flower cells are pathognomonic (Fig. 2).[16] To secure the clinical diagnosis of ATLL, the patient must be seropositive for HTLV-1 with histologically/cytologically confirmed peripheral T-cell malignancy.[16] The minimum requirements for ATLL diagnosis via immunophenotyping involves analysis of CD3, CD4, CD7, CD8, and CD25.[16] ATLL cells are a mature CD4 T-cell population exhibiting CD2, CD5, CD25, CD45RO, CD29, T-cell receptor, and HLA-DR.[16] In accordance, our patient's cells expressed CD2, CD3, CD4, CD5, CD25, CD30 (weakly), CD43, HLA-DR (weakly), and alpha-beta T-cell receptor. Lastly, although not required due to accessibility, cytogenetic analysis and testing for monoclonal integration of HTLV-1 proviral DNA are recommended when possible.[16] Unfortunately, testing for monoclonal integration, cytogenetic analysis, and HTLV-1 genotyping were all unavailable at our facility. Regardless, our patient did meet diagnostic criteria for acute ATLL, and thus began treatment.\n\n3.5 Treatment\n\nTreatment regimens for acute ATLL must be determined on a case-by-case basis, taking into account prognostic factors (i.e., age, performance status, serum calcium, and LDH), exclusion criteria nuances from prior clinical trials, and contraindications to chemotherapeutics.[3,16,24] As the best treatment regimen is unknown, patients are encouraged to enroll in clinical trials when possible.[16] Regarding survival outcomes, LSG-15 (VCAP-AMP-VECP) presents the longest survival time (10.9 months) in acute ATLL patients, yet because patients with renal dysfunction were excluded and several of the medications utilized are not available outside of Japan (including the United States), treatment standard of care is not yet established; recent unpublished data indicates etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, doxorubicin hydrochloride (EPOCH) yields similar results.[24,68,69] In our case, treatment options were limited by the patient's liver dysfunction, for etoposide and doxorubicin (in EPOCH) are unsafe with hyperbilirubinemia, hence dictating the rational for CVP selection: a 21-day cycle regimen involving prednisone 100 mg (for 5 days), cyclophosphamide 750 mg2m, and vincristine 1 mg. Moreover, due to meta-analysis data indicating enhanced treatment response and prolonged survival, zidovudine 250 mg BID was initiated indefinitely; although standard of care is unclear, some recommend an antiviral with interferon prior to starting chemotherapy, but our patient's precipitous decline in health warranted immediate initiation of chemotherapy, reduction of zidovudine dosage (900 mg/day recommended), and exclusion of interferon due to side effect profile.[24] With chemotherapy initiation, LDH levels precipitously dropped from 1153 IU/L to 318 IU/L within 165 hours (roughly 7 days) (Fig. 1A). Likewise, serum calcium levels returned within normal limits after 72 hours of starting chemotherapy (Fig. 1C). CNS prophylaxis was also planned outpatient, for when acute ATLL relapses at a new site the CNS is involved more than half the time.[24]\n\n3.6 Hyperbilirubinemia management\n\nAlthough LDH and calcium levels responded to chemotherapy, total bilirubin continued to rise (Fig. 1B). The patient's hyperbilirubinemia worsened from admission, peaking at 27.7 mg/dL with diffuse pruritus and mucosal jaundice developing. The origin of the hyperbilirubinemia was likely secondary to malignant infiltration and hepatocellular injury, as aspartate-aminotransferase, alanine-aminotransferase, and international normalized ratio were elevated, and biliary tree obstruction was ruled out. Moreover, on admission the patient had proper renal function, which deteriorated only throughout the hospital course, indicating a possible etiology of bile cast nephropathy and/or hepatorenal syndrome. As the hyperbilirubinemia precluded administration of certain chemotherapeutics (i.e., doxorubicin, etoposide, as part of EPOCH), daily cholestyramine 4 g with ursodiol 300 mg was initiated. Immediately, decline in total bilirubin was observed, with values dropping to 4.7 mg/dL at discharge; however, the decline in bilirubin was only correlative, instead likely resulting from delayed response to chemotherapy and reduced hepatic tumor burden.\n\n3.7 Opportunistic infections\n\nAs patient with ATLL are functionally immunocompromised, often patients succumb to opportunistic infections, including malignant strongyloidiasis, Pneumocystis jiroveci pneumonia, herpes, cytomegalovirus, fungi (i.e., Candida, disseminated cryptococcosis), toxoplasmosis, and bacterial infections (i.e., abscesses, sepsis).[24,60] In particular, patients are recommended to have screening for Strongyloides stercoralis via a stool ova and parasite, and if positive treated with thiobendazole, ivermectin, or albendazole.[24,60] Although our patient tested negative for S. stercoralis and had no clinically evident P. jiroveci pneumonia, he did develop herpes simplex virus esophagitis and oroesophageal candidiasis, which required treatment with acyclovir and anidulafungin. Overall, Japanese trials have recommended patients be on trimethoprim-sulfamethoxazole, valacyclovir, and antifungals to provide prophylaxis against P. jiroveci pneumonia, viral, and fungal infections.[69]\n\n4 Conclusion\n\nOverall, our case highlights how clinicians should remain vigilant that ATLL can not only present as isolated acute liver failure, but also in nontraditional populations. Unlike the 3 prior reports of ATLL presenting as liver dysfunction, combined antiviral with CVP chemotherapy was effective in our case.[25–27] Furthermore, our case represents the second indexing of ATLL in a Marshallese patient, despite HTLV-1 infection exceedingly rare in Micronesia.[28–31] Although only correlative, our experience indicates possible utility of ursodiol and cholestyramine as adjuncts to chemotherapy for intractable hyperbilirubinemia. Overall, we hope to increase awareness of the atypical presentations ATLL may assume.\n\nAuthor contributions\n\nConceptualization: Arash Ghaffari-Rafi, Young Soo Rho, Masayuki Nogi.\n\nData curation: Arash Ghaffari-Rafi, Young Soo Rho, Andrew Hall, Masayuki Nogi.\n\nFormal analysis: Arash Ghaffari-Rafi, Andrew Hall, Nicolas Villanueva, Masayuki Nogi.\n\nFunding acquisition: Arash Ghaffari-Rafi.\n\nInvestigation: Arash Ghaffari-Rafi, Young Soo Rho, Masayuki Nogi.\n\nMethodology: Arash Ghaffari-Rafi, Young Soo Rho, Masayuki Nogi.\n\nProject administration: Arash Ghaffari-Rafi, Masayuki Nogi.\n\nResources: Arash Ghaffari-Rafi, Young Soo Rho, Andrew Hall, Masayuki Nogi.\n\nSoftware: Arash Ghaffari-Rafi.\n\nSupervision: Arash Ghaffari-Rafi, Young Soo Rho, Masayuki Nogi.\n\nValidation: Arash Ghaffari-Rafi, Masayuki Nogi.\n\nVisualization: Arash Ghaffari-Rafi, Masayuki Nogi.\n\nWriting – original draft: Arash Ghaffari-Rafi.\n\nWriting – review & editing: Arash Ghaffari-Rafi, Young Soo Rho, Andrew Hall, Nicolas Villanueva, Masayuki Nogi.\n\nAbbreviations: ATLL = adult T-cell lymphoma/leukemia, BID = bis in die, CVP = cyclophosphamide, vincristine, and prednisone, EPOCH = etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, doxorubicin hydrochloride, HTLV-1 = human T-lymphocytic virus-1, LDH = lactate dehydrogenase, RR = reference range.\n\nHow to cite this article: Ghaffari-Rafi A, Rho YS, Hall A, Villanueva N, Nogi M. HTLV-1 associated acute adult T-cell lymphoma/leukemia presenting as acute liver failure in Micronesian: a case report. Medicine. 2021;100:28(e26236).\n\nUniversity of California, Davis provided partial funding.\n\nEthics approval and consent was provided by both the patient and University of Hawaii institutional review board.\n\nSigned consent for publication of the case report was attained from the patient, however all material was anonymized.\n\nThe authors have no conflicts of interests to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Poiesz BJ . Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980;77 :7415–9.6261256\n[2] Yoshida M Miyoshi I Hinuma Y . 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"title": "HTLV-1 associated acute adult T-cell lymphoma/leukemia presenting as acute liver failure in Micronesian: A case report.",
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"medicinalproduct": "LACTULOSE"
}
],
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{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
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},
{
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}
],
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},
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"literaturereference": "Ghaffari-Rafi A, Rho YS, Hall A, Villanueva N, Nogi M.. HTLV-1 associated acute adult T-cell lymphoma/leukemia presenting as acute liver failure in Micronesian: A case report. Medicine. 2021;100: 28(e26236):1 to 9",
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},
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},
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},
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] |
{
"abstract": "Despite the availability of several human epidermal growth factor receptor 2 (HER2)-directed treatments, many HER2-positive (HER2+) breast cancers eventually progress because of primary or acquired resistance.\n\n\n\nA 2-part, open-label, multicenter phase I/II study was conducted to determine the recommended dose of neratinib when administered with trastuzumab (part I), and to assess the antitumor activity of this combination in women with locally advanced or metastatic HER2+ breast cancer previously treated with at least 1 prior trastuzumab-based regimen (part II). Patients received oral neratinib (160 or 240 mg/d) once daily plus intravenous trastuzumab 4 mg/kg (loading dose) then 2 mg/kg weekly. Diarrhea prophylaxis was not permitted. The primary endpoint in part II was investigator-assessed 16-week progression-free survival (PFS).\n\n\n\nForty-five patients received neratinib plus trastuzumab (part I: neratinib 160 mg/d, n = 4; neratinib 240 mg/d, n = 4; part II: neratinib 240 mg/d, n = 37). In part I, there were no dose-limiting toxicities and the recommended neratinib dose was 240 mg/d. In part II, the 16-week PFS rate was 44.8% (90% confidence interval, 28.8%-59.6%), and the median PFS was 15.9 weeks (95% confidence interval, 15.1-31.3 weeks) in 28 evaluable patients. Three patients had durable clinical benefit lasting 9.4 to 9.7 years. Diarrhea was the most common adverse event (grade 3, n = 7 [15.6%]; grade 4, n = 0). No clinically significant cardiac toxicity was seen.\n\n\n\nNeratinib in combination with trastuzumab was well-tolerated and had encouraging antitumor activity in patients with advanced trastuzumab-pretreated HER2+ breast cancer. Durable responses can be achieved in some patients.",
"affiliations": "Duke Multidisciplinary Breast Program, Duke University Medical Center, Durham, NC. Electronic address: black034@mc.duke.edu.;Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.;Department of Oncology, 81 Hospital of Chinese People's Liberation Army, Nanjing, China.;University of Maryland, Greenebaum Comprehensive Cancer Center, Baltimore, MD.;Department of Medical Oncology, Centre René Gauducheau, Saint Herblain, Nantes, France.;Puma Biotechnology Inc, Los Angeles, CA.;Puma Biotechnology Inc, Los Angeles, CA.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA.",
"authors": "Blackwell|Kimberly L|KL|;Zaman|Khalil|K|;Qin|Shukui|S|;Tkaczuk|Katherine H R|KHR|;Campone|Mario|M|;Hunt|Daniel|D|;Bryce|Richard|R|;Goldstein|Lori J|LJ|;|||",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C487932:neratinib; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2018.12.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "19(2)",
"journal": "Clinical breast cancer",
"keywords": "Combination drug therapy; HER2; Neratinib; Trastuzumab; Tyrosine kinase inhibitor; breast cancer",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "97-104.e4",
"pmc": null,
"pmid": "30655172",
"pubdate": "2019-04",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neratinib in Combination With Trastuzumab for the Treatment of Patients With Advanced HER2-positive Breast Cancer: A Phase I/II Study.",
"title_normalized": "neratinib in combination with trastuzumab for the treatment of patients with advanced her2 positive breast cancer a phase i ii study"
} | [
{
"companynumb": "US-ROCHE-2253464",
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},
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"drugindication": "HER-2 POSITIVE BREAST CANCER",
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},
{
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},
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"medicinalproduct": "TRASTUZUMAB."
},
{
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},
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},
{
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},
{
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},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRASTUZUMAB."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyperbilirubinaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haemoglobin decreased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Metastases to central nervous system",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BLACKWELL K, ZAMAN K, QIN S, TKACZUK K, CAMPONE M, HUNT D, BRYCE R AND GOLDSTEIN L. NERATINIB IN COMBINATION WITH TRASTUZUMAB FOR THE TREATMENT OF PATIENTS WITH ADVANCED HER2-POSITIVE BREAST CANCER: A PHASE I/II STUDY. CLINICAL BREAST CANCER ELSEVIER INC 2019?:1-8.",
"literaturereference_normalized": "neratinib in combination with trastuzumab for the treatment of patients with advanced her2 positive breast cancer a phase i ii study",
"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20190204",
"receivedate": "20190204",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "We report a case of phlegmonous gastritis that followed an episode of acute pharyngitis. A 21-year-old man visited our emergency room because of intense epigastric pain. Fourteen days before the visit, he had symptoms of a sore throat and high fever. He was diagnosed with acute pharyngitis and treated with antibiotics. Although the symptoms of acute pharyngitis were relieved, epigastric pain began 5 days before the emergency visit. Computed tomography showed diffuse gastric wall thickening, and emergent esophagogastroduodenoscopy revealed diffusely spreading hyperemic mucosa with multiple erosions. He was admitted with a diagnosis of acute phlegmonous gastritis and was treated with antibiotics. The antibiotic treatment was effective and resulted in resolution of his clinical symptoms and normalized C-reactive protein concentrations. On hospital day 29, he was discharged. However, he was re-admitted because of recurrence of phlegmonous gastritis 5 days after discharge and 15 days after finishing the antibiotics. Cultures of gastric biopsies and juice were both positive for Streptococcus constellatus/milleri. Antibiotic treatment was effective, and he recovered without recurrence. A possible association between upper respiratory infections and subsequent phlegmonous gastritis has been reported, and this case supports causality. However, further studies are needed to evaluate causality and pathogenesis.",
"affiliations": "Internal Medicine, Tottori Municipal Hospital, 1-1 Matoba, Tottori, 6808501, Japan. taniguchi.hideaki@gmail.com.;Internal Medicine, Tottori Municipal Hospital, 1-1 Matoba, Tottori, 6808501, Japan.;Internal Medicine, Tottori Municipal Hospital, 1-1 Matoba, Tottori, 6808501, Japan.;Internal Medicine, Tottori Municipal Hospital, 1-1 Matoba, Tottori, 6808501, Japan.",
"authors": "Taniguchi|Hideaki|H|http://orcid.org/0000-0003-4958-2358;Aimi|Masahito|M|;Matsushita|Hiroshi|H|;Shimazaki|Gaku|G|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01345-2",
"fulltext": null,
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"issn_linking": "1865-7265",
"issue": "14(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Acute pharyngitis; Phlegmonous gastritis; Recurrence; Streptococcus spp.",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D005756:Gastritis; D005773:Gastroscopy; D006801:Humans; D008297:Male; D010612:Pharyngitis; D055815:Young Adult",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "500-505",
"pmc": null,
"pmid": "33539005",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7952775;5954120;31938333;14748323;16372771;20262238;19262050",
"title": "A case of phlegmonous gastritis after acute pharyngitis.",
"title_normalized": "a case of phlegmonous gastritis after acute pharyngitis"
} | [
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{
"abstract": "Rocuronium bromide is a muscle relaxant used in general anesthesia, inhibiting cholinergic neurotransmission of neuromuscular junction. Donepezil used for the treatment of Alzheimer's disease inhibits decomposition of acetylcholine. We describe a case in which donepezil most obviously weakened the muscle relaxation induced by rocuronium. Because the interaction may impair intubation and surgery conditions, anesthesiologists should be aware of it. Prior to general anesthesia, a 2-4-week pause in anticholinesterase medication has been recommended. So far, reliable scientific data on the subject is lacking.",
"affiliations": "Pohjois-Karjalan keskussairaala, kirurgian klinikka.",
"authors": "Pautola|Lauri|L|;Reinikainen|Matti|M|",
"chemical_list": "D000732:Androstanols; D002800:Cholinesterase Inhibitors; D007189:Indans; D003473:Neuromuscular Nondepolarizing Agents; D010880:Piperidines; D000077265:Donepezil; D000077123:Rocuronium",
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"issue": "128(10)",
"journal": "Duodecim; laaketieteellinen aikakauskirja",
"keywords": null,
"medline_ta": "Duodecim",
"mesh_terms": "D000544:Alzheimer Disease; D000732:Androstanols; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004347:Drug Interactions; D006801:Humans; D007189:Indans; D003473:Neuromuscular Nondepolarizing Agents; D010880:Piperidines; D000077123:Rocuronium",
"nlm_unique_id": "0373207",
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"pmid": "22724318",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interaction of donepezil with rocuronium.",
"title_normalized": "interaction of donepezil with rocuronium"
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
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},
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},
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] |
{
"abstract": "A subgroup of patients with gouty arthritis have a chronic recurring form that is particularly difficult to treat. Such patients experience repeated flares and often have abundant tophi. Many also have underlying comorbidities, such as renal impairment, cardiovascular disease, gastrointestinal disorders, obesity, and hypertension, which contraindicate the use of standard anti-inflammatory medications. Five patients with difficult to treat gouty arthritis who were either candidates and/or treated with anti-IL therapy are described.",
"affiliations": "Medical Doctor; Immanuel Krankenhaus Berlin, Medical Centre for Rheumatology Berlin - Buch, Berlin, Germany.;Rheumatologist, Rheumatology Department, Centro Hospitalar, Universitario de Coimbra, Coimbra, Portugal.;Medical Doctor, Department of Rheumatology, Hospital Garcia de 'Orta, Lisbon, Portugal; University Hospital of Alexandroupolis, Alexandroupolis, Greece.;Rheumatologist, First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.;Professor of Internal Medicine, First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.;Head, Department of Nephrology and Dialysis, Ospedale AUSL \"Guglielmo da Saliceto\", Piacenza, Italy.;Deputy Director, Immanuel Krankenhause Berline Medical Centre for Rheumatology Berlin - Buch, Berlin, Germany. Electronic address: w.schmidt@immanuel.de.;Assistant Professor of Internal Medicine, First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.",
"authors": "Avram|Annalina|A|;Duarte|Cátia|C|;Santos|Maria José|MJ|;Papagoras|Charalampos|C|;Ritis|Konstantinos|K|;Scarpioni|Roberto|R|;Schmidt|Wolfgang A|WA|;Skendros|Panagiotis|P|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006074:Gout Suppressants; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D000069465:Febuxostat; C541220:canakinumab; D011239:Prednisolone; D003078:Colchicine",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "82 Suppl 1()",
"journal": "Joint bone spine",
"keywords": "Anakinra; Anti-IL-1β therapy; Canakinumab; Gouty arthritis; Tophaceous gout",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015210:Arthritis, Gouty; D002908:Chronic Disease; D003078:Colchicine; D015897:Comorbidity; D000069465:Febuxostat; D006074:Gout Suppressants; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008297:Male; D018579:Patient Selection; D011239:Prednisolone; D012008:Recurrence",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "eS17-29",
"pmc": null,
"pmid": "26717798",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Identifying Patient Candidates for IL-1 Inhibition: Lessons From Real-World Cases.",
"title_normalized": "identifying patient candidates for il 1 inhibition lessons from real world cases"
} | [
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"companynumb": "DE-FRESENIUS KABI-FK201607117",
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"abstract": "BACKGROUND\nTransient pacing failure caused by transient increased pacing threshold has been reported in patients with transient left ventricular apical dysfunction (Takotsubo cardiomyopathy [TC]). Normal pacing thresholds usually recover after normalization of systolic dysfunction.\n\n\nOBJECTIVE\nPacing failure correlates with clinics of TC.\n\n\nMETHODS\nWe report the case of a 76-year-old man with a dual chamber pacemaker, admitted for acute chest pain and dyspnea and final diagnosis of TC. One month after index admission, the patient came back complaining again of chest pain. Unexpectedly, admission electrocardiogram showed ventricular pacing failure and an increased pacing threshold. In the following weeks, pacing threshold gradually recovered with left ventricular ejection fraction and QTc values.\n\n\nRESULTS\nVentricular pacing threshold correlated directly to QTc values and inversely to left ventricular ejection fraction over time (P < 0.05).\n\n\nCONCLUSIONS\nThis is one of the first cases of delayed transient ventricular pacing failure in a male patient with transient left ventricular apical ballooning, in the presence of spared right ventricular function. Given the possibility of acute transient anomalies in myocardial impedance and pacing failure even in the subacute phase of TC several weeks after clinical onset of transient systolic dysfunction, pacing threshold should be carefully monitored in subjects with TC, both during the acute phase of the disease and in first months of follow-up after discharge. Ventricular pacing threshold correlated directly to QTc values and inversely to left ventricular ejection fraction over time.",
"affiliations": "Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.;Cardiology Department, Ospedali Riuniti University Hospital, Foggia, Italy.;Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.;Cardiology Department, Ospedali Riuniti University Hospital, Foggia, Italy.;Cardiology Department, Ospedali Riuniti University Hospital, Foggia, Italy.;Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.;Cardiology Department, GVM Care and Research, Bari, Italy.",
"authors": "Brunetti|Natale D|ND|https://orcid.org/0000-0001-9610-7408;D'Arienzo|Girolamo|G|;Sai|Rafel|R|;Pellegrino|Pier L|PL|;Ziccardi|Luigi|L|;Santoro|Francesco|F|https://orcid.org/0000-0001-9909-6513;Di Biase|Matteo|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/clc.23082",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-9289",
"issue": "41(11)",
"journal": "Clinical cardiology",
"keywords": "Takotsubo cardiomyopathy; male gender; myocardial edema; pacing failure",
"medline_ta": "Clin Cardiol",
"mesh_terms": "D000200:Action Potentials; D000368:Aged; D001281:Atrial Fibrillation; D002304:Cardiac Pacing, Artificial; D004562:Electrocardiography; D006339:Heart Rate; D006801:Humans; D008297:Male; D012804:Sick Sinus Syndrome; D013318:Stroke Volume; D054549:Takotsubo Cardiomyopathy; D013997:Time Factors; D017211:Treatment Failure; D016277:Ventricular Function, Left; D016278:Ventricular Function, Right",
"nlm_unique_id": "7903272",
"other_id": null,
"pages": "1487-1490",
"pmc": null,
"pmid": "30251410",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30251410;25633530;24184904;21410309;22974729;21135591;22975421;12860233;16243117;24342406;8672516;24562801;18593700",
"title": "Delayed ventricular pacing failure and correlations between pacing thresholds, left ventricular ejection fraction, and QTc values in a male with Takotsubo cardiomyopathy.",
"title_normalized": "delayed ventricular pacing failure and correlations between pacing thresholds left ventricular ejection fraction and qtc values in a male with takotsubo cardiomyopathy"
} | [
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"literaturereference": "BRUNETTI ND, D^ARIENZO G, SAI R, PELLEGRINO PL, ZICCARDI L, SANTORO F ET AL.. DELAYED VENTRICULAR PACING FAILURE AND CORRELATIONS BETWEEN PACING THRESHOLDS, LEFT VENTRICULAR EJECTION FRACTION, AND QTC VALUES IN A MALE WITH TAKOTSUBO CARDIOMYOPATHY. CLINICAL CARDIOLOGY. 2018?41(11):1487-90",
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},
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{
"abstract": "Background: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose.Methods: This was a prospective multicenter cohort study at >50 hospital sites across the US using the ToxIC Registry between 2015 and 2018. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease).Results: From 25,303 patients screened, 6473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron.Conclusions: This large US cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.",
"affiliations": "Toxicology Investigators Consortium, American College of Medical Toxicology, Phoenix, AZ, USA.;Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.;Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Emergency Medicine, UT Southwestern Medical Center, Dallas, TX, USA.;Division of Medical Toxicology, Department of Emergency Medicine, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Campleman|Sharan L|SL|;Brent|Jeffery|J|;Pizon|Anthony F|AF|;Shulman|Joshua|J|;Wax|Paul|P|;Manini|Alex F|AF|0000-0001-8276-9320;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2020.1746330",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "58(12)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Overdose; QT prolongation; electrocardiography; poisoning; toxicology",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D062313:Databases, Pharmaceutical; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D016015:Logistic Models; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014481:United States",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "1326-1334",
"pmc": null,
"pmid": "32252558",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "23312127;15345781;11296551;18570170;25326372;21120454;30090465;3941198;28895028;27387786;20361362;18929686;26514310;9138706;17560554;26720490;24438862;24201980;10534216;24811951;30094774;19556032;18803119;26187900;28159815;21956161;19386945;16389666;20693799;2376181;10730737;29247520;25903997;18072176;12386111;20211602;27140989;21370605;29677462;12841807;18634780;11391127;24313745;2424891;25639523;22725631;11603256;12398578;19540606;18167038;21623902;15362595;25101129;20053229;16183450;443464;24131328;30260244",
"title": "Drug-specific risk of severe QT prolongation following acute drug overdose.",
"title_normalized": "drug specific risk of severe qt prolongation following acute drug overdose"
} | [
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{
"abstract": "Pulmonary hypertension (PHT) is a pathological condition determined as an increase in mean pulmonary arterial pressure ≥25 mmHg. Pulmonary arterial hypertension (PAH) is precapillary PHT and a life-threatening disease group which consists of different etiologies with the same pathological and clinical findings, and which is characterized by elevated pulmonary vascular resistance. Dasatinib is a dual Src/Abl kinase inhibitor associated with higher affinity for BCR/ABL kinase than imatinib, and is used in the treatment of chronic myelocytic leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). We describe a case with ALL, in whom dasatinib treatment induced PAH, and who recovered with bosentan treatment.",
"affiliations": "Department of Cardiology, Gazi University Faculty of Medicine, Ankara, Turkey. gtacoy@yahoo.com.;Department of Cardiology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Cardiology, Gazi University Faculty of Medicine, Ankara, Turkey.",
"authors": "Taçoy|Gülten|G|;Çengel|Atiye|A|;Özkurt|Zübeyde Nur|ZN|;Türkoğlu|Sedat|S|",
"chemical_list": "D000970:Antineoplastic Agents; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib",
"country": "Turkey",
"delete": false,
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"keywords": null,
"medline_ta": "Turk Kardiyol Dern Ars",
"mesh_terms": "D000970:Antineoplastic Agents; D000069439:Dasatinib; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011743:Pyrimidines; D013844:Thiazoles",
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"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Dasatinib-induced pulmonary hypertension in acute lymphoblastic leukemia: case report.",
"title_normalized": "dasatinib induced pulmonary hypertension in acute lymphoblastic leukemia case report"
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"abstract": "OBJECTIVE\nTo report a case of severe immune-mediated thrombocytopenia after intravitreal bevacizumab administration.\n\n\nMETHODS\nA 77-year-old man with right-sided macular degeneration received intravitreal bevacizumab. After his third treatment dose, he was hospitalized for symptomatic thrombocytopenia (platelet count of 3 k/μL) and underwent testing to determine the etiology.\n\n\nRESULTS\nInitial platelet counts on admission were 3 k/μL, down from 238 k/μL 3 months before. A peripheral smear, coagulation studies, and an abdominal CT were unremarkable. A bone marrow biopsy revealed hypercellular marrow with megakaryocytic hyperplasia. Serum antiplatelet antibody testing identified antibodies against glycoprotein IV and human leukocyte antigens. A total of 13 units of platelets were administered and resulted in no significant response. Treatment with rituximab, romiplostim, and human leukocyte antigen-matched platelets resulted in slow recovery and normalization of platelet counts.\n\n\nCONCLUSIONS\nThe case presented shows apparent severe immune-mediated thrombocytopenia after intravitreal bevacizumab administration.",
"affiliations": "Department of Internal Medicine, William Beaumont Army Medical Center, El Paso, TX.;Department of Flight Medicine, Weed Army Community Hospital, Fort Irwin, CA; and.;Departments of Ophthalmology.;Hematology and Oncology, and.;Pathology, William Beaumont Army Medical Center, El Paso, TX.",
"authors": "Li|Tianyi|T|;Witteman|Derek T|DT|;Weber|Eric D|ED|;Alexander|Warren L|WL|;Schaber|John D|JD|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor",
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"issn_linking": "1935-1089",
"issue": "14(3)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D008297:Male; D040262:Receptors, Vascular Endothelial Growth Factor; D013921:Thrombocytopenia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "251-254",
"pmc": null,
"pmid": "29227349",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "SEVERE IMMUNE-MEDIATED THROMBOCYTOPENIA AFTER INTRAVITREAL BEVACIZUMAB INJECTION.",
"title_normalized": "severe immune mediated thrombocytopenia after intravitreal bevacizumab injection"
} | [
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"reaction": [
{
"reactionmeddrapt": "Off label use",
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"reactionmeddrapt": "Immune thrombocytopenia",
"reactionmeddraversionpt": "23.0",
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"literaturereference": "LI, T.. SEVERE IMMUNE-MEDIATED THROMBOCYTOPENIA AFTER INTRAVITREAL BEVACIZUMAB INJECTION. RETINAL CASES + BRIEF REPORTS. 2020?14 (3):251-254",
"literaturereference_normalized": "severe immune mediated thrombocytopenia after intravitreal bevacizumab injection",
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"receiptdate": "20200604",
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"serious": 1,
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{
"abstract": "BACKGROUND\nAdult hyperammonemia is most often the result of hepatic dysfunction. Hyperammonemia in the setting of normal hepatic function is a much less common phenomenon and has usually been associated with medications and certain disease states. Here, we present an unusual case of severe hyperammonemia caused physiologically by intense muscle activity in a patient lacking any evidence of liver disease.\nA 36-year-old woman was brought to the emergency department for a suicide attempt after being found covered in Lysol and Clorox germicidal bleach. She was noted to be in a state of violent psychosis with extreme agitation and had to be sedated and intubated for airway protection.\nInitial labs revealed hyperammonemia, lactic acidosis, and anion gap metabolic acidosis. Aminotransferases, bilirubin, and creatine kinase (CK) were normal. Renal function, prothrombin time, activated partial thromboplastin time, and international normalized ratio were also unremarkable and remained so at 24 hours. Ethyl alcohol, acetaminophen, salicylate, and valproic acid were all undetectable in blood. She received 2 doses of lactulose overnight, with a subsequent bowel movement. Next day, her mentation, serum ammonia level, and lactic acid level were back to normal, and she was extubated. Aminotransferases and CK levels were elevated but improved with supportive care. A detailed history and relevant biochemical investigations were unremarkable for any other etiology of hyperammonemia including the common inborn errors of metabolism (IEM). The combination of clinical findings of extreme skeletal muscle activity along with hyperammonemia and lactic acidosis, and subsequently rhabdomyolysis in the setting of unremarkable history and otherwise normal hepatic function strongly suggest the myokinetic origin of hyperammonemia in the patient.\n\n\nRESULTS\nThe patient recovered well with supportive care and was discharged on day 5.\n\n\nCONCLUSIONS\nThis unique case illustrates the important role of skeletal muscle in the human metabolism of ammonia. In our discussion, we also elucidate the underlying pathophysiology, with the objective of improving clinician understanding of various differential diagnoses.",
"affiliations": "Orlando Regional Medical Center, Orlando, FL.;Materials and Nanotechnology Program, North Dakota State University, Fargo, ND.",
"authors": "Taneja|Vikas|V|;Jasuja|Haneesh|H|",
"chemical_list": "D003408:Cresols; C045926:Lysol; D012973:Sodium Hypochlorite",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000017981",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31764807MD-D-19-0552710.1097/MD.0000000000017981179814500Research ArticleClinical Case ReportSevere hyperammonemia from intense skeletal muscle activity A rare case report and literature reviewTaneja Vikas MDa∗Jasuja Haneesh MSbNA. a Orlando Regional Medical Center, Orlando, FLb Materials and Nanotechnology Program, North Dakota State University, Fargo, ND.∗ Correspondence: Vikas Taneja, Orlando Regional Medical Center, 52W Underwood St, Orlando, FL 32806 (e-mail: Taneja.Vikas@outlook.com).11 2019 22 11 2019 98 47 e1798123 7 2019 4 10 2019 17 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nAdult hyperammonemia is most often the result of hepatic dysfunction. Hyperammonemia in the setting of normal hepatic function is a much less common phenomenon and has usually been associated with medications and certain disease states. Here, we present an unusual case of severe hyperammonemia caused physiologically by intense muscle activity in a patient lacking any evidence of liver disease.\n\nPatient concerns:\nA 36-year-old woman was brought to the emergency department for a suicide attempt after being found covered in Lysol and Clorox germicidal bleach. She was noted to be in a state of violent psychosis with extreme agitation and had to be sedated and intubated for airway protection.\n\nDiagnosis and interventions:\nInitial labs revealed hyperammonemia, lactic acidosis, and anion gap metabolic acidosis. Aminotransferases, bilirubin, and creatine kinase (CK) were normal. Renal function, prothrombin time, activated partial thromboplastin time, and international normalized ratio were also unremarkable and remained so at 24 hours. Ethyl alcohol, acetaminophen, salicylate, and valproic acid were all undetectable in blood. She received 2 doses of lactulose overnight, with a subsequent bowel movement. Next day, her mentation, serum ammonia level, and lactic acid level were back to normal, and she was extubated. Aminotransferases and CK levels were elevated but improved with supportive care. A detailed history and relevant biochemical investigations were unremarkable for any other etiology of hyperammonemia including the common inborn errors of metabolism (IEM). The combination of clinical findings of extreme skeletal muscle activity along with hyperammonemia and lactic acidosis, and subsequently rhabdomyolysis in the setting of unremarkable history and otherwise normal hepatic function strongly suggest the myokinetic origin of hyperammonemia in the patient.\n\nOutcome:\nThe patient recovered well with supportive care and was discharged on day 5.\n\nLessons:\nThis unique case illustrates the important role of skeletal muscle in the human metabolism of ammonia. In our discussion, we also elucidate the underlying pathophysiology, with the objective of improving clinician understanding of various differential diagnoses.\n\nKeywords\nexercisehyperammonemiaskeletal muscleOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHyperammonemia has been well documented to be involved in the etiology of hepatic encephalopathy, sometimes heralding transition from liver injury to hepatic failure. The liver is a vital organ involved in ammonia metabolism. Ammonia is primarily generated in the gastrointestinal (GI) tract with a minor contribution from renal tubules and is eventually metabolized into urea by hepatocytes before being renally excreted. This coordination is responsible for maintaining a state of ammonia homeostasis in the body. In adults, the most common etiology of disturbance of this state of equilibrium is hepatic dysfunction, impairing the body's ability to metabolize physiologically produced ammonia. Skeletal muscle usually consumes ammonia,[1] but with activity it may itself become a producer causing clinically significant hyperammonemia.[2] We present this case to highlight such a scenario with the aim of improving understanding of underlying pathophysiology and etiology of nonhepatic hyperammonemia.\n\n2 Case\nA 36-year-old woman was brought to the emergency department (ED) after a suicide attempt with Lysol daily cleanser (sodium chloride − <0.5%, hypochlorous acid − <0.05%) and Clorox germicidal bleach (sodium hypochlorite − 6.15%, sodium hydroxide − <1%). The patient was found in her room covered in these household chemicals along with partially empty bottles. She was extremely agitated and violent, and had to be restrained. En route to the hospital, she also received ketamine for sedation. In the ED, the patient was still agitated, but otherwise hemodynamically stable; vitals were noted to be: blood pressure − 162/94 mm Hg, heart rate − 108/minute, respiratory rate − 28/minute, and pulse oximetry − 90% on room air. She was subsequently sedated and intubated for airway protection. Laboratory studies revealed hyperammonemia and anion gap metabolic acidosis (arterial pH − 7.11 on arterial blood gas analysis) secondary to lactic acidosis. Rest of the workup was unremarkable and is as follows (Table 1). Urine drug screen was positive for benzodiazepines and cocaine. Acute hepatitis profile was negative.\n\nTable 1 Initial laboratory values with reference range.\n\nShe subsequently underwent imaging including computed tomography (CT) of head, chest, and abdomen and pelvis, which did not show any abnormalities. Due to a concern of chemical ingestion, the patient promptly underwent urgent esophagogastroduodenoscopy (EGD), which did not reveal any evidence of caustic mucosal injury to suggest toxic ingestion. The patient received 2 doses of lactulose overnight through nasogastric tube and was noted to have a nonmelanotic bowel movement. Next morning, her mentation improved significantly, and she was extubated. Surprisingly, repeat ammonia level 12 hours postadmission was normal (lactic acid had also returned to the normal level at 3 hours). Aspartate aminotransferase (AST) level was noted to be elevated at 164 U/L, and creatine kinase spiked to 6039 U/L. She was continued on aggressive IV hydration with improvement in creatine kinase (5450 U/L) and AST (148 U/L) levels at 36 hours (Fig. 1). Repeat ammonia level was again unremarkable. The patient was complaining of vague right upper quadrant pain on day 3 and subsequently underwent a hepatobiliary iminodiacetic acid scan, which did not reveal any evidence of cholecystitis, cholelithiasis, or biliary dyskinesia. Fasting quantitative plasma amino acid analysis performed on day 3 revealed normal levels of citrulline = 30 μmol/L (reference range 16–51 μmol/L), arginine = 58 μmol/L (reference range 43–407 μmol/L), and glutamine = 510 μmol/L (reference range 428–747 μmol/L).\n\nFigure 1 Graphical representation of temporal serum creatine kinase (CK) and aminotransferase trends during admission.\n\nA detailed history was obtained later when the patient was back to baseline. She apparently drenched those disinfectants on herself to seek family's attention and did not actually ingest them. Social history was significant for rare alcohol intake, with her last drink being 3 months ago. She also denied smoking but had been using cocaine off and on for a few years. Medication review revealed infrequent acetaminophen intake and absence of any prescription medications in the preceding few weeks. She also denied any history of chronic abdominal pain, diarrhea, nausea/vomiting, or any specific food intolerances or any GI symptoms during early mornings, or after any fasting or after a protein-rich meal. She also denied any family history of liver disease. The patient reported that she had otherwise been a healthy child while growing up with appropriate height and weight (163 cm and 77.2 kg currently with a body mass index [BMI] of 29.06). Given the unremarkable work-up, hyperammonemia was most likely secondary to intense muscle activity during the psychotic episode. She was subsequently discharged to inpatient behavioral health unit on day 5 in stable condition.\n\n3 Discussion\nMost of the ammonia in the human body is generated in the gut by bacterial metabolism and dietary protein digestion.[2] Enterocytes, predominantly in small bowel, also produce ammonia from circulating glutamine.[3] Small amounts are also produced by kidneys primarily in the proximal tubule, 60% to 70% in the normal basal state, and increasing to up to 80% in metabolic acidosis.[4] Glutamine is again the primary substrate resulting in the generation of equimolar amounts of ammonium and bicarbonate ions.[5] This ammonia is either excreted in urine or released in systemic circulation. Metabolic acidosis stimulates renal ammoniagenesis with proportionate urinary excretion where it combines with H+ ions to promote acid excretion.[6] Ammonia is eventually taken up from the portal and systemic venous circulation by hepatocytes and incorporated into urea cycle to produce urea, which is excreted by kidneys.[7] The brain also metabolizes small amounts of circulating ammonia, which crosses the blood–brain barrier utilizing glutamine synthetase (GS), which is exclusive to glia in central nervous system. Cerebral edema noted in hyperammonemia is largely the result of osmotic astrocyte swelling secondary to intracellular accumulation of glutamine. Interorgan exchange of ammonia exchange is shown in Figure 2.\n\nFigure 2 Schematic representation of interorgan transfer of ammonia and its metabolites in humans. Solid straight lines represent urea exchange, solid curved lines represent glutamine exchange, and dotted curved lines represent ammonia exchange.\n\n4 Role of skeletal muscle in ammonia metabolism\nSkeletal muscle is normally a net consumer of ammonia[8] utilizing GS to produce glutamine. But with activity, it also starts producing ammonia. And when local GS activity is overcome, it becomes a net producer, as has been shown by the proportionate increase in ammonia levels with increasing exercise intensity.[9] The etiology of this ammonia production is branched-chain amino acid catabolism[10] and deamination of adenosine monophosphate (AMP).\n\nIntensely exercising muscle can generate adenosine triphosphate (ATP) almost immediately using the adenylate kinase/myokinase reaction, which catalyzes the conversion of 2 adenosine diphosphate (ADP) molecules into 1 molecule of ATP and 1 molecule of AMP. If the muscle continues exercising, AMP is deaminated to inosine monophosphate (IMP) to maintain equilibrium for the upstream dephosphorylation reactions. The reaction is catalyzed by myoadenylate deaminase/AMP deaminase, with concurrent production of ammonia (NH3).[11]\n\n2ADP → ATP + AMP\n\nAMP + H2O → IMP + NH3\n\nThis ammonia is then released in the venous circulation either unchanged or combined with glutamate to produce glutamine, which is an energy-consuming step, and when muscle ATP is depleted, the proportion of ammonia release increases. Interestingly, this excess glutamine is in turn used by proximal tubule for ammoniagenesis, which may be used to counterbalance any metabolic acidosis from anaerobic skeletal muscle activity.[12]\n\n5 Common differential diagnoses for hyperammonemia in adults\n5.1 Hepatic dysfunction\nHyperammonemia in adults most commonly results from the impaired hepatic ability to metabolize physiologically produced ammonia. In cirrhotics, the portocaval shunting is also contributory. The role of hyperammonemia in hepatic encephalopathy associated with acute liver failure is well documented.[13] Nonhepatic cases of hyperammonemia in the pediatric population usually result from inborn errors of metabolism (IEM), most commonly urea cycle disorders, organic acidurias (OA), and carnitine deficiency. The pathway of the urea cycle is depicted in Figure 3. Median age at diagnosis for OAs and urea cycle disorders is within the first year of life except for hyperornithinemia hyperammonemia homocitruliuria (HHH) and ornithine transcarbamoylase (OTC) deficiency which may not manifest till later in childhood.[14] Adult-onset IEM cases presenting with hyperammonemia have been reported but are rare and are associated with other characteristic symptoms, so this discussion focuses on acquired etiologies in adult patients (Table 2).\n\nFigure 3 Schematic urea cycle. The enzymes involved are: I – CPS, II – OTC, III – arginosuccinate synthetase, IV – arginosuccinate lyase, V – arginase, and VI – NAG synthetase. NAG acts as an activator of CPS, which is the rate-limiting step. Reactions above the dotted line are intramitochondrial. CPS = carbamoyl phosphate synthetase, NAG = N-acetyl glutamate, OTC = ornithine transcarbamoylase.\n\nTable 2 Common differential diagnoses for hyperammonemia in adults.\n\n5.2 Antiepileptic drugs\nValproic acid causes dose-dependent increases in plasma ammonia levels without causing overt liver injury[15] by inhibiting the activity of carbamoyl phosphate synthetase 1.[16] This risk is increased with higher doses (>20 mg/kg/day) or concomitant use of other enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbiturate, and carbamazepine.[17] Concomitant use of topiramate also increases the risk of hepatic encephalopathy by 2 mechanisms: By blocking carbonic anhydrase and producing a degree of metabolic acidosis, which shifts the ammonium ion equilibrium towards ammonia; and By inhibiting cerebral GS preventing the conversion of ammonia and glutamate to glutamine. Interestingly, phenobarbiturate and carbamazepine also inhibit cerebral GS. Also, there are reports of hyperammonemia associated with carbamazepine monotherapy.[18]\n\n5.3 Chemotherapy\nAsparagine is a critical component for leukemic cell growth, as they lack asparagine synthetase. Asparaginase hydrolyzes asparagine, which is an otherwise nonessential amino acid, into aspartic acid and ammonia, thus directly increasing serum ammonia levels.[19] Another chemotherapeutic agent associated with hyperammonemia is 5-fluorouracil (5-FU) that can cause hyperammonemia by increasing ammonia production. Administration of 5-FU induces intracellular accumulation of fluoroacetate, which is structurally similar to acetate. The fluoroacetate combines with coenzyme A to generate fluoroacetyl CoA, which replaces acetyl CoA in Kreb cycle, eventually producing fluorocitrate, which binds tightly to aconitase, thereby disrupting the cycle. Hence, transient hyperammonemia develops due to impairment of ATP-dependent urea cycle.[20] As it is renally excreted, this potential is augmented with concurrent renal dysfunction. The risk is also increased during systemic infections due to increased catabolism.[21]\n\n5.4 Gastrointestinal bleeding\nGI bleed had been hypothesized to cause hyperammonemia from increased protein degradation by colonic flora and mucosal oxidation, but there is also evidence of increased renal ammoniagenesis in response to elevated circulating levels of amino acids particularly glutamine and alanine.[22] Patients with decompensated cirrhosis have reduced hepatic glycogen stores secondary to loss of hepatocytes and reduced enzyme activity. Reduced hepatic glycogen content produces a state of relative hyperglucagonemia.[23] This subsequently promotes peripheral gluconeogenesis in renal tubules too.[24] Alanine is the predominant amino acid in hemoglobin molecule[25] and enters the systemic vascular pool following GI bleed. Being a gluconeogenic amino acid, it undergoes transamination in renal tubules to produce glutamate and pyruvate. Glutamate subsequently undergoes deamination to produce alpha ketoglutarate which is again available for upstream transamination, while pyruvate is used for gluconeogenesis.[26] The pathway is shown in Figure 4. This cascade of reactions results in the production of ammonia, some of which is excreted in the urine and the rest is absorbed into systemic circulation.\n\nFigure 4 Renal tubular metabolism of alanine following GI bleed. In cirrhosis, tubular (along with remaining hepatic) ALT is upregulated secondary to hyperglucagonemia, shunting available alanine to pyruvate to promote gluconeogenesis and subsequent ammoniagenesis. The enzymes involved are: I – ALT, II – glutamate dehydrogenase. ALT = alanine aminotransferase, GI = gastrointestinal.\n\n5.5 Malignancies\nHyperammonemia may be seen in acute lymphoblastic leukemia, likely as a result of increased catabolism and impaired ureagenesis.[27] Multiple myeloma cells have been shown to produce ammonia in vivo.[28] The mechanism may involve excess protein metabolism and cytokine and immunoglobulin production.\n\n5.6 Urinary tract infection (UTI)\nHyperammonemia may seldom be seen in association with UTIs with urease-producing bacteria, including proteus, klebsiella, corynebacterium, and ureaplasma.[29] The urease splits urea to produce ammonia, alkalinizing the urine. With the progressive increase in pH, the ammonia equilibrium shifts from ammonium ion toward gaseous ammonia, which diffuses into circulation through inflamed urothelium.\n\nUrea + H2O → 2NH3 + CO2\n\n5.7 Exercise-induced hyperammonemia\nAmmonia produced during intense exercise has the potential of producing central fatigue which may present with symptoms such as lethargy, incoherence, and eventually loss of consciousness.[30] This condition is usually averted as ammonia is rapidly cleared from venous circulation by a normally functioning liver. However, this could become clinically significant in the case of coexistent hepatic dysfunction. Our case highlights the importance of recognition of acute onset nonhepatic hyperammonemia in the ED or inpatient setting. Regardless of the etiology, prompt treatment must be initiated. This can be achieved by decreasing ammoniagenic substrates in the colon by absorption through lactulose, or inhibition of ammonia generation through antibiotics like rifaximin or metabolic ammonia removal through sodium benzoate or ornithine-aspartate to prevent and/or treat hepatic encephalopathy. More recently, polyethylene glycol (PEG) has also been shown to be effective in reducing ammonia levels through direct laxative effect and thereby removing all nitrogenous load and potential ammoniagenic substrates from the bowel.[31]\n\n5.8 Miscellaneous\nProtein catabolic states such as trauma, burns, starvation, and steroid administration may also cause elevation of systemic ammonia levels by increasing the nitrogen load. The shock causes hyperammonemia by direct hepatic injury and increasing protein catabolism.\n\nTotal parenteral nutrition (TPN) administration may elevate serum ammonia levels by exacerbating carnitine deficiency, particularly in cirrhotics who may already be carnitine deficient.[32] Carnitine is an essential factor in long-chain fatty acid metabolism, as it is involved in translocation of fatty acid residues from cytosol to mitochondria. Its deficiency causes accumulation of unoxidized fatty acids in the cytosol, which inhibit the urea cycle, thereby impairing the primary pathway of ammonia clearance.\n\n5.9 Interesting facts about our case\n(1) Severe lactic acidosis in our patient was also likely secondary to intense muscle activity. There is prior evidence of proportionate lactic acidosis with hyperammonemia associated with exercise.[33]\n\n(2) The choice of ketamine was likely influenced by its safety[34] and its potential role in the treatment of suicidal ideation in subanesthetic doses.[35]\n\n(3) There have been reports of late presentation of IEM, but even with diagnosis at a late age, there is consistently a prior history of neuropsychiatric problems usually associated with digestive issues.[36,37] The classical history of late-onset urea cycle defects is intermittent episodes of encephalopathy, loss of consciousness, or seizures precipitated by catabolic stress, for example, infections, surgery, pregnancy, or even a high dietary protein load. There may also be clinical evidence of neurological sequelae ranging from minimal psychomotor delay to severe mental retardation.[38] Our patient did not have any such previous history or of any neurogastric attacks nor any relevant family history to suggest an IEM. Her serum amino acid profile was unremarkable, and she also seemed to have age appropriate IQ.\n\n(4) Also, our patient did not display the typical signs and symptoms of hepatic encephalopathy likely due to the hyperacute onset of hyperammonemia and rapid resolution.\n\n6 Conclusion\n(1) Adult nonhepatic hyperammonemia is a relatively less common, albeit significant clinical scenario, which requires a good understanding of pathophysiology for accurate diagnosis.\n\n(2) Differential diagnoses are broad but can usually be narrowed based on clinical presentation. Informed investigation guided by meticulous history and physical exam remain the cornerstone for early diagnosis.\n\n(3) Regardless of the etiology, prompt treatment must be initiated to prevent hepatic encephalopathy.\n\nAuthor contributions\nConceptualization: Vikas Taneja.\n\nFormal analysis: Vikas Taneja, Haneesh Jasuja.\n\nInvestigation: Vikas Taneja.\n\nSoftware: Haneesh Jasuja.\n\nWriting – original draft: Vikas Taneja, Haneesh Jasuja.\n\nWriting – review & editing: Vikas Taneja.\n\nvikas taneja orcid: 0000-0003-3638-5355.\n\nAbbreviations: AMP = adenosine monophosphate, ATP = adenosine triphosphate, GI = gastrointestinal, GS = glutamine synthetase, IEM = inborn error of metabolism.\n\nHow to cite this article: Taneja V, Jasuja H. Severe hyperammonemia from intense skeletal muscle activity: a rare case report and literature review. Medicine. 2019;98:47(e17981).\n\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 in chief of this journal.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Clemmesen JO Kondrup J Ott P \nSplanchnic and leg exchange of amino acids and ammonia in acute liver failure . Gastroenterology \n2000 ;118 :1131 –9 .10833488 \n[2] Bachmann C \nMechanisms of hyperammonemia . Clin Chem Lab Med \n2002 ;40 :653 –62 .12241009 \n[3] Windmueller HG Spaeth AE \nUptake and metabolism of plasma glutamine by the small intestine . J Biol Chem \n1974 ;249 :5070 –9 .4605420 \n[4] Good DW Burg MB \nAmmonia production by individual segments of the rat nephron . J Clin Invest \n1984 ;73 :602 –10 .6323523 \n[5] Taylor L Curthoys NP \nGlutamine metabolism: role in acid-base balance . Biochem Mol Biol Educ \n2004 ;32 :291 –304 .21706743 \n[6] Weiner ID Verlander JW \nRenal ammonia metabolism and transport . Compr Physiol \n2013 ;3 :201 –20 .23720285 \n[7] Siegel GJ Agranoff BW Albers RW \nBasic Neurochemistry: Molecular, Cellular and Medical Aspects . 6th ed. Philadelphia :Lippincott-Raven ; 1999 .\n[8] Bessman SP Bradley JE \nUptake of ammonia by muscle . N Engl J Med \n1955 ;253 :1143 –7 .13272854 \n[9] Graham TE Bangsbo J Gollnick PD \nAmmonia metabolism during intense dynamic exercise and recovery in humans . Am J Physiol \n1990 ;259 (2 Pt 1) :E170 –6 .2382711 \n[10] MacLean Da Spriet LL Hultman E \nPlasma and muscle amino acid and ammonia responses during prolonged exercise in humans . J Appl Physiol \n1991 ;70 :2095 –103 .1864791 \n[11] Goodman MN Lowenstein JM \nThe purine nucleotide cycle. Studies of ammonia production by skeletal muscle in situ and in perfused preparations . J Biol Chem \n1977 ;252 :5054 –60 .873929 \n[12] Van Slyke DD Phillips RA Hamilton PB \nGlutamine as source material of urinary ammonia . J Biol Chem \n1943 ;150 :481 –2 .\n[13] Parekh PJ Balart LA \nAmmonia and its role in the pathogenesis of hepatic encephalopathy . Clin Liver Dis \n2015 ;19 :529 –37 .26195206 \n[14] Kolker S Garcia-Cazorla A Valayannopoulos V \nThe phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation . J Inherit Metab Dis \n2015 ;38 :1041 –57 .25875215 \n[15] Tseng Y-L Huang C-R Lin C-H \nRisk factors of hyperammonemia in patients with epilepsy under valproic acid therapy . Medicine (Baltimore) \n2014 ;93 :e66 .25192484 \n[16] Wadzinski J Franks R Roane D \nValproate-associated hyperammonemic encephalopathy . J Am Board Fam Med \n2007 ;20 :499 –502 .17823470 \n[17] Yamamoto Y Takahashi Y Suzuki E \nRisk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients . Epilepsy Res \n2012 ;101 :202 –9 .22542569 \n[18] Fraser CM Sills GJ Forrest G \nEffects of anti-epileptic drugs on glutamine synthetase activity in mouse brain . Br J Pharmacol \n1999 ;126 :1634 –8 .10323596 \n[19] Müller HJ Boos J \nUse of L-asparaginase in childhood ALL . Crit Rev Oncol Hematol \n1998 ;28 :97 –113 .9768345 \n[20] Koenig H Patel A \nBiochemical basis for fluorouracil neurotoxicity: the role of Krebs cycle inhibition by fluoroacetate . Arch Neurol \n1970 ;23 :155 –60 .5430334 \n[21] Liaw CC Wang HM Wang CH \nRisk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection . Anticancer Drugs \n1999 ;10 :275 –81 .10327032 \n[22] Olde Damink SWM Jalan R Deutz NEP \nThe kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis . Hepatology \n2003 ;37 :1277 –85 .12774005 \n[23] Kabadi UM \nIs hepatic glycogen content a regulator of glucagon secretion? \nMetabolism \n1992 ;41 :113 –5 .1736031 \n[24] Mpabanzi L Deutz N Hayes PC \nOvernight glucose infusion suppresses renal ammoniagenesis and reduces hyperammonaemia induced by a simulated bleed in cirrhotic patients . Aliment Pharmacol Ther \n2012 ;35 :921 –8 .22360430 \n[25] Konigsberg W Hill RJ \nThe structure of human hemoglobin. III. The sequence of amino acids in the tryptic peptides of the alpha chain . J Biol Chem \n1962 ;237 :2547 –61 .14458212 \n[26] Battezzati A Caumo A Martino F \nNonhepatic glucose production in humans . Am J Physiol Metab \n2004 ;286 :E129 –35 .\n[27] Watson AJ Karp JE Gordon Walker W \nTransient idiopathic hyperammonaemia in adults . Lancet \n1985 ;326 :1271 –4 .\n[28] Otsuki T Yamada O Sakaguchi H \nIn vitro excess ammonia production in human myeloma cell lines . Leukemia \n1998 ;12 :1149 –58 .9665203 \n[29] Kaveggia FF Thompson JS Schafer EC \nHyperammonemic encephalopathy in urinary diversion with urea-splitting urinary tract infection . Arch Intern Med \n1990 ;150 :2389 –92 .2241451 \n[30] Banister E Cameron B \nExercise-induced hyperammonemia: peripheral and central effects . Int J Sports Med \n1990 ;11 : Suppl 2 : S129 –42 .2193891 \n[31] Rahimi RS Singal AG Cuthbert JA \nLactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial . JAMA Intern Med \n2014 ;174 :1727 –33 .25243839 \n[32] Bowyer BA Fleming CR Ilstrup D \nPlasma carnitine levels in patients receiving home parenteral nutrition . Am J Clin Nutr \n1986 ;43 :85 –91 .3079943 \n[33] Buono MJ Clancy TR Cook JR \nBlood lactate and ammonium ion accumulation during graded exercise in humans . J Appl Physiol \n1984 ;57 :135 –9 .6469774 \n[34] Lester L Braude DA Niles C \nLow-dose ketamine for analgesia in the ED: a retrospective case series . Am J Emerg Med \n2010 ;28 :820 –7 .20837262 \n[35] Murrough JW Soleimani L DeWilde KE \nKetamine for rapid reduction of suicidal ideation: a randomized controlled trial . Psychol Med \n2015 ;45 :3571 –80 .26266877 \n[36] Summar ML Barr F Dawling S \nUnmasked adult-onset urea cycle disorders in the critical care setting . Crit Care Clin \n2005 ;21 : 4 Suppl : S1 –8 .16227111 \n[37] Gaspari R Arcangeli A Mensi S \nLate-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma . Ann Emerg Med \n2003 ;41 :104 –9 .12514690 \n[38] Nassogne MC Héron B Touati G \nUrea cycle defects: management and outcome . J Inherit Metab Dis \n2005 ;28 :407 –14 .15868473\n\n",
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"abstract": "The best approach to treatment of de-novo rheumatoid arthritis in solid organ transplant recipients on typical immunosuppression is not well established. The use of biologics targeting specific cell types, cytokines, and immunological pathways has been gaining interest in the treatment of both, auto- and alloimmunity. We present a case of de-novo rheumatoid arthritis in a kidney transplant recipient 10 years post-transplant while receiving cyclosporine, mycophenolate mofetil, and also prednisone. Initial presentation included features of polymyalgia rheumatica and nephrotic range proteinuria. Kidney biopsy showed membranous nephropathy. The patient was initially treated with methotrexate, while mycophenolate mofetil was discontinued. Clinical symptoms improved, but creatinine significantly increased, which led to discontinuation of methotrexate and mycophenolate mofetil was restarted. The kidney function improved, but the patient experienced a flare of rheumatoid arthritis. Costimulatory blocker, abatacept, was initiated and cyclosporine was gradually tapered off. Graft function remained stable for a follow-up period of 7 years. Joint pain, weakness, and stiffness resolved. Follow-up plain film radiographs at 5 years post initial presentation showed no new joint erosions in hands or feet. Costimulatory blockers may broaden the therapeutic choices of transplant recipients with de-novo autoimmune diseases.",
"affiliations": "South Carolina Nephrology/Hypertension, Orangeburg, SC.;Division of Renal Diseases and Hypertension.;Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, and.;Department of LaboratoryMedicine and Pathology, University of Minnesota, Minneapolis, MN, USA.;Division of Renal Diseases and Hypertension.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, and.",
"authors": "Sheta|Mohamed|M|;Riad|Samy|S|;Deepak|Udayakumar|U|;Issa|Naim|N|;Birkenbach|Mark|M|;Ibrahim|Hassan N|HN|;Kukla|Aleksandra|A|",
"chemical_list": null,
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"doi": "10.5414/CNCS108875",
"fulltext": "\n==== Front\nClin Nephrol Case StudClin Nephrol Case StudDustriClinical Nephrology. Case Studies2196-5293Dustri-Verlag Dr. Karl Feistle 10.5414/CNCS108875Case ReportNephrologyCostimulation pathway blockade in kidney transplant recipients with de-novo rheumatoid arthritis Sheta Mohamed 1Riad Samy 2Deepak Udayakumar 3Issa Naim 4Birkenbach Mark 5Ibrahim Hassan N. 2Kukla Aleksandra 41 South Carolina Nephrology/Hypertension, Orangeburg, SC,2 Division of Renal Diseases and Hypertension,3 Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN,4 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, and5 Department of LaboratoryMedicine and Pathology, University of Minnesota, Minneapolis, MN, USACorrespondence to Aleksandra Kukla, MD 717 Delaware Street SE, Division of Renal Diseases and Hypertension, University of Minnesota Medical School, Minneapolis, MN 55414, USA kukla003@umn.edu2017 17 2 2017 5 16 19 1 3 2016 27 5 2016 © Dustri-Verlag Dr. K. Feistle2017 This is an open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.The best approach to treatment of de-novo rheumatoid arthritis in solid organ transplant recipients on typical immunosuppression is not well established. The use of biologics targeting specific cell types, cytokines, and immunological pathways has been gaining interest in the treatment of both, auto- and alloimmunity. We present a case of de-novo rheumatoid arthritis in a kidney transplant recipient 10 years post-transplant while receiving cyclosporine, mycophenolate mofetil, and also prednisone. Initial presentation included features of polymyalgia rheumatica and nephrotic range proteinuria. Kidney biopsy showed membranous nephropathy. The patient was initially treated with methotrexate, while mycophenolate mofetil was discontinued. Clinical symptoms improved, but creatinine significantly increased, which led to discontinuation of methotrexate and mycophenolate mofetil was restarted. The kidney function improved, but the patient experienced a flare of rheumatoid arthritis. Costimulatory blocker, abatacept, was initiated and cyclosporine was gradually tapered off. Graft function remained stable for a follow-up period of 7 years. Joint pain, weakness, and stiffness resolved. Follow-up plain film radiographs at 5 years post initial presentation showed no new joint erosions in hands or feet. Costimulatory blockers may broaden the therapeutic choices of transplant recipients with de-novo autoimmune diseases. \n\nrheumatoid arthritismembranous nephropathykidney transplantbelatacept\n==== Body\nCase report \nA 63-year-old white male, with a history of end-stage renal disease secondary to granulomatosis with polyangiitis (GPA), received a living donor kidney transplant in 1996. His past medical history included hypertension, coronary artery disease, gout, dyslipidemia, and obstructive sleep apnea. He was maintained on cyclosporine, with trough levels ranging from 80 to 100 µg/L, mycophenolate mofetil 500 mg 3 times a day, and prednisone 5 mg daily. In addition, the patient was on amlodipine, metoprolol, allopurinol, and lisinopril. Baseline creatinine was 1.5 – 1.7 mg/dL. There was no family history of rheumatoid arthritis (RA). Kidney biopsy done 3 years post-transplant was unremarkable. \n\n10 years post-transplant he developed bilateral shoulder pain, subjective muscle weakness, and stiffness with an elevated erythrocyte sedimentation rate (ESR) above 100 mm/hg and was diagnosed with polymyalgia rheumatica (PMR). He was treated with prednisone 60 mg daily, which was gradually decreased to 40 mg daily with symptomatic improvement. Further attempts to decrease steroid dose were unsuccessful, as symptoms of muscle weakness and myalgias recurred. The patient was referred to our institution for further evaluation. Detailed musculoskeletal examination showed symmetrical synovitis over the proximal interphalangeal, metacarpophalangeal joints, and wrists. He had boutonniere and swan neck deformities of both hands and bilateral lower extremities edema. Cardiopulmonary and abdominal examinations were normal. Relevant laboratory results included serum creatinine 1.6 mg/dL, elevated inflammatory markers and rheumatoid factor (Table 1). IgG antibody against cyclic citrullinated peptide was weakly positive at 21 U/mL (< 5 µ/mL). Urine analysis was positive for albumin (300 mg/dL) without blood; protein to creatinine ratio was 6.8 g/g of creatinine. \n\nHand X-rays showed medial subluxation of the first metacarpophalangeal joints bilaterally with scattered poorly-defined erosions. Feet X-rays revealed erosions at the tarsometatarsal joints. Based on clinical presentation, laboratory, and radiologic findings, the patient was diagnosed with RA with PMR features. Based on the clinical symptoms and laboratory findings, the patient met the 1987 American College of Rheumatology (ACR) classification criteria and the 2010 ACR classification criteria for the diagnosis of rheumatoid arthritis. The patient denied a family history of autoimmune diseases. \n\nThe patient underwent transplant kidney biopsy for evaluation of proteinuria. Light microscopy showed moderate interstitial fibrosis and tubular atrophy in a pattern which was attributed to cyclosporine exposure accompanied by mild scattered interstitial lymphoplasmacytic infiltrate and scattered tubulitis. Glomeruli demonstrated basement membrane spikes on silver Jones-stained sections, and direct immunofluorescence showed diffuse and global fine granular staining in peripheral capillary loops for IgG (1+) and C3. Electron microscopy showed subepithelial and intramembranous electron-dense deposits consistent with immune complexes, with rare subendothelial and scattered mesangial deposits also identified. In all, biopsy findings were consistent with membranous nephropathy (MN). There was no histological evidence of relapse of GPA. \n\nThe patient underwent thorough work-up for other autoimmune diseases and malignancy considering the strong association of MN with these conditions. Antinuclear antibody, anti-double-stranded deoxyribonucleic acid antibody, complement (C3, C4, and CH-50) levels, antineutrophil cytoplasmic antibodies (P-ANCA, C-ANCA), prostate specific antigen, hepatitis panel, colonoscopy, CT of the chest, abdomen, and pelvis were all unremarkable. \n\nThe patient was started on methotrexate, while mycophenolate mofetil was discontinued and prednisone dose was tapered down to 10 mg daily. He remained on cyclosporine. After 4 – 6 weeks of therapy, joint pains and stiffness improved, but creatinine increased to 3.6 mg/dL. Repeated kidney transplant biopsy results were consistent with previous findings. Given the lack of alternative explanations for acute worsening of kidney function, methotrexate was discontinued and mycophenolate mofetil was restarted at the dose of 750 mg twice a day. Kidney function improved. Approximately 3 weeks later, he presented with profound fatigue, synovitis over the proximal interphalangeal and metacarpophalangeal joints, and elevated inflammatory markers. Prednisone dose was increased to 40 mg daily and the patient was started on abatacept at the dose of 1,000 mg IV infusion every 4 weeks (weight: 120 kg), together with discontinuation of cyclosporine. 2 weeks after initiation of abatacept, his symptoms of myalgia, fatigue, and arthritis significantly improved. Prednisone was gradually tapered down to the current dose of 5 mg. Renal function stabilized (Figure 1). 7 years post initiation of abatacept, his creatinine is 1.5 mg/dL, and urine protein to creatinine ratio is 0.4 g/g of creatinine, while rheumatoid arthritis continues to be in remission (Table 1). The patient remained on abatacept, 1,000 mg IV infusion every 4 weeks, mycophenolate mofetil 750 mg daily and prednisone 5 mg daily. Plain film radiographs repeated 5 years post original diagnosis showed no new joint erosions in hands or feet. \n\nDiscussion \nTreatment of RA in kidney transplant recipients poses a significant challenge. Patients are already exposed to immunosuppression and adding additional agents to control RA symptoms may lead to additive toxicity including increased risks of infection and malignancy. The patient described in our case report has not experienced any adverse effects related to immunosuppression. To our knowledge, only a single case report of de-novo RA in a kidney transplant recipient exists in a literature. Forslund et al. [1] reported de-novo seropositive erosive RA in a patient who was 7 years post deceased donor kidney transplantation for end-stage renal disease secondary to diabetes. Similarly to our case, the patient was receiving triple immunosuppression at the time of diagnosis, including cyclosporine, steroids, and azathioprine. Diagnosis was based on the clinical symptoms, elevated RF, CRP, and X-ray examination. The patient was switched from azathioprine to methotrexate, while cyclosporine and prednisone was continued. Contrary to our patient, he tolerated methotrexate well and had a good response to therapy with the resolution of clinical symptoms and normalization of inflammatory markers [1]. In nontransplant population, 30 – 40% of affected individuals may not adequately respond to methotrexate alone. For these patients, biologic disease-modifying antirheumatic drugs (DMARDs) are offered [2]. Our case report proposes that use of co-stimulatory pathway blockade in those challenging patients may be effective in controlling both auto- and alloimmunity. T-cells play a central role in adaptive immunity and therefore are involved in both allogeneic immune responses to transplanted organs and aberrant one, as seen in RA. Two signals are necessary for full T-lymphocyte activation: signal 1 is antigen-specific and is initiated by antigen-binding to the T-cell receptor complex; and signal 2, or costimulatory pathway involving interactions between CD28 molecule on T-lymphocyte surface and its ligands, CD80 and CD86 expressed on antigen-presenting cell (APC). CD86 seems to be more critical in initial T-cell activation, as it is constantly expressed on APC, with rapid up-regulation during initial T-cell-APC interaction. Up-regulation of CD80 requires more prolonged T-cell stimulation, and therefore may be more important in maintaining immune response [3]. \n\nCytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a transmembrane protein expressed in T-cells after activation that binds both CD80 and CD86 with higher affinity than CD28. By effectively competing with CD28 for ligand binding, CTLA-4 acts to suppress T-cell activation. This property has been exploited to develop immunosuppressive therapeutic agents. The first therapeutic inhibitor of the CD28 pathway comprised the extracellular domain of CTLA-4 fused to the Fc portion of immunoglobulin G (CTLA-4-Ig). This agent significantly prolonged graft survival in rodent transplantation models. Unfortunately, those results were not reproduced in non-human primates, likely due to significantly more potent ability of CTLA-4-Ig to inhibit CD 80 driven co-stimulation as compared to CD 86 [4]. When tested in patients with RA, CTLA-4-Ig use led to significant improvement in signs and symptoms of disease, as well as decreased progression of structural joint damage [5, 6, 7]. The fusion protein CTLA-4-Ig is commercially available as Orencia (abatacept). Subsequently, a modified version of CTLA-4-Ig (belatacept) was developed with much higher avidity to CD86 [3]. This agent is currently approved for maintenance immunosuppression in kidney transplant recipients, and it has shown to be as effective as traditionally used cyclosporine in prevention of acute rejection [8]. When tested in patients with RA in the pilot study, its effectiveness to reduce the signs and symptoms of disease was comparable to abatacept [9]. \n\nThe significant improvement in RA symptoms in our patient can be attributed to the use of abatacept. Its role in maintenance post-transplant immunosuppression, however, is less certain. Low immunologic-risk transplant recipients may be adequately immunosuppressed with mycophenolate mofetil and prednisone alone following cyclosporine withdrawal [10]. Therefore, it seemed feasible to discontinue cyclosporine with an introduction of abatacept in this case. Belatacept could have been considered in our patient, but was not approved in kidney transplantation at his initial presentation. \n\nConclusions \nAbatacept may broaden the therapeutic choices of transplant recipients with de-novo RA and possibly others. This case illustrates its potential utility. \n\nConflict of interest \nAuthors declare no conflicts of interest and no sources of support. \n\n\nTable 1. Laboratory data at the initial presentation and last follow-up. \nInvestigation\tResult at initial presentation\tResult at last follow-up\t\nCreatinine (0.6 – 1.25 mg/dL)\t1.5\t1.5\t\nAlbumin (3.4 – 5.0 g/dL)\t3.7\t4.3\t\nESR (0 – 20 mm/h)\t107\t12\t\nCRP (0 – 8 mg/L)\t141\t\t\nRF (0 – 14 IU/mL)\t264\t24\t\nCholesterol (0 – 200 mg/dL)\t269\t163\t\nUrine protein to creatinine ratio (0 – 0.2 g/g creatinine)\t6.8\t0.6\t\n\n\n\nFigure 1. Creatinine and immunosuppressive therapy timeline in the first 72 days post diagnosis of rheumatoid arthritis. MMF = mycophenolate mofetil; CSA = cyclosporine; pred = prednisone; MTX = methotrexate.\n==== Refs\nReferences\n1 \nForslund T \nAhonen J \nElomaa E \nParviainen T \nMatinlauri I \nDe novo seropositive rheumatoid arthritis during immunosuppressive treatment after kidney transplantation. \nClin Nephrol .\n2005 ;\n64 :\n231 –235 .\n16175949 \n2 \nYazici Y \nTreatment of rheumatoid arthritis: we are getting there. \nLancet .\n2009 ;\n374 :\n178 –180 .\n19560809 \n3 \nVincenti F \nLuggen M \nT cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. \nAnnu Rev Med .\n2007 ;\n58 :\n347 –358 .\n17020493 \n4 \nLevisetti MG \nPadrid PA \nSzot GL \nMittal N \nMeehan SM \nWardrip CL \nGray GS \nBruce DS \nThistlethwaite JR \nBluestone JA \nImmunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation. \nJ Immunol .\n1997 ;\n159 :\n5187 –5191 .\n9548454 \n5 \nGenant HK \nPeterfy CG \nWesthovens R \nBecker JC \nAranda R \nVratsanos G \nTeng J \nKremer JM \nAbatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial. \nAnn Rheum Dis .\n2008 ;\n67 :\n1084 –1089 .\n18086727 \n6 \nGenovese MC \nSchiff M \nLuggen M \nBecker JC \nAranda R \nTeng J \nLi T \nSchmidely N \nLe Bars M \nDougados M \nEfficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. \nAnn Rheum Dis .\n2008 ;\n67 :\n547 –554 .\n17921185 \n7 \nSchiff M \nPritchard C \nHuffstutter JE \nRodriguez-Valverde V \nDurez P \nZhou X \nLi T \nBahrt K \nKelly S \nLe Bars M \nGenovese MC \nThe 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. \nAnn Rheum Dis .\n2009 ;\n68 :\n1708 –1714 .\n19074911 \n8 \nVincenti F \nLarsen C \nDurrbach A \nWekerle T \nNashan B \nBlancho G \nLang P \nGrinyo J \nHalloran PF \nSolez K \nHagerty D \nLevy E \nZhou W \nNatarajan K \nCharpentier B \nCostimulation blockade with belatacept in renal transplantation. \nN Engl J Med .\n2005 ;\n353 :\n770 –781 .\n16120857 \n9 \nMoreland LW \nAlten R \nVan den Bosch F \nAppelboom T \nLeon M \nEmery P \nCohen S \nLuggen M \nShergy W \nNuamah I \nBecker JC \nCostimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. \nArthritis Rheum .\n2002 ;\n46 :\n1470 –1479 .\n12115176 \n10 \nAbramowicz D \nDel Carmen Rial M \nVitko S \ndel Castillo D \nManas D \nLao M \nGafner N \nWijngaard P \nCyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: results of a five-year, prospective, randomized study. \nJ Am Soc Nephrol .\n2005 ;\n16 :\n2234 –2240 .\n15917338\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2196-5293",
"issue": "5()",
"journal": "Clinical nephrology. Case studies",
"keywords": "belatacept ; kidney transplant; membranous nephropathy; rheumatoid arthritis",
"medline_ta": "Clin Nephrol Case Stud",
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"nlm_unique_id": "101638685",
"other_id": null,
"pages": "16-19",
"pmc": null,
"pmid": "29043142",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "16175949;18086727;16120857;15917338;19560809;9548454;12115176;19074911;17020493;17921185",
"title": "Costimulation pathway blockade in kidney transplant recipients with de-novo rheumatoid arthritis.",
"title_normalized": "costimulation pathway blockade in kidney transplant recipients with de novo rheumatoid arthritis"
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{
"abstract": "Avascular osteonecrosis (AVN) is a bone complication that indicates poor functional prognosis. Modern immunosuppressive and steroid-sparing drugs have significantly lowered the occurrence of AVN after kidney transplantation (KT). However, recent data on its incidence rates and risk factors are lacking. Using a large, recent cohort, we sought to investigate AVN incidence and risk factors, with a special focus on mineral and bone disorders. We conducted a cohort study in 805 patients who underwent KT between 2004 and 2014. AVN was identified in 32 patients (4%): before KT in 15 (1.8%) and after KT in 18 (2.2%) cases, including one patient with both. In the group with post-KT AVN, the median time intervals from KT to 1) first symptoms and 2) AVN diagnosis were 12 months [1-99] and 20 months [4-100], respectively. Being overweight/obese, having pre-transplant diabetes or hyperparathyroidism at transplantation, developing acute rejection, and receiving higher cumulative corticosteroid doses were associated with AVN occurrence. Multivariate analysis revealed that BMI ≥ 26 kg/m2 and higher cumulative corticosteroid doses were predictive of AVN. In conclusion, overweight/obesity is a strong risk factor for AVN. Despite a low maintenance dose, the use of corticosteroids-mostly for treatment of acute rejection-remains an independent risk factor.",
"affiliations": "Department of Rheumatology, University Hospital, Strasbourg, France.;Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Department of Rheumatology, University Hospital, Strasbourg, France.",
"authors": "Felten|Renaud|R|0000-0002-4951-4032;Perrin|Peggy|P|;Caillard|Sophie|S|0000-0002-0525-4291;Moulin|Bruno|B|;Javier|Rose-Marie|RM|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0212931",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0212931PONE-D-18-26610Research ArticleMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationOrgan TransplantationRenal TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresUrinary System ProceduresRenal TransplantationMedicine and Health SciencesClinical MedicineClinical ImmunologyTransplantation ImmunologyTransplant RejectionBiology and Life SciencesImmunologyClinical ImmunologyTransplantation ImmunologyTransplant RejectionMedicine and Health SciencesImmunologyClinical ImmunologyTransplantation ImmunologyTransplant RejectionMedicine and Health SciencesEpidemiologyMedical Risk FactorsMedicine and Health SciencesPharmacologyDrugsImmunosuppressivesMedicine and Health SciencesEndocrinologyEndocrine DisordersDiabetes MellitusMedicine and Health SciencesMetabolic DisordersDiabetes MellitusBiology and Life SciencesPhysiologyPhysiological ParametersBody WeightBody Mass IndexMedicine and Health SciencesPhysiologyPhysiological ParametersBody WeightBody Mass IndexMedicine and Health SciencesNephrologyMedical DialysisBiology and Life SciencesBiochemistryHormonesParathyroid HormoneAvascular osteonecrosis in kidney transplant recipients: Risk factors in a recent cohort study and evaluation of the role of secondary hyperparathyroidism Avascular osteonecrosis in kidney transplant recipientshttp://orcid.org/0000-0002-4951-4032Felten Renaud ConceptualizationData curationFormal analysisWriting – original draftWriting – review & editing12Perrin Peggy ConceptualizationData curationFormal analysisWriting – original draftWriting – review & editing23*http://orcid.org/0000-0002-0525-4291Caillard Sophie Formal analysisSupervisionWriting – review & editing23Moulin Bruno Writing – review & editing23Javier Rose-Marie ConceptualizationFormal analysisMethodologySupervisionWriting – review & editing121 \nDepartment of Rheumatology, University Hospital, Strasbourg, France2 \nFédération de Médecine Translationnelle (FMTS), Strasbourg, France3 \nDepartment pf Nephrology-Transplantation, University Hospital Strasbourg, FranceLee John Richard EditorWeill Cornell Medicine, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: peggy.perrin@chru-strasbourg.fr22 2 2019 2019 14 2 e021293111 9 2018 12 2 2019 © 2019 Felten et al2019Felten 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.Avascular osteonecrosis (AVN) is a bone complication that indicates poor functional prognosis. Modern immunosuppressive and steroid-sparing drugs have significantly lowered the occurrence of AVN after kidney transplantation (KT). However, recent data on its incidence rates and risk factors are lacking. Using a large, recent cohort, we sought to investigate AVN incidence and risk factors, with a special focus on mineral and bone disorders. We conducted a cohort study in 805 patients who underwent KT between 2004 and 2014. AVN was identified in 32 patients (4%): before KT in 15 (1.8%) and after KT in 18 (2.2%) cases, including one patient with both. In the group with post-KT AVN, the median time intervals from KT to 1) first symptoms and 2) AVN diagnosis were 12 months [1–99] and 20 months [4–100], respectively. Being overweight/obese, having pre-transplant diabetes or hyperparathyroidism at transplantation, developing acute rejection, and receiving higher cumulative corticosteroid doses were associated with AVN occurrence. Multivariate analysis revealed that BMI ≥ 26 kg/m2 and higher cumulative corticosteroid doses were predictive of AVN. In conclusion, overweight/obesity is a strong risk factor for AVN. Despite a low maintenance dose, the use of corticosteroids—mostly for treatment of acute rejection—remains an independent risk factor.\n\nThe authors received no specific funding for this work. 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\nAvascular osteonecrosis (AVN) is a disabling bone complication that can occur after kidney transplantation (KT). Before the use of modern immunosuppressive drugs, AVN developed in approximately one third of post-transplant patients [1,2]. Corticosteroids play a central role in the genesis of AVN, and recent reports suggest that the use of steroid-sparing anti-calcineurin agents has reduced incidence rates to less than 5% [3–5]. There is a lack of recent data regarding incidence rates, clinical features, or AVN risk factors, as most studies evaluate few risk factors in a limited population. Few studies concerning recipients with renal transplant performed after the year 2000 are available [6–10].\n\nThe underlying pathophysiological mechanism that leads to AVN is a diminished blood flow to the bone, leading to necrosis and bone destruction. The femoral head is the most commonly affected region, followed by other weight-bearing long bones. Optimal treatment aims to prevent the collapse of affected bones. This makes identifying high-risk patients and diagnosing AVN in the earlier stages essential. Some risk factors are already known to associate with AVN in both the general population [11] and kidney transplant (KT) recipients, such as corticosteroids [7,12–14], alcohol consumption [15], dyslipidemia [16], and hemostatic disorders [6,17]. Several other risk factors are also suspected in the KT population, such as osteopenia [8,12,15] and secondary hyperparathyroidism [2,6].\n\nTo address this, we conducted a retrospective study using a large and recent cohort of KT patients to determine AVN incidence rates, disease-related characteristics, and patient-associating factors. We particularly focused on the role of secondary hyperparathyroidism and pre-transplant bone mineral density (BMD) in AVN occurrence.\n\nPatients and methods\nStudy population\nIn this retrospective cohort study, we included all adult patients who had undergone KT between January 2004 and June 2014 in the Nephrology-Transplantation Department of Strasbourg University Hospital, Strasbourg, France (n = 888). Subjects with multi-organ transplantation (n = 44), or incomplete data during the first three months (n = 39), were excluded. Patients were followed after KT until June 2016. This period was selected to allow a minimum follow-up period of two years after transplantation.\n\nThe Institutional Review Board of Strasbourg University Hospital approved the collection of cohort data and subsequent analysis in the study (approval number: DC-2013-1990) and waived the requirement for informed consent. All data were fully anonymized before we accessed them. The transplantation database of our center was used to collect patient characteristics and potential risk factors for AVN. AVN was established by cross-referencing the transplantation database, the university hospital diagnostic database, the radiological data set, and medical records. AVN was only collected if a diagnosis was confirmed by imaging. For each case of AVN, the associated patient medical record was reviewed and AVN characteristics recorded, including date of symptom onset, presence before KT, the type and number of affected sites, and surgical treatment performed. During the follow-up period, delayed graft function (use of dialysis or creatininemia > 250 μmol/L at day 7 after KT), occurrence of biopsy-proven acute rejection, and immunosuppressive treatments were recorded.\n\nWith regards to the immunosuppressive treatments, immunologically high-risk recipients were treated with thymoglobulin, tacrolimus, mycophenolate mofetil (MMF), and steroids, and immunologically low-risk patients received basiliximab, cyclosporine (CsA), MMF, and steroids. At induction, corticosteroid boluses (2×250 mg) were administered. Prednisone was given at 1 mg/kg/day (with a maximal limit dose of 80 mg/day) during the first week and then gradually tapered and discontinued between the third and sixth month, except in patients with specific immunological risks or acute rejection (who were maintained at 0.1 mg/kg/day). Target trough levels of tacrolimus were 8 to 12 ng/mL in the first 6 months, and 6 to 8 ng/mL thereafter. Target trough levels of CsA were 150 to 200 ng/mL in the first 6 months, 125 to 150 ng/mL from 6 to 12 months, and 75 to 125 ng/mL thereafter. Initial dose of MMF was 3 g by day in association with CsA and 2 g by day in association with tacrolimus, which was adapted for a target of M3 MMF AUC between 30 to 60 h.mg/L. In cases of acute cellular rejection, steroid pulses (500 mg) were administered for 3 days, followed by oral steroids at a dose of 1 mg/kg per day, and a switch to tacrolimus in patients treated with CsA. CNI trough levels were not adjusted during rejection episodes. The management of our patients was not changed throughout our study. The cumulative doses of oral and bolus corticosteroids were calculated during the first three months and the first year.\n\nBone and mineral metabolism evaluation\nVarious biochemical parameters were prospectively determined at transplantation (before the surgical transplant procedure) and in the routine post-transplant follow-up. Serum PTH levels were measured using intact PTH assays (Elecsys; Roche, reference range: 15–65 pg/mL replaced by Centaur, Siemens; reference range 11–79 pg/mL since June 2013). Estimated glomerular filtration rates (eGFRs) were calculated using the four-variable equation derived from the Modification of Diet in Renal Disease (MDRD) Study. Radioimmunoassays were used to determine the serum 25OH-vitamin D (Diasorin, Stillwater), bone alkaline phosphatase serum (Access Ostase; Beckman; reference range: 2.2–14.5 μg/L), and C-telopeptide serum levels (Elecsys; Roche; reference: < 0.54 μg/L). Pre-transplant bone mineral density (BMD) was measured during routine pre-transplant evaluation using a dual-energy X-ray absorptiometry placed at the lumbar spine, femoral neck, and total hip. Following the World Health Organization criteria [18], osteopenia was defined as a T-score between -1 and −2.5, whereas osteoporosis was defined as a T-score < −2.5.\n\nStatistical analysis\nData are shown as the means ± standard deviation, the medians [minimum–maximum] or (IQR1-IQR3), or the percentages for parametric and nonparametric parameters, and categorical variables, respectively. Normality was tested using Shapiro-Wilk tests. In order to limit biases, patients with AVN before transplantation (PreT-AVN group) and patients with new onset of AVN after transplantation (NOAVN group) were analyzed separately and compared to patients without AVN. Variables between groups were compared using Student’s t-tests, Mann-Whitney U-tests, Wilcoxon test, Fisher tests, or chi-square tests, as appropriate. Association factors and the occurrence of post-transplant development of NOAVN were tested using log-rank tests. The time of AVN onset was assumed to be the date of AVN diagnosis, with patients censored at death, loss to follow up, kidney loss, or at the end of the follow-up period. Correlations were assessed by linear regression, Spearman’s test, or Pearson’s test as appropriate.\n\nPotential predictive risk factors that showed an association with a p < 0.2 in the univariate analysis were examined as covariates in a multivariable Cox regression model (covariates: gender, pre-transplant diabetes, BMI ≥ 26 kg/m2 at KT, PTH > 300 pg/mL at KT, cumulative corticosteroid dose at M3, and acute rejection if occurred before AVN event). The 26 kg/m2 threshold for the BMI was chosen based on BMI analysis using a receiver operating characteristic (ROC) curve. The 300 pg/mL threshold for PTH at time of transplantation was chosen as this had been independently shown to associate with fractures after KT [19]. This threshold also associates with histomorphometric signs of high-turnover bone disease in dialysis patients [20]. Values of p < 0.05 were considered statistically significant. The analyses were performed using SAS JMP Software 7.1 (SAS Institute Inc).\n\nResults\nPatient characteristics and immunosuppressive treatments\nIn total, 805 patients were analyzed at both transplantation and month 3 (M3), 784 at M12, 742 at M24, and 433 at M60. Among 805 KT, 184 cases were re-transplants (22.9%) as compared to 621 primary KT. The median post-transplant follow-up was 67 months [range 3–150], and 89.6% were deceased donor transplantations. An overview of patient characteristics and outcomes after transplantation is shown in Table 1. Specifically, the cohort was 61% males and 39% females, 95% Caucasians, the median age was 51 years, and 25% of KT recipients had pre-transplant diabetes.\n\n10.1371/journal.pone.0212931.t001Table 1 Summary of patient characteristics at the time of kidney transplantation (n = 805) and details concerning immunosuppressive treatments and acute rejection.\nMale (%)/Female (%)\t492 (61.1)/313 (38.9)\t\nAge at transplantation (years)\t51.0 [18.0–83.0]\t\nPrimary kidney disease (%)\t\t\n• Glomerulonephritis\t33.9\t\n• Diabetic nephropathy\t9.3\t\n• Interstitial nephropathy\t36.4\t\n• Vascular nephropathy\t7.6\t\n• Other/unknown\t12.8\t\nDialysis duration (months)\t33 [0–452]\t\nHD/PD/preemptive transplantation (%)\t70.6/19.2/10.2\t\nTransplantation rank ≥ 2 (%)\t22.9\t\nPre-transplant corticotherapy, n = 419 (%)\t59.6\t\nBody mass index (kg/m2)\t24.7 [13.6–39.1]\t\nPre-transplant diabetes Type 1/Type 2\t1.4/23.9\t\nDyslipidemia, n = 758 (%)\t50.4\t\nCurrent or former smoker, n = 274 (%)\t59.9\t\nPre-transplant BMD status, n = 707 (%):\t\t\n• Normal/osteopenia/osteoporosis\t31.3/45.8/22.9\t\nImmunosuppressive treatments\t\t\n• Anti-IL2 receptor antibody/Thymoglobulin (%)\t36.7/58.3\t\n• Cyclosporin A/Tacrolimus/mTOR inhibitor (%)\t60.7/38.5/1.2\t\n• Total (oral + bolus) corticosteroid dose at M3 (mg)\t2075 [500–4790]\t\n• Total (oral + bolus) corticosteroid dose at M12 (mg)\t2978 [500–9855]\t\nDelayed graft function (%)\t28.5\t\nAcute rejection\t\t\n• Cumulative incidence at M3/M12/M24 (%)\t7.7/16.2/19.8\t\n• Pure TCMR/pure ABMR/mixed (%)\t14.9/2.2/2.5\t\nData are given as percentages or medians [minimum–maximum], as appropriate. HD, hemodialysis; PD, peritoneal dialysis; BMD: bone mineral density; mTOR, mammalian target of rapamycin; n, number of analyzed patients; TCMR, T cell-mediated rejection; ABMR, antibody-mediated rejection.\n\nIncidence rates and AVN characteristics\nWe identified AVN in 32 recipients, leading to an overall prevalence rate of 3.98%. AVN had developed before transplantation in 15 patients (1.86%) and after transplantation in 18 patients (2.24%). One patient displayed both pre- and post-transplantation AVN. The rate of NOAVN among the primary transplant cases was 2.4% (15/621). The post-transplant incidence was 0.6% at M12 and 1.5% at M24 (Fig 1).\n\n10.1371/journal.pone.0212931.g001Fig 1 A Kaplan-Meier plot of the time to first symptoms of new onset of avascular osteonecrosis (NOAVN) and to NOAVN diagnosis after kidney transplantation.\nTwelve of 15 pre-transplant AVN cases (80%) had received a previous transplant. (Table 2). PreT-AVN patients were more likely to have been treated with corticosteroids before transplantation (p = 0.006), more likely to have had a longer duration of dialysis (p < 0.001), and more often received a second or further transplant (p < 0.0001) compared to patients without AVN (Table 2).\n\n10.1371/journal.pone.0212931.t002Table 2 Summary of patient characteristics at the time of kidney transplantation, according to AVN diagnosis.\n\tPatients without AVN\nn = 773\tNew Onset AVN group \nn = 18\tpa\tPre-transplant \nAVN group\nn = 15\tpb\t\nMale (%)/Female (%)\t468 (60.5)/305 (39.5)\t14 (77.8)/4 (22.2)\t0.151\t11 (73.3)/4 (26.7)\t0.42\t\nAge at transplantation, years [range]\t51.0 [18–83]\t54.5 [24–72]\t0.69\t52.0 [33–66]\t0.26\t\nPrimary kidney disease (%)\t\t\t0.64\t\t0.33\t\n • Glomerulonephritis\t35.7\t44.4\t\t60\t\t\n • Vascular nephropathy\t7.5\t11.1\t\t6.7\t\t\n • Diabetic nephropathy\t9.7\t0\t\t0\t\t\n • Interstitial nephropathy\t34.0\t33.3\t\t26.7\t\t\n • Other or unknown\t13.1\t11.2\t\t6.7\t\t\nDialysis duration, months [range]\t33 [0–422]\t39 [16–161]\t0.36\t189 [17–452]\t< 0.001\t\nPreemptive KT/PD/HD (%)\t10.2/19.7/70.1\t0/11.1/88.9\t0.185\t20.0/6.7/73.3\t0.26\t\nDeceased donor (%)\t89.1\t100\t0.24\t100\t0.39\t\nTransplantation rank ≥ 2 (%)\t22.9\t16.7\t0.77\t80\t< 0.001\t\nPre-transplant corticotherapy, n = 419 (%)\t227 (58.7)\t10 (55.6)\t0.81\t14 (93.3)\t0.006\t\nBMI (kg/m2) (IQR1–IQR3)\t24.7 (21.6–28.1)\t27.6 (26.0–32.6)\t0.003\t22.2 (19.3–25.3)\t0.140\t\nBMI ≥ 25 kg/m2 (%)\t360 (46.6)\t17 (94.4)\t< 0.001\t6 (42.9)\t0.9\t\nBMI ≥ 30 kg/m2 (%)\t108 (14.0)\t6 (33.3)\t0.020\t0\t0.245\t\nPre-transplant Diabetes (%)\t191 (24.7)\t8 (44.4)\t0.093\t5 (33.3)\t0.545\t\nDyslipidemia, n = 758 (%)\t370 (50.9)\t8 (44.4)\t0.63\t4 (26.7)\t0.072\t\nSmoker, n = 274 (%)\t147 (60.7)\t9 (50)\t0.45\t9 (60)\t0.9\t\nHIV seropositivity\t3\t0\t0.9\t0\t0.9\t\nPregnancies 0 - ≥ 1, n = 247\t38–201\t1–3\t0.50\t0–4\t0.9\t\nSickle cell disease, n = 382 (%)\t7 (2)\t0\t0.9\t0\t0.9\t\nHemostasis disorders, n = 669 (%)\t171 (26.8)\t7 (41.1)\t0.28\t2 (13.3)\t0.37\t\nSerum level of PTH, median (IQR1–IQR3), n = 773\t202.5 (106.0–382.9)\t337.0 (215.5–472.3)\t0.042\t199.4 (59.2–388.2)\t0.51\t\nSerum level of 25-hydroxy-vitamin D median (IQR1–IQR3), n = 292\t18.7 (10.7–31.1)\t25.1 (15.3–29.8)\t0.33\t18.0 (5.9–39.6)\t0.80\t\nPre-transplant osteopenia-osteoporosis,\nn = 707 (%)\t313(46.2)–154(22.8)\t5(31)–5(31)\t0.48\t6(40)–3(20)\t0.75\t\npa: New Onset AVN group compared to patients without AVN, pb: pre-transplant AVN group compared to patients without AVN.Data are given as percentages or medians [minimum–maximum], or (interquartile IQR1-IQR3), as appropriate. AVN, avascular osteonecrosis; BMI, body mass index; HD, hemodialysis; HIV, human immunodeficiency virus; KT, kidney transplantation; n, number of analyzed patients; PD, peritoneal dialysis\n\nAmong the patients with new onset AVN after transplantation (NOAVN group, n = 18), 14 (78%) were males. The median age at diagnosis was 50 years [range 25–75]. The median times between transplantation to the appearance of articular pain and AVN diagnosis were 12 months [range 1.2–99.2 months] and 20 months [3.9–99.8], respectively. The median delay between first symptoms and diagnosis was 3.4 months [0.3–34.5] (Fig 1). In 88% of cases, the first symptoms appeared within 24 months of transplantation. MRI and computed tomography confirmed diagnosis in 13 and three patients, respectively. Radiographs and bone scintigraphy confirmed AVN in one patient each. In a single patient, AVN was asymptomatic and was diagnosed using a computed tomography scan performed for another reason. At diagnosis, 10 (55.6%) had localized regions of AVN at a minimum of two different sites. These AVN sites included the femoral head (15 patients), the femoral condyle (two patients), and the ankle (one patient). Seven patients received a pamidronate infusion to improve pain and function. Nine patients were treated with total hip arthroplasty during the follow-up period.\n\nComparison of patients with NOAVN and without AVN\nVarious factors were compared between patients with NOAVN and those without any AVN (Tables 2 and 3). Patients with NOAVN were characterized by a higher BMI, higher acute rejection rate, and greater cumulative doses of corticosteroids (Fig 2). Oral cumulative doses at M3 were higher in the NOAVN group (Table 3). Serum levels of PTH and phosphorus at transplantation were also higher in the NOAVN group than in patients without AVN (Table 4). Pre-transplant BMD statuses were comparable between groups.\n\n10.1371/journal.pone.0212931.g002Fig 2 Occurrence of new onset of avascular osteonecrosis (NOAVN), according to acute rejection, BMI, and cumulative corticosteroid dose.\nNS, not significant; *, p<0.05; **, p<0.01, ***, p<0.001.\n\n10.1371/journal.pone.0212931.t003Table 3 Outcomes and immunosuppressive treatments after kidney transplantation, according to new onset AVN diagnosis (patients with pre-transplant AVN were excluded).\n\tPatients without AVN\nn = 773\tNOAVN group\nn = 18\tp\t\nFollow-up duration, months [range]\t64.7 [3–149.9]\t55.2 [28.1–143.9]\t0.85\t\nDelayed graft function (%)\t217 (28.1)\t8 (44.4)\t0.128\t\nAcute rejection (TCMR and/or ABMR)\t\t\t\t\n • At M3 (%)\t55 (7.1)\t5 (27.8)\t0.008\t\n • At M12 (%)\t118 (15.7)\t7 (38.9)\t0.016\t\n • At M24 (%)\t138 (19.4)\t7 (38.9)\t0.065\t\nBody mass index at M3 (kg/m2) (IQR1–IQR3)\t24.6 (21.8–27.9)\t26.9 (26.2–30.9)\t0.003\t\nDiabetes after transplantation (%)\t311/702 (44.3)\t10 (55.6)\t0.35\t\nDyslipidemia after transplantation (%)\t460/667 (69.0)\t12 (66.7)\t0.801\t\nImmunosuppressive regimen at induction\t\t\t\t\n • Anti-IL2 receptor antibody (%)\t282 (36.6)\t10 (55.6)\t0.099\t\n • Thymoglobulin (%)\t451 (58.5)\t8 (44.4)\t0.23\t\n • Cyclosporin (%)-Tacrolimus (%)\t470 (61.3)-297 (38.7)\t14 (77.8)-4 (22.2)\t0.15\t\nCorticosteroid dose (IQR1–IQR3)\t\t\t\t\n • Oral cumulative dose at M3, mg\t1758 (1348–2078)\t2094 (2028–2105)\t<0.001\t\n • Bolus dose at M3, mg\t500 (500–500)\t500 (500–500)\t0.73\t\n • Total (oral + Bolus) dose at M3, mg\t2035 (1675–2578)\t2594 (2527–2605)\t<0.001\t\n • Oral cumulative dose at M12, mg\t2280 (1680–3165)\t3453 (3267–4314)\t<0.001\t\n • Bolus dose at M12, mg\t500 (500–500)\t500 (500–2000)\t0.008\t\n • Total (oral + Bolus) dose at M12, mg\t2780 (2270–3928)\t3970 (3767–6314)\t<0.001\t\n • Total (oral + Bolus) dose at M12, mg/kg\t39.8 (32.3–56.4)\t49.7 (44.5–67.9)\t0.034\t\n • Use of bolus after discharge in the first year (%)\t116 (17.7)\t7 (38.9)\t0.011\t\nData are given as percentages or medians [minimum–maximum] or (interquartile IQR1–IQR3), as appropriate. AVN: avascular osteonecrosis; NOAVN: new Onset AVN; M3, M12, M24: 3, 12 and 24 post-transplant months; TCMR: T cell-mediated rejection; ABMR: antibody-mediated rejection\n\n10.1371/journal.pone.0212931.t004Table 4 Biochemical parameters at transplantation and at M3, according to AVN presence.\n\tPatients without AVN\nn = 773\tNew onset AVN group\nn = 18\tp\t\nSerum level of PTH\t\t\t\t\n At transplantation (pg/mL)\t202 [0–2095]\t337 [78–640]\t0.042\t\n PTH < 130 pg/mL (%)\t30.9\t11.8\t0.090\t\n PTH 130–300 pg/mL (%)\t35.4\t29.4\t0.61\t\n PTH > 300 pg/mL (%)\t33.7\t58.8\t0.031\t\n At M3 (pg/mL)\t108 [1–1384]\t149 [37–418]\t0.27\t\n PTH > 130 pg/mL (%)\t40.8\t55.6\t0.20\t\nSerum level of calcium\t\t\t\t\n At transplantation (mg/dL)\t9.0 [4.2–12.3]\t8.8 [7.4–10.5]\t0.50\t\n At M3 (mg/dL)\t9.6 [7.3–12.4]\t9.5 [8.1–10.8]\t0.9\t\nSerum level of phosphorus\t\t\t\t\n At transplantation (mg/dL)\t3.1 [1.0–10.1]\t3.9 [2.2–6.3]\t0.019\t\n At M3 (mg/dL)\t2.9 [1.6–7.7]\t2.9 [1.7–4.8]\t0.66\t\nSerum level of 25-hydroxy-vitamin D\t\t\t\t\n At transplantation (μg/L)\t18.7 [2.0–106.0]\t25.1 [6.0–57.9]\t0.32\t\n At M3 (μg/L)\t25.5 [1.4–84.8]\t20.6 [11.1–51.6]\t0.62\t\nSerum level of bone alkaline phosphatase\t\t\t\t\n At transplantation (μg/L)\t14.4 [4.9–190.8]\t17.8 [9.0–33.7]\t0.57\t\n At M3 (μg/L)\t14.4 [4.5–104.4]\t12.9 [6.8–28.2]\t0.59\t\nSerum level of C-telopeptide (μg/L) at M3\t0.9 [0.1–3.2]\t0.8 [0.2–2.3]\t0.65\t\neGFR (mL/min/1.73 m2) at M3\t48.9 [6.0–128.4]\t48.7 [8.7–100.2]\t0.69\t\nData are given as percentages or medians [minimum–maximum], as appropriate. AVN: avascular osteonecrosis, eGFR: estimated glomerular filtration rate (MDRD), M3: post-transplant month three, PTH: intact parathyroid hormone\n\nPredictive factors of NOAVN\nUnivariate survival analysis revealed that factors that associated with NOAVN at transplantation were a BMI ≥ 26 kg/m2 (p = 0.0004), pre-transplant diabetes (p = 0.040), and PTH > 300 pg/mL (p = 0.044). There was a nonsignificant trend for more AVN in male patients (p = 0.11). AVN was not statistically associated with dyslipidemia (p = 0.57). Factors that associated with NOAVN at M3 were BMI ≥ 26 kg/m2 (p = 0.0003), acute rejection in the first three months (p = 0.0045), and a higher cumulative corticosteroid dose in the first three months (p < 0.0001). The multivariate analysis identified higher cumulative corticosteroid dose at M3 and BMI ≥ 26 kg/m2 as independent risk factors for NOAVN development (Table 5). There was no statistical difference in new onset AVN after transplantation in re-transplant patients compared to primary transplant recipients.\n\n10.1371/journal.pone.0212931.t005Table 5 Cox multivariate analyses: Factors associated with new onset AVN.\n\tUnivariate\n HR (CI 95%)\tp\tMultivariate\nAHR (CI 95%)\tp\t\nGender (male)\t2.32 (0.76–7.04)\t0.14\t2.07 (0.57–7.48)\t0.24\t\nPre-transplant diabetes\t2.76 (1.08–7.01)\t0.033\t2.27 (0.85–6.08)\t0.10\t\nBMI at transplantation ≥ 26 kg/m2\t4.77 (1.70–13.4)\t0.0030\t3.30 (1.00–10.86)\t0.049\t\nPTH at transplantation > 300 ng/L\t2.68 (1.02–7.05)\t0.046\t2.10 (0.79–5.60)\t0.13\t\nCumulative corticosteroid dose at M3\t2.11 (1.52–2.93) *\t< 0.0001\t1.55 (1.03–2.32) *\t0.034\t\nAcute rejection at M24 and before AVN\t2.48 (0.93–6.64)\t0.070\t1.69 (0.55–5.17)\t0.35\t\nModel included factors associated with NOAVN in univariate analysis with p < 0.2\n\nAHR: adjusted hazard ratio; AVN: avascular osteonecrosis; BMI: body mass index: M3 and M24: 3 and 24 post-transplant months\n\n* by 500 mg of corticosteroid\n\nCumulative corticosteroid dose at M12 was positively associated with acute rejection at M12 (p < 0.0001). Cumulative oral and bolus were positively correlated (rho = 0.42, p < 0.0001). BMI ≥ 25 kg/m2 at transplantation was associated with PTH > 300 pg/mL at transplantation (p = 0.0002) and with pre-transplant diabetes (p < 0.0001).\n\nDiscussion\nHere, we report a recent retrospective cohort study that assessed AVN in a large population of 805 kidney allograft recipients. Our rate of 4% is comparable with most recent studies of symptomatic AVN, with rates ranging between 4 and 7% [4,21–23]. The two-year post-transplant incidence is about 1% and is comparable to the most recent study [10]. Contrary to this study, we assessed AVN occurrence before transplantation and distinguished it from AVN occurring after transplantation, limiting bias in the analysis of factors associated with AVN after transplantation, and thus, allowing better identification of AVN risk factors after KT. We also assessed the cumulative corticosteroid dose in the first year to improve the external validity of the study.\n\nWe confirmed that AVN developed early after transplantation in most patients (within two years). AVN most commonly affected the femoral head, but it was found across several sites in half of patients. Our study allowed us to determine the delay between the emergence of first symptoms and diagnosis. It also highlights a long diagnosis delay with a median of three months, limiting early management. The prognoses for half of these patients were particularly poor, requiring total hip replacement during the follow-up period. The difficulty of early diagnosis can be explained by the fact that AVN has subtle symptoms, with few disabling features during the early stages.\n\nInterestingly–in order to improve the identification of high-risk patients, we found that a high body mass index (BMI) was a strong independent predictor for AVN after KT. Our finding is consistent with another KT-focused study [6] and a survey of the general population [24]. Previously, a study by Takao et al. failed to find an association between AVN and BMI in Japanese recipients, likely explained by the absence of overweight and obese patients in their cohort. High BMI may be involved in AVN development due to fatty infiltration of the bone marrow, resulting in elevated intraosseous extravascular pressure, diminished blood flow, and bone ischemia. Indeed, BMI is also a good measure for adiposity and correlates with bone marrow fat [25]. Furthermore, a study by Ferrari et al. suggested that obesity can lead to a decline in epiphysis blood flow as it associates with higher levels of fibrinolysis inhibitor [6]. Another possible underlying mechanism is the role of weight in generating subchondral fractures that lead to secondary ischemia. Weight-bearing sites are typically affected during AVN. Finally, a recent study using an animal model has indicated that leptin resistance during obesity is important to AVN pathogenesis [26]. This result strongly suggests that high BMI is a new predictive risk factor for AVN. Importantly, this risk factor is increasing in prevalence. Indeed, the mean BMI among patients receiving transplant in the United States has steadily increased from 25.5 kg/m2 to more than 28 kg/m2 between 1995 and 2009 [27].\n\nIn addition to BMI, the use of corticosteroids was still identified as a risk factor in the current study. Corticotherapy is traditionally considered as the main AVN risk factor, also showing a strong relationship with dose [13,14,28]. Consistent improvements in immunosuppressive regimens have led to progressively lower effective steroid doses, which were parallelled by a decrease in AVN incidence [7,13,29]. However, most recent studies have shown contradictory results–with some reports demonstrating that even the reduced doses of corticosteroids in use today continue to be associated with AVN occurrence [7,13,29]. In contast, other studies failed to find similar associations [17,30]. Unfortunately, recent data on cumulative corticosteroid doses are frequently unavailable [4,6,10]. Using a steroid-free maintenance regimen (methylprednisolone 500 mg administered intraoperatively followed by prednisone, 1 mg/kg on posttransplant day 1; tapering over 4 days and discontinued after day 5), Kwaja et al did not observe any case of avascular osteonecrosis in their sample of 349 kidney transplant recipients [31]. However, our current data indicate that the cumulative dose of corticosteroids remains a major risk factor for post-transplant AVN. In our study, the cumulative corticosteroid dose was more than 2-fold lower than that used in most recent publications [3,13,17]. Despite a low corticosteroid cumulative dose (most frequently required by the occurrence of biopsy-proven acute rejection), patients with acute rejection should be regarded as being at high risk of devoping AVN. It would be interesting to differentiate the prognostic effect of bolus dosing versus oral corticosteroid dose that is not clearly determined in the literature in all populations. In our study, we failed to discriminate the role of bolus vs. oral because these factors are highly correlated. Acute rejection is classically, and in our study, treated both by corticosteroid bolus and an increased oral dose of corticosteroid.\n\nMoreover, to our knowledge, we are the first to specifically address the relation between hyperparathyroidism and osteonecrosis. An association was suggested [2,6] and found in a study which analyzed the PTH level in 215 patients transversally [6]. The PTH level decreased progressively after transplantation and varied according to the time of measurement after transplantation [19]. High persistent levels of PTH persist in about one third of patients one year after transplantation. To address this issue, we analyzed PTH levels prospectively determined at the time of transplantation and at three month post-transplantation and identified a significant association between secondary hyperparathyroidism and AVN. However, we did not find greater significance in this association in our multivariate analysis. This may be explained by an insufficient number of events or that secondary hyperparathyroidism was associated with being overweight [19]. Secondary hyperparathyroidism induces extensive bone marrow fibrosis [32] and may, therefore, lead to diminished blood flow. As hyperparathyroidism is a risk factor that contributes to fracture after KT [19], it could lead to small subchondral fractures in the third state of Arlet and Ficat classification [33], causing secondary ischemia. Similarly, we did not identify an increased risk in cases with pre-existing osteopenia or osteporosis at transplantation; this result is at variance with previous reports [8,12,15]. The lack of significant differences in our study can be attributed to the negligible impact of lower BMD on epiphyseal ischemia, which is responsible for AVN. We also did not find any association between dyslipidemia and AVN, contrary to some studies [16]. This may be due to statin treatment reducing AVN incidence [4,34].\n\nFinally, our study did not find association between the use of CsA vs. tacrolimus and AVN after transplantation. This association was suggested in a recent cohort study [10]. Nevertheless, the authors do not mention on what criteria they chose tacrolimus vs. ciclosporin in their patients. The hypothesis that bone remodeling is increased more than tacrolimus is weak. This association may be explained by the fact that the rate of biopsy-proven acute rejection is lower in renal transplant patients receiving tacrolimus than in those receiving CsA [35] and that patients treated by CsA may have received more corticosteroids.\n\nOur study has some limitations. Alcohol consumption, known to be related to AVN in the general [36] and KT populations [15], was not evaluated. Some previously recognized risk factors were not identified in our study, including hemostatic abnormalities, HIV seropositivity, and number of pregnancies, suggesting a possible lack of patients. Some asymptomatic AVN cases may have been missed. Previous screening studies using MRI indicated that AVN incidence among renal recipients ranges widely from 4 to 25%, depending on the corticosteroid dose administered [3,5,7,37]. However, a previous study by Ferrari et al. that screened 81 asymptomatic kidney recipients using MRI found no evidence of AVN [6]. This suggests that asymptomatic AVN cases are rare. [10].\n\nNevertheless, this study has enabled the identification of high-risk patients that have high BMI or have received treatment for acute rejection. These recipients would benefit from targeted radiological screening after transplantation or from determination of genetic factors that predispose them for steroid-induced osteonecrosis [7,38,39]. Indeed, early diagnosis is important to delay the progression of AVN and to prevent bone collapse. Medical management, biophysical treatments, and joint preserving procedures may be more effective in the earlier stages of disease [11]. Currently, the reduction or early withdrawal of corticosteroid therapy remains the only documented preventive treatment available for AVN [40]. However, corticosteroid sparing is not possible in situations of acute rejection or in high-risk immunological recipients. As such, other preventive treatments may be possible in these high-risk patients, although they are not well documented. They include reducing BMI before transplantation and avoiding alcohol. Some pharmacological treatments, such as statins [34] and bisphosphonates [11], are also of interest. Bisphosphonates have not yet been evaluated for AVN prevention but have been shown to diminish pain and to improve joint function of avascular necrosis of the femoral head [41,42]. However, evidence suggesting a reduction in joint collapse has not been demonstrated [43].\n\nIn conclusion, our study with a large and recent cohort of KT patients has revealed that high BMI and corticosteroid treatment for acute rejection are strong predictors of AVN after transplantation. Clinicians should, therefore, seek to screen this high-risk group for earlier diagnosis of AVN and to optimize treatment that prevents bone collapse and preserves joints.\n\nSupporting information\nS1 Dataset Anonymized complete dataset.\n(XLS)\n\nClick here for additional data file.\n\n The authors thank the clinicians who followed the kidney transplant recipients included in this cohort study. The authors are also grateful to Laurent Arnaud and François Lefebvre for their help in statistical methods.\n\nAbbreviations\n25OHD25-hydroxy-vitamin D or calcidiol\n\n95CI95% confidence interval\n\nABMRantibody-mediated rejection\n\nAHRadjusted hazard ratio\n\nAVNavascular osteonecrosis\n\nBMDbone mineral density\n\nBMIbody mass index\n\nCsAcyclosporine A\n\neGFRestimated glomerular filtration rate\n\nHDhemodialysis\n\nHIVhuman immunodeficiency virus\n\nKTkidney transplantation\n\nM3, M12, M24month 3, 12 or 24 post-transplantation\n\nMDRDmodification of diet in renal disease\n\nMMFmycophenolate mofetil\n\nMRImagnetic resonance imaging\n\nORodds ratio\n\nPDperitoneal dialysis\n\npreT-AVNpre-transplant AVN\n\nNOAVNnew onset AVN\n\nPTHparathyroid hormone\n\nSDstandard deviation\n\nTCMRT cell-mediated rejection\n==== Refs\nReferences\n1 Cruess RL , Blennerhassett J , Macdonald FR , Maclean LD , Dossetor J . Aseptic Necrosis Following Renal Transplantation . J Bone Jt Surg Am . 1968 ;50 : 1577 –1590 .\n2 Nehme D , Rondeau E , Paillard F , Moreau JF , Nussaume O , Kanfer A , et al\nAseptic necrosis of bone following renal transplantation: relation with hyperparathyroidism . Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc—Eur Ren Assoc . 1989 ;4 : 123 –128 .\n3 Takao M , Sakai T , Nishii T , Yoshikawa H , Takahara S , Sugano N . Incidence and predictors of osteonecrosis among cyclosporin- or tacrolimus-treated renal allograft recipients . Rheumatol Int . 2011 ;31 : 165 –170 . 10.1007/s00296-009-1241-8 \n19862528 \n4 Ajmal M , Matas AJ , Kuskowski M , Cheng EY . Does statin usage reduce the risk of corticosteroid-related osteonecrosis in renal transplant population? \nOrthop Clin North Am . 2009 ;40 : 235 –239 . 10.1016/j.ocl.2009.01.004 \n19358908 \n5 Lopez-Ben R , Mikuls TR , Moore DS , Julian BA , Bernreuter WK , Elkins M , et al\nIncidence of hip osteonecrosis among renal transplantation recipients: a prospective study . Clin Radiol . 2004 ;59 : 431 –438 . 10.1016/j.crad.2003.11.001 \n15081848 \n6 Ferrari P , Schroeder V , Anderson S , Kocovic L , Vogt B , Schiesser D , et al\nAssociation of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroid-treated renal allograft recipients . Transplantation . 2002 ;74 : 1147 –1152 . 10.1097/01.TP.0000035848.73883.1B \n12438962 \n7 Saito M , Ueshima K , Fujioka M , Ishida M , Goto T , Arai Y , et al\nCorticosteroid administration within 2 weeks after renal transplantation affects the incidence of femoral head osteonecrosis . Acta Orthop . 2014 ;85 : 266 –270 . 10.3109/17453674.2014.916490 \n24786907 \n8 Paydas S , Balal M , Demir E , Sertdemir Y , Erken U . Avascular osteonecrosis and accompanying anemia, leucocytosis, and decreased bone mineral density in renal transplant recipients . Transplant Proc . 2011 ;43 : 863 –866 . 10.1016/j.transproceed.2011.02.072 \n21486616 \n9 Shibatani M , Fujioka M , Arai Y , Takahashi K , Ueshima K , Okamoto M , et al\nDegree of corticosteroid treatment within the first 2 months of renal transplantation has a strong influence on the incidence of osteonecrosis of the femoral head . Acta Orthop . 2008 ;79 : 631 –636 . 10.1080/17453670810016641 \n18839369 \n10 Schachtner T , Otto NM , Reinke P . Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study . Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc—Eur Ren Assoc . 2018 ; 10.1093/ndt/gfy148 \n29868874 \n11 Moya-Angeler J , Gianakos AL , Villa JC , Ni A , Lane JM . Current concepts on osteonecrosis of the femoral head . World J Orthop . 2015 ;6 : 590 –601 . 10.5312/wjo.v6.i8.590 \n26396935 \n12 Patton PR , Pfaff WW . Aseptic bone necrosis after renal transplantation . Surgery . 1988 ;103 : 63 –68 . 3276031 \n13 Lausten GS , Jensen JS , Olgaard K . Necrosis of the femoral head after renal transplantation . Acta Orthop Scand . 1988 ;59 : 650 –654 . 3063055 \n14 Harrington KD , Murray WR , Kountz SL , Belzer FO . Avascular Necrosis of Bone after Renal Transplantation . J Bone Jt Surg Am . 1971 ;53 : 203 –215 .\n15 Naiker IP , Govender S , Naicker S , Dawood S , Haffejee AA , Seedat YK . Avascular necrosis of bone following renal transplantation . South Afr Med J Suid-Afr Tydskr Vir Geneeskd . 1993 ;83 : 646 –649 .\n16 Hirata T , Fujioka M , Takahashi KA , Asano T , Ishida M , Akioka K , et al\nLow molecular weight phenotype of Apo(a) is a risk factor of corticosteroid-induced osteonecrosis of the femoral head after renal transplant . J Rheumatol . 2007 ;34 : 516 –522 . 17143965 \n17 Ekmekci Y , Keven K , Akar N , Egin Y , Sengul S , Kutlay S , et al\nThrombophilia and avascular necrosis of femoral head in kidney allograft recipients . Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc—Eur Ren Assoc . 2006 ;21 : 3555 –3558 . 10.1093/ndt/gfl400 \n16968732 \n18 Assessment of fracture risk and its application to screening for postmenopausal osteoporosis . Report of a WHO Study Group . World Health Organ Tech Rep Ser . 1994 ;843 : 1 –129 . 7941614 \n19 Perrin P , Caillard S , Javier RM , Braun L , Heibel F , Borni-Duval C , et al\nPersistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation . Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg . 2013 ;13 : 2653 –2663 . 10.1111/ajt.12425 \n24034142 \n20 Sprague SM , Bellorin-Font E , Jorgetti V , Carvalho AB , Malluche HH , Ferreira A , et al\nDiagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis . Am J Kidney Dis Off J Natl Kidney Found . 2016 ;67 : 559 –566 . 10.1053/j.ajkd.2015.06.023 \n26321176 \n21 Hedri H , Cherif M , Zouaghi K , Abderrahim E , Goucha R , Ben Hamida F , et al\nAvascular osteonecrosis after renal transplantation . Transplant Proc . 2007 ;39 : 1036 –1038 . 10.1016/j.transproceed.2007.02.031 \n17524885 \n22 Celik A , Tekis D , Saglam F , Tunali S , Kabakci N , Ozaksoy D , et al\nAssociation of corticosteroids and factor V, prothrombin, and MTHFR gene mutations with avascular osteonecrosis in renal allograft recipients . Transplant Proc . 2006 ;38 : 512 –516 . 10.1016/j.transproceed.2005.12.062 \n16549163 \n23 Tang S , Lui SL , Li FK , Lo WK , Chan TM , Lai KN . Long-term renal allograft recipients from South-east Asia in the pre-cyclosporin era . Int J Artif Organs . 1999 ;22 : 131 –137 . 10357240 \n24 Zhao D-W , Yu M , Hu K , Wang W , Yang L , Wang B-J , et al\nPrevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey . Chin Med J (Engl) . 2015 ;128 : 2843 –2850 . 10.4103/0366-6999.168017 \n26521779 \n25 Bredella MA , Torriani M , Ghomi RH , Thomas BJ , Brick DJ , Gerweck AV , et al\nVertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women . Obes Silver Spring Md . 2011 ;19 : 49 –53 . 10.1038/oby.2010.106 \n20467419 \n26 Zhou L , Jang KY , Moon YJ , Wagle S , Kim KM , Lee KB , et al\nLeptin ameliorates ischemic necrosis of the femoral head in rats with obesity induced by a high-fat diet . Sci Rep . 2015 ;5 : 9397 \n10.1038/srep09397 \n25797953 \n27 Potluri K , Hou S . Obesity in kidney transplant recipients and candidates . Am J Kidney Dis Off J Natl Kidney Found . 2010 ;56 : 143 –156 . 10.1053/j.ajkd.2010.01.017 \n20452710 \n28 Pierides AM , Simpson W , Stainsby D , Alvarez-ude F , Uldall PR . Avascular necrosis of bone following renal transplantation . Q J Med . 1975 ;44 : 459 –480 . 1101287 \n29 Tang S , Chan TM , Lui SL , Li FK , Lo WK , Lai KN . Risk factors for avascular bone necrosis after renal transplantation . Transplant Proc . 2000 ;32 : 1873 –1875 . 11119978 \n30 Tervonen O , Mueller DM , Matteson EL , Velosa JA , Ginsburg WW , Ehman RL . Clinically occult avascular necrosis of the hip: prevalence in an asymptomatic population at risk . Radiology . 1992 ;182 : 845 –847 . 10.1148/radiology.182.3.1535906 \n1535906 \n31 Khwaja K , Asolati M , Harmon J , Melancon JK , Dunn T , Gillingham K , et al\nOutcome at 3 Years with a Prednisone-Free Maintenance Regimen: A Single-Center Experience with 349 Kidney Transplant Recipients . Am J Transplant . 2004 ;4 : 980 –987 . 10.1111/j.1600-6143.2004.00443.x \n15147433 \n32 Rao DS , Shih MS , Mohini R . Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia . N Engl J Med . 1993 ;328 : 171 –175 . 10.1056/NEJM199301213280304 \n8417383 \n33 Arlet J , Ficat P , Lartigue G , Tran MA . [Clinical research on intraosseous pressure in the upper femoral metaphysis and epiphysis in humans. Application to the diagnosis of ischemia and necrosis ]. Rev Rhum Mal Ostéo-Articul . 1972 ;39 : 717 –723 .\n34 Pritchett JW . Statin therapy decreases the risk of osteonecrosis in patients receiving steroids . Clin Orthop . 2001 ; 173 –178 .\n35 Ekberg H , Tedesco-Silva H , Demirbas A , Vítko S , Nashan B , Gürkan A , et al\nReduced exposure to calcineurin inhibitors in renal transplantation . N Engl J Med . 2007 ;357 : 2562 –2575 . 10.1056/NEJMoa067411 \n18094377 \n36 Jacobs B. \nAlcoholism-induced bone necrosis . N Y State J Med . 1992 ;92 : 334 –338 . 1513511 \n37 Atallah AM , Abou El-Ghar ME , Ghoneim MA . Osteonecrosis in kidney recipients: has hypocalcaemia a role? \nRheumatol Int . 2009 ;30 : 75 –79 . 10.1007/s00296-009-0918-3 \n19360409 \n38 Asano T , Takahashi KA , Fujioka M , Inoue S , Okamoto M , Sugioka N , et al\nABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation . Pharmacogenetics . 2003 ;13 : 675 –682 . 10.1097/01.fpc.0000054135.14659.65 \n14583680 \n39 Hirata T , Fujioka M , Takahashi KA , Arai Y , Asano T , Ishida M , et al\nApoB C7623T polymorphism predicts risk for steroid-induced osteonecrosis of the femoral head after renal transplantation . J Orthop Sci Off J Jpn Orthop Assoc . 2007 ;12 : 199 –206 . 10.1007/s00776-007-1110-9 \n17530370 \n40 Serrano OK , Kandaswamy R , Gillingham K , Chinnakotla S , Dunn TB , Finger E , et al\nRapid Discontinuation of Prednisone in Kidney Transplant Recipients: 15-Year Outcomes From the University of Minnesota . Transplantation . 2017 ;101 : 2590 –2598 . 10.1097/TP.0000000000001756 \n28376034 \n41 Lai K-A , Shen W-J , Yang C-Y , Shao C-J , Hsu J-T , Lin R-M . The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study . J Bone Joint Surg Am . 2005 ;87 : 2155 –2159 . 10.2106/JBJS.D.02959 \n16203877 \n42 Agarwala S , Shah SB . Ten-Year Follow-Up of Avascular Necrosis of Femoral Head Treated With Alendronate for 3 Years . J Arthroplasty . 2011 ;26 : 1128 –1134 . 10.1016/j.arth.2010.11.010 \n21256699 \n43 Yuan H-F , Guo C-A , Yan Z-Q . The use of bisphosphonate in the treatment of osteonecrosis of the femoral head: a meta-analysis of randomized control trials . Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA . 2016 ;27 : 295 –299 . 10.1007/s00198-015-3317-5 \n26370828\n\n",
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"title": "Avascular osteonecrosis in kidney transplant recipients: Risk factors in a recent cohort study and evaluation of the role of secondary hyperparathyroidism.",
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"abstract": "Extranodal natural killer T-cell lymphoma, nasal type (ENKL), formerly called lethal midline granuloma or angiocentric T-cell lymphoma, is a predominantly extranodal non-Hodgkin lymphoma characterized by vascular damage, necrosis, and an association with Epstein-Barr virus. In the United States, it is more frequently seen in Asian, Asian Pacific Islander, and Hispanic descent populations and is more prevalent in males in their fifth decade. Clinical presentation of NK nasal lymphoma most commonly involves epistaxis; obstruction; discharge; destructive mass in sinuses, palate, and nose; and skin ulceration. These symptoms can mimic invasive fungal infections and other sinonasal disorders. Furthermore, ENKL has a broad cytologic spectrum and induces a mixture of inflammatory cells, causing difficulty in establishing the diagnosis, especially in initial biopsies. We present a case of refractory Pseudomonas aeruginosa facial cellulitis in a young woman whose treatment course was complicated by septic shock and resistance to multiple antibiotics, resulting in a delayed diagnosis of ENKL nasal type.",
"affiliations": "New York University, New York, NY, USA.;New York University, New York, NY, USA.;Saint George's University, West Indies, Grenada.;NYU Lutheran Medical Center, Brooklyn, NY, USA.;New York University, New York, NY, USA.;New York University, New York, NY, USA.",
"authors": "Reategui Schwarz|Erika|E|;Oikonomou|Katerina G|KG|;Reynolds|Megan|M|;Kim|Juliette|J|;Balmiki|Rajeev L|RL|;Sterling|Stephanie A|SA|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961771647110.1177_2324709617716471Case ReportExtranodal NK/T-Cell Lymphoma, Nasal Type, Presenting as Refractory Pseudomonas aeruginosa Facial Cellulitis Reategui Schwarz Erika MD12Oikonomou Katerina G. MD, PhD12Reynolds Megan 3Kim Juliette PharmD2Balmiki Rajeev L. MD12Sterling Stephanie A. MD, MPH121 New York University, New York, NY, USA2 NYU Lutheran Medical Center, Brooklyn, NY, USA3 Saint George’s University, West Indies, GrenadaStephanie A. Sterling, 150 55th Street, Brooklyn, NY 11220, USA. Email: stephanie.sterling@nyumc.org06 7 2017 Jul-Sep 2017 5 3 232470961771647110 4 2017 25 4 2017 © 2017 American Federation for Medical Research2017American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Extranodal natural killer T-cell lymphoma, nasal type (ENKL), formerly called lethal midline granuloma or angiocentric T-cell lymphoma, is a predominantly extranodal non-Hodgkin lymphoma characterized by vascular damage, necrosis, and an association with Epstein-Barr virus. In the United States, it is more frequently seen in Asian, Asian Pacific Islander, and Hispanic descent populations and is more prevalent in males in their fifth decade. Clinical presentation of NK nasal lymphoma most commonly involves epistaxis; obstruction; discharge; destructive mass in sinuses, palate, and nose; and skin ulceration. These symptoms can mimic invasive fungal infections and other sinonasal disorders. Furthermore, ENKL has a broad cytologic spectrum and induces a mixture of inflammatory cells, causing difficulty in establishing the diagnosis, especially in initial biopsies. We present a case of refractory Pseudomonas aeruginosa facial cellulitis in a young woman whose treatment course was complicated by septic shock and resistance to multiple antibiotics, resulting in a delayed diagnosis of ENKL nasal type.\n\nlymphomaextranodal NK-T-cell/pathologyEpstein-Barr virus infections/virologyUnited StatesENKLhumanscover-dateJuly-September 2017\n==== Body\nIntroduction\nExtranodal natural killer T-cell lymphoma, nasal type (ENKL), formerly called lethal midline granuloma or angiocentric T-cell lymphoma, is a predominantly extranodal non-Hodgkin lymphoma characterized by vascular damage, necrosis, and an association with Epstein-Barr virus (EBV).1 The term is designated as “NK/T” (instead of “NK”) due to some cases showing a cytotoxic T-cell phenotype (CD56-, TCR gene rearrangement).2\n\nNK/T lymphoma is a rare entity more prevalent in Asia and Latin America (3% to 10%) as opposed to the United States and Europe (<1%).3 In the United States, it is more frequently seen in Asian, Asian Pacific Islander, and Hispanic descent populations and is more prevalent in males in their fifth decade.4,5\n\nClinical presentation of NK nasal lymphoma most commonly involves epistaxis; obstruction; discharge; destructive mass in sinuses, palate, and nose; and skin ulceration, and its presentation can mimic invasive fungal infections and other sinonasal disorders.5\n\nSystemic symptoms like fever, hemophagocytosis, and disseminated intravascular coagulation may also be present. This disease is often localized to the upper aerodigestive tract at presentation, but may disseminate to skin, soft tissue, gastrointestinal tract, testis, and cervical lymph nodes. Occurrences outside the nasal cavity vary in presentation depending on the site of involvement; however, bone marrow involvement is uncommon and is associated with aggressive NK-cell leukemia.6\n\nWe present a case of refractory Pseudomonas aeruginosa facial cellulitis in a young woman whose treatment course was complicated by septic shock and multidrug antibiotic resistance, resulting in a delayed diagnosis of ENKL nasal type.\n\nCase Presentation\nA 23-year-old Hispanic woman presented to the emergency department (ED) with persistent and worsening edema, erythema, tenderness, and warmth of the right nares and periorbital area associated with purulent nasal drainage. The patient had multiple ED visits over a 6-week period for her condition. She was initially diagnosed with severe sinus infection and was discharged on amoxicillin/clavulanate potassium, then switched to cephalexin 500 mg every 6 hours and clindamycin 300 mg every 8 hours for inadequate response. The patient was hospitalized on her third ED visit, and initiated on empiric intravenous (IV) vancomycin plus ceftriaxone. Computed tomography (CT) scan at the time showed right paranasal and inferior periorbital/premaxillar soft tissue swelling with subcutaneous sinus fat induration. On her fifth hospital day, culture of her nasal drainage grew P aeruginosa. She was discharged on oral ciprofloxacin 750 mg twice a day, based on antibiogram sensitivities.\n\nThe patient returned to the hospital 1 week after completion of her oral antibiotic therapy for worsening of skin erythema, right facial edema, and nasal discharge. Vital signs on admission were the following: temperature, 103°F; pulse, 133 beats per minute; blood pressure, 82/40; respiratory rate, 30 per minute. Laboratory tests were significant for white blood cell count, 4200/µL; lactic dehydrogenase, 387 IU/L; and lactic acid, 1.6 mmol/L. She was admitted to the intensive care unit with septic shock secondary to nonresolving facial cellulitis, received aggressive fluid resuscitation, vasopressors, and was started on IV vancomycin 1 g every 8 hours, gentamycin 210 mg daily, and meropenem 1 g every 8 hours. Magnetic resonance imaging of the face and orbits disclosed right nasal abscess and the patient underwent debridement in the operating room. The deep wound cultures grew multidrug-resistant P aeruginosa sensitive to meropenem; she was continued on this antibiotic. Antifungal coverage with amphotericin was initially added but then discontinued on tissue culture results. Pathology from nasal tissue was diagnostic for ENKL, nasal type. Immunohistochemical studies showed malignant cells CD3+, CD20−, and weakly cytoplasmic CD2+ and CD56+ (Figure 1).6 In situ hybridization for Epstein-Barr virus–encoded small nuclear RNAs (EBER) showed patchy positivity. Epstein-Barr virus antigen antibody (EBNA AB) was 4.64 U/mL, EBV viral capsid antigen (VCA) IgG was 4.93 U/mL, EBV VCA IgM of <0.91 U/mL. EBV quantitative viral load showed 3162 copies/mL.\n\nFigure 1. Right premaxillary mass immunohistochemistry: (a) Immunohistochemistry CD3+ MP ×10; (b) Immunohistochemistry CD3+ HP ×40.\n\nThe patient continued to spike fevers despite clinical improvement throughout her hospitalization. Subsequent nasal cultures showed P aeruginosa growth, increasingly resistant to antibiotics. Polymyxin 130 mg daily was added to meropenem 1 g every 8 hours on return of positive synergy testing. Staging CT scan of chest, abdomen, and pelvis and bone marrow microscopic examination were negative for metastatic disease. On clinical exam, the patient’s facial swelling continued to worsen, now with extension to the left face. Repeat nasal discharge cultures 10 days later revealed 2 different strains of P aeruginosa were growing, one extensively drug resistant and the other sensitive to her current antibiotic regimen. Antibiotic therapy was switched to ceftolozane/tazobactam 1.5 g every 8 hours. Chemoradiation was initiated 10 days later with a resultant deeffervescence and marked improvement in the diffuse bilateral facial swelling. Patient was discharged home from the hospital after completing a 4-week total IV antibiotic course. A posttreatment positron emission tomography (PET)/CT scan performed 3 months after revealed changes concerning for progression of systemic disease. She underwent a biopsy of a left thigh swelling, which was positive for ENKL, and commenced systemic chemotherapy at a nearby cancer center and completed 4 cycles of SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide). Posttreatment PET/CT scan showed no evidence of disease and EBV quantitative polymerase chain reaction showed an undetectable copy number. Patient is currently undergoing evaluation for autologous stem cell transplant.\n\nDiscussion\nENKL is a rare disease in the United States, though its prevalence is increasing, especially among Hispanic and Asian Pacific Islander populations.5 Men are affected more frequently, usually within the fifth decade of life, unlike our young female patient.\n\nNK lymphoma has been reported to present as epistaxis; obstruction; discharge; destructive mass in sinuses, palate, and nose; and skin ulceration. Compared to other documented cases, septic shock is an uncommon presentation (Table 1).\n\nTable 1. Review of NK Lymphoma Case Reports: Presentation, Treatment, and Outcome Comparison.\n\nAuthor\tPMID\tAge\tLocation\tPresentation\tTreatment\tOutcome\t\nTermote et al7\t24831171\t45\t● Left lower eyelid\t● Painless swelling\t● CHOP + radiation\t● Died 5 months after diagnosis\t\n\t\t20\t● Left upper and lower eyelid\t● Painless swelling\t● SMILE + DHAP + DEXA BEAM + radiation + autologous stem cell transplantation\t● Died 9 months after diagnosis\t\n\t\t55\t● Right upper and lower eyelid\t● Painless swelling of the right eye and double vision\t● SMILE + intrathechal methotrexate-cytarabine-hydrocortisone\t● Died 35 months after diagnosis\t\nKim and An8\t24621697\t58\tRight-sided orbit\tSwelling and pain\tDexamethasone, ifosfamide, and etoposide regimen\tSurvived at the time of publication of case report\t\nMarchino et al3\t24317101\t67\tLeft orbit\tExophthalmos, pain, swelling, and limited extrinsic ocular motility\tCHOP + SMILE\tDied 10 months after diagnosis\t\nPine et al9\t23387455\t52\tLeft orbit\tSwelling, proptosis, vision loss, and diplopia\tMethotrexate/cytarabine and L-aspariginase combination + radiation\tDied 5 months after diagnosis\t\nKunami et al10\t20622489\t72\tLeft forearm\tPainless swelling\tSMILE + radiation + amputation\tSurvived without progression 2 years after amputation\t\nJia and Sun11\t15359650\t62\tRight orbit\tSwelling and purulent nasal drainage\tUnavailable\tUnavailable\t\nHuang et al12\t14719563\t22\tLeft side of face\tSwelling nasal obstruction\tCisplatin, cytosine arabinoside, and methotrexate + surgery\tDied 7 months after diagnosis\t\nAbbreviations: CHOP, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; SMILE, steroid = dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide; DHAP, dexamethasone, high-dose cytarabine, cisplatin; DEXA BEAM, dexamethasone, carmustine, etoposide, cytarabine, and melphalan.\n\nIn our patient, it was unclear if septic shock was secondary to facial cellulitis or if the release of cytokines/interleukins from the tumor burden played a role on presentation. ENKL diagnosis was done from deep wound tissue biopsy from the right nares and paranasal sinuses biopsy. ENKL has a broad cytologic spectrum and induces a mixture of inflammatory cells, causing difficulty in establishing the diagnosis, especially in the initial biopsies. Miyake et al reported a case series in which up to 5 biopsies were required to achieve a definitive diagnosis.13 Out of 23 patients with ENKL treated at Ohio State University and 2 patients at the University of Colorado, a median time of symptoms to diagnosis of 5 months was established.5 Twelve of these patients required more than one diagnostic biopsy leading up to 36 months in delay of diagnosis.5\n\nIn our case, the initial biopsy did not show malignancy but the second biopsy showed malignant cells CD3+, CD20−, and weakly positive for cytoplasmic CD2 and CD56. In situ hybridization for EBER showed patchy positivity. Haverkos et al reported a consistent association of ENKTL-NT with EBV.5 In a 6-year prospective study, Au et al found that in all cases of EBV-positive lymphomas, EBV DNA paralleled the clinical course, with EBV DNA becoming undetectable at remission and remaining elevated in refractory disease.14 High levels of EBV DNA at presentation (>7.3 × 107 copies/mL) were significantly associated with an inferior overall survival. In the NK cell lymphomas subgroup (the largest cohort), EBV DNA was correlated with disease stage and lactate dehydrogenase.14 For this reason, EBV viral load should be trended.\n\nOur patient’s EBV quantitative viral load was 3162 copies/mL. Her fevers resolved after radiotherapy and chemotherapy was initiated, although a new antibiotic regimen with ceftolozane/tazobactam was started few days prior. Therefore, it remains unclear if clinical improvement was attributed to the new antibiotic, to chemo/radiotherapy, or to the combination of the two. Although ceftolozane/tazobactam is not a conventional antibiotic used for cellulitis, in our case it was associated with initial limitation of local disease and improvement in cosmetic sequelae (Figure 2). Ceftolozane/tazobactam has been reported to successfully treat respiratory and intraabdominal infections secondary to multidrug-resistant Pseudomonas spp; however, to our knowledge, ours is the first reported case where this antibiotic cleared a cellulitis infection (cultures on patient discharge were negative).\n\nFigure 2. Right nares lesion during hospitalization course and after discharge: (a) Initiation of chemotherapy; (b) Three months after discharge.\n\nCombined radiotherapy and chemotherapy is the standard treatment in early stage NK/T-cell lymphoma. Despite the initial response to radiotherapy alone, a high relapse rate of around 50% is reported due to possible systemic dissemination in nasal NK/T-cell lymphoma initially considered localized. Prognostic factors for NK/T-cell lymphoma are not yet fully established: biological parameters such as circulating EBV DNA and interim PET/CT findings should be considered in the construction of future prognostic models.2,4 In EBV-positive lymphomas, plasma EBV DNA is valuable as tumor biomarker and prognostication; however, ENKL has a poor outcome in general.14\n\nConclusion\nEarly diagnosis of ENKL nasal type proves challenging due to the fact that its presentation mimics other sinonasal disorders and its broad cytological spectrum affects the accuracy of initial biopsies. Internists who encounter prolonged, complicated cases of facial cellulitis, sinusitis, or pharyngitis refractory to conventional treatment, especially in Asian, Asian Pacific Islander, or Hispanic populations and in the presence of EBV should consider testing for NKTCL, nasal type, in order to prevent rapid disease progression. Given the low level of suspicion for this neoplasm, diagnosis is often delayed because the biopsy specimen is necrotic or because bacterial and fungal stains are incorrectly interpreted as evidence that the primary process is an invasive bacterial or fungal sinusitis, rather than lymphoma, leading to repeated, but unsuccessful, courses of antimicrobial therapy.5\n\nThis delay in diagnosis may result in increased risk of extension of the disease compromising survival and cosmetic damage. Our case exhibits an unusual and life-threatening presentation of ENKL with superimposed bacterial infection leading to septic shock. Detecting the primary disease and starting chemoradiation along with ceftolozane/tazobactam ultimately yielded clinical improvement.\n\nThe authors thank Laura Gabbe, MS, from the Clinical Research Department at NYU Lutheran Medical Center, Brooklyn, New York, for her invaluable assistance with editing this article.\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\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nCampo E Swerdlow SH Harris NL Pileri S Stein H Jaffe ES \nThe 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications . Blood . 2011 ;117 :5019 -5032 .21300984 \n2 \nTse E Kwong YL \nHow I treat NK/T-cell lymphomas . Blood . 2013 ;121 :4997 -5005 .23652805 \n3 \nMarchino T Ibáñez N Prieto S \nAn aggressive primary orbital natural killer/T-cell lymphoma case: poor response to chemotherapy . Ophthal Plast Reconstr Surg . 2014 ;30 :e131 -e134 .\n4 \nGill H Liang RH Tse E \nExtranodal natural-killer/T-cell lymphoma, nasal type . Adv Hematol . 2010 ;2010 :627401 .21234094 \n5 \nHaverkos BM Pan Z Gru AA \nExtranodal NK/T cell lymphoma, nasal type (ENKTL-NT): an update on epidemiology, clinical presentation, and natural history in North American and European cases . Curr Hematol Malig Rep . 2016 ;11 :514 -527 .27778143 \n6 \nMeer S van Heerden WF \nClinicopathologic conference: case 2 . Head Neck Pathol . 2008 ;2 :279 -282 .20614294 \n7 \nTermote K Dierickx D Verhoef G Jorissen M Tousseyn T Mombaerts I \nSeries of extranodal natural killer/T-cell lymphoma, nasal type, with periorbital involvement . Orbit . 2014 ;33 :245 -251 .24831171 \n8 \nKim JW An JH \nExtranodal natural killer/T-cell lymphoma, nasal type, of the orbit mimicking recurrent orbital cellulitis . J Craniofac Surg . 2014 ;25 :509 -511 .24621697 \n9 \nPine RR Clark JD Sokol JA \nCD56 negative extranodal NK/T-cell lymphoma of the orbit mimicking orbital cellulitis . Orbit . 2013 ;32 :45 -48 .23387455 \n10 \nKunami N Takamatsu Y Fujita M \nExtranodal NK/T-cell lymphoma arising from soft tissue of the left forearm [in Japanese] . Rinsho Ketsueki . 2010 ;51 :422 -426 .20622489 \n11 \nJia H Sun T \nExtranodal NK/T-cell lymphoma mimicking cellulitis . Leuk Lymphoma . 2004 ;45 :1467 -1470 .15359650 \n12 \nHuang KJ Wang LF Lee KW \nSinonasal NK/T-cell lymphoma with upper gastrointestinal bleeding: a case report . Kaohsiung J Med Sci . 2003 ;19 :639 -643 .14719563 \n13 \nMiyake MM Oliveira MV Miyake MM Garcia JO Granato L \nClinical and otorhinolaryngological aspects of extranodal NK/T cell lymphoma, nasal type . Braz J Otorhinolaryngol . 2014 ;80 :325 -329 .25183183 \n14 \nAu WY Pang A Choy C Chim CS Kwong YL \nQuantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients . Blood . 2004 ;104 :243 -249 .15031209\n\n",
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"title": "Extranodal NK/T-Cell Lymphoma, Nasal Type, Presenting as Refractory Pseudomonas aeruginosa Facial Cellulitis.",
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"abstract": "The patient was a 78-year-old woman. She was referred to our hospital and diagnosed with advanced gastric cancer with para-aortic lymph node(#16)metastasis. She received the SOX regimen(L-OHP 100mg/m2)chemotherapy and developed fatigue, anorexia, and neutropenia. After 4 courses of the SOX regimen, the #16 metastasis was reduced remarkably. A curative operation was performed and histological evaluation of the primary and lymphatic lesion after chemotherapy showed Grade 3 findings. The SOX regimen is tolerable in the outpatient clinic and is useful as part of multidisciplinary treatment for advanced gastric cancer.",
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"authors": "Mori|Kazunori|K|;Kishi|Kentaro|K|;Masuzawa|Toru|T|;Tsukada|Ryo|R|;Tanemura|Masahiro|M|;Tei|Mitsuyoshi|M|;Suzuki|Yozo|Y|;Otsuka|Masahisa|M|;Furukawa|Kenta|K|;Akamatsu|Hiroki|H|",
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"abstract": "Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children.",
"affiliations": "University of Birmingham Birmingham, United Kingdom ; Murdoch Childrens Research Institute Parkville, Australia ; Monash University Clayton, Australia.;Murdoch Childrens Research Institute Parkville, Australia ; Monash University Clayton, Australia.;Murdoch Childrens Research Institute Parkville, Australia.;Murdoch Childrens Research Institute Parkville, Australia.;Murdoch Childrens Research Institute Parkville, Australia ; Royal Children's Hospital Parkville, Australia.;Murdoch Childrens Research Institute Parkville, Australia.;University of Queensland St Lucia, Australia.;The University of Melbourne Parkville, Australia ; Royal Melbourne Hospital Parkville, Australia.;The University of Melbourne Parkville, Australia ; Australian Pregnancy Register for Women with Epilepsy and Allied Conditions Kew, Australia.",
"authors": "Wood|Amanda G|AG|;Chen|Jian|J|;Barton|Sarah|S|;Nadebaum|Caroline|C|;Anderson|Vicki A|VA|;Catroppa|Cathy|C|;Reutens|David C|DC|;O'Brien|Terence J|TJ|;Vajda|Frank|F|",
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"fulltext": "\n==== Front\nAnn Clin Transl NeurolAnn Clin Transl Neurolacn3Annals of Clinical and Translational Neurology2328-95032328-9503BlackWell Publishing Ltd Oxford, UK 10.1002/acn3.74Brief CommunicationsAltered cortical thickness following prenatal sodium valproate exposure Wood Amanda G 123Chen Jian 23Barton Sarah 2Nadebaum Caroline 2Anderson Vicki A 24Catroppa Cathy 2Reutens David C 5O'Brien Terence J 67Vajda Frank 681 University of BirminghamBirmingham, United Kingdom2 Murdoch Childrens Research InstituteParkville, Australia3 Monash UniversityClayton, Australia4 Royal Children's HospitalParkville, Australia5 University of QueenslandSt Lucia, Australia6 The University of MelbourneParkville, Australia7 Royal Melbourne HospitalParkville, Australia8 Australian Pregnancy Register for Women with Epilepsy and Allied ConditionsKew, AustraliaCorrespondence Amanda G. Wood, School of Psychology, University of Birmingham, Birmingham B15 2TT, United Kingdom. Tel: +44 0121 414 3338; Fax: +44 0121 414 4897; E-mail: a.g.wood@bham.ac.ukFunding Information Research funding was awarded by The Australian Research Council (LP0669648) and Murdoch Childrens Research Institute (Critical Care and Neurosciences). Financial support for the study was provided by MCRI Theme funds, APEX Foundation for Intellectual Disabilities, and Pearson Pls. A. W. received research fellowships from NHMRC (251755) and Rotary Health Australia (Geoffrey Betts Award). C. N. and S. B. were supported by Australian Postgraduate Award Scholarships.\n\n7 2014 03 7 2014 1 7 497 501 03 5 2014 20 5 2014 20 5 2014 © 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.2014This 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.Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children.\n==== Body\nIntroduction\nChildren whose mothers took antiepileptic drugs (AEDs) during pregnancy are at increased risk of poor cognitive and behavioural outcomes. Sodium valproate (VPA) exposure is associated with impaired intellectual1–3 and language ability.4 The probable causal pathway for the longer term effects of fetal AED exposure is the child's brain development during exposure.\n\nBrain changes occur in adults taking VPA, including increased atrophy in dementia5 and reduced parietal lobe cortical thickness in people with epilepsy.6 One study of adults with in utero AED exposure found reduced grey matter volume in lentiform nucleus and hypothalamus,7 but the heterogeneous sample (18 people with 14 different AED combinations) precludes drug-specific interpretations.\n\nRodent studies suggest that prenatal exposure impacts on brain development. VPA affects neuronal progenitor proliferation,8 increases the number of GABAergic neurons, enhances neuronal differentiation,9 causes morphological changes in hippocampal astrocytes10,11 and impairs synaptic plasticity.12,13 Bittigau et al.14 found widespread and dose-dependent apoptotic neurodegeneration although others report global cerebral volume loss associated with high-dose VPA exposure,15 yet increased cerebral volume with lower doses. VPA-treated adult rats show significant reduction in cell differentiation following VPA-exposure16 without volume changes, suggesting that measures such as cortical thickness may prove useful.\n\nHere, we report imaging findings in children exposed to VPA prenatally. We predicted that widespread reductions in cortical thickness would be present in exposed children compared to age- and sex-matched controls.\n\nMethods and Materials\nParticipants\nParticipants were 16 children (seven male, one left-handed) exposed to VPA in utero, recruited to our prospective long-term cognitive outcomes study4,3 and 16 age- and sex-matched controls recruited via hospital and community advertisements whose mothers did not take AEDs or have epilepsy. The average age of cases was 7.2 years (SD = 0.6; range 6–8 years) and in controls was 8.1 (SD = 1.0; range 6–9 years), representing a small but significant difference in age (P < 0.05). There were no differences in ethnicity between groups. One child's mother took VPA and Levetiracetam, and all others were VPA monotherapy. The mean VPA dose across pregnancy was 885 mg (SD = 421). The average IQ of the VPA group was 96.2 (SD = 11.6) and five children's scores fell in the low average or borderline range. There was no significant difference in IQ between VPA exposed children and controls (Control mean = 104.3, SD = 12.4, P > 0.05). Written consent from a parent/guardian and verbal assent from the child was obtained in all cases.\n\nData acquisition\nFull neuropsychological assessment details are reported elsewhere.4,3 The two-subtest short-form of the Wechsler Abbreviated Scale of Intelligence (WASI) was used to measure controls' IQ. Magnetic resonance imaging (MRI) scans were acquired on the 3T Siemens Magnetom Trio at Murdoch Childrens Research Institute, Melbourne, using a 12-channel coil. High-resolution 3D T1-weighted images were acquired (TR = 1900 msec, TE = 2.15 msec, flip angle = 9°, FOV = 256 mm, 176 slices, 1 mm isotropic voxels). As part of our routine research practice, T2-weighted scans are included for clinical reporting by paediatric radiologists.\n\nImage analysis\nData were analysed using Freesurfer, an automated segmentation and cortical reconstruction tool. For imaging processing details, see http://surfer.nmr.mgh.harvard.edu/fswiki/FreeSurferMethodsCitation. Voxelwise group comparisons were conducted, correcting for multiple comparisons (P < 0.05, Monte Carlo method). Only differences that survived this stringent correction step are presented here. Analyses were repeated excluding data from one child whose mother took VPA and Levetiracetam. The findings were unchanged and the total group results are reported here. Values of significantly different regions were then used in subsequent statistical analyses (SPSS 21, IBM Corp, 2011). Freesurfer volumes were used to examine whole brain group differences.\n\nResults\nIncreased cortical thickness was found in the left inferior frontal gyrus (IFG) (Pars Opercularis; x, y, z: −52.5, 23.8, 11.3) and left medial occipital cortex (Pericalcarine; x, y, z: −12.3, −80.6, 14.1). The differences remained when age was included as a covariate. Total cortical white and grey matter did not differ between groups (both P > 0.1). Asymmetry of cortical thickness in the inferior frontal lobes was seen in controls but not cases; a significant interaction between group and hemispheric thickness in the inferior frontal region, controlling for age, was detected (F(1, 29) = 12.38, P = 0.001; Fig.1). Post-hoc analysis showed greater right than left inferior frontal cortical thickness in controls but no such right-left asymmetry in VPA cases. VPA dose across pregnancy did not correlate significantly with left inferior frontal thickness (r = −0.17, P = 0.53), however, there was a significant relationship with the homologous right hemisphere region (r = 0.57, P = 0.02, two-tailed; Fig.2A). A trend towards poorer verbal abilities (Wechsler Intelligence Scale for Children – 4th Edition WISC Verbal Comprehension Index Scores) and greater thickness was observed in VPA cases (r = −0.42, P = 0.12, two-tailed; Fig.2B). No abnormalities were detected on visual inspection of the data by a paediatric radiologist.\n\nFigure 1 A significant interaction between hemispheric inferior frontal gyrus cortical thickness in cases (hashed line, square end) and controls (solid line, round end).\n\nFigure 2 (A) Valproate (VPA) dose in pregnancy correlates significantly with right inferior frontal gyrus thickness (B) Left inferior frontal gyrus thickness is associated with poorer verbal abilities.\n\nDiscussion\nOur data demonstrate regional structural cortical brain changes in humans exposed to VPA in utero. Increases in cortical thickness were identified in children exposed prenatally to VPA, which is a potent and effective anti-epileptic drug, widely considered the treatment of choice for genetic generalized epilepsies. Our findings provide the first direct insight into its central neural impact on the developing human brain.\n\nDifferences in left IFG cortical thickness and absence of the usual hemispheric asymmetry in this region are compelling given the known association between language impairments and prenatal VPA exposure. Atypical hemispheric language specialization in VPA-exposed children was predicted by Meador and colleagues2 on the basis of the pattern of neuropsychological impairment in their cohort of children. Several groups, including our own, report significantly reduced verbal intellectual function and we also showed that specific language impairments occur in VPA-exposed children.4 Meador's group also had a higher than usual rate of left handedness, which is associated with an increased likelihood of atypical (i.e. bilateral or right-sided) language representation in the brain. Taken together, these data led to the conclusion that VPA exposure in utero impacts on the normal functional specialization for language. An alternative explanation is that the atypical hemispheric specialization is inherited from the child's mother. Epilepsy is associated with a higher than usual rate of atypical language representation.17,18 Nevertheless, this seems unlikely to account for Meador and colleagues' hypothesis and our findings because atypical language dominance is typically a feature of lesional epilepsy, and VPA is used most often for idiopathic generalized epilepsy. Second, although the mechanism underlying atypical language in epilepsy is not well characterized, it is assumed to reflect a shift away from pathological eloquent cortex19,20 rather than a genetic factor. Our findings support the idea that there may be altered functional hemispheric specialization in children exposed to VPA and future studies will examine this hypothesis directly.\n\nThe minor age discrepancy between our groups is not the basis for differences in cortical thickness. The findings were not altered when age was covaried was and the pattern of results is opposite to the expected developmental processes; greater cortical development in the controls would in fact minimize the cortical differences found here. Although there is an overall reduction in grey matter volume and cortical thickness during childhood and adolescence,21,22 thickness in specific regions such as left IFG increases with age.21 Thus, controls would show greater cortical thickness in controls. We found the opposite, suggesting that either the VPA-exposed cases have enhanced postnatal cortical development relative to their peers or that the increased thickness represents perturbed prenatal neurodevelopmental processes.\n\nThe association between poorer verbal abilities and increased cortical thickness in the left IFG suggests that our results cannot be accounted for by “enhanced” cortical development in the children exposed to VPA. Positive correlations between IQ and cortical thickness are reported in adults23; this relationship is not evident in young children (i.e. similar to our cohort) but emerges later.24 Indeed, the rate of change in cortical thickness is the salient factor in the relationship with intellectual skills, with higher levels of ability associated with a later onset of thinning.24 Thus, existing data that link the magnitude and developmental trajectory of cortical thickness to intellectual abilities are inconsistent with our findings. Instead, our findings suggest that there may be a direct relationship between the structural changes in this region and cognitive deficits.\n\nThe alteration of cortical development in our cohort is consistent with perturbed prenatal brain development. The specific basis for this is difficult to discern on the basis of our findings and the various mechanisms of action of VPA. For example, VPA increases the availability of GABA, which plays a critical role in cortical development.25,26 Increased bioavailability in the fetus could affect the normal execution of GABA-related processes such as neurite branching and dendrite outgrowth. The trophic function of GABA is well recognized,25 and regionally-increased cortical thickness is seen in fetal alcohol disorder,27 in which GABA is implicated. Alternative mechanisms may also be relevant to understanding the effects of VPA exposure during brain development. For example, VPA impacts on the activity of histone deacetylase and these changes have been shown to influence social behavior in animal models28 and neural plasticity.29\n\nPatterns of morphological changes may vary in relation to the timing of AED exposure,7 and dose may also play a role. VPA-exposed rodents show abnormalities of cortical development including increased apoptosis,8,14 however, volume changes depend on dose, with volume loss at high dose, yet increased volume at medium doses.15 Our cohort was exposed to a relatively low average VPA dose; future studies should include a range of doses to better understand this effect in humans. In conclusion, this study demonstrates regional structural brain changes in children exposed to VPA in utero, and highlights a need for additional research.\n\nThe authors thank the staff of the Australian Pregnancy Register for their support in recruitment, the families who travelled across Australia to participate and the radiographers at Murdoch Childrens Research Institute's MRI facility. Financial support for the study was provided by MCRI Theme funds, APEX Foundation for Intellectual Disabilities, Australian Research Council (LP0669648) and Pearson Pls. A. W. received research fellowships from NHMRC (251755) and Rotary Health Australia (Geoffrey Betts Award). C. N. and S. B. were supported by Australian Postgraduate Award Scholarships.\n\nConflict of Interest\nDr. Wood reports grants from Australian Research Council, Apex Foundation for Intellectual Disabilities, Pearson Pls, Murdoch Childrens Research Institute, during the conduct of the study.\n\nDr. Reutens reports grants from Australian Research Council, Apex Foundation for Intellectual Disabilities, during the conduct of the study.\n\nDr. Vajda reports grants from Australian Research Council, Apex Foundation for Intellectual Disabilities, during the conduct of the study; grants from RMH Neuroscience Foundation, UCB Pharma, Jansen-Cilag, Sanofi, Epilepsy Society of Australia, outside the submitted work.\n\nDr. O'Brien reports grants from NHMRC, RMH Neuroscience Foundation, UCB Pharma, Jansen-Cilag, Sanofi-Genzyme, Scigen, Epilepsy Society of Australia, outside the submitted work.\n==== Refs\nReferences\nMeador KJ Baker GA Browning N Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs N Engl J Med 2009 360 1597 1605 19369666 \nMeador KJ Baker GA Browning N Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age Brain 2011 134 396 404 21224309 \nNadebaum C Anderson V Vajda F The Australian brain and cognition and antiepileptic drugs study: IQ in school-aged children exposed to sodium valproate and polytherapy J Int Neuropsychol Soc 2011 17 133 142 21092354 \nNadebaum C Anderson V Vajda F Language skills of school-aged children prenatally exposed to antiepileptic drugs Neurology 2011 76 719 726 21339499 \nTariot PN Schneider LS Cummings J Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease Arch Gen Psychiatry 2011 68 853 861 21810649 \nPardoe HR Berg AT Jackson GD Sodium valproate use is associated with reduced parietal lobe thickness and brain volume Neurology 2013 80 1895 1900 23616155 \nIkonomidou C Sheer I Wilhelm T Brain morphology alterations in the basal ganglia and the hypothalamus following prenatal exposure to antiepileptic drugs Eur J Paediatr Neurol 2007 11 297 301 17418601 \nFinnell RH Waes JG Eudy JD Rosenquist TH Molecular basis of environmentally induced birth defects Annu Rev Pharmacol Toxicol 2002 42 181 208 11807170 \nLaeng P Pitts R Lemire A The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells J Neurochem 2004 91 238 251 15379904 \nFennrich S Ray D Nau H Schlosshauer B Radial astrocytes: toxic effects induced by antiepileptic drug in the developing rat hippocampus in vitro Eur J Cell Biol 1998 77 142 150 9840464 \nSobaniec-Lotowska M Ultrastructure of astrocytes in the cortex of the hippocampal gyrus and in the neocortex of the temporal lobe in experimental valproate encephalopathy and after valproate withdrawal Int J Exp Pathol 2003 84 115 126 12974941 \nLee G Brown L Teyler T The effects of anticonvulsant drugs on long-term potentiation (LTP) in the rat hippocampus Brain Res Bull 1996 39 39 42 8846106 \nZhang M Yu K Xiao C Ruan D The influence of developmental periods of sodium valproate exposure on synaptic plasticity in the CA1 region of rat hippocampus Neurosci Lett 2003 351 165 168 14623132 \nBittigau P Sifringer M Genz K Antiepileptic drugs and apoptotic neurodegeneration in the developing brain Proc Natl Acad Sci USA 2002 99 15089 15094 12417760 \nFrisch C Husch K Angenstein F Dose-dependent memory effects and cerebral volume changes after in utero exposure to valproate in the rat Epilepsia 2009 50 1432 1441 19374658 \nUmka J Mustafa S ElBeltagy M Valproic acid reduces spatial working memory and cell proliferation in the hippocampus Neuroscience 2010 166 15 22 20006675 \nLoring DW Meador KJ Lee GP King DW Amobarbital effects and lateralized brain function: the Wada test 1992 New York Springer-Verlag \nHelmstaedter C Kurthen M Linke DB Elger C Patterns of language dominance in focal left and right hemisphere epilepsies: relation to MRI findings, EEG, sex, and age of onset of epilepsy Brain Cogn 1997 33 135 150 9073369 \nSass KJ Silberfien CM Platis I Right hemisphere mediation of verbal learning and memory in acquired right hemisphere speech dominant patients J Int Neuropsychol Soc 1995 1 554 560 9375242 \nHelmstaedter C Kurthen M Linke DB Elger CE Right hemisphere restitution of language and memory functions in right hemisphere language-dominant patients with left temporal lobe epilepsy Brain 1994 117 729 737 7922460 \nSowell ER Thompson PM Leonard CM Longitudinal mapping of cortical thickness and brain growth in normal children J Neurosci 2004 24 8223 8231 15385605 \nGogtay N Giedd JN Lusk L Dynamic mapping of human cortical development during childhood through early adulthood Proc Natl Acad Sci USA 2004 101 8174 8179 15148381 \nNarr KL Woods RP Thompson PM Relationships between IQ and regional cortical gray matter thickness in healthy adults Cereb Cortex 2007 17 2163 2171 17118969 \nShaw P Greenstein D Lerch J Intellectual ability and cortical development in children and adolescents Nature 2006 440 676 679 16572172 \nRepresa A Ben-Ari Y Trophic actions of GABA on neuronal development Trends Neurosci 2005 28 278 283 15927682 \nBen-Ari Y Gaiarsa JL Tyzio R Khazipov R GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations Physiol Rev 2007 87 1215 1284 17928584 \nYang Y Roussotte F Kan E Abnormal cortical thickness alterations in fetal alcohol spectrum disorders and their relationships with facial dysmorphology Cereb Cortex 2012 22 1170 1179 21799209 \nMoldrich RX Leanage G She D Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice Behav Brain Res 2013 257 253 264 24103642 \nTaniura H Sng JCG Yoneda Y Histone modifications in the brain Neurochem Int 2007 51 85 91 17543419\n\n",
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"abstract": "Impaired cell-mediated, as well as antibody-mediated immunity predisposes a renal transplant recipient to a wide variety of atypical infection. With an increasing number of re-transplant, the balance between immunosuppression and the risk of recurrent disease poses a clinical and therapeutic challenge. Here, we report a successful re-transplantation in a case of parvovirus B19 infection leading to anaemia and collapsing glomerulopathy in the allograft managed with intravenous immunoglobulin (IVIG) and reduction of immunosuppression. This case emphasizes re-consideration to renal transplant after clearance of the virus in a previous renal allograft lost to PVB19 infection.",
"affiliations": "Department of Nephrology, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Histopathology, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Immunopathology, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Transplant Surgery, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Transplant Surgery, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Transplant Surgery, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Nephrology, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Nephrology, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Nephrology, Post graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Nephrology, Post graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Inamdar|Neeraj|N|;Nada|Ritambhra|R|;Minz|Ranjana|R|;Kenwar|Deepesh Benjamin|DB|;Singh|Sarabpreet|S|;Sharma|Ashish|A|;Kumar|Vivek|V|;Rathi|Manish|M|;Kohli|Harbir S|HS|;Ramachandran|Raja|R|https://orcid.org/0000-0002-1273-9107",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents",
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"mesh_terms": "D064591:Allografts; D016731:Erythema Infectiosum; D005921:Glomerulonephritis; D006084:Graft Rejection; D006801:Humans; D016867:Immunocompromised Host; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D016732:Parvovirus B19, Human; D012008:Recurrence; D012010:Red-Cell Aplasia, Pure; D012086:Reoperation; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome; D055815:Young Adult",
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"abstract": "Hypomagnesemia can cause various unspecific neurological complications, which can lead to diagnostic confusion. One of these complications is the posterior reversible encephalopathy syndrome (PRES), which is extremely uncommon and has been reported only twice in the English-language literature.\nWe report the case of a 60-year-old man who presented with PRES involving only the cerebellar hemispheres and associated with hypomagnesemia. After excluding all the other possible etiologies of PRES, we started magnesium replacement therapy, which led to a remarkable but fluctuating clinical and chemical improvement. A full recovery with no need for further supplementation was achieved only after discontinuation of a proton pump inhibitor.\nThis case highlights the role of magnesium in the pathophysiology of PRES; thereby, underlying hypomagnesemia should be considered in every PRES case with unclear etiology.",
"affiliations": "Department of Neurology, St. Josef Hospital, The Academic Hospital of Duisburg-Essen University, Mülheimer Strasse 83, 46045 Oberhausen, Germany.;Department of Neurology, St. Josef Hospital, The Academic Hospital of Duisburg-Essen University, Mülheimer Strasse 83, 46045 Oberhausen, Germany.;Department of Neurology, St. Josef Hospital, The Academic Hospital of Duisburg-Essen University, Mülheimer Strasse 83, 46045 Oberhausen, Germany.;Department of Neurology, St. Josef Hospital, The Academic Hospital of Duisburg-Essen University, Mülheimer Strasse 83, 46045 Oberhausen, Germany.;Department of Neurology, St. Josef Hospital, The Academic Hospital of Duisburg-Essen University, Mülheimer Strasse 83, 46045 Oberhausen, Germany.",
"authors": "Almoussa|Mohamad|M|0000-0001-9589-4702;Goertzen|Angelika|A|;Brauckmann|Stephan|S|;Fauser|Barbara|B|;Zimmermann|Christoph W|CW|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/1980638Case ReportPosterior Reversible Encephalopathy Syndrome due to Hypomagnesemia: A Case Report and Literature Review http://orcid.org/0000-0001-9589-4702Almoussa Mohamad mohamad.almoussa@lvr.deGoertzen Angelika Brauckmann Stephan Fauser Barbara Zimmermann Christoph W. Department of Neurology, St. Josef Hospital, The Academic Hospital of Duisburg-Essen University, Mülheimer Strasse 83, 46045 Oberhausen, GermanyAcademic Editor: Georgios D. Kotzalidis\n\n2018 29 11 2018 2018 19806388 9 2018 30 10 2018 Copyright © 2018 Mohamad Almoussa et al.2018This 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.Background\n Hypomagnesemia can cause various unspecific neurological complications, which can lead to diagnostic confusion. One of these complications is the posterior reversible encephalopathy syndrome (PRES), which is extremely uncommon and has been reported only twice in the English-language literature. \n\nCase presentation\n We report the case of a 60-year-old man who presented with PRES involving only the cerebellar hemispheres and associated with hypomagnesemia. After excluding all the other possible etiologies of PRES, we started magnesium replacement therapy, which led to a remarkable but fluctuating clinical and chemical improvement. A full recovery with no need for further supplementation was achieved only after discontinuation of a proton pump inhibitor. \n\nConclusions\n This case highlights the role of magnesium in the pathophysiology of PRES; thereby, underlying hypomagnesemia should be considered in every PRES case with unclear etiology.\n==== Body\n1. Background\nMagnesium is the second most abundant intracellular cation after potassium and the fourth most abundant extracellular cation overall. Ninety-nine percent of the magnesium is stored intracellularly, principally in the bone and to a lesser extent in the muscles. The plasma magnesium, which comprises only 1% of total magnesium, can be ionized or bound to anions or protein. Magnesium plays a crucial role in numerous physiological functions; therefore, its hemostasis in the body is strictly regulated by uptake in the small intestine and excretion in the kidney [1]. Hypomagnesemia is usually defined as having a magnesium level below 0.66 mmol/L (1.6 mg/dl) [2]. To avoid hypomagnesemia, the German Society for Nutrition recommends a sufficient daily intake. Common etiologies of hypomagnesemia include chronic inadequate intake, alcoholism, vomiting, and diarrhea. Other conditions associated with increased gastrointestinal magnesium loss include malabsorption, steatorrhea, short gut syndrome, pancreatitis, and genetic disorders affecting magnesium absorption. Similarly, hypomagnesemia may be the consequence of enhanced magnesium renal wasting caused by some medications (diuretics, EGFR inhibitors, calcineurin inhibitors, cisplatin, carboplatin, aminoglycoside antibiotics, pentamidine, rapamycin, and amphotericin B) and genetic disorders such as Bartter and Gitelman syndromes [1]. Proton pump inhibitors cause hypomagnesemia, probably by affecting its intestinal absorption [1]. Patients with mild magnesium deficiency may suffer nonspecific symptoms such as depression, tiredness, muscle spasms, and muscle weakness [1]. Critically low magnesium concentrations can cause serious complications such as cardiac arrhythmias, seizures, neuromuscular irritability, muscular weakness, and respiratory depression [3]. Hypomagnesemia may also lead to a wide spectrum of neurological disorders, such as primary downbeat spontaneous nystagmus with ataxia [4–6], cerebellar syndrome [7–9], myopathy [10], and posterior reversible encephalopathy syndrome (PRES) [11, 12]. Other symptoms such as depression, agitation, cognitive confusion, and coma have been also reported [13].\n\nHere, we report a case of PRES in the setting of hypomagnesemia and provide a literature review on cerebellar symptoms attributed to it.\n\n2. Case Presentation\nA 60-year-old man was admitted to the internal department of our hospital due to thoracic discomfort, vertigo, nausea, and ataxia. After excluding acute coronary artery disease, he was referred to us because of the progression of the neurological symptoms during his one-week stationary therapy in the internal department.\n\nOn clinical examination, he demonstrated a remarkable limb and truck ataxia, a rest, postural, and intention tremor, a severe dysarthria, nystagmus, and a mild cognitive impairment. The patient could not walk or eat unassisted. His current oral medication consisted of acetylsalicylic acid, pantoprazole 40 mg/d, atorvastatin, spironolactone, opipramol, Ferro Sanol, and ramipril.\n\nHis medical history included hypertension, coronary artery disease, an episode of gastrointestinal bleeding by angiodysplasia in 2015, and pulmonary embolism in 2013. In addition, he had a medical history of persistent diarrhea over the last two years without any organic etiology, a vitamin D deficiency in spite of substitution, and recurrent hypokalemia. The patient was a habitual drinker consuming two glasses of wine daily. Six months ago, he was hospitalized in another neurological department because of a one-week persistent dysarthria. An obtained cranial magnetic resonance imaging (MRI) at that time revealed a symmetric hyperintensity in both cerebellar hemispheres (Figure 1(a)). To exclude a cerebellar paraneoplastic syndrome and viral or autoimmune encephalitis, a lumbar puncture was performed. The analysis result of the cerebrospinal fluid was normal. Antibodies against NMDA-receptors, AMPA1-receptors, AMPA2-receptors, and autoantibodies against Ma2 and M2, as well as herpes simplex antibodies (HSV1- and HSV2-DNA), were not detected in the cerebrospinal fluid. A computed tomographic scan of the thorax and abdomen was unremarkable. An empirical therapy with Rocephin and aciclovir was started, but after excluding herpes simplex in the cerebrospinal fluid, the antiviral therapy was discontinued. The blood pressure was slightly high during monitoring; therefore, an antihypertensive therapy was initiated. A further coloscopy and gastroscopy revealed only a Helicobacter pylori-negative gastritis. The dysarthria improved, and the patient was discharged with the diagnosis of a possible PRES according to the cranial MRI finding.\n\nThe laboratory investigations disclosed a severely low magnesium level (0.4 mg/dl; range: 1.7–2.55 mg/dl), a hypocalcemic level (1.7 mmol/l; range: 2.1–2.5 mmol/l), a normal potassium level (3.6 mmol/l; range: 3.5–5.1 mmol/l), a low hemoglobin count (12.3 g/l; range: 14–17.5 g/l), a low erythrocyte count (3.69 × 106/µl; range: 4.5–5.9 × 106/µl), a low 25-OH vitamin D level (7 ng/ml; range: 31–100 ng/ml) despite the replacement therapy, and a normal parathormone (PTH) level (22.3 pg/ml; range: 14.5–87.1 pg/ml). Sodium and phosphate levels were within the normal range. The creatine kinase level was high (450 U/l; range <174 U/I). The other laboratory tests including serum electrophoresis were within the normal range. During the stationary therapy, he developed a mild hypokalemia; an oral supplementation was started.\n\nThe cranial MRI displayed a weak residual hyperintensity in the right cerebellar hemisphere, probably as a residual indicator of the cerebellar bihemispheric hyperintensities described in the previous external MRI (Figure 1(b)). The electroencephalography results were normal. To exclude a paraneoplastic syndrome, we performed a lumbar puncture, which revealed an unremarkable finding. Another possible cause for PRES such as high hypertension was missing. Thus, we suspected the cerebellar syndrome due to hypomagnesemia and started an intravenous magnesium supplementation and an oral calcium intake.\n\nThe patient received an intravenous supplementation of 1 g magnesiumsulfat-heptahydrat (equivalent to 4.05 mmol/mg) every two days, in addition to oral supplementation of calcium and potassium.\n\nThe magnesium level returned to the normal range after two weeks of supplementation, as did the calcium level within four days. The patient exhibited a clear clinical improvement of the ataxia; he could walk and eat unassisted (Figure 2). After 14 days of hospitalization, the patient was discharged. The patient received poststationary magnesium intravenous supplementation three times per week for two months. Notably, excreted magnesium in the 24-hour urine specimen was normal excluding the renal waste of magnesium. However, fluctuations in magnesium levels and the clinical symptoms were still observed under the poststationary intravenous supplementation until the proton pump inhibitor (PPI) was discontinued and a therapy with ranitidine was started. Subsequently, the replacement therapy was discontinued. The patient has remained symptom-free for over five months.\n\n3. Discussion\nPosterior reversible encephalopathy syndrome is a neurological syndrome characterized by clinical and radiological features. It encompasses heterogeneous etiologies sharing similar findings on imaging studies. Although the pathophysiology underlying PRES remains unclear, it is believed that it is related to disordered cerebral autoregulation and endothelial dysfunction leading to a vasogenic edema in the posterior cerebral regions [14]. PRES due to magnesium depletion is rare and has been described, in just two case reports [8, 9]. In the present case, MRI studies revealed a PRES depiction involving only the cerebellar hemispheres. Isolated cerebellar involvement in the setting of PRES is extremely rare [15]. Various conditions associated with PRES have been identified; these include blood pressure fluctuations, renal failure, immunosuppressive therapy, autoimmune disorders, and eclampsia [14]. In our case, a high blood pressure level was documented on admission to the internal department, which was rapidly decreased without any complications. In addition, during the previous external hospitalization, only a slightly high blood pressure level was documented although the radiological finding at that time suggested PRES. Therefore, and after ruling out another possible etiology for PRES, we suspected hypomagnesemia. This was confirmed in the chemical analysis that disclosed a particularly low magnesium level of 0.4 mg/dl (range: 1.7–2.55 mg/dl). This severe hypomagnesemia may have resulted from chronic diarrhea, the intake of PPI, the habitual alcohol consumption, or a combination of these factors. Our patient had been taking PPI for several years and suffered chronic diarrhea for the last two years. In addition, he used to drink two glasses of wine daily for many years. Notably, the magnesium level in the 24-hour urine collection was normal excluding the renal wasting. Only ending the use of the PPI led to a stable, normal magnesium level after discontinuing the supplementation.\n\nBlood tests disclosed a severe hypomagnesemia, accompanied by hypocalcemia, mild hypokalemia, and a chronic vitamin D deficiency but a normal PTH level. Magnesium depletion is known to induce renal potassium secretion and cause hypocalcemia by impairing PTH production or inducing resistance against it on target organs [1]. In the present case, PTH was within the normal range despite the severe hypocalcemia indicating a secondary hypoparathyroidism due to the hypomagnesemia. But, in two reported cases, hypomagnesemia and hypocalcemia were associated with an elevated PTH [8, 11].\n\nThe parenteral replacement therapy of magnesium led to rapid clinical improvement. Even before reaching the normal range, the patient could resume his daily activities without assistance. After replacement of PPI with ranitidine, we ended the poststationary magnesium intravenous supplementation.\n\nThere are ten case reports in the literature describing cerebellar syndrome due to hypomagnesemia (11 patients, six men and five women; Table 1). In four cases, hypomagnesemia developed due to short bowel syndrome after surgery. Notably, and similar to our case, hypomagnesemia was overlooked in all the reported cases and diagnosed only during the second or third hospitalization after ruling out other possible causes. For example, a lumbar puncture and an investigation for malignancies were performed in 4 of the 11 patients due to the suspicion of a paraneoplastic syndrome. An antiviral therapy with aciclovir was initiated in two patients. Regardless of the supplementation regimes applied, full recovery or clinical improvement was observed in 8 of 11 cases; reoccurrence of the symptoms was reported in three cases. Altogether, hypomagnesemia represents a curable cause of cerebellar and PRES syndrome.\n\n4. Conclusions\nHypomagnesemia can cause serious neurological symptoms, including cerebellar syndrome and PRES. Investigation of underlying hypomagnesemia should be considered in these disorders, especially in the presence of other laboratory disorders and long-term PPI therapy. Intravenous supplementation and replacement of the PPI could resolve the symptoms. This can save time and avoid costly unnecessary investigations.\n\nAbbreviations\nPRES:Posterior reversible encephalopathy syndrome\n\nPPI:Proton pump inhibitor\n\nEGFR:Epidermal growth factor receptor\n\nMRI:Magnetic resonance imaging\n\nNMDA-receptors:\nN-methyl-D-aspartate receptor\n\nAMPA-receptors:a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptors\n\nMg:Magnesium\n\nPTH:Parathormone.\n\nConsent\nInformed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Cranial MRI displays high signal intensity in both cerebellar hemispheres six months prior to admission (a); and, currently, a residual hyperintensity in the right cerebellar hemisphere on T2-weighted and FLAIR images (b).\n\nFigure 2 Serum magnesium, potassium, and calcium during the stationary therapy. At day 14, with a magnesium level of 1.6 mg/dl, the patient clinically remarkably improved and was discharged.\n\nTable 1 Cerebellar syndrome due to hypomagnesemia in the literature.\n\nPublication\tAge (years)\tSex\tNeurological symptoms on admission\tImaging\tMg\tNa\tCa\tK\tPTH\tEtiology\tFollow-up\t\n[4]\t78\tM\tPDBN\tCCT: n\nMRI: cerebrovascular chronic ischemia and slight cerebral and cerebellar atrophy\tNot detectable\tn\t↓\tn\tN/A\tProbably attacks of diarrhea caused by diverticulitis\tPDBN disappeared after two weeks.\nA temporary reoccurrence was observed on day 17\t\n\n\n\t\n[12]\t61\tF\tAtaxia, paresthesia, cognitive impairment\tBrain and cord MRI: n\t1.5 mEq/l\tN/A\tN/A\tN/A\tN/A\tTRPM6 mutation\tReoccurrence after 2 months\t\n\n\n\t\n[8]\t72\tM\tSevere dysarthria, ataxia, dysphagia, nystagmus\tMRI: hyperintensities within both cerebellar hemispheres similar to PRES\t0.15 mmol/l\tN/A\t↓\tN/A\t↑\tShort bowel syndrome after surgical treatment of adenocarcinoma and diarrhea\tMRI and clinic were unremarkable after 2 months\t\n\n\n\t\n[11]\t68\tF\tSeizure, PDBN\tMRI: a lesion within the cerebellar nodulus\t7 mg/l (range: 18–24 mg/l)\tn\t↓\t↓\t↑\tUndetermined\tReoccurrence after 2 months\t\n\n\n\t\n[7]\t59\tM\tAtaxia, vertical nystagmus, seizures, PDBN\tMRI: hyperintensity and swelling of the cerebellar nodulus\t<0.08 mmol/l (normal range: 0.75–1.0 mmol/l)\t↓\t↓\t↓\tN/A\tShort bowel syndrome after ileostomy due to ulcerative colitis\tN/A\t\n\n\n\t\n[16]\t66\tF\tDysphagia, diplopia, vertical nystagmus, weakness, cognitive impairment\tN/A\t0.21 mEq/l (range: 1.4–2.0 mEq/l)\tn\tn\tn\tN/A\tShort bowel syndrome after colectomy due to metastases of cervix carcinoma\tSymptoms improved, dysphagia resolved after 2 months\t\n\n\n\t\n[17]\t67\tF\tPDBN, ataxia\tN/A\t1.1–1.4 mmol/l (range: 1.5–2.5 mmol/l)\tN/A\t↓\tN/A\tN/A\tSide effect of lithium carbonate\tSymptoms resolved in 4 months\t\n\n\n\t\n[5]\t21\tM\tPDBN, ataxia, dysphagia, tachycardia, seizures\tCCT: n\t<1 mg/dl\tN/A\tN/A\t↓\tN/A\tParenteral nutrition, short bowel syndrome after ileocolectomy for Crohn's disease\tComplete recovery after 6 weeks\t\n\n\n\t\n[5]\t44\tF\tSeizures, PDBS\tCCT: n\t0.9 mg/ml (range: 1.5–3.5 mg/dl)\tN/A\t↓\t↓\tN/A\tParenteral nutrition, resection of terminal ileum and cecum because of metastatic fallopian adenocarcinoma\tPersistence of downbeat nystagmus; death because of cancer complications after 3 months\t\n\n\n\t\n[9]\t57\tM\tSeizure, dysarthria, ataxia\tMRI: hyperintense lesions in both cerebellar hemispheres and the vermis resembling PRES\t0.19 mmol/l\tN/A\tN\t↓\tN/A\tAlcohol abuse\tSignificant improvement after 6 months\t\n\n\n\t\n[18]\t65\tM\tAtaxia, cognitive impairment, seizure\tMRI: hyperintensities within the cerebellar vermis\t0.08 mmol/l (range: 0.7–0.9 mmol/l)\tN/A\t↓\t↓\t↓↓↓\tPantoprazole\tMild memory deficit is still observed after 6 months\t\nM: male; F: female; PDBN: paroxysmal downbeat nystagmus; n: normal; N/A: not available; Mg: magnesium; Ca: calcium; K: potassium; PTH: parathormone hormone; MRI: magnetic resonance imaging; CCT: cranial computed tomography. mEq/l: milliequivalents per liter; mmol/l: millimoles per liter; mg/dl: milligrams per deciliter; mg/ml: milligrams per milliliter. ↓: low; ↓↓↓: very low; ↑: high.\n==== Refs\n1 de Baaij J. H. F. Hoenderop J. G. J. Bindels R. J. M. Magnesium in man: implications for health and disease Physiological Reviews 2015 95 1 1 46 10.1152/physrev.00012.2014 2-s2.0-84919782110 25540137 \n2 Pham P.-C. T. Pham P.-A. T. Pham S. V. Hypomagnesemia: a clinical perspective International Journal of Nephrology and Renovascular Disease 2014 7 219 230 10.2147/IJNRD.S42054 2-s2.0-84902207795 24966690 \n3 Upala S. Jaruvongvanich V. Wijarnpreecha K. Sanguankeo A. Hypomagnesemia and mortality in patients admitted to intensive care unit: a systematic review and meta-analysis QJM 2016 109 7 453 459 10.1093/qjmed/hcw048 2-s2.0-84977142634 27016536 \n4 Comacchio F. Markova V. Accordi D. Magnavita P. Primary downbeat spontaneous nystagmus and severe Hypomagnesemia Monitoring and Follow-Up 2015 2 2 7 \n5 Saul R. F. Selhorst J. B. Downbeat nystagmus with magnesium depletion Archives of Neurology 1981 38 10 650 652 10.1001/archneur.1981.00510100078014 2-s2.0-0019489437 7295110 \n6 Du Pasquier R. Vingerhoets F. Safran A. B. Landis T. Periodic downbeat nystagmus Neurology 1998 51 5 1478 1480 10.1212/wnl.51.5.1478 2-s2.0-0031743473 9818889 \n7 Sedehizadeh S. Keogh M. Wills A. J. Reversible hypomagnesaemia-induced subacute cerebellar syndrome Biological Trace Element Research 2011 142 2 127 129 10.1007/s12011-010-8757-3 2-s2.0-79959542091 20607440 \n8 Boulos M. I. Shoamanesh A. Aviv R. I. Severe hypomagnesemia associated with reversible subacute ataxia and cerebellar hyperintensities on MRI Neurologist 2012 18 4 223 225 10.1097/NRL.0b013e31825bbf07 2-s2.0-84863589756 22735253 \n9 Te Riele M. G. E. Verrips A. Severe hypomagnesaemia causing reversible cerebellopathy The Cerebellum 2014 13 5 659 662 10.1007/s12311-014-0567-2 2-s2.0-84929516442 24838431 \n10 Pall H. S. Williams A. C. Heath D. A. Hypomagnesaemia causing myopathy and hypocalcaemia in an alcoholic Postgraduate Medical Journal 1987 63 742 665 667 10.1136/pgmj.63.742.665 2-s2.0-0023224259 3422869 \n11 Santos A. F. Sousa F. Rodrigues M. Reversible cerebellar syndrome induced by hypomagnesemia Neurology and Clinical Neuroscience 2015 3 5 190 191 10.1111/ncn3.183 \n12 Blasco L. M. Cerebellar syndrome in chronic cyclic magnesium depletion Cerebellum 2013 12 4 587 588 10.1007/s12311-012-0431-1 2-s2.0-84892374467 23184528 \n13 Pasina L. Zanotta D. Puricelli S. Bonoldi G. Acute neurological symptoms secondary to hypomagnesemia induced by proton pump inhibitors: a case series European Journal of Clinical Pharmacology 2016 72 5 641 643 10.1007/s00228-016-2024-2 2-s2.0-84957941509 26874835 \n14 Fugate J. E. Rabinstein A. A. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions The Lancet Neurology 2015 14 9 914 925 10.1016/S1474-4422(15)00111-8 2-s2.0-84939511933 26184985 \n15 Li D. Lian L. Zhu S. Isolated cerebellar involvement in posterior reversible encephalopathy syndrome Journal of the Neurological Sciences 2015 357 1-2 101 105 10.1016/j.jns.2015.07.004 2-s2.0-84956572700 26163418 \n16 Hamed I. A. Lindeman R. D. Dysphagia and vertical nystagmus in magnesium deficiency Annals of Internal Medicine 1978 89 2 222 223 10.7326/0003-4819-89-2-222 2-s2.0-0017886736 677587 \n17 Coppeto J. R. Monteiro M. L. Lessell S. Downbeat nystagmus. Long-term therapy with moderate-dose lithium carbonate Archives of Neurology 1983 40 12 754 755 10.1001/archneur.1983.04050110072013 2-s2.0-0021027207 6625991 \n18 Fatuzzo P. Portale G. Scollo V. Proton pump inhibitors and symptomatic hypomagnesemic hypoparathyroidism Journal of Nephrology 2016 30 2 297 301 10.1007/s40620-016-0319-0 2-s2.0-85015734663 27206762\n\n",
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"medicinalproduct": "ACETYLSALICYLIC ACID"
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},
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}
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"literaturereference": "ALMOUSSA M, GOERTZEN A, BRAUCKMANN S, FAUSER B, ZIMMERMANN C. POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME DUE TO HYPOMAGNESEMIA: A CASE REPORT AND LITERATURE REVIEW. CASE REPORTS IN MEDICINE. 2018?.",
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},
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}
] |
{
"abstract": "The paper describes the first three deaths reported in Europe involved in isotonitazene consumption, a potent benzimidazole derivate opioid consumed in the recreational drug scene. Isotonitazene powder and purity determination was performed on the sample collected in the first death scene by NMR, HRMS, GC-FTIR, ATR-FTIR and GC-MS. Isotonitazene purity was determined by GC-MS analysis and proton NMR, and was defined to be above 95 % and 98 %, respectively. Quantification of isotonitazene in biological samples was performed using a targeted analysis based on SPE extraction and ultra-high performance liquid chromatography tandem mass spectrometry. The isotonitazene median concentration in femoral whole blood was 1.20ng/mL. Isotonitazene concentration in hair was similar or even lower compared to that seen in fentanyl abusers. Isotonitazene distribution in tissues converges in the brain, lungs and heart, respectively. Surprisingly, isotonitazene concentration in liver is the lowest measured for all tissues and fluids analyzed. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of all three deaths was an acute intoxication with isotonitazene. Since isotonitazene toxic concentration levels are very low, the consumption of this new psychoactive drug is a real hazard for human health.",
"affiliations": "Alpine Foundation for Life Sciences (FASV), 6718, Olivone, Switzerland; University of Geneva, Rue du Général-Dufour 24, 1211, Genève 4, Switzerland. Electronic address: francesco.mueller@fasv.ch.;Zurich Forensic Science Institute, Zeughausstrasse 11, 8004, Zürich, Switzerland.;Institute for Pharmaceutical Science (IPW), ETH Zürich, 8057, Zürich, Switzerland.;Forensic Medicine Canton Ticino, Via Guisan 3, 6500, Bellinzona, Switzerland.;Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliere Cantonale, Lugano, Switzerland; Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland.;Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital-Geneva University Hospitals, Switzerland; Faculty Unit of Toxicology, CURML, Lausanne University Hospital, Faculty of Biology and Medicine, University of Lausanne, Switzerland.;Alpine Foundation for Life Sciences (FASV), 6718, Olivone, Switzerland.",
"authors": "Mueller|F|F|;Bogdal|C|C|;Pfeiffer|B|B|;Andrello|L|L|;Ceschi|A|A|;Thomas|A|A|;Grata|E|E|",
"chemical_list": "D001562:Benzimidazoles; D011619:Psychotropic Drugs; C000710769:isotonitazene",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2021.110686",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "320()",
"journal": "Forensic science international",
"keywords": "Hair; Human tissues post-mortem redistribution; Isotonitazene quantification; LC-MS/MS; New psychoactive substances",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D001562:Benzimidazoles; D002853:Chromatography, Liquid; D062787:Drug Overdose; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011619:Psychotropic Drugs; D017550:Spectroscopy, Fourier Transform Infrared; D019966:Substance-Related Disorders; D013557:Switzerland; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "110686",
"pmc": null,
"pmid": "33497988",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Isotonitazene: Fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland.",
"title_normalized": "isotonitazene fatal intoxication in three cases involving this unreported novel psychoactive substance in switzerland"
} | [
{
"companynumb": "CH-ALVOGEN-2021-ALVOGEN-116533",
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"actiondrug": "6",
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{
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}
],
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"literaturereference": "MUELLER F, BOGDAL C, PFEIFFER B, ANDRELLO L, CESCHI A, THOMAS A, ET AL. ISOTONITAZENE: FATAL INTOXICATION IN THREE CASES INVOLVING THIS UNREPORTED NOVEL PSYCHOACTIVE SUBSTANCE IN SWITZERLAND. FORENSIC SCIENCE INTERNATIONAL. 2021?ARTICLE NUMBER 110686?320:1?13.",
"literaturereference_normalized": "isotonitazene fatal intoxication in three cases involving this unreported novel psychoactive substance in switzerland",
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},
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},
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"transmissiondate": "20210420"
},
{
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"medicinalproduct": "DUROGESIC MATRIX"
}
],
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"reaction": [
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "23.1",
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},
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MUELLER F, BOGDAL C, PFEIFFER B, ANDRELLO L, CESCHI A, THOMAS A, ET AL. ISOTONITAZENE: FATAL INTOXICATION IN THREE CASES INVOLVING THIS UNREPORTED NOVEL PSYCHOACTIVE SUBSTANCE IN SWITZERLAND. FORENSIC SCIENCE INTERNATIONAL 2021 320 110686",
"literaturereference_normalized": "isotonitazene fatal intoxication in three cases involving this unreported novel psychoactive substance in switzerland",
"qualification": "3",
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},
"primarysourcecountry": "CH",
"receiptdate": "20210211",
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},
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},
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}
] |
{
"abstract": "OBJECTIVE\nTo our knowledge, this is the first published case report of an adolescent girl with a mitochondrial disorder and depression who displayed both new-onset psychotic and increased mood symptoms during treatment with risperidone.\n\n\nMETHODS\nA 16-year-old girl was treated with risperidone for mood lability and impulsivity at a community hospital. Within days, she developed paranoid ideation, profound psychomotor retardation, increased depression, and fatigue. She was transferred to an inpatient psychiatric hospital, where she was taken off risperidone. Within 48 hours after discontinuation of the medication, she had complete resolution of psychotic symptoms, fatigue, and psychomotor retardation, and her depression improved.\n\n\nCONCLUSIONS\nThis observation of \"on-off\" risperidone treatment suggests that risperidone may have worsened both psychiatric and physical manifestations of the mitochondrial disorder in this adolescent. These findings are consistent with recent in vitro literature, which implicate a series of neuroleptic medications with mitochondrial dysfunction. Furthermore, the authors provide diagnostic and treatment options that are available for mitochondrial disorders, which are of interest to child psychiatrists due to the central nervous system manifestations of these disorders.",
"affiliations": "Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. mahn@fourwindshospital.com",
"authors": "Ahn|Mary S|MS|;Sims|Katherine B|KB|;Frazier|Jean A|JA|",
"chemical_list": "D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2005.15.520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "15(3)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D003866:Depressive Disorder; D004830:Epilepsy, Tonic-Clonic; D005260:Female; D006801:Humans; D028361:Mitochondrial Diseases; D019964:Mood Disorders; D011605:Psychoses, Substance-Induced; D018967:Risperidone",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "520-5",
"pmc": null,
"pmid": "16092915",
"pubdate": "2005-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Risperidone-induced psychosis and depression in a child with a mitochondrial disorder.",
"title_normalized": "risperidone induced psychosis and depression in a child with a mitochondrial disorder"
} | [
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"activesubstancename": "PAROXETINE"
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"medicinalproduct": "RISPERIDONE."
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"abstract": "This was a study of a 33-year-old man with bipolar disorder treated with lithium who developed cerebellar atrophy after an event of extreme hyperthermia. Unlike previously reported cases of acute cerebellar atrophy after heat stroke, neuroleptic syndrome or lithium toxicity, this case was characterized by a chronic cerebellar atrophy that developed after sepsis-induced hyperthermia in the setting of non-toxic lithium levels. Unique to this case also was the early finding of cerebellar atrophy on MRI 2 weeks after the episode of hyperthermia, long-term neurotoxicity after the novo lithium therapy, and longest follow-up case of chronic cerebellar syndrome after hyperthermia with non-toxic lithium levels.",
"affiliations": "Department of Neurology, Veteran Health Care System, Orlando, FL, 32827, USA. Fabian.Rossi@va.gov.;Department of Neurology, Veteran Health Care System, Orlando, FL, 32827, USA.;Department of Neurology, Veteran Health Care System, Orlando, FL, 32827, USA.;Department of Neurology, Veteran Health Care System, Honolulu, HI, 96701, USA.;Department of Neurology, Veteran Health Care System, Orlando, FL, 32827, USA.;Department of Pharmacy, Veteran Health Care System, Orlando, FL, 32827, USA.;UCF Medical School, Orlando, FL, 32827, USA.;Department of Neurology, Veteran Health Care System, Orlando, FL, 32827, USA.;Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA.;Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA.;Department of Neurology, Veteran Health Care System, St Louis, MO, 63104, USA.",
"authors": "Rossi|Fabian H|FH|;Rossi|Elisa Marie|EM|;Hoffmann|Michael|M|;Liu|Welwin|W|;Cruz|Ramon Rodriguez|RR|;Antonovich|Natasha|N|;Rezaei|Arash|A|;Gonzalez|Elizabeth|E|;Franco|Maria Clara|MC|;Estevez|Alvaro|A|;Thomas|Florian|F|",
"chemical_list": "D018692:Antimanic Agents; D018020:Lithium Compounds",
"country": "United States",
"delete": false,
"doi": "10.1007/s12311-017-0868-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-4222",
"issue": "16(5-6)",
"journal": "Cerebellum (London, England)",
"keywords": "Ataxia; Cerebellar degeneration; Cerebellum; Drug toxicity; Hyperthermia; Intoxication; Lithium; Lithium carbonate; Neuroleptics; Neurological sequel; Neurotoxicity; Serum levels; Therapeutic lithium",
"medline_ta": "Cerebellum",
"mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D001284:Atrophy; D001714:Bipolar Disorder; D002526:Cerebellar Diseases; D002531:Cerebellum; D005334:Fever; D006801:Humans; D018020:Lithium Compounds; D008297:Male",
"nlm_unique_id": "101089443",
"other_id": null,
"pages": "973-978",
"pmc": null,
"pmid": "28593454",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "6625989;18813728;4646505;3431613;19842945;20491363;6123874;6838176;3668585;16806624;7933706;2492186;7998783;10073618;1680244;19393483;2647908;9773090;9020392;17260335;9008777;15282355;6712185;8763043;8604705;1906787;17396741;25511637;21531323;8078888;3568517;11527234;1416324;24730717;4479505;2055063;2024795;25583292",
"title": "Permanent Cerebellar Degeneration After Acute Hyperthermia with Non-toxic Lithium Levels: a Case Report and Review of Literature.",
"title_normalized": "permanent cerebellar degeneration after acute hyperthermia with non toxic lithium levels a case report and review of literature"
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] |
{
"abstract": "A 64-year-old woman was diagnosed with diffuse large B-cell lymphoma (DLBCL) in 2013. After eight courses of R-CHOP therapy followed by local irradiation of the remaining retroperitoneal soft tissue shadow, complete response was confirmed on 18F-2-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Early in 2016, patient's serum LDH and soluble IL-2 receptor levels elevated. With suspected recurrence of DLBCL, FDG-PET/CT was performed that showed no lymphadenopathy or abnormal FDG uptake. By the end of July 2016, the patient developed fever and night sweating. Intravascular large B-cell lymphoma (IVLBCL) was suspected, and the patient underwent random skin biopsies, which revealed large atypical cells infiltrating peripheral and intravascular regions of the subcutaneous adipose tissue. Cell morphology, immunostaining, and PCR analysis of the immunoglobulin heavy chain gene suggested the recurrence of DLBCL. Despite salvage chemotherapy and autologous peripheral stem cell transplantation with high-dose chemotherapy, approximately 15 months later, DLBCL recurred and involved the lungs. The patient again received chemotherapy and achieved a second remission. Because DLBCL may recur like intravascular lymphoma, the same tests used for IVLBCL diagnosis are required in cases of suspected recurrence of DLBCL based on clinical and laboratory findings.",
"affiliations": "Department of Hematology, National Hospital Organization Okayama Medical Center.;Department of Hematology, National Hospital Organization Okayama Medical Center.;Department of Hematology, National Hospital Organization Okayama Medical Center.;Department of Hematology, National Hospital Organization Okayama Medical Center.;Department of Pathology, National Hospital Organization Okayama Medical Center.;Department of Hematology, National Hospital Organization Okayama Medical Center.;Department of Hematology, National Hospital Organization Okayama Medical Center.;Department of Pathology, National Hospital Organization Okayama Medical Center.;Department of Hematology, National Hospital Organization Okayama Medical Center.",
"authors": "Ishikawa|Tatsunori|T|;Fukumi|Takuya|T|;Moriyama|Takashi|T|;Murakami|Hiroyuki|H|;Nagakita|Keina|K|;Yoshioka|Takanori|T|;Makita|Masanori|M|;Shinno|Yoko|Y|;Sunami|Kazutaka|K|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D019788:Fluorodeoxyglucose F18; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.1455",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "60(10)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Diffuse large B-cell lymphoma; Intravascular lymphoma; Recurrence",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D000072078:Positron Emission Tomography Computed Tomography; D049268:Positron-Emission Tomography; D011241:Prednisone; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D019043:Vascular Neoplasms; D014750:Vincristine",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1455-1461",
"pmc": null,
"pmid": "31695007",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diffuse large B-cell lymphoma relapsing with intravascular large B-cell lymphoma-like perivascular and intravascular lesions.",
"title_normalized": "diffuse large b cell lymphoma relapsing with intravascular large b cell lymphoma like perivascular and intravascular lesions"
} | [
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"occurcountry": "JP",
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},
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] |
{
"abstract": "The use of propranolol for the treatment of subglottic haemangioma has become hugely popular due to its effectiveness and safety profile. We report a case of 7-month-old boy who presented with stridor and histopathology suggestive of subglottic haemangioma following microlaryngoscopy and bronchoscopy (MLB). However, he did not respond to propranolol treatment. This could be due to an older age of propranolol commencement. In general, early commencement of propranolol is necessary when diagnosis of symptomatic infantile haemangioma is made to achieve maximal improvement in symptoms and prevent further proliferation. There should be a high index of suspicion for subglottic haemangioma in children presenting with chronic biphasic stridor, with early MLB and diagnosis. This will allow early treatment, giving the best chance to avoid our situation.",
"affiliations": "Nottingham University Hospitals NHS Trust, Nottingham, UK.;Queen's University Belfast, Belfast, UK.;Royal Belfast Hospital for Sick Children, Belfast, UK.;Royal Belfast Hospital for Sick Children, Belfast, UK.",
"authors": "Liu|Zhaobo|Z|http://orcid.org/0000-0001-6886-7274;Yeo|Yen Huan|YH|;Jackson|Conor|C|;Trimble|Keith|K|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "congenital disorders; ear, nose and throat",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists; D006391:Hemangioma; D006801:Humans; D007223:Infant; D007822:Laryngeal Neoplasms; D008297:Male; D011433:Propranolol; D012135:Respiratory Sounds; D017211:Treatment Failure",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31088811",
"pubdate": "2019-05-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27729127;20846505;24641194;11559219;28833230;21569112;18550886;23093810;24495884;22897120;23369213;26884900",
"title": "Treatment failure with propranolol for subglottic haemangioma.",
"title_normalized": "treatment failure with propranolol for subglottic haemangioma"
} | [
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"abstract": "Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease involving thrombosis at the proximal corpus cavernosum. We describe the case of a 39-year-old African American man presenting with right groin pain who was diagnosed with PSTCC. Classic sonographic, computed tomography (CT), and magnetic resonance imaging (MRI) features were present. After conservative treatment with systemic anticoagulation, he had no long-term adverse effects or erectile dysfunction. Although various risk factors for PSTCC have been reported, this is the first documented case associated with recreational use of a phosphodiesterase inhibitor.",
"affiliations": "Brooke Army Medical Center, JBSA Fort Sam Houston, TX, 78234, USA.;Brooke Army Medical Center, JBSA Fort Sam Houston, TX, 78234, USA.;Brooke Army Medical Center, JBSA Fort Sam Houston, TX, 78234, USA.;Brooke Army Medical Center, JBSA Fort Sam Houston, TX, 78234, USA.;Brooke Army Medical Center, JBSA Fort Sam Houston, TX, 78234, USA.",
"authors": "Baaklini|Gina|G|;Reed|Amy|A|;Tafti|Dawood|D|;Henry|Ashley|A|;Stackhouse|Danielle|D|",
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"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(21)00033-4\n10.1016/j.eucr.2021.101593\n101593\nInflammation and Infection\nPartial segmental thrombosis of the corpus cavernosum associated with recreational use of sildenafil\nBaaklini Gina gina.t.baaklini.mil@mail.mil∗ Reed Amy amy.m.reed18.mil@mail.mil Tafti Dawood dawood.a.tafti.mil@mail.mil Henry Ashley ashley.m.henry4.mil@mail.mil Stackhouse Danielle danielle.a.stackhouse.mil@mail.mil Brooke Army Medical Center, JBSA Fort Sam Houston, TX, 78234, USA\n∗ Corresponding author. Urology Clinic, Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr.JBSA Fort Sam Houston, TX, 78234, USA. gina.t.baaklini.mil@mail.mil\n05 2 2021 \n5 2021 \n05 2 2021 \n36 10159321 1 2021 1 2 2021 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease involving thrombosis at the proximal corpus cavernosum. We describe the case of a 39-year-old African American man presenting with right groin pain who was diagnosed with PSTCC. Classic sonographic, computed tomography (CT), and magnetic resonance imaging (MRI) features were present. After conservative treatment with systemic anticoagulation, he had no long-term adverse effects or erectile dysfunction. Although various risk factors for PSTCC have been reported, this is the first documented case associated with recreational use of a phosphodiesterase inhibitor.\n\nKeywords\nPartial segmental thrombosis of the corpus cavernosumPSTCCPartial priapism\n==== Body\nIntroduction\nPartial segmental thrombosis of the corpus cavernosum (PSTCC), also called partial priapism, is a rare condition with fewer than 60 cases reported over the last 40 years.1 Most information regarding imaging findings and treatment relies on case reports. There are several hypothesized risk factors but most cases are idiopathic. Patients have been managed with a variety of diagnostic and treatment modalities; however, the majority of cases can successfully be managed conservatively with good long-term outcomes. We present a case related to recreational use of sildenafil in a healthy 39-year-old African American man managed conservatively. We also demonstrate sonographic, CT, and MRI findings relating to this poorly understood entity in relation to our patient. To the best of our knowledge, this is the first reported case of PSTCC associated with recreational sildenafil use in our review of the literature.\n\nCase description\nA healthy, 39-year-old African American man presented to the Emergency Department with two days of right groin pain that radiated to the perineum. The patient denied history of trauma and reported having normal erections prior to the onset of symptoms. He admitted to intermittently using sildenafil off-label without a diagnosis of erectile dysfunction. The patient's medical history was otherwise unremarkable and he denied taking other medications. On physical examination, there was tenderness and rigidity to his proximal right corpus cavernosum at the base of his penis which extended into the perineum. The distal right corpus cavernosum, left corpus cavernosum, and glans penis were flaccid. The remainder of the examination was unremarkable. The patient was admitted for further evaluation and pain control.\n\nThe proximal right corpus cavernosum was aspirated and negative for abnormal cells and the corporal blood gas was consistent with ischemia. Sickle cell screen and peripheral blood smear were normal. He had an elevated D-dimer (0.72 mcg/mL) and C-reactive protein (10.4 mg/dL). His other laboratory results were unremarkable. Hematology was consulted for a hypercoagulability work-up. Initial contrast-enhanced CT of the pelvis demonstrated a marked edematous appearance of the proximal right corpus cavernosum with fascial enhancement (Fig. 1). A curvilinear focus of hyperattenuation was also noted and likely corresponded to a small region of tunica albuginea enhancement on the ventral right corpus cavernosum (Fig. 1). The left corpus cavernosum demonstrated minimal fascial enhancement without significant edema or enlargement. Penile ultrasound showed asymmetric fullness of the right corpus cavernosum and decreased blood flow (Fig. 2). The left corpus cavernosum was normal in sonographic appearance. MRI of the pelvis displayed a diffusely enlarged appearance of the proximal portion of the right corpus cavernosum with T2-weighted sequence signal hypointensity compared to the left (Fig. 3). The proximal left corpus cavernosum also demonstrated a mild degree of T2 hypointensity possibly secondary to restricted blood flow due to mass effect from right corpus cavernosum edema. The constellation of findings from these three imaging modalities and his physical examination were consistent with PSTCC of the right corpus cavernosum. Hematology recommended treatment with rivaroxaban 15mg twice daily for 21 days followed by 20mg once daily for a total of six months. Two weeks after discharge he reported resolution of pain and his examination showed significantly improved palpable fullness. He had normal erectile function and was no longer using sildenafil. At two months post-discharge, his examination had returned to baseline and at six months post-discharge, he did not have painful erections or erectile dysfunction.Fig. 1 Axial contrast enhanced CT images through the proximal corpora cavernosum. a The right corpus cavernosum demonstrates marked enlargement (black arrowhead). Fascial enhancement is also appreciated (white arrowhead). b Curvilinear enhancement is noted on more caudal slices likely corresponding to focal enhancement of the right corpus cavernosum and ventral tunica albuginea (arrow).\n\nFig. 1Fig. 2 Two ventral and cross sectional still sonographic images from the patient's penile sonographic exam. a Color doppler image shows decreased blood flow of an enlarged right corpus cavernosum. b The right corpus cavernosum is demonstrated to a better extent and demonstrates marked enlargement (arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2Fig. 3 T2 MRI sequences through the level of the corpora cavernosa. a Axial T2/STIR image demonstrated T2 hypointense signal within the proximal corpus cavernosum (arrow). A milder degree of T2 low signal is also appreciated within the proximal left corpus cavernosum (arrowhead). b An axial T2 sequence demonstrates T2 low signal within the right corpus cavernosum (arrowhead). No color is needed for Fig. 1 or Fig. 3. Color is needed for Fig. 2.\n\nFig. 3\n\nDiscussion\nThe pathophysiology of PSTCC is poorly understood. Cases that have been managed surgically report a septum of fibrous connective tissue located at the cruro-cavernosal junction, which may predispose patients to forming PSTCC at this location.2 While the majority of cases appear to be idiopathic, suggested risk factors include bike riding, perineal trauma, vigorous sexual activity, or hematological conditions. While priapism is a known potential complication associated with the use of sildenafil, the overall incidence is quite low. PSTCC has been reported in an older man with the use of prescribed sildenafil.2 To our knowledge, we present the first case of PSTCC associated with recreational use of sildenafil in a male with no documented diagnosis of erectile dysfunction.\n\nThe diagnosis of PSTCC can be made based on physical examination and with the aid of different imaging modalities. On physical examination, there is unilateral tender rigidity of the proximal corpus cavernosum in the setting of distal and contralateral flaccidity. Noninvasive imaging options include ultrasound, CT, and MRI. Ultrasound is readily available and noninvasive but technique can often be operator dependent. Findings can be confirmed with MRI as it can better delineate the segmental thrombosis and may demonstrate a thickened septum within the affected corpus cavernosum.3\n\nSuggested treatment modalities have varied from conservative regimens to surgical intervention. Conservative medical treatment regimens include subcutaneous injections of low molecular weight heparin for at least six weeks with the addition of aspirin 325mg by mouth once daily or non-steroidal anti-inflammatory drugs.3,4 Rivaroxaban for up to six months combined with daily sildenafil, which can also be used to treat stuttering priapism, has also been reported.1 Alternatively, surgical intervention for refractory pain to evacuate the thrombus has been reported after aspiration/injection methods have failed.2 In conjunction with Hematology recommendations, we would recommend a six month course of rivaroxaban to prevent further thrombotic events. There is the added benefit of improved patient compliance and tolerability with oral medications. We also recommend close follow-up with Hematology to ensure a complete hypercoagulability evaluation. To date, there was no reported erectile dysfunction following resolution of the thrombus in our patient.\n\nConclusion\nPartial segmental corpus cavernosum thromboses are typically the result of idiopathic or traumatic etiologies. Recreational use of sildenafil may place men at a higher risk of developing PSTCC and use should be documented in the initial evaluation. Diagnosis can be made with the combination of physical examination, sonography, CT, and MRI. PSTCC can be successfully treated conservatively with systemic anticoagulation with resolution of symptoms within three months.\n\nDeclaration of competing interest\nDisclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government.\"\n==== Refs\nReferences\n1 Christodoulidou M. Parnham A. Ramachandran N. Muneer A. Partial segmental thrombosis of the corpus cavernosum presenting with perineal pain BMJ Case Rep 2016 2016 \n2 Hoyerup P. Azawi N.H. Partial priapism BMJ Case Rep 2013 2013 \n3 Asbach P. Oelrich B. Haase O. Lenk S.V. Loening S.A. Acute partial segmental thrombosis of the corpus cavernosum: imaging findings on ultrasound, computed tomography, and magnetic resonance imaging Clin Imag 32 5 2008 400 402 \n4 Ilicki J. Krauss W. Andersson S.O. Partial segmental thrombosis of the corpus cavernosum: a case report and a review of the literature Urology 79 3 2012 708 712 22386425\n\n",
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{
"abstract": "BACKGROUND\nLeishmaniasis is a parasitic disease caused by different Leishmania species. L. infantum is found in the Mediterranean area. It usually causes visceral or cutaneous leishmaniasis, but rarely mucosal leishmaniasis (ML).\n\n\nMETHODS\nA 62-year-old man with metastatic non-small-cell lung carcinoma visited the outpatient clinic because of a painful and swollen tongue. Initially, oral candidiasis was suspected and patient was unsuccessfully treated accordingly. Subsequently, a biopsy from the tongue was taken.\n\n\nRESULTS\nHistology of the tongue biopsy showed an inflammation with histiocytes and Leishmania amastigotes. Molecular analysis determined these parasites as L. donovani complex. Based on the patient's travel history, ML caused by L. infantum was diagnosed.\n\n\nCONCLUSIONS\nML is an unusual presentation of L. infantum. ML is not only caused by Leishmania species endemic in Latin America, but also should be considered in the differential diagnosis for European patients. A biopsy of the affected location is needed to confirm the diagnosis.",
"affiliations": "Erasmus MC University Medical Center, Department of Medical Microbiology & Infectious Diseases, Rotterdam, the Netherlands. Electronic address: g.chong@erasmusmc.nl.;Franciscus Gasthuis & Vlietland, Department of Medical Microbiology and Infection Control, Rotterdam, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Department of Epidemiology, Utrecht, the Netherlands.;Erasmus MC University Medical Center, Department of Medical Microbiology & Infectious Diseases, Rotterdam, the Netherlands; Erasmus MC University Medical Center, Department of Internal Medicine, Rotterdam, the Netherlands.;Erasmus MC University Medical Center, Department of Medical Microbiology & Infectious Diseases, Rotterdam, the Netherlands.",
"authors": "Chong|Ga-Lai M|GM|;Ong|David Sy|DS|;de Mendonça Melo|Mariana|M|;van Hellemond|Jaap J|JJ|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2021.09.071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "113()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Leishmania infantum; Mucosal leishmaniasis; parasitic disease",
"medline_ta": "Int J Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "109-112",
"pmc": null,
"pmid": "34597767",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Painful and swollen tongue: mucosal leishmaniasis due to Leishmania infantum.",
"title_normalized": "painful and swollen tongue mucosal leishmaniasis due to leishmania infantum"
} | [
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},
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},
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}
],
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},
{
"reactionmeddrapt": "Visceral leishmaniasis",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Off label use",
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"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20180301"
}
},
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},
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},
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}
],
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},
{
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "Chong G-LM, Ong DS, de Mendonca Melo M, van Hellemond JJ. Painful and swollen tongue: mucosal leishmaniasis due to Leishmania infantum. Int-J-Infect-Dis 2021;113:109-112.",
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},
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},
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},
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"drugdosagetext": "40 MILLIGRAM, DAILY",
"drugenddate": null,
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"drugindication": "Toxic skin eruption",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "PREDNISOLONE"
},
{
"actiondrug": "5",
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"activesubstancename": "CARBOPLATIN"
},
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"drugindication": "Non-small cell lung cancer metastatic",
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"medicinalproduct": "CARBOPLATIN"
},
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"actiondrug": "5",
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"activesubstancename": "NIVOLUMAB"
},
"drugadditional": "3",
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"drugdosagetext": "UNK",
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"drugindication": "Non-small cell lung cancer metastatic",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "NIVOLUMAB"
}
],
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"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Mucocutaneous leishmaniasis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Chong G-LM, Ong DS, de Mendonca Melo M, van Hellemond JJ. Painful and swollen tongue: mucosal leishmaniasis due to Leishmania infantum. Int J Infect Dis. 2021;113:109-112",
"literaturereference_normalized": "painful and swollen tongue mucosal leishmaniasis due to leishmania infantum",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20211226",
"receivedate": "20211208",
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},
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"safetyreportversion": 3,
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"sendertype": "2"
},
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}
] |
{
"abstract": "BACKGROUND\nElderly patients are particularly vulnerable to adverse drug reactions as a result of polypharmacy and metabolic changes associated with aging. We present a case of leukocytoclastic vasculitis induced by olanzapine, a medication commonly used in elderly patients.\n\n\nMETHODS\nAn 82-year-old woman was admitted to the extended-care center for short-term rehabilitation after prolonged hospitalization for a pulmonary embolism requiring mechanical ventilation. The pulmonary problem resolved, but her hospitalization and subsequent rehabilitation were complicated by agitated delirium, which was treated with olanzapine and modification of contributory factors. At the time of admission to the rehabilitation facility, the patient had been receiving warfarin for 2 weeks and olanzapine for 6 days. On the eighth day after initiation of olanzapine, erythematous skin lesions developed on dependent areas. The international normalized ratio for warfarin was within the acceptable range; however, because warfarin has been associated with subcutaneous bleeding presenting as petechiae and ecchymosis, subcutaneous enoxaparin was substituted for warfarin. The skin lesions continued to worsen over the next week and developed into palpable lesions. Biopsy of the rash revealed leukocytoclastic vasculitis. In the absence of another cause, olanzapine was discontinued and the rash improved significantly. When the agitation recurred, risperidone was initiated, but the patient experienced dizziness with this agent. Olanzapine was resumed and the skin lesions recurred. Olanzapine was then changed to quetiapine, and the skin lesions improved over the next few weeks.\n\n\nCONCLUSIONS\nOlanzapine is commonly used in elderly patients to control behavioral disturbances associated with dementia, delirium, and other psychiatric disorders. Leukocytoclastic vasculitis is an infrequently reported adverse drug reaction with olanzapine. Its exact pathogenic mechanism is unknown, but both cell-mediated and humoral immunity appear to play important roles. Because drug-induced vasculitis has an identical clinical presentation and identical serologic/pathologic parameters to idiopathic forms of vasculitis, a high index of suspicion is necessary for its accurate diagnosis.\n\n\nCONCLUSIONS\nBecause adverse drug reactions are common in elderly patients taking multiple medications, physicians should be vigilant when starting new medications and should attempt to eliminate unnecessary medications. Clinicians should be aware of the potential for leukocytoclastic vasculitis in association with olanzapine.",
"affiliations": "Department of Geriatric Medicine, Wills Memorial Hospital, Washington, Georgia 30673, USA. mkduggal@nu-z.net",
"authors": "Duggal|Mahesh K|MK|;Singh|Amritpal|A|;Arunabh|||;Lolis|James D|JD|;Guzik|Howard J|HJ|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjopharm.2005.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-7761",
"issue": "3(1)",
"journal": "The American journal of geriatric pharmacotherapy",
"keywords": null,
"medline_ta": "Am J Geriatr Pharmacother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003693:Delirium; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D000077152:Olanzapine; D011655:Pulmonary Embolism; D012121:Respiration, Artificial; D012867:Skin; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "101190325",
"other_id": null,
"pages": "21-4",
"pmc": null,
"pmid": "16089244",
"pubdate": "2005-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olanzapine-induced vasculitis.",
"title_normalized": "olanzapine induced vasculitis"
} | [
{
"companynumb": "US-APOTEX-2019AP010739",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
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"medicinalproduct": "OLANZAPINE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
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"medicinalproduct": "OLANZAPINE."
},
{
"actiondrug": "1",
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},
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"drugindication": "PULMONARY EMBOLISM",
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"medicinalproduct": "WARFARIN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
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"drugcharacterization": "1",
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"drugindication": "AGITATION",
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"medicinalproduct": "RISPERIDONE."
},
{
"actiondrug": "1",
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"activesubstancename": "OLANZAPINE"
},
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"drugadministrationroute": null,
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"drugenddateformat": null,
"drugindication": "ABNORMAL BEHAVIOUR",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "1",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OLANZAPINE."
}
],
"patientagegroup": null,
"patientonsetage": "82",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypersensitivity vasculitis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DUGGAL M.K, SINGH A, ARUNABH, LOLIS J.D, GUZIK H.J.. OLANZAPINE-INDUCED VASCULITIS?DOI:10.1016/J.AMJOPHARMA.2005.03.003. AMERICAN JOURNAL GERIATRIC PHARMACOTHERAPY. 2005?3 (1):21-23",
"literaturereference_normalized": "olanzapine induced vasculitis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190404",
"receivedate": "20190404",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16158488,
"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\nExtravasation of intravenously infused vesicant solutions is a common problem in medical practice, which can lead to severe and progressive tissue dysfunction, ranging from persistent tissue oedema and fibrosis to delayed tissue necrosis. Acyclovir is a known vesicant medication administrated in paediatric patients, which appears to irritate venous and soft tissue if extravasated.\n\n\nMETHODS\nWe present the first case involving the extravasation of intravenously infused acyclovir in a female adolescent patient, which caused tissue necrosis and left behind a residual scar lesion. Nursing and medical staff should be aware of the potential dermatological side effects of intravenously infused acyclovir and other medications, even a long time after infusion, and the possible lack of initial local symptoms and signs.\n\n\nCONCLUSIONS\nEarly recognition of extravasation and prompt management are critical in preventing further morbidity, and optimizing outcomes.",
"affiliations": "Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece. xneoc@yahoo.gr.;Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece.;Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece.;Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece.;Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece.;Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece.;Department of Medical Pediatrics, Thriasio General Hospital, Athens, Greece.",
"authors": "Neocleous|Charalambos|C|;Andonopoulou|Eleni|E|;Adramerina|Alkistis|A|;Pegkou|Antigoni|A|;Savelieva|Olga|O|;Georgiadou|Petroula|P|;Drikos|Ioannis|I|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Bosnia and Herzegovina",
"delete": false,
"doi": "10.5644/ama2006-124.187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1840-1848",
"issue": "46(1)",
"journal": "Acta medica academica",
"keywords": "Acyclovir; Extravasation; Tissue necrosis",
"medline_ta": "Acta Med Acad",
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{
"abstract": "OBJECTIVE; To analyze the access and utilization profile of biological medications for psoriasis provided by the judicial system in Brazil.\n\n\nMETHODS\nThis is a cross-sectional study. We interviewed a total of 203 patients with psoriasis who were on biological medications obtained by the judicial system of the State of Sao Paulo, from 2004 to 2010. Sociodemographics, medical, and political-administrative characteristics were complemented with data obtained from dispensation orders that included biological medications to treat psoriasis and the legal actions involved. The data was analyzed using an electronic data base and shown as simple variable frequencies. The prescriptions contained in the lawsuits were analyzed according to legal provisions.\n\n\nRESULTS\nA total of 190 lawsuits requesting several biological drugs (adalimumab, efalizumab, etanercept, and infliximab) were analyzed. Patients obtained these medications as a result of injunctions (59.5%) or without having ever demanded biological medication from any health institution (86.2%), i.e., public or private health services. They used the prerogative of free legal aid (72.6%), even though they were represented by private lawyers (91.1%) and treated in private facilities (69.5%). Most of the patients used a biological medication for more than 13 months (66.0%), and some patients were undergoing treatment with this medication when interviewed (44.9%). Approximately one third of the patients discontinued treatment due to worsening of their illness (26.6%), adverse drug reactions (20.5%), lack of efficacy, or because the doctor discontinued this medication (13.8%). None of the analyzed medical prescriptions matched the legal prescribing requirements. Clinical monitoring results showed that 70.3% of the patients had not undergone laboratory examinations (blood work, liver and kidney function tests) for treatment control purposes.\n\n\nCONCLUSIONS\nThe plaintiffs resorted to legal action to get access to biological medications because they were either unaware or had difficulty in accessing them through institutional public health system procedures. Access by means of legal action facilitated long-term use of this type of medication through irregular prescriptions and led to a high rate of adverse drug reactions as well as inappropriate clinical monitoring.",
"affiliations": "Universidade de Sorocaba, Sorocaba, SP, Brasil.;Universidade de Sorocaba, Sorocaba, SP, Brasil.;Universidade de Sorocaba, Sorocaba, SP, Brasil.;Universidade de Sorocaba, Sorocaba, SP, Brasil.;Universidade de Sorocaba, Sorocaba, SP, Brasil.;Núcleo de Assistência Farmacêutica, Escola Nacional de Saúde Pública Sérgio Arouca, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.",
"authors": "Lopes|Luciane Cruz|LC|;Silveira|Miriam Sanches do Nascimento|MS|;Camargo|Iara Alves de|IA|;Barberato-Filho|Silvio|S|;Del Fiol|Fernando de Sá|Fde S|;Osorio-de-Castro|Claudia Garcia Serpa|CG|",
"chemical_list": "D000911:Antibodies, Monoclonal",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nRev Saude PublicaRev Saude PublicaRevista de Saúde Pública0034-89101518-8787Faculdade de Saúde Pública da Universidade de São Paulo 2521082410.1590/S0034-8910.2014048005109Public Health Practice Original ArticlesBiological drugs for the treatment of psoriasis in a public health system Medicamentos biológicos para o tratamento de psoríase em sistema público de saúde Lopes Luciane Cruz \nI\nSilveira Miriam Sanches do Nascimento \nI\nde Camargo Iara Alves \nI\n\nII\nBarberato Silvio Filho\nI\nDel Fiol Fernando de Sá \nI\nOsorio-de-Castro Claudia Garcia Serpa \nIII\nI Universidade de Sorocaba, Sorocaba, SP, Brasil, Programa de Pós-Graduação em Ciências Farmacêuticas. Universidade de Sorocaba. Sorocaba, SP, BrasilII Secretaria Estadual de Saúde de São Paulo, São Paulo, SP, Brasil, Coordenação das Demandas Estratégicas do Sistema Único de Saúde. Secretaria Estadual de Saúde de São Paulo. São Paulo, SP, BrasilIII Núcleo de Assistência Farmacêutica, Escola Nacional de Saúde Pública Sérgio Arouca, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil, Núcleo de Assistência Farmacêutica. Escola Nacional de Saúde Pública Sérgio Arouca. Fundação Oswaldo Cruz. Rio de Janeiro, RJ, Brasil Correspondence: Luciane Cruz Lopes. Rua Gomes Carneiro, 570 apto 141. 13400-530 Piracicaba, SP, Brasil. E-Mail: luciane.lopes@prof.uniso.br8 2014 48 4 651 661 27 8 2013 7 4 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.OBJECTIVE\n To analyze the access and utilization profile of biological medications for psoriasis provided by the judicial system in Brazil.\n\nMETHODS\nThis is a cross-sectional study. We interviewed a total of 203 patients with psoriasis who were on biological medications obtained by the judicial system of the State of Sao Paulo, from 2004 to 2010. Sociodemographics, medical, and political-administrative characteristics were complemented with data obtained from dispensation orders that included biological medications to treat psoriasis and the legal actions involved. The data was analyzed using an electronic data base and shown as simple variable frequencies. The prescriptions contained in the lawsuits were analyzed according to legal provisions.\n\nRESULTS\n A total of 190 lawsuits requesting several biological drugs (adalimumab, efalizumab, etanercept, and infliximab) were analyzed. Patients obtained these medications as a result of injunctions (59.5%) or without having ever demanded biological medication from any health institution (86.2%), i.e., public or private health services. They used the prerogative of free legal aid (72.6%), even though they were represented by private lawyers (91.1%) and treated in private facilities (69.5%). Most of the patients used a biological medication for more than 13 months (66.0%), and some patients were undergoing treatment with this medication when interviewed (44.9%). Approximately one third of the patients discontinued treatment due to worsening of their illness (26.6%), adverse drug reactions (20.5%), lack of efficacy, or because the doctor discontinued this medication (13.8%). None of the analyzed medical prescriptions matched the legal prescribing requirements. Clinical monitoring results showed that 70.3% of the patients had not undergone laboratory examinations (blood work, liver and kidney function tests) for treatment control purposes.\n\nCONCLUSIONS\n The plaintiffs resorted to legal action to get access to biological medications because they were either unaware or had difficulty in accessing them through institutional public health system procedures. Access by means of legal action facilitated long-term use of this type of medication through irregular prescriptions and led to a high rate of adverse drug reactions as well as inappropriate clinical monitoring.\n\nOBJETIVO\n Analisar o acesso e o perfil de utilização, por via judicial, de medicamentos biológicos para o tratamento de psoríase.\n\nMÉTODOS\n Estudo transversal descritivo. Foram entrevistados 203 pacientes com psoríase que demandaram medicamentos biológicos, por via judicial, ao Estado de São Paulo, entre 2004 e 2010. Informações sobre características sociodemográficas, médico-sanitárias e político-administrativas foram complementadas com dados obtidos das respectivas ordens de dispensação quanto a medicamento biológico para tratamento de psoríase e autos correspondentes. Os dados foram analisados em banco eletrônico e as variáveis sumarizadas por frequência simples. As prescrições contidas nos processos foram analisadas quanto aos preceitos legais contidos na lei.\n\nRESULTADOS\n Foram analisados 190 autos referentes aos medicamentos biológicos: adalimumabe, efalizumabe, etanercepte e infliximabe. Os proponentes obtiveram o medicamento por mandado de segurança (59,5%), sem nunca ter solicitado o medicamento biológico para outra instituição (86,2%), por sistema de saúde público ou privado. Utilizaram-se da prerrogativa de gratuidade de justiça (72,6%), embora fossem representados por advogado particular (91,1%) e atendidos em consultórios médicos privados (69,5%). Utilizaram o medicamento biológico por período > 13 meses (66,0%) e 44,9% faziam uso do medicamento no momento da entrevista. Quase um terço daqueles que deixaram de usar os medicamentos abandonou o tratamento por piora do quadro (26,6%), efeitos adversos (20,5%), falta de eficácia ou suspensão pelo médico (13,8%). Nenhuma prescrição médica atendeu aos preceitos legais; 70,3% dos pacientes não haviam realizado exames laboratoriais (hemograma, função hepática e renal) para controle do tratamento.\n\nCONCLUSÕES\n Os demandantes recorreram à via judicial para obtenção de medicamentos biológicos por desconhecimento ou por dificuldades de acesso pelas vias institucionais do sistema público de saúde O acesso facilitado pela via judicial favorece o uso do medicamento por tempo prolongado por meio de prescrições não conformes, frequência elevada de efeitos adversos e monitoramento clínico inadequado.\n\nPsoriasisAntibodiesMonoclonaltherapeutic usePharmaceutical ServiceslegislationjurisprudenceJudicial DecisionsEquity in Access.Fundação de Amparo à Pesquisa do Estado de São Paulo2009/53084-1This study was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP – Process 2009/53084-1).\n==== Body\nINTRODUCTION\nPsoriasis (PSO) is a recurrent, inflammatory, genetic, and chronic disease characterized by epidermal proliferation and inflammation. This disease causes scaly and erythematous lesions that target the skin, nails, and joints. The prevalence rates vary between 0.6% and 4.8% and equally affect men and women of all races.\na\n\n\n\nDespite showing benign progression, worsening of the conditions causes significant physical and psychological morbidity and has a major impact on the patient’s quality of life. The treatment is based on the criteria of the Psoriasis Area Severity Index (PASI) and in the impact on the quality of life with respect to disease remission or increase in the period free of skin lesions.\nb\n\n\n\nAccording to the national therapeutic guidelines\nc\n and international guidelines, the treatment of moderate to severe PSO should begin with phototherapy.\n16\n\n,\n\na\n\n,\n\nb\n In case of failure, treatment should be continued with systemic medications (e.g., methotrexate, acitretin, and cyclosporine) before proceeding with the biological medications (e.g., etanercept, infliximab, and adalimumab). The Protocolo Clínico e Diretrizes Terapêuticas (PCDT – Clinical Protocol and Therapeutic Guidelines) for the treatment of PSO in the Public Health System (SUS) was published in 2013.\nd\n The treatment excludes biological medications and follow-up includes clinical monitoring of the evolution of disease and analysis of adverse drug reactions.\n\nThe access to biological medicines is achieved through the judicial system or via administrative means, which makes it difficult to plan and manage the expenses involved.\n2\n\n,\n\n6\n\n,\n\n16\n The latter is implemented by some health departments to request medications that are not available at SUS but both generate a conflict regarding the principle of comprehensiveness proposed by SUS.\n\nThe process that plaintiffs undergo to obtain access to biological medications is challenging, and the data pertaining to drug use, prescription, and effects (results and safety) are scarcely available. In addition, the documentation regarding the judicialization process is rarely disclosed in this type of study. Therefore, the purpose of our study was to analyze the access and utilization profile, obtained by judicial means, of biological medications for the treatment of PSO in Brazil.\n\nMETHODS\nWe performed a descriptive cross-sectional study with patients with PSO who were either undergoing treatment or had been treated with biological medications by means of judicial actions against the state of Sao Paulo between 2004 and 2010.\n\nThe dispensation orders (DO) containing the biological medication to be supplied per patient with PSO (International Classification of Diseases – ICD-L40), which was made available by the court control system of the Sao Paulo State Health Department (SCJ/SES-SP), provided an estimate of the population under treatment in the referred period. The following variables were collected: contested medication, author and type of action, and sociodemographic characteristics of the plaintiff and prescriber.\n\nAfter locating corresponding records, we analyzed the documents presented to the court with information regarding the medical report, prescription, legal representation, type of injunction, appointed justice system, defendant, civil or district court, and the origin of prescription.\n\nPatients who had retrieved and used biological medication during our study period and were willing to participate were included. They were found through injunctions filed against the state government, with a judicial decision in favor of the authors in any instance that were submitted to 14 public circuit courts of the capital of the State of Sao Paulo. We excluded patients who provided their contact as their lawyer’s office number, those who were not located after five attempts, and deceased patients.\n\nTelephone contact was elected because it is effective and inexpensive.\n10\n All interviews were performed using the computer-assisted telephone interviewing technique, with the use of a microcomputer coupled to a telephone device with a headset; specific management and recording software were connected simultaneously. This apparatus allows monitoring interviews, avoiding inconsistencies in the questionnaire and developing features related with research management such as automatic control of follow-up calls, control of time per interview/interviewer, remote listening system, and real time control.\n\nWe developed a Microsoft Office Access® electronic form, based on the instrument used for the interviews with 16 screens to record the data. The language of the questionnaire was adapted for a telephone conversation. The team of interviewers was previously trained to standardize language and interview time.\n\nThe questionnaire included the following information: patient, type of medical assistance, access to medication for the treatment of PSO before the injunction, participation in a support group, meetings with the lawyer, contact with the pharmaceutical manufacturer, evolution of the disease, and use of medicine (time involved in diagnosis and treatment), provided pharmacotherapy follow-up, and suspected adverse drug reactions. This instrument\ne\n was previously validated by rheumatology and public health experts. The SCJ/SES-SP data, regarding injunctions and interviews, were organized in an electronic spreadsheet. The data was analyzed with the 2013 version of Excel® software, and the results were shown as simple variable frequencies. The quality control of data collection was achieved by periodic crosschecking of information, which was performed by one of the researchers who was not part of the on-the-spot data collection.\n\nThe prescriptions involved in the proceedings were analyzed in terms of legal provisions of the Law 5.991/1973.\nf\n\n\n\nData collection was authorized by the Health Department of Sao Paulo State. This study was approved by the Research Ethics Committee of the University of Sorocaba (Protocol 011/2009 of August 17, 2009), according to Resolution 196/96 of the National Health Council. All participants signed the informed consent form.\n\nRESULTS\nA total of 25,184 DO were analyzed regarding the lawsuits filed to obtain medication and other health products between 2004 and 2010. Of 218 identified patients, 11 did not meet the inclusion criterion and 4 were excluded. Of 203 interviewed plaintiffs, 190 processes were located (Figure).\n\n\nFigure Flowchart of the phases of sample composition. State of Sao Paulo, 2004-2010.\n\n\n\nAdalimumab, etanercept, infliximab, and efalizumab were part of these DO. The sociodemographic characteristics and the process toward access to a biological medicine are described in Table 1. A total of 44.9% patients used a biological medicine, of which 89.7% never requested the medicine to SUS before filing a lawsuit. Patients with access to private medical care (69.5%) were assisted by SUS (3.5%). Among SUS patients (30.5%), 12.9% were treated at University Hospitals (Hospital São Paulo, Puccamp, HU-USP, ABC Santo André University and Unicamp) (Table 1).\n\n\nTable 1 Sociodemographic characteristics and ways used to gain access to biological medicines to treat PSO by the authors of injunction filed against the state of Sao Paulo, 2004-2010.\nVariable\tAdalimumab\tEfalizumab\tEtanercept\tInfliximab\tTotal\t\n%\tn\t%\tn\t%\tn\t%\tn\t%\tn\t\n \t6.8\t14\t21.2\t43\t17.3\t35\t54.7\t111\t100.0\t203\t\nGender\t\n Male\t64.3\t9\t60.5\t26\t60.0\t21\t65.8\t73\t63.6\t129\t\n Female\t35.7\t5\t38.6\t17\t40.0\t14\t34.2\t38\t36.4\t74\t\nCity\t \t \t \t \t \t \t \t \t \t \t\n Sao Paulo\t85.7\t12\t46.5\t20\t71.4\t25\t58.6\t65\t60.1\t122\t\n Other locations\t14.3\t2\t53.5\t23\t26.6\t10\t41.4\t46\t39.9\t81\t\nAge (years)\t \t \t \t \t \t \t \t \t \t \t\n 19 to 59\t57.1\t8\t81.4\t35\t74.3\t26\t78.4\t87\t76.8\t156\t\n ≥ 60\t42.9\t6\t18.6\t8\t25.7\t9\t21.6\t24\t23.2\t47\t\nType of medical assistance\t\n Non-SUS\t92.9\t13\t62.8\t27\t65.7\t23\t70.3\t78\t69.5\t141\t\n SUS\t7.1\t1\t37.2\t16\t34.3\t12\t29.7\t33\t30.5\t62\t\nRegistered at CEAF\t \t \t \t \t \t \t \t \t \t \t\n Information provided by the patient (Yes)\t42.9\t6\t65.1\t28\t40.0\t14\t51.4\t57\t51.7\t105\t\n Information confirmed in the system (Yes)\t71.4\t10\t0.0\t0\t34.3\t12\t4.5\t5\t13.3\t27\t\n Patient was being treated by a biological medicine\na\n\n\t50.0\t7\t0.0\t0\t25.7\t9\t0.9\t1\t8.4\t17\t\nGuidance to obtain a biological medicine via lawsuit\t\n Doctor\t71.4\t10\t79.1\t34\t80.0\t28\t72.1\t80\t74.9\t152\t\n NGO, Family, and others\t14.3\t2\t11.6\t5\t34.3\t12\t37.0\t41\t6.9\t60\t\n Lawyer\t0.0\t0\t4.7\t2\t0.0\t0\t2.7\t3\t2.5\t5\t\n Pharmaceutical Laboratory\t7.1\t1\t4.7\t2\t0.0\t0\t1.8\t2\t2.5\t5\t\n NI\t7.1\t1\t0.0\t0\t0.0\t0\t0.9\t1\t1.0\t2\t\nUse of biological medicine before lawsuit\t \t \t \t \t \t \t \t \t \t \t\n Yes\t92.9\t13\t93.0\t40\t65.7\t23\t95.5\t106\t89.7\t182\t\n NI\t0.0\t0\t0.0\t0\t0.0\t0\t3.6\t4\t2.0\t4\t\nForm of acquisition of medicine beforelawsuit\t\n Pharmaceutical laboratory\t7.1\t1\t6.8\t3\t14.3\t5\t0.0\t0\t4.4\t9\t\n Other (city hall, State, NGO)\t0.0\t0\t0.0\t0\t8.6\t3\t0.9\t1\t2.0\t4\t\n Supplied by doctor\t0.0\t0\t0.0\t0\t5.7\t2\t0.0\t0\t1.0\t2\t\n Own resources\t0.0\t0\t0.0\t0\t2.9\t1\t0.0\t0\t0.5\t1\t\n NI\t0.0\t0\t0.0\t0\t2.9\t1\t0.0\t0\t0.5\t1\t\nRequest of medication for an institutionb before filing the lawsuit\t\n No\t92.9\t13\t95.3\t41\t77.1\t27\t84.7\t94\t86.2\t175\t\n NI\t0.0\t0\t0.0\t0\t0.0\t2\t1.8\t2\t2.0\t4\t\nInstitution activated for provision of medicine before lawsuit\t\n Privatec\n\t0.0\t0\t0.0\t0\t5.7\t2\t9.0\t10\t5.9\t12\t\n Public\t7.1\t1\t2.3\t1\t17.1\t6\t2.7\t3\t5.4\t11\t\n NGO\t0.0\t0\t2.3\t1\t0.0\t0\t0.0\t0\t1.5\t1\t\nRequest fulfilled\t \t \t \t \t \t \t \t \t \t \t\n Yes\t7.1\t1\t0.0\t0\t2.9\t1\t1.8\t2\t1.5\t3\t\nSupply of biological medication by another institution (time in months)\t\n < 6\t0.0\t0\t0.0\t0\t0.0\t0\t1.8\t2\t0.5\t2\t\n > 6\t7.1\t1\t0.0\t0\t2.9\t1\t0.0\t0\t0.5\t1\t\nParticipation in a support group for patients\t\n Yes\t14.3\t2\t11.6\t5\t17.1\t6\t9.0\t10\t11.3\t23\t\nNumber of meetings with the lawyer\t\n None\t64.3\t9\t58.1\t25\t62.9\t22\t62.2\t69\t61.6\t125\t\n One or more\t35.7\t5\t34.9\t15\t34.3\t12\t37.9\t42\t36.5\t74\t\n NI\t0.0\t0\t7.0\t3\t2.9\t1\t0.9\t0\t2.5\t4\t\nContacted by the pharmaceutical laboratory\t\n Yes\t64.3\t9\t62.8\t27\t62.9\t22\t37.9\t42\t49.3\t100\t\nNI: not informed; SUS: Public Health System; NGO: Non-governmental organizations; CEAF: Specialized Pharmaceutical Care Program\n\n\na Patients who were receiving a biological medicine because they were registered at CEAF.\n\n\nb Any public or private institution (City hall, NGO, laboratory, and others).\n\n\nc Laboratory, private hospitals.\n\n\n\n\nAll patients treated with efalizumab (banned in Brazil since 2009) (n = 43) were not taking this medicine any longer when interviewed. Approximately 20.5% of the patients discontinued the use of biological medicines due to suspicion of adverse drug reactions which was confirmed by doctors. Adverse drug reactions included local reactions (70.0%), hospitalization after use of medicine, cardiovascular events (arrhythmia and high blood pressure), liver disease, blood dyscrasia, pneumonia, and kidney injury. The majority of patients discontinued using the biological medicine due to dropout (26.6%) or suspension by the physician (13.8%), which was caused by their worsening condition or lack of efficacy of medication (Table 2).\n\n\nTable 2 Features of the pharmacotherapy follow-up provided to the plaintiff. Sao Paulo, SP, Southeastern Brazil, 2004-2010.\nVariable\tAdalimumab\tEfalizumab\tEtanercept\tInfliximab\tTotal\t\n%\tn\t%\tn\t%\tn\t%\tn\t%\tn\t\n \t6.8\t14\t21.2\t43\t17.3\t35\t54.7\t111\t100.0\t203\t\nDiagnosis time\t\n ≥ 6 years\t85.7\t12\t90.7\t39\t85.7\t30\t86.5\t96\t87.2\t177\t\n 2 to 5 years\t14.3\t2\t9.3\t4\t14.3\t5\t12.6\t14\t12.3\t25\t\n Up till 6 months\t0.0\t0\t0.0\t0\t0.0\t0\t0.9\t1\t0.5\t1\t\nConcurrent disease\t\n Yes\t50.0\t7\t51.1\t22\t37.1\t13\t29.8\t33\t37.0\t75\t\nTreatment time with biological medicine (months)\t\n Up to 12\t35.7\t5\t51.2\t22\t22.9\t8\t30.6\t34\t34.0\t69\t\n 13 to 48\t35.7\t5\t48.9\t21\t74.3\t26\t66.7\t74\t62.0\t126\t\n 49 to 72\t28.6\t4\t0.0\t0\t2.9\t1\t2.7\t3\t4.0\t8\t\n Average (SD)\t31.4 (22.2)\t16.8 (10.2)\t26.4 (14.4)\t25.2 (14.6)\t24.0 (14.9)\t\nPatient was using obtained biological medicine\t\n Yes\t64.3\t9\t0.0\t0\t62.9\t22\t54.0\t60\t44.9\t91\t\nClinical monitoringa\n\t\n Medical visit\t100.0\t9\t0.0\t0\t100.0\t22\t100.0\t60\t100.0\t91\t\n Laboratory exams\t55.5\t5\t0.0\t0\t68.2\t15\t73.3\t44\t70.3\t64\t\nReasons to discontinue the use of biological medicine\t\n Stopped usingb\n\t0.0\t0\t100\t43\t5.7\t2\t8.1\t9\t26.6\t54\t\n Suspension by the doctor\t14.3\t2\t0.0\t0\t22.9\t8\t16.2\t18\t13.8\t28\t\n Suspicion of ADR\t21.4\t3\t0.0\t0\t5.7\t2\t16.2\t18\t11.3\t23\t\n Suspended by a court decision\t0.0\t0\t0.0\t0\t2.9\t1\t6.4\t6\t34.5\t7\t\nPerception of the efficacy of the biological medicine\t\n Yes\t71.4\t10\t76.2\t32\t91.4\t32\t82.0\t91\t81.3\t165\t\n No\t28.6\t4\t21.0\t9\t8.6\t3\t17.1\t19\t17.2\t35\t\n NI\t0.0\t0\t4.7\t2\t0.0\t0\t0.9\t1\t2.7\t3\t\nPerception of the evolution of the disease with the use of biological medicines\t\n Improved/Cured\t57.1\t8\t60.5\t26\t71.4\t25\t67.6\t75\t66.0\t134\t\n Stationary\t28.6\t4\t23.3\t10\t20.0\t7\t21.7\t24\t22.2\t45\t\n Worsened\t14.3\t2\t11.7\t5\t2.9\t1\t10.9\t12\t9.9\t20\t\n NI\t0.0\t0\t4.7\t2\t5.7\t2\t0.0\t0\t2.0\t4\t\nNI: not informed; ADR: adverse drug reactions, SD: standard deviation\n\n\na According to recommendations of therapeutic guidelines.\n\n\nb Other reasons.\n\n\n\n\nThe highest request rate was for infliximab (57.4%), followed by efalizumab (21.6%), etanercept (16.3%), and adalimumab (4.7%). The Associação dos Portadores de Vitiligo e Psoríase do Estado de São Paulo (APVPESP – Association of Vitilligo and Psoriasis Patients of Sao Paulo State) provided legal representation to 12.6% patients (Table 3).\n\n\nTable 3 Technical characteristics of injunctions filed against the state of Sao Paulo, 2004-2010.\nVariable\tAdalimumab\tEfalizumab\tEtanercept\tInfliximab\tTotal\t\n%\tn\t%\tn\t%\tn\t%\tn\t%\tn\t\n \t4.7\t9\t21.6\t41\t16.3\t31\t57.4\t109\t100.0\t190\t\nNumber of authors per injunction\t\n 1\t11.1\t1\t95.1\t39\t93.5\t29\t100.0\t109\t93.7\t178\t\n 2 to 6\t88.9\t8\t4.9\t2\t6.5\t2\t0.0\t0\t6.3\t12\t\nType of injunction\t\n CI\t88.9\t8\t48.8\t20\t58.1\t18\t61.5\t67\t59.5\t113\t\n RO\t11.1\t1\t51.2\t21\t41.9\t13\t37.5\t41\t40.0\t76\t\n Public Defender\t0.0\t0\t0.0\t0\t0.0\t0\t0.9\t1\t0.5\t1\t\nCivil Society Representation\t\n No\t100.0\t9\t51.2\t21\t96.8\t30\t92.7\t101\t84.7\t161\t\n Yes\t0.0\t0\t48.8\t20\t3.2\t1\t7.3\t8\t15.3\t29\t\nDefendant\t\n State\t88.9\t8\t100.0\t41\t100.0\t31\t100.0\t109\t99.5\t189\t\n Union\t11.1\t1\t0.0\t0\t0.0\t0\t0.0\t0\t0.5\t1\t\nJudicial Representation\t\n Private\t100.0\t9\t48.8\t20\t96.8\t30\t92.7\t101\t84.2\t160\t\n APVPESP\t0.0\t0\t48.8\t20\t3.4\t1\t2.8\t3\t12.6\t24\t\n MP\t0.0\t0\t2.4\t1\t0.0\t0\t1.8\t2\t1.6\t3\t\n PD\t0.0\t0\t0.0\t0\t0.0\t0\t2.8\t3\t1.6\t3\t\nFree Legal Aid\t\n Yes\t56.6\t5\t75.6\t31\t64.5\t20\t75.2\t82\t72.6\t138\t\n No\t11.1\t1\t12.2\t5\t9.7\t3\t16.5\t18\t14.2\t27\t\n NI\t33.3\t3\t12.2\t5\t25.8\t8\t8.3\t9\t13.2\t25\t\nPrimary injunction\t\n Yes\t88.9\t8\t53.7\t22\t61.3\t19\t56.0\t61\t57.9\t110\t\n No\t11.1\t1\t31.7\t13\t25.8\t8\t24.4\t32\t28.4\t54\t\n NI\t0.0\t0\t14.6\t6\t12.9\t4\t14.7\t16\t13.7\t26\t\nDistrict injunction /Civil injunction of Sao Paulo/Osasco\t\n 1 to 5\t55.6\t5\t43.9\t18\t35.5\t11\t30.3\t33\t35.3\t67\t\n 6 to 10\t44.4\t4\t29.3\t12\t41.9\t13\t46.8\t51\t42.1\t80\t\n 11 to 14\t0.0\t0\t26.8\t11\t22.6\t7\t21.1\t23\t21.6\t41\t\n Osasco (1 to 2)\t0.0\t0\t0.0\t0\t0.0\t0\t1.8\t2\t1.1\t2\t\nLegal representation of author(s) – OAB\t\n A\t88.9\t8\t48.8\t20\t0.0\t0\t55.0\t60\t46.3\t88\t\n B\t11.1\t1\t4.9\t2\t35.5\t11\t25.7\t28\t22.1\t42\t\n C\t0.0\t0\t39.0\t16\t22.6\t7\t4.6\t5\t14.7\t28\t\n D\t0.0\t0\t2.4\t1\t41.9\t13\t11.9\t13\t14.2\t27\t\n PD\t0.0\t0\t2.4\t1\t0.0\t0\t2.8\t3\t2.1\t4\t\n NI\t0.0\t0\t2.4\t1\t0.0\t0\t0.0\t0\t0.5\t1\t\nCI: court injunction; RO: ordinary proceedings; PD: Public Defender; MP: Public Prosecutor’s Office or Public Ministry; APVPESP: Association of Vitilligo and Psoriasis of the state of Sao Paulo; NI: not informed; OAB: Brazilian Bar Association; A: three lawyers had between 21 and 35 representations; B: four lawyers had between 10 and 13 representations; C: 12 lawyers had between two and seven representations; D: 22 lawyers had at least one representation per medicine\n\n\n\n\nOf the 42 lawyers that represented the 203 plaintiffs in 90 lawsuits, three lawyers (7.1%; Group A) filed 88 (46.3%) lawsuits; four lawyers (9.5%; Group B) filed 42 lawsuits (22.1%); and 35 lawyers (83.3%; Groups C and D) filed between one and seven lawsuits each.\n\nA total of 189 medical prescriptions attached to the lawsuits (n = 190) were analyzed. One lawsuit did not provide a prescription for the medicine etanercept. Legible names of patients were also absent in 5.3% of prescriptions. Neither the generic name of the medicine nor the pharmaceutical dosage form were reported in 59.8% of cases, among other missing or incomplete information that are required by law, totaling 94.7% of cases (Table 4).\n\n\nTable 4 Medical prescriptions linked to lawsuits, according to legal precepts(Law 5.991/1973).a Sao Paulo, SP, Southeastern Brazil, 2004-2010.\nVariable\tAdalimumab\tEfalizumab\tEtanercept\tInfliximab\tTotal\t\n%\tn\t%\tn\t%\tn\t%\tn\t%\tn\t\n \t4.8\t9\t21.7\t41\t15.9\t30\t57.7\t109\t100.0\t189\t\nLegible name of author (patient)\t\n No\t0.0\t0\t2.4\t1\t6.7\t2\t6.4\t7\t5.3\t10\t\nAuthor’s address (patient)\t\n No\t100.0\t9\t100.0\t41\t100.0\t30\t100.0\t109\t100.0\t189\t\nGeneric name\t\n No\t77.8\t7\t39.0\t16\t66.7\t20\t64.2\t70\t59.8\t113\t\nTrade name\t\n No\t22.2\t2\t0.0\t0\t23.3\t7\t21.1\t23\t16.9\t32\t\nPharmaceutical form\t\n No\t88.9\t8\t100.0\t41\t86.7\t26\t95.4\t104\t94.7\t179\t\nConcentration\t\n No\t44.4\t4\t58.5\t24\t13.3\t4\t19.3\t21\t28.0\t53\t\nAdministration route\t\n No\t11.1\t1\t12.2\t5\t13.3\t4\t20.2\t22\t16.9\t32\t\nDosage\t\n No\t11.1\t1\t53.7\t22\t66.7\t20\t56.0\t61\t55.0\t104\t\nDuration of treatment\t\n No\t77.8\t7\t85.4\t35\t90.0\t27\t89.9\t98\t88.4\t167\t\nInterval between doses\t\n No\t11.1\t1\t7.3\t3\t16.7\t5\t13.8\t15\t12.7\t24\t\nTotal quantity\t\n No\t77.8\t7\t85.4\t35\t90.0\t27\t89.9\t98\t88.4\t167\t\nName of the Doctor\t\n No\t0.0\t0\t2.4\t1\t3.3\t1\t3.7\t4\t3.2\t6\t\nCRM\t\n No\t0.0\t0\t0.0\t0\t0.0\t0\t0.9\t1\t0.5\t1\t\n Illegible\t0.0\t0\t7.3\t3\t16.7\t5\t11.9\t13\t11.1\t21\t\nAddress of prescribing practitioner’s medical institution\t\n No\t0.0\t0\t4.9\t2\t3.3\t1\t10.1\t11\t7.4\t14\t\nDate\t\n No\t0.0\t0\t4.9\t2\t0.0\t0\t11.0\t12\t7.4\t14\t\n Illegible\t0.0\t0\t0.0\t0\t0.0\t0\t0.9\t1\t0.5\t1\t\nSource: lawsuits. Coordination of Strategic Demands of SUS (Codes). Health Department of Sao Paulo State.\n\nCRM: Conselho Regional de Medicina (Regional Council of Medicine)\n\n\na Presidência da República. Lei nº 5.991, de 17 de dezembro de 1973. Dispõe sobre o Controle Sanitário do Comércio de Drogas, Medicamentos, Insumos Farmacêuticos e Correlatos, e dá outras Providências. Brasília (DF); 1973 [cited 2014 Mar 31]. Available from: http://www.planalto.gov.br/ccivil_03/leis/L5991.htm\n\n\n\n\nDISCUSSION\nThe majority of the analyzed lawsuits (n = 190) did not explicitly justify the prescription of a biological medicine or provide information regarding previous treatment, evolution of the disease, supplementary exams, or diagnoses according to the ICD-10. Applicants used biological medicines for periods of more than 13 months (4.0% of the patients have been using this medicine for > 49 months), which extrapolates any follow-up of a high-quality clinical study up to this date.\n8\n\n,\n\n14\n As for medicine discontinuation, 11.3% of the patients were discontinued because of either suspicion of an adverse drug reaction or by their own or their physician’s decision, which was always related with worsening of the condition or lack of efficacy of the medicine. Ninety-one patients were still using a biological medicine when interviewed.\n\nPatients (n = 203) were mostly male, age ranging from 19 to 59 years, and residing in Sao Paulo. They acquired the medicine through an injunction, obtained in 7-10 days (average time). They used the prerogative of free legal aid, despite having legal representation by a private lawyer and having been assisted in private care facilities. Three private lawyers represented patients in more than 40.0% of these lawsuits filed against the state.\n\nInstructions to obtain medicines via judicial process came from the medical doctors who assisted these patients (approximately three clinical practitioners prescribed 80.0% of requested medicines). Approximately 60.0% of patients never had a meeting with their lawyers, having signed power of attorneys at the doctor’s office. In 20.0% of lawsuits, a Non-governmental organization (patient associations) was responsible for instructing patients to request a medicine through the courts.\n\nAll patients visited their doctors once a year, but 70.3% of them visited for follow-up laboratory examinations (blood work, liver and kidney function tests), which would help them to detect possible adverse drug reactions.\na\n\n\n\nWhilst the use of biological medication for the treatment of moderate to severe PSO is considered a therapeutic breakthrough with some short-term effectiveness and tolerance,\na\n meta-analyses\n1\n\n,\n\n17\n and field synopses\ng\n advise caution in terms of long-term effectiveness and safety. National and international references\n3\n\n,\n\n15\n\n,\n\na\n\n,\n\nc\n recommend these medicines as a third line of action, followed by careful monitoring for early identification of adverse drug reactions.\n\nBiological medications are administered via the IV route,\n9\n which can cause several local reactions, which were experienced by the patients in our study. Adverse drug reactions differ from those caused by conventional chemical compounds because they are heterogeneous\n5\n\n,\n\n11\n\n,\n\n18\n and may appear years after patients discontinue their use.\n4\n Adverse drug reactions resulting from 1 year of use include malignancies, opportunist infections caused by fungi, tuberculosis, hypertension, among others.\n13\n\n,\n\n14\n Clinical monitoring of patient, as well as of the way to use the medication, duration of use, dose, and recommendations to patients are all essential ways to reduce and control these events.\n\nThe fact that the court granted petitions containing prescriptions lacking not only relevant legal requirements (almost 100% of this study) but also important data (name of patient, name of the prescribing practitioner registered in local Regional Medical Board, date, duration of treatment, dose, generic name, among others), which are fundamental elements for proper prescribing and compulsory under current legislation, highlights the faulty drug use rationale evident in these petitions. Moreover, the situation exposes these plaintiffs to risks (disability, death) and also leads to other health issues (use of hospital beds, chronic treatments due to disability, among others) for the Health System, including direct and indirect costs.\n\nThe (i) recommendations of the Comissão Nacional de Incorporação e Tecnologias (National Committee of Technology Incorporation) of SUS; (ii) Law 12.401/2011\nh\n regarding therapeutic assistance and health technology incorporation in the scope of SUS; (iii) Decree 7.508/2011,\ni\n with provisions related to planning, health assistance, and joint federal actions; and (iv) the current PCDT,\nd\n do not recommend the use of these agents for the treatment of PSO. Brazilian physicians, even those working in SUS (30.5%) (Table 1), do not comply with the official recommendations and prescribe these agents to patients with PSO.\n\nThe supply of biological medicines used to treat PSO in the state of Sao Paulo is offered via registration of administrative requests in the Componente Especializado da Assistência Farmacêutica (CEAF – Specialized Pharmaceutical Care Program) but it does not require a proper clinical protocol follow-up of patients. After the publication of Resolution SS-54, of May 11, 2012,\nj\n a Comissão de Farmacologia (Pharmacology Committee) was established in SES-SP to provide a computerized processing of administrative requests. It is the prescribing practitioner’s responsibility to justify the need for a biological medicine. However, although the above measures have favored the management of requests and granted them a technical nature (based on scientific eligibility for the use of medicines), they have not lowered the number of lawsuits requesting biological medicines.\n\nThe majority of patients with PSO (69.5%) pursue a biological medicine through the public system, but their prescription is generated by a private system. Doctors’ visits and monitoring are performed at private facilities and medicines are supplied by the public system. Patient care is not comprehensive in any of the pathways, which does not comply with the principles of SUS.\n\nThe pharmaceutical manufacturers maintained frequent contact with more than 50.0% of patients. This suggests possible influence on patients’ needs, transforming them into legal demands.\n\nThe legal request of medicines without scientific evidence weakens pharmaceutical services because it exposes the patient to risks and promotes the financing of technologies devoid of proper proof of efficacy and safety.\n6\n\n,\n\n8\n Efalizumab was approved for the treatment of PSO in the USA and Europe in 2003. Its marketing was suspended due to safety concerns in 2009 (three cases of progressive multifocal leukoencephalopathy), in addition to efficacy issues, rending it inferior to other biological medicines.\n5\n Then, the access to this drug was obtained via lawsuits in Brazil. Approximately 21.2% of patients in our study gained access to efalizumab via lawsuits deferred by the state of Sao Paulo.\n\nMost of the interviewees were diagnosed more than six years ago. Some of the data may have suffered from recall bias. Patients who are still being treated with a biological medicine have been receiving it for more than 24 months. On the other hand, most of the data was crosschecked with the SES-SP database and with the clinical lab results provided by the patients themselves during interviews. The utilization data of biological medications were confirmed by the pharmacy from which each of the patients received these medicines.\n\nConsidering the limitations of any observational study, the results of this study may play an important role in the process of decision making in Public Health in Brazil. To the best of our knowledge, this is the first set of data on the use of biological medicines by patients with PSO financed by judicial demands in Brazil. This is important information for dermatologists, because it provides a real-life view of clinical practice, a goal that is hard to achieve with randomized controlled clinical trials.\n\nSome treatments are associated with potentially serious adverse drug reactions. Therefore, in the long-term observational studies may provide additional and important information for doctors, users, manufacturers and researchers to assess the risks and benefits of treatments.\n\nTo perceive the public health system as one that may provide services without the requirements of in-place regulation, planning, forecasting of financial resources or epidemiological background is imprudent and can collapse the system.\n\nThe plaintiffs selected the judicial procedures to obtain biological medicines because they are either unaware of other routes or find difficulty in accessing the institutional pathways of SUS. Easy access provided by courts favors the use of biological medicines for an extended period of time through irregular prescriptions, the high frequency of adverse drug reactions and inappropriate clinical monitoring. Strict compliance to PCDT may guarantee access, effectiveness, and safety of an appropriate therapy for PSO.\n\nThis study was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP – Process 2009/53084-1).\n\na Scottish Intercollegiate Guidelines Network. Diagnosis and management of psoriasis and psoriatic arthritis in adults: a national clinical guideline. Edinburgh: SIGN; 2010 [cited 2014 Mar 31]. Available from: http://www.sign.ac.uk/pdf/sign121.pdf\n\nb National Institute for Health and Clinical Excellence. Psoriasis: the assessment and management of psoriasis. London; 2012 [cited 2014 Mar 31]. Available from: http://guidance.nice.org.uk/cg153\n\nc Sociedade Brasileira de Dermatologia. Consenso Brasileiro de Psoríase 2012: guias de avaliação e tratamento. 2. ed. Rio de Janeiro; 2012 [cited 2014 Mar 31]. Available from: http://www.ufrgs.br/textecc/traducao/dermatologia/files/outros/Consenso_Psoriase_2012.pdf\n\nd Ministério da Saúde, Secretaria de Atenção à Saúde. Portaria nº 1.229, de 5 de novembro de 2013. Aprova o Protocolo Clínico e Diretrizes Terapêutica da Psoríase. Diario Oficial Uniao. 6 nov 2013;Seção 1:52.\n\ne For those interested in the questionnaire, please contact the authors.\n\nf Presidência da República. Lei nº 5.991, de 17 de dezembro de 1973. Dispõe sobre o Controle Sanitário do Comércio de Drogas, Medicamentos, Insumos Farmacêuticos e Correlatos, e dá outras Providências. Brasília (DF); 1973[cited 2014 Mar 31]. Available from: http://www.planalto.gov.br/ccivil_03/leis/L5991.htm\n\ng Naldi L, Rzany B. Psoriasis (chronic plaque). Clin Evid(Online). 2009[cited 2014 Mar 31];2009:1706. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907770/pdf/2009-1706.pdf\n\nh Presidência da República. Lei nº 12.401, de 28 de abril de 2011. Altera a Lei nº 8.080, de 19 de setembro de 1990, para dispor sobre a assistência terapêutica e a incorporação de tecnologia em saúde no âmbito do Sistema Único de Saúde - SUS. Brasília (DF); 2011 [cited 2014 Mar 31]. Available from: http://www.planalto.gov.br/ccivil_03/_Ato2011-2014/2011/Lei/L12401.htm\n\ni Presidência da República. Decreto nº 7.508, de 28 de junho de 2011. Regulamenta a Lei nº 8.080, de 19 de setembro de 1990, para dispor sobre a organização do Sistema Único de Saúde - SUS, o planejamento da saúde, a assistência à saúde e a articulação interfederativa, e dá outras providências. Brasília (DF); 2011 [cited 2014 Mar 31]. Available from: http://www.planalto.gov.br/ccivil_03/_ato2011-2014/2011/decreto/D7508.htm\n\nj Secretaria de Estado da Saúde de São Paulo. Resolução SS-54, de 11 de maio de 2012. Aprova, no âmbito da Pasta, estrutura e funcionamento da Comissão de Farmacologia da Secretaria de Estado da Saúde de São Paulo, e dá outras providências. Diario Oficial Estado Sao Paulo. 12 maio 2012;Seção 1:37. [cited 2014 Mar 31]. Available from: www.adj.org.br/download/pdf/2012jur_resol54.pdf\n\nThis study was based on the master’s dissertation of Silveira MSN, titled: “Monitoramento do uso de medicamentos biológicos fornecidos por determinação judicial a pacientes com psoríase no Estado de São Paulo”, presented to the Programa de Pós-Graduação em Ciências Farmacêuticas of the Universidade de Sorocaba, in 2013.\n\nThe authors declare no conflict of interest.\n\nHIGHLIGHTS\nThis study aimed to analyze the legal access to and usage profile of biological drugs for the treatment of psoriasis. The legal access to medications distorts planning and spending and undermines the principle of a comprehensive health care system proposed by the Brazilian Unified Health System (SUS).\n\nA total of 203 applicants were interviewed, and 190 patients requiring biological drugs for psoriasis (adalimumab, efalizumab, etanercept, and infliximab) were examined. The patients obtained the drugs through a writ of mandamus (59.5%); without the need to request the drugs from another institution, either private or through SUS (86.2%); and using the prerogative of gratuity justice (72.6%). However, 91.1% of the patients were represented by a private attorney, 69.5% received assistance in private medical offices, and 60.0% had never met with their attorneys and therefore needed to sign proxies at the doctor’s office.\n\nIn addition, 20.5% of the patients discontinued the use of biological drugs because they reported suspected adverse reactions previously confirmed by doctors – reactions at the application site, hospitalization after medication use, cardiovascular events (arrhythmia, hypertension), liver disease, blood dyscrasia, pneumonia, renal injury, etc. Most patients discontinued the use of these drugs on their own (26.6%) or following doctor’s recommendation (13.8%) because of the worsening of the clinical status or lack of efficacy.\n\nImportant differences between clinical practice and guideline recommendations are evident in the treatment of these patients.\n\nProfessor Rita de Cássia Barradas Barata\n\nScientific Editor\n==== Refs\nREFERENCES\n1 Brimhall AK King LN Licciardone JC Jacobe H Menter A. Safety and efficacy of alefacept, efalizumab, etanercept and infliximab in treating moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Br J Dermatol 2008 159 2 274 285 10.1111/j.1365-2133.2008.08673.x 18547300 \n2 Chieffi AL Barata RCB Ações judiciais: estratégia da indústria farmacêutica para introdução de novos medicamentos. Rev Saude Publica 2010 44 3 421 429 10.1590/S0034-89102010000300005 20549017 \n3 Dommasch ED Abuabara K Shin DB Nguyen J Troxel AB Gelfand JM. The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials. J Am Acad Dermatol 2011 64 6 1035 1050 10.1016/j.jaad.2010.09.734 21315483 \n4 Girolomoni G Altomare G Ayala F Berardesca E Calzavara-Pinton P Chimenti S et al. Safety of anti-TNFα agents in the treatment of psoriasis and psoriatic arthritis. Immunopharmacol Immunotoxicol 2012 34 4 548 560 10.3109/08923973.2011.653646 22296031 \n5 Hausmann OV Seitz M Villiger PM Pichler WJ. The complex clinical picture of side effects to biologicals. Med Clin North Am 2010 94 4 791 804 xi ii 10.1016/j.mcna.2010.03.001 20609863 \n6 Lopes LC Barberato S Filho Costa AC Osorio-de-Castro CGS Uso racional de medicamentos antineoplásicos e ações judiciais no Estado de São Paulo. Rev Saude Publica 2010 44 4 620 628 10.1590/S0034-89102010000400005 20676553 \n7 Lucka TC Pathirana D Sammain A Bachmann F Rosumeck S Erdmann R et al. Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment. J Eur Acad Dermatol Venereol 2012 26 11 1331 1344 10.1111/j.1468-3083.2012.04492.x 22404617 \n8 Macedo EI Lopes LC Barberato S. Filho Análise técnica para a tomada de decisão do fornecimento de medicamentos pela via judicial. Rev Saude Publica 2011 45 4 706 713 10.1590/S0034-89102011005000044 21739077 \n9 Mazurek J Jahnz-Różyk K. The variety of types of adverse side-effects during treatment with biological drugs. Int Rev Allergol Clin Immunol Family Med 2012 18 1 34 40 \n10 Monteiro CA Moura EC Jaime PC Lucca A Florindo AA Figueiredo ICR et al. Monitoramento de fatores de risco para doenças crônicas por entrevistas telefônicas. Rev Saude Publica 2005 39 1 47 57 10.1590/S0034-89102005000100007 15654460 \n11 Pichler WJ. Adverse side-effects to biological agents Allergy 2006 61 8 912 920 10.1111/j.1398-9995.2006.01058.x 16867042 \n12 Rustin MHA Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. Br J Dermatol 2012 167 Suppl 3 3 11 10.1111/j.1365-2133.2012.11208.x 23082810 \n13 Sánchez-Regaña M Dilme E Puig L Bordas X Carrascosa JM Ferran M et al. Adverse reactions during biological therapy for psoriasis: results of a survey of the Spanish Psoriasis Group. Actas Dermosifiliogr 2010 101 2 156 163 10.1016/S1578-2190(10)70602-8 20223158 \n14 Singh JA Wells GA Christensen R Tanjong Ghogomu E Maxwell L Macdonald JK et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 2011 16 2 CD008794 10.1002/14651858.CD008794.pub2 \n15 Smith CH Anstey AV Barker JNWN Burden AD Chalmers RJG Chandler DA et al British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009 161 5 987 1019 10.1111/j.1365-2133.2009.09505.x 19857207 \n16 Vieira FS Zucchi P. Distortions to national drug policy caused by lawsuits in Brazil. Rev Saude Publica 2007 41 2 214 222 10.1590/S0034-89102007000200007 17384795 \n17 Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol 2010 160 4 810 820 10.1111/j.1476-5381.2010.00702.x 20590580 \n18 Zemková M Jebavý L Kotlárová J Vlcek J Meyboom RH. The spectrum and types of adverse side effects to biological immune modulators: a proposal for new classification. Folia Biol (Praha). 2007 53 4 146 155 17706021\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0034-8910",
"issue": "48(4)",
"journal": "Revista de saude publica",
"keywords": null,
"medline_ta": "Rev Saude Publica",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D001938:Brazil; D003430:Cross-Sectional Studies; D005260:Female; D006297:Health Services Accessibility; D006801:Humans; D008297:Male; D008875:Middle Aged; D009313:National Health Programs; D028701:Patient Rights; D011565:Psoriasis; D011634:Public Health; D055815:Young Adult",
"nlm_unique_id": "0135043",
"other_id": null,
"pages": "651-61; discussion 661",
"pmc": null,
"pmid": "25210824",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22296031;17706021;17384795;22404617;20676553;18547300;19857207;16867042;20609863;21739077;15654460;23082810;20223158;21315483;21328309;20590580",
"title": "Biological drugs for the treatment of psoriasis in a public health system.",
"title_normalized": "biological drugs for the treatment of psoriasis in a public health system"
} | [
{
"companynumb": "BR-JNJFOC-20140908499",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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"abstract": "OBJECTIVE\nDravet syndrome (DS) is characterized by high epilepsy-related premature mortality with a markedly young age at death, however, autopsy report of sudden unexpected death with DS has been fewer than expected.\n\n\nMETHODS\nWe report two autopsy cases with sudden unexpected death from DS. Case 1 was a 13-year-old male who drowned in a bathtub, and Case 2 was a 3-year-old female who died while sleeping. In Case 1, the blood concentration of the anticonvulsant, valproic acid, was below the recommended therapeutic range. Neuropathological investigation and genetic analysis of 402 cardiovascular disease-related and 146 epilepsy-related genes by next generation sequencing were applied.\n\n\nRESULTS\nNo significant neuronal loss with gliosis was observed in the brain of either patient. Although possible mild malformations of cortical development were found in both, the degree thereof was similar to that of age-matched controls. Genetic analysis identified a novel variant in SCN1A intron 23 (c.4477-3T > C) in Case 1 that falls outside of the minor splicing consensus sequence. In vitro splicing functional assays with minigene constructs revealed that this intronic variant leads to a 2-bp insertion immediately before exon 24 that results in protein truncation. Similarly, a novel de novo missense mutation of unknown significance, SCN1A_Arg187Pro, was identified in Case 2. In both cases, we also identified cardiomyopathy-related variants classified as likely pathogenic; however, the effect of these variants at death was minimal because there was an absence of pathological change indicating inherited cardiomyopathy.\n\n\nCONCLUSIONS\nThe present cases emphasize the need for multifaceted examination of DS cases so as to obtain a definitive autopsy diagnosis and to explore the mechanism of sudden unexpected death.",
"affiliations": "Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.;Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.;Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.;Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.;Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama, Japan.;Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Japan.;Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan. Electronic address: nishida@med.u-toyama.ac.jp.",
"authors": "Hata|Yukiko|Y|;Oku|Yuko|Y|;Taneichi|Hiromichi|H|;Tanaka|Tomomi|T|;Igarashi|Noboru|N|;Niida|Yo|Y|;Nishida|Naoki|N|",
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"journal": "Brain & development",
"keywords": "Cardiovascular disease; Dravet syndrome; Epilepsy; Neuropathology; SCN1A; Sudden death",
"medline_ta": "Brain Dev",
"mesh_terms": "D000293:Adolescent; D001344:Autopsy; D002675:Child, Preschool; D003645:Death, Sudden; D004831:Epilepsies, Myoclonic; D004827:Epilepsy; D005260:Female; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel",
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"title": "Two autopsy cases of sudden unexpected death from Dravet syndrome with novel de novo SCN1A variants.",
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"literaturereference": "HATA Y, OKU Y, TANEICHI H, ET AL. TWO AUTOPSY CASES OF SUDDEN UNEXPECTED DEATH FROM DRAVET SYNDROME WITH NOVEL DE NOVO SCN1A VARIANTS. BRAIN + DEVELOPMENT. 2019 OCT 30?.",
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"abstract": "Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. The clinical manifestations of NIID are complex and easily misdiagnosed. Based on the current knowledge of this disease, it is usually chronic, with almost no acute cases. Stroke-like disease is an extremely rare type of NIID. Case Presentation: A 61-year-old woman was admitted to our hospital with sudden left limb weakness. Diffusion magnetic resonance imaging (MRI) demonstrated high signal intensity in the skin-medullary junction area. Tissue pathology showed eosinophilic inclusions in the nuclei of the sweat gland cells and fat cells of the skin. Subsequent genetic analysis of the fragile X chromosome mental retardation gene 1 (FMR1) gene showed that the CGG repeat number was in the normal range, excluding fragile X-related tremor/ataxia syndrome (FXTAS). After 3 weeks of hospitalization, the patient's condition improved, and the left limb muscle strength recovered. Her symptoms were almost completely diminished after 3 months. Conclusion: This case demonstrates the strong clinical heterogeneity of NIID. NIID can manifest as acute hemiplegia and a stroke-like attack. This case study provides new information for the diagnosis of NIID and the classification of the clinical characteristics.",
"affiliations": "Department of Neurology, The Second Hospital of Longyan City, Longyan, China.;Neuroscience Centre, Department of Neurology, The First Hospital of Jilin University, Changchun, China.;Department of Neurology, The Second Hospital of Longyan City, Longyan, China.;Department of Neurology, The Second Hospital of Longyan City, Longyan, China.;Department of Neurology, First Affliated Hospital of Fujian Medical University, Fuzhou, China.;Department of Neurology, Fujian Sanbo Funeng Brain Hospital, Fuzhou, China.;Department of Neurology, Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Capital Medical University, Beijing, China.",
"authors": "Lin|Pan|P|;Jin|Hang|H|;Yi|Kun-Chang|KC|;He|Xiang-Sheng|XS|;Lin|Shi-Fang|SF|;Wu|Gang|G|;Zhang|Zai-Qiang|ZQ|",
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"doi": "10.3389/fneur.2020.00530",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.00530\nNeurology\nCase Report\nA Case Report of Sporadic Adult Neuronal Intranuclear Inclusion Disease (NIID) With Stroke-Like Onset\nLin Pan 1 Jin Hang 2* Yi Kun-Chang 1 He Xiang-Sheng 1 Lin Shi-Fang 3 Wu Gang 4 Zhang Zai-Qiang 5 1Department of Neurology, The Second Hospital of Longyan City, Longyan, China\n2Neuroscience Centre, Department of Neurology, The First Hospital of Jilin University, Changchun, China\n3Department of Neurology, First Affliated Hospital of Fujian Medical University, Fuzhou, China\n4Department of Neurology, Fujian Sanbo Funeng Brain Hospital, Fuzhou, China\n5Department of Neurology, Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Capital Medical University, Beijing, China\nEdited by: Aurel Popa-Wagner, University Hospital Essen, Germany\n\nReviewed by: Yasuo Miki, Hirosaki University, Japan; Reymundo Lozano, Mount Sinai Medical Center, United States\n\n*Correspondence: Hang Jin doctorjinhang@hotmail.comThis article was submitted to Neurodegeneration, a section of the journal Frontiers in Neurology\n\n\n10 6 2020 \n2020 \n11 53007 12 2019 13 5 2020 Copyright © 2020 Lin, Jin, Yi, He, Lin, Wu and Zhang.2020Lin, Jin, Yi, He, Lin, Wu and ZhangThis 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.Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. The clinical manifestations of NIID are complex and easily misdiagnosed. Based on the current knowledge of this disease, it is usually chronic, with almost no acute cases. Stroke-like disease is an extremely rare type of NIID.\n\nCase Presentation: A 61-year-old woman was admitted to our hospital with sudden left limb weakness. Diffusion magnetic resonance imaging (MRI) demonstrated high signal intensity in the skin-medullary junction area. Tissue pathology showed eosinophilic inclusions in the nuclei of the sweat gland cells and fat cells of the skin. Subsequent genetic analysis of the fragile X chromosome mental retardation gene 1 (FMR1) gene showed that the CGG repeat number was in the normal range, excluding fragile X-related tremor/ataxia syndrome (FXTAS). After 3 weeks of hospitalization, the patient's condition improved, and the left limb muscle strength recovered. Her symptoms were almost completely diminished after 3 months.\n\nConclusion: This case demonstrates the strong clinical heterogeneity of NIID. NIID can manifest as acute hemiplegia and a stroke-like attack. This case study provides new information for the diagnosis of NIID and the classification of the clinical characteristics.\n\nneuronal intranuclear inclusion diseasestrokeneurodegenerative diseaseskin biopsyFXTAS\n==== Body\nIntroduction\nNIID is a rare, slowly progressive neurodegenerative disease characterized by the presence of eosinophilic hyaluronan inclusions in the central and peripheral nervous system and internal organs. It is difficult to diagnose NIID only through clinical symptoms and signs, and as a result, this condition is often misdiagnosed. In the last century, NIID could only be diagnosed through invasive methods, including a nerve biopsy and necropsy. Since Sone et al. (1) found in 2011 that a skin biopsy could be used to diagnose NIID, the number of confirmed cases of NIID has increased.\n\nThe clinical manifestations of NIID are very complex, involving the central nervous system and peripheral nervous system, as well as non-nervous tissue, such as the kidney (2). NIID can commonly present as a chronic neurodegenerative disease but occasionally presents acutely. According to published case reports, acute NIIDs consist mainly of paroxysmal encephalopathy. Most patients present with sudden headache and fever as the first symptom (3), accompanied by a consciousness disorder or epilepsy (4). The above symptoms can also be recurrent (5, 6). However, we could not locate any reports of a stroke-like onset of hemiplegia in NIID. Recently, we encountered a case of a typical sporadic adult NIID patient with stroke-like onset in routine clinical practice. The first symptom in our patient was acute left hemiplegia, and MR imaging showed diffusion-weighted imaging (DWI) high signal intensity in the cortex medullary junction area. Finally, the diagnosis was confirmed by pathological examination of the patient's skin biopsy and genetic analysis. This case report describes a rare clinical manifestation of NIID, which is helpful to update the understanding of the clinical characteristics of NIID and provide a reference for future research.\n\nCase Presentation\nIn December 2017, a 61-year-old woman was admitted to our hospital because she had been suffering from sudden left limb weakness for 3.5 h. She denied a history of smoking, high blood pressure, diabetes, and other cerebrovascular disease risk factors. She denied hereditary cerebrovascular history and other neurological genetic history. The clinical examination found that she had slurred speech, with a left limb strength of Grade 3, a positive left Babinski sign, and a National Institute of Health stroke scale (NIHSS) score of 6 points. An emergency computed tomography (CT) scan of her brain showed leukoaraiosis and senile brain changes (Figure 1A). An initial diagnosis of cerebral infarction was made, with indications for intravenous thrombolysis, and intravenous thrombolytic therapy was initiated with 40.5 mg rt-PA. Following thrombolysis, the patient's condition worsened the next day with new symptoms of lethargy, poor spirit, poor understanding, and the inability to move her left limbs. Additionally, there were new abnormal symptoms, including a bilateral positive Babinski sign accompanied by high fever, high body temperature between 38.5 and 39.3°C, but no headache, vomiting, limb convulsions, or incontinence. After active anti-thrombotic, anti-infective, anti-pyretic, and other treatments, the patient's condition stabilized. The MRI (Figures 1B,C) and magnetic resonance angiography (MRA) (Figure 1D) of the head showed improvement. The DWI (Figure 1B) was suspicious for “neuronal intranuclear inclusion disease,” and a skin biopsy of the right thigh was performed.\n\nFigure 1 Imaging examination. (A) The head CT shows a low-density lesion in the white matter area. (B) The DWI sequence of the head MRI suggests a high signal shadow in the white matter and gray matter junction area, especially on the left side, which is characteristic of the inclusion disease in the nuclei of the neurons. (C) The T2 Flair sequence of the skull MRI also shows abnormal signals in the white matter region of the brain. (D) No significant intracranial aortic stenosis or occlusion changes are observed in the head MRA.\n\nOther hospital-related examinations were carried out, including routine blood testing. The results showed a white blood cell count of 10.68 × 109/L, a neutrophil ratio of 90.6%, C-reactive protein < 1.28 mg/L, procalcitonin 0.129 ng/ml, and an erythrocyte sedimentation rate (ESR) of 25 mm/h. Fasting blood glucose concentration 5.70 mmol/L, total cholesterol concentrations 4.66 mmol/L, low density lipoprotein concentration (LDL-C) 2.78 mmol/L, other biochemical indicators, routine urine and stool testing, glycosylated hemoglobin, tumor markers, thyroid function, five indicator test for Hepatitis B, human immunodeficiency virus antibody, the toluidine red non-heated serum test, and all other indicators were normal. Anti-nuclear, anti-double-stranded DNA, anti-SM, anti-SSB, anti-SSA, anti-JO-1, and all other autoantibody tests were negative. The Widal test and the Weil–Felix test were negative. A pharyngeal swab for bacterial and pathogen culture showed no abnormalities, and a lumbar puncture showed an intracranial pressure of 85 mmH2O. There were no abnormal findings in the cerebrospinal fluid cytological, biochemical, or bacteriological tests, or other indicators. No abnormalities were seen on vascular ultrasonography, echocardiography, or abdominal color Doppler ultrasound. Electromyography (EMG) showed that the bilateral ulnar nerve and common peroneal nerve conduction velocity were slightly slower than normal, and the shortest latency of the bilateral phrenic nerve F wave was prolonged. Subsequent analysis for the fragile X chromosome mental retardation gene 1 (FMR1) showed that the CGG repeat number was in the normal range, excluding fragile X-related tremor/ataxia syndrome (FXTAS). The pathology report of the skin biopsy (Figure 2) showed eosinophilic inclusions in the nuclei of the sweat gland cells and fat cells of the skin.\n\nFigure 2 Pathological examination. (A) Anti-P62 immunohistochemical staining. Visible inclusion bodies in the nucleus of some skin sweat gland cells (× 400). (B) Anti-P62 immunohistochemical staining. Visible inclusion bodies in the nucleus of some fat cells (× 400). (C) Electron microscopy shows a circular inclusion body structure in the nucleus of a sweat gland (× 15,000). (D) Hematoxylin-eosin staining shows eosinophilic inclusion bodies in some sweat gland cells. The inset on the upper right shows amplification of one of the nuclei (× 400).\n\nWith characteristic image support, definitive pathological diagnosis, and optimal gene detection, the case was diagnosed as sporadic adult neuronal intranuclear inclusion disease. This patient experienced a stroke-like NIID, the first symptom of which was left limb weakness, followed by the gradual appearance of fever and a disturbance in consciousness. After 3 weeks of hospitalization, the patient regained consciousness, her fever subsided, and her left limb muscle strength recovered to Grade 4+. She could walk slowly. In March 2018, her symptoms were almost completely relieved. Her left limb muscle strength was close to normal, and there were no abnormal neuropsychiatric symptoms or signs.\n\nDiscussion\nSone and colleagues summarized the clinical characteristics of 38 cases of sporadic NIID, most of which presented as the first and main clinical manifestations of dementia. Other clinical symptoms of sporadic NIID included consciousness disorders, limb weakness, sensory disorders, tremors, convulsions, behavioral abnormalities, and ataxia (7). In the aforementioned study, no cases of stroke-like acute onset were mentioned. Even if the first symptom of the patient is weakness of the limbs, it will progress slowly. Here, we reported a stroke-like case with hemiplegia of the left limb as the first symptom.\n\nBecause there was no specific diagnostic sign on emergency CT, this patient was considered to be a stroke victim at the ultra-early stage and received intravenous thrombolysis treatment. In this case, the patient's condition worsened after admission, and new symptoms, including a change in consciousness and fever, appeared. In addition, the positive Babinski signs on both feet indicated that the lesions might be located in the brainstem, so we considered whether this case was a post-circulation stroke. At this time, MRI is particularly important because it can confirm the location of the diagnosis. Unexpectedly, the MRI of the head showed that the focus was not in the posterior circulation, but in the anterior circulation of the corticomedullary junction area, with no macrovascular lesions on MRA. If it is not stroke, we suspected that it is an acute encephalitis, metabolic disease, or poisoning. With limited knowledge in neurodegenerative or NIID-related areas, we did not immediately recognize the characteristic imaging of NIID. This patient had a very small range of imaging lesions, and did not reconcile with the severity of her clinical symptoms. We consulted peers, searched the literature, and explained the case from the perspective of monism, with a likely diagnosis of NIID.\n\nMRI showed DWI high signal intensity in the skin-medullary junction area, also known as the “cortical line sign,” a characteristic imaging manifestation of NIID (7, 8). Abe et al. (9) reported that over a 10-year period, imaging of a NIID patient showed that high signal intensity persisted in the DWI skin-to-medullary junction zone and progressed from the frontal lobe to the occipital lobe. This characteristic does not generally disappear throughout the course of the disease and can be an important marker for the diagnosis of NIID. Recently, some scholars found that the fragile X-related tremor/ataxia syndrome (FXTAS) also had similar features on imaging (10), and the clinical symptoms of the two are quite similar. Therefore, NIID should be distinguished from FXTAS by the number of CGG repeats in the FMR1 gene (11). Along with the strong evidence from imaging and gene detection, we finally confirmed this case as NIID by pathological examination of the skin biopsy.\n\nWe observed that this patient with NIID developed a fever and a mild disturbance in consciousness after a stroke-like onset, which seems to be explained by the characteristics of paroxysmal encephalopathy. This is somewhat similar to a case reported by Tong (5), demonstrating that NIID may present differently in different stages. The EMG of this case also showed an abnormality of the peripheral nerve, implying that the central damage of the NIID patient was accompanied by hidden peripheral nerve damage. In summary, the clinical heterogeneity of NIID at different stages of the disease increased the difficulty and complexity of our diagnosis. This case provides an excellent example of the utility of diagnostic imaging in the diagnosis of rare diseases such as NIID. Only when we fully understand a disease are we able to diagnose it correctly.\n\nSimilar to other neurodegenerative diseases, NIID has no specific recommended treatment. At present, there are no appropriate methods to treat the pathophysiological mechanism of NIID, only supportive therapy and symptomatic treatment. In this case, NIID was treated with non-specific treatment, careful observation, and care. The symptoms of weakness, fever, and other symptoms gradually decreased after more than 3 months, and the patient's condition was temporarily improved. In the future, international studies with larger numbers of patients could elucidate the pathogenesis of NIID, enabling the development of more effective treatments for this condition.\n\nData Availability Statement\nThe datasets analyzed in this article are not publicly available. Requests to access the datasets should be directed to 1192260154@qq.com.\n\nEthics Statement\nThe patients/participants provided written informed consent for the publication of this case report.\n\nAuthor Contributions\nPL and HJ wrote the report. K-CY and X-SH care for the patient. S-FL and GW performed the diagnostic testing. Z-QZ confirmed the pathological diagnosis. Written consent to publish was obtained from the patient.\n\nConflict of Interest\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==== Refs\nReferences\n1. Sone J Tanaka F Koike H Inukai A Katsuno M Yoshida M . Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease\n. Neurology. (2011 ) 76 :1372 –6\n. 10.1212/WNL.0b013e3182166e13 21411744 \n2. Horino T Matsumoto T Inoue K Ichii O Terada Y . A case of neuronal intranuclear inclusion disease associated with lupus nephritis–like nephropathy\n. eNeurologicalSci . (2018 ) 10 :28 –30\n. 10.1016/j.ensci.2018.01.002 29430526 \n3. Xiao F Tian X Wang XF . Cerebral atrophy and leukoencephalopathy in a young man presenting with encephalitic episodes\n. JAMA Neurol . (2018 ) 75 :1563 –4\n. 10.1001/jamaneurol.2018.2333 30167633 \n4. Yamanaka H Hashimoto S Suenaga T . Neuronal intranuclear inclusion disease with prolonged impaired consciousness and status epilepticus: a case report\n. Rinsho Shinkeigaku. (2019 ) 59 :425 –30\n. 10.5692/clinicalneurol.cn-001264 31243248 \n5. Tong Q Ju KJ Zhu XF Tian XY Zheng JL Xue LJ . Two cases of adult-onset neuronal intranuclear inclusion disease diagnosed by skin biopsy\n. Zhonghua Nei Ke Za Zhi . (2019 ) 58 :685 –7\n. 10.3760/cma.j.issn.0578-1426.2019.09.010 31461821 \n6. Han X Han M Liu N Xu J Zhang Y Zhang Y . Adult-onset neuronal intranuclear inclusion disease presenting with typical MRI changes\n. Brain Behav . (2019 ) 9 :e01477 . 10.1002/brb3.1477 31749292 \n7. Sone J Mori K Inagaki T Katsumata R Takagi S Yokoi S . Clinicopathological features of adult-onset neuronal intranuclear inclusion disease\n. Brain. (2016 ) 139 :3170 –86\n. 10.1093/brain/aww249 27797808 \n8. Sone J Kitagawa N Sugawara E Iguchi M Nakamura R Koike H . Neuronal intranuclear inclusion disease cases with leukoencephalopathy diagnosed via skin biopsy\n. J Neurol Neurosurg Psychiatr . (2014 ) 85 :354 –56\n. 10.1136/jnnp-2013-306084 24039026 \n9. Abe K Fujita M . Case report: over 10 years MRI observation of a patient with neuronal intranuclear inclusion disease\n. BMJ Case Rep. (2017 ) 2017 :bcr2016218790 . 10.1136/bcr-2016-218790 28237949 \n10. Padilha IG Nunes RH Scortegagna FA Pedroso JL Marussi VH Rodrigues Gonçalves MR . MR imaging features of adult-onset neuronal intranuclear inclusion disease may be indistinguishable from fragile X–associated tremor/ataxia syndrome\n. AJNR Am J Neuroradiol . (2018 ) 39 :E100 –1\n. 10.3174/ajnr.A5729 30072371 \n11. Hoem G Koht J . Fragile X-associated tremor/ataxia syndrome\n. Tidsskr Nor Laegeforen . (2017 ) 137 . 10.4045/tidsskr.17.0317 29094559\n\n",
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"title": "A Case Report of Sporadic Adult Neuronal Intranuclear Inclusion Disease (NIID) With Stroke-Like Onset.",
"title_normalized": "a case report of sporadic adult neuronal intranuclear inclusion disease niid with stroke like onset"
} | [
{
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{
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] |
{
"abstract": "Tumour lysis syndrome is rare in solid malignancies. Here, we report a case of tumour lysis syndrome and acute kidney injury in a 23-year-old female with gestational trophoblastic neoplasia. Hydration and early dialysis therapy were started with good recovery. On follow up she progressed to chronic kidney disease. After 6 years of follow up, the patient conceived and delivered successfully.",
"affiliations": "Nephrology and Renal Transplantation Centre, The Medical City, Baghdad, Iraq, Email: ala.ali@meciq.edu.iq.;Baghdad Teaching Hospital, The Medical City, Baghdad, Iraq.",
"authors": "Ali|Ala|A|;Al-Janabi|Rawaa D|RD|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.4997/JRCPE.2020.109",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-2715",
"issue": "50(1)",
"journal": "The journal of the Royal College of Physicians of Edinburgh",
"keywords": "AKI; GTN; TLS; acute kidney injury; gestational trophoblastic neoplasia; tumour lysis syndrome",
"medline_ta": "J R Coll Physicians Edinb",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D005260:Female; D006801:Humans; D006435:Renal Dialysis; D015275:Tumor Lysis Syndrome; D055815:Young Adult",
"nlm_unique_id": "101144324",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "32539034",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A rare cause of tumour lysis syndrome and acute kidney injury.",
"title_normalized": "a rare cause of tumour lysis syndrome and acute kidney injury"
} | [
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}
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},
{
"reactionmeddrapt": "Tubulointerstitial nephritis",
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},
{
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},
{
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},
{
"reactionmeddrapt": "Tumour lysis syndrome",
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},
{
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}
],
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}
] |
{
"abstract": "A 36-year-old woman presented with a 2-month history of dry cough, bilateral pain in the upper chest, and low-grade fever. She had a 1-year history of ulcerative colitis (UC), which was treated with mesalazine. Cultures of sputum and bronchoalveolar lavage (BAL) fluid were negative. Chest radiograph and a computed tomography (CT) scan showed dense bilateral subpleural infiltrates in both upper lobes. A c-ANCA test was positive in a 1:1280 titer, and further specification showed antibodies against proteinase-3 antigen. Due to the possibility of mesalazine toxicity, this medication was stopped. Within 2 weeks, the patient's symptoms markedly improved, together with the chest roentgenogram.",
"affiliations": "Department of Internal Medicine, VU University Medical Center, Postbus 7057, 1007 MB Amsterdam, The Netherlands.",
"authors": "Nanayakkara|Prabath W B|PW|;de Jong|Evelien|E|;Postmus|Piet E|PE|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejim.2004.08.007",
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"issn_linking": "0953-6205",
"issue": "15(7)",
"journal": "European journal of internal medicine",
"keywords": null,
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"mesh_terms": null,
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "470-472",
"pmc": null,
"pmid": "15581755",
"pubdate": "2004-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bilateral pulmonary infiltrates in a patient with ulcerative colitis receiving mesalazine.",
"title_normalized": "bilateral pulmonary infiltrates in a patient with ulcerative colitis receiving mesalazine"
} | [
{
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
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"drugdosagetext": "500 MG, TID",
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"drugindication": "COLITIS ULCERATIVE",
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"drugdosagetext": "1000 MG, BID",
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"drugindication": "COLITIS ULCERATIVE",
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"medicinalproduct": "MESALAZINE UNK"
}
],
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"reaction": [
{
"reactionmeddrapt": "Antineutrophil cytoplasmic antibody positive",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pulmonary toxicity",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pneumonitis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "NANAYAKKARA PWB, DE JONG E, POSTMUS PE. BILATERAL PULMONARY INFILTRATES IN A PATIENT WITH ULCERATIVE COLITIS RECEIVING MESALAZINE. EUR J INTERN MED. 2004;15:470-472",
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},
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"abstract": "Macitentan treatment for chronic thromboembolic pulmonary hypertension (CTEPH) in the routine clinical setting is increasing. However, 'real world' macitentan experience is scarce and is needed to differentiate from controlled clinical trial settings.\n\n\n\nWe describe our outcomes and clinical 'real world' experience of macitentan mono- and combination therapy with riociguat or sildenafil in CTEPH.\n\n\n\nWe included all consecutive CTEPH patients, either non-operated or with residual PH after pulmonary endarterectomy (PEA), treated with macitentan in the St. Antonius hospital in Nieuwegein, the Netherlands, between 01-2014 and 11-2019. We describe clinical outcomes and adverse events (AEs) until 2 years after macitentan initiation.\n\n\n\nIn total 73 CTEPH patients on macitentan were included, of which 18 patients were clinically inoperable (n = 7 declined PEA, n = 11 nonacceptable risk-benefit) and 55 had technically inoperable CTEPH (n = 48)/residual PH (n = 7). Clinically inoperable patients (mean age 72.4 ± 10.2 years, 61% female, 28% macitentan monotherapy, observation period 2.0 (1.9-2.0) years) had a survival of 100% and clinical worsening (CW)-free survival of 88% at 2-year follow-up respectively, with a significant increased 6-min walking distance (6MWD). Technically inoperable/residual PH patients (mean age 62.1 ± 14.1 years, 60% female, 27% macitentan monotherapy, observation period 2.0 (1.0-2.0) years) had a 2-year survival and CW-free survival of 86% and 68% respectively, with significant improved 6MWD and NT-proBNP. Nonsevere AEs were reported in 30% of all patients.\n\n\n\nMacitentan mono- and combination therapy in non-operated CTEPH and residual PH is safe and improves clinical outcomes till 2-year follow-up.",
"affiliations": "Dept of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands; Dept of Pulmonary Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands.;Dept of Pulmonary Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands.;Dept of Pulmonary Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands.;Dept of Pulmonary Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands.;Dept of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands. Electronic address: m.post@antoniusziekenhuis.nl.",
"authors": "van Thor|M C J|MCJ|;Ten Klooster|L|L|;Snijder|R J|RJ|;Mager|J J|JJ|;Post|M C|MC|",
"chemical_list": "D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2020.105966",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "167()",
"journal": "Respiratory medicine",
"keywords": "Chronic thromboembolic pulmonary hypertension; Clinical worsening; Combination therapy; Macitentan; Survival",
"medline_ta": "Respir Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011655:Pulmonary Embolism; D011743:Pyrimidines; D013449:Sulfonamides; D013997:Time Factors; D016896:Treatment Outcome; D000070857:Walk Test; D016138:Walking",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "105966",
"pmc": null,
"pmid": "32421542",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term real world clinical outcomes of macitentan therapy in chronic thromboembolic pulmonary hypertension.",
"title_normalized": "long term real world clinical outcomes of macitentan therapy in chronic thromboembolic pulmonary hypertension"
} | [
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"companynumb": "NL-ACTELION-A-CH2020-204860",
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"reaction": [
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Upper respiratory tract infection",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
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{
"reactionmeddrapt": "Headache",
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"literaturereference": "VAN THOR M, TEN KLOOSTER L, SNIJDER R, MAGER J, POST M.. LONG-TERM REAL WORLD CLINICAL OUTCOMES OF MACITENTAN THERAPY IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION. RESPIRATORY MEDICINE. 2020?167",
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{
"abstract": "The efficacy and safety of immune checkpoint inhibitor (ICI) monotherapy in elderly patients with non-small cell lung cancer (NSCLC) remain unclear, especially in patients older than 80 years. We retrospectively reviewed the records of 10 patients older than 80 years with NSCLCs treated by ICIs. The median age was 85 years (range, 82-93 years), and 7 patients were men. The median length of follow-up was 13 months (range, 4.5-23 months). Eight patients had adenocarcinoma (3 of whom had exon 19 deletions), and two had squamous cell carcinoma. Expression of programmed cell death ligand 1 (PD-L1) was ≥ 50% in 3 patients, between 1% and 49% in 4 patients, < 1% in 1 patient, and undetected in 2 patients. Patients with undetected PD-L1 underwent transbronchial lung biopsy. Performance status was graded zero, one, and two in two, seven, and one patients, respectively. First-, second-, and third-line treatments were administered to three, three, and four patients, respectively. The 2-year overall survival rate was 30.0% (median, 285 days). Time to treatment failure rate on the 2 years was 10.0% (median, 167 days). One patient achieved a partial response, and one achieved a complete response. ICI-associated adverse events occurred in five patients. In summary, ICIs were effective in some patients older than 80 years; however, some experienced adverse effects. Elderly patients must be selected carefully for ICI treatment.",
"affiliations": "Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.;Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.;Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.;Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.;Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.;Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.",
"authors": "Chikaishi|Yasuhiro|Y|https://orcid.org/0000-0001-5015-8787;Inoue|Masaaki|M|;Kusanagi|Kasumi|K|;Honda|Yohei|Y|;Yoshida|Junichi|J|;Tanaka|Masao|M|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1002/agm2.12147",
"fulltext": "\n==== Front\nAging Med (Milton)\nAging Med (Milton)\n10.1002/(ISSN)2475-0360\nAGM2\nAging Medicine\n2475-0360\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/agm2.12147\nAGM212147\nShort Communication\nShort Communication\nEfficacy and safety of immune checkpoint inhibitor monotherapy in elderly patients with non‐small cell lung cancer\nCHIKAISHI et al.\nChikaishi Yasuhiro https://orcid.org/0000-0001-5015-8787\n1 cywmd0k2@med.uoeh-u.ac.jp\n\nInoue Masaaki 1\nKusanagi Kasumi 1\nHonda Yohei 1\nYoshida Junichi 1\nTanaka Masao 1\n1 Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan\n* Correspondence\nYasuhiro Chikaishi, Department of chest surgery, Shimonoseki City Hospital, 1‐13‐1 Kouyouchou, Shimonoseki, 750‐8520, Japan.\nEmail: cywmd0k2@med.uoeh-u.ac.jp\n\n29 1 2021\n3 2021\n4 1 10.1002/agm2.v4.1 4246\n28 12 2020\n04 1 2021\n10 1 2021\n© 2021 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nThe efficacy and safety of immune checkpoint inhibitor (ICI) monotherapy in elderly patients with non‐small cell lung cancer (NSCLC) remain unclear, especially in patients older than 80 years. We retrospectively reviewed the records of 10 patients older than 80 years with NSCLCs treated by ICIs. The median age was 85 years (range, 82‐93 years), and 7 patients were men. The median length of follow‐up was 13 months (range, 4.5‐23 months). Eight patients had adenocarcinoma (3 of whom had exon 19 deletions), and two had squamous cell carcinoma. Expression of programmed cell death ligand 1 (PD‐L1) was ≥ 50% in 3 patients, between 1% and 49% in 4 patients, < 1% in 1 patient, and undetected in 2 patients. Patients with undetected PD‐L1 underwent transbronchial lung biopsy. Performance status was graded zero, one, and two in two, seven, and one patients, respectively. First‐, second‐, and third‐line treatments were administered to three, three, and four patients, respectively. The 2‐year overall survival rate was 30.0% (median, 285 days). Time to treatment failure rate on the 2 years was 10.0% (median, 167 days). One patient achieved a partial response, and one achieved a complete response. ICI‐associated adverse events occurred in five patients. In summary, ICIs were effective in some patients older than 80 years; however, some experienced adverse effects. Elderly patients must be selected carefully for ICI treatment.\n\nelderly patient\nimmune checkpoint inhibitor\nnon‐small cell lung cancer\nsource-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:13.03.2021\nChikaishi Y , Inoue M , Kusanagi K , Honda Y , Yoshida J , Tanaka M . Efficacy and safety of immune checkpoint inhibitor monotherapy in elderly patients with non‐small cell lung cancer. Aging Med. 2021;4 :42–46. 10.1002/agm2.12147\n==== Body\nKey Point\n\nSignificant findings of this study\n\nWe evaluated the efficacy and safety of immune checkpoint inhibitor (ICI) monotherapy in elderly patients with non‐small cell lung cancer.\n\nWhat this study adds\n\nIn some patients older than 80 years, ICIs were effective, but others experienced adverse effects. Patients older than 80 years must be selected carefully for ICI treatment.\n\n1 INTRODUCTION\n\nImmunotherapy directed against programmed cell death protein 1 signaling has produced good responses in patients with advanced non‐small cell carcinoma (NSCLC). 1 , 2 , 3 , 4 , 5 Immune checkpoint inhibitors (ICIs) have been used to treat NSCLC, and even chemotherapy‐resistant patients have shown good results. 1 , 2 Nivolumab, which was the first ICI approved for chemotherapy‐resistant patients, produced better rates of progression‐free survival than did standard second‐line chemotherapy in a phase III clinical trial. 1 , 2 Three ICIs have been approved for NSCLC as monotherapy in Japan: nivolumab, pembrolizumab, and atezolizumab. Pembrolizumab is approved as first‐line chemotherapy for patients with positive expression of programmed cell death ligand 1 (PD‐L1). 3 , 6 Nivolumab and atezolizumab are approved for chemotherapy‐resistant patients. Moreover, for patients with untreated NSCLC, platinum‐based doublet combinations with ICI therapy have resulted in better progression‐free survival and overall survival. 7 , 8\n\nSeveral studies have shown that certain cytotoxic agents are safe and effective in elderly patients. 9 , 10 , 11 , 12 Standard chemotherapy for elderly patients is docetaxel monotherapy or carboplatin plus pemetrexed. 11 , 12 However, the safety and effectiveness of ICIs in patients with NSCLC who are elderly or have poor performance status remain unclear. It is important to investigate the safety and effectiveness of ICIs.\n\nHerein, we present data from patients older than 80 years in whom NSCLC was treated by ICIs at a single institution.\n\n2 PATIENTS AND METHODS\n\nWe retrospectively examined data from patients older than 80 years who received ICIs at our institution from December 2015 to April 2019 for NSCLC, regardless of treatment duration. The population included patients with advanced and recurrent disease.\n\nBaseline clinical characteristics were determined by retrospective review of medical records at the beginning of ICI administration.\n\nSpecimens for diagnosis were obtained after surgery, transbronchial biopsy, computed tomography‐guided biopsy, and pleural effusion.\n\nPatients were administered the full ICI dose in each treatment session. Patients continued treatment until the emergence of progressive disease, development of unacceptable toxic effects, or withdrawal of consent to treatment. When ICI treatment was suspended, some patients then selected systemic chemotherapy, and others selected best supportive care.\n\nWe assessed overall survival, time to treatment failure after initial ICI administration, and the detailed treatment course of each patient. Overall survival was determined from the date of ICI initiation to the date of death from any cause or the follow‐up during survival. Time to treatment failure was measured from the first day of initial ICI intake to the date of discontinuance for any reason or the last follow‐up during survival. We set November 2020 as the time of data cutoff. Tumor responses were classified as complete responses, partial responses, stable disease, or progressive disease, according to the Response Evaluation Criteria in Solid Tumors guidelines. 13\n\nThe Kaplan–Meier method was used to calculate survival curves. Statview version 5.0 (Abacus Concepts, Inc.) was used for all statistical analyses.\n\n3 RESULTS\n\n3.1 Patients\n\nFrom December 2015 to April 2019, 10 patients older than 80 years received ICIs for NSCLC at our institution. Table 1 summarizes the patients’ characteristics at baseline, initiation of ICI administration, and patients’ demographic and clinical characteristics. Detailed descriptions are provided in Table 2.\n\nTABLE 1 Baseline clinical and pathological characteristics of the enrolled patients\n\nClinical factor\tCategory\tNo. of patients\t\nGender\tFemale/male\t3/7\t\nAge, y\tMedian/average\t85/86\t\nRange\t82‐93\t\nSmoking status\tCurrent smoker\t2\t\nNever smoker\t2\t\nFormer smoker\t3\t\nUnknown\t3\t\nPS (ECOG)\t0/1/2\t2/7/1\t\nHistology\tAdenocarcinoma (19del)\t8 (3)\t\nSquamous\t2\t\nPD‐L1\tOver 50%\t3\t\n1%‐49%\t3\t\nUnder 1%\t2\t\nUndecidable\t2\t\nTreatment history\tYes\t7\t\nSecond line/over third line\t3/4\t\nNo\t3\t\nStage\tIII/IV/recurrence\t1/7/2\t\nInitial ICIs\tNivolumab\t2\t\nPembrolizumab\t6\t\nAtezolizumab\t2\t\nAbbreviations: ECOG, Eastern Cooperative Oncology Group; ICIs, immune checkpoint inhibitors; PD‐L1, programmed cell death ligand 1; PS, Performance Status\n\nJohn Wiley & Sons, Ltd\n\nTABLE 2 Baseline clinical and pathological characteristics of the enrolled each patient\n\nCase\tAge, y/sex\tPS\tSmoking status\tHistology\tPD‐L1, %\tTiming of ICI\tSpecimens for diagnosis\tStage\tInitial ICIs\t\n1\t82/F\t1\tNever\tAdenoca.\t50‐60\t7th\tSurgery\tRecurrence\tPembrolizumab\t\n2\t93/M\t1\tUnknown\tAdenoca.\t10\t2nd\tSurgery\tIVA\tPembrolizumab\t\n3\t85/M\t1\tCurrent\tAdenoca.\t1‐24\t6th\tPleural effusion\tIVA\tNivolumab\t\n4\t82/M\t1\tUnknown\tSq.\t< 1\t2nd\tSurgery\tRecurrence\tAtezolizumab\t\n5\t84/M\t1\tCurrent\tAdenoca.\tUndecidable\t3rd\tTBB\tIV A\tNivolumab\t\n6\t89/F\t0\tUnknown\tAdenoca.\t75\t1st\tSurgery\tIV A\tPembrolizumab\t\n7\t88/M\t1\tFormer\tAdenoca.\t1\t3rd\tSurgery\tIV B\tPembrolizumab\t\n8\t82/M\t1\tUnknown\tAdenoca.\t90\t1st\tTBB\tIV B\tPembrolizumab\t\n9\t84/M\t0\tFormer\tSq.\t1 ~ 24\t1st\tTBB\tIII B\tPembrolizumab\t\n10\t91/F\t2\tFormer\tAdenoca.\tUndecidable\t2nd\tCT guided biopsy\tIVA\tAtezolizumab\t\nAbbreviations: Adenoca., adenocarcinoma; CT, computed tomography; F, female; ICI, immune checkpoint inhibitor; M, male; PD‐L1, programmed cell death ligand 1; PS, performance status; Sq., squamous cell carcinoma; TBB, transbronchial lung biopsy.\n\nJohn Wiley & Sons, Ltd\n\nThe median age was 85 years (range, 82‐93 years); 2 patients were older than 90 years. Performance status was rated zero for two patients, one for seven patients, and two for one patient. Seven patients (70%) were men; eight patients had a diagnosis of adenocarcinoma (3 of whom had exon 19 deletions), and two had a diagnosis of squamous cell carcinoma. Before ICI treatment, seven patients had undergone at least first‐line treatment for NSCLC. At initiation of ICI treatment, two patients had exhibited recurrent disease postoperatively, one patient had stage III disease, and seven patients had stage IV disease. For initial ICI treatment, two patients received nivolumab, six received pembrolizumab, and two received atezolizumab.\n\n3.2 Efficacy\n\nAt the time of data cutoff, the median length of follow‐up was 13 months (range, 4.5‐28 months). Among the 10 patients, the 2‐year overall survival rate was 30.0% (Figure 1A). Time to treatment failure rate on the 2 years was 10.0% (Figure 1B). Initial treatment outcomes for all patients administered ICIs are depicted in Figure 2 as swimmer plots. One patient achieved a partial response, and one achieved a complete response. Adverse events associated with ICIs occurred in five patients: ulcerative colitis in three, interstitial lung disease in one, and myasthenia gravis in one. Three of the five patients were treated with steroids. In 9 patients, ICIs were administered over a 4‐month period. Treatment lasted longest for one patient (case 2 in Table 2), in whom stable disease was achieved. In this case, the patient complained of diarrhea (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0, 14 grade 2). Pembrolizumab was discontinued, and methylprednisolone (500 mg/body) was administered for 3 days. Pembrolizumab treatment resume after methylprednisolone treatment. Two patients (cases 5 and 6 in Table 2) achieved long survival after ICI treatment was discontinued because of immune‐related adverse events (irAEs). In case 5, the patient complained of diarrhea (CTCAE grade 4), ulcerative colitis was diagnosed by colonoscopy, and methylprednisolone treatment (1 mg/kg/day) was started. Methylprednisolone treatment was administered for 2 months with tapering. In case 6, the tumor response was a complete response; however, interstitial lung disease occurred. Methylprednisolone treatment (1 mg/kg/day) was started; maintenance treatment (5‐10 mg/body) was necessary for approximately 8 months in this patient.\n\nFIGURE 1 Kaplan–Meier curves for all patients who received immune checkpoint inhibitor (ICI) monotherapy for non‐small cell lung cancer. A, Overall survival. B, Time to treatment failure\n\nFIGURE 2 Individual swimmer pilots for all patients (denoted by numbers in circles) who received immune checkpoint inhibitor (ICI) monotherapy for non‐small cell lung cancer (0 represents the beginning of ICI treatment). Black arrows indicate patients who were alive at the time of data cutoff. Atezo, atezolizumab; BSC, best supportive care; CR, complete response; ILD, interstitial lung disease; MG, myasthenia gravis; nabPTX, nab‐paclitaxel; NE, not evaluated; Nivo, nivolumab; PD, progressive disease; Pembro, pembrolizumab; PR, partial response; SD, stable disease; UC, ulcerative colitis\n\n4 DISCUSSION\n\nTo the best of our knowledge, this is the only retrospective study of ICI treatment in patients older than 80 years in a real‐world single institution setting; in some reports, patients have been 75 years of age or older. 15 , 16 Moreover, there are few retrospective studies from the Department of Chest Surgery of the single institution.\n\nIn our study, 9 of 10 patients received ICIs over a 4‐month period. It seems controversial whether these results should be considered long or short term, but other studies of ICI have demonstrated progression‐free survival for < 4 months. 1 , 2 Because our study included patients with progressive disease, it is not possible to conclude that our data reflected similar treatment outcomes.\n\nOf our patients, one (case 2) received treatment for more than 2 years, and two (cases 5 and 6) are still alive more than 2 years since ICI treatment, despite the need to discontinue treatment because of irAEs. According to some reports, 1 , 2 , 3 , 4 ICIs can achieve long‐term survival (the so‐called tail plateau 17 ). As in our older patients, ICIs may be administered safely and effectively in selected cases.\n\nIn this study, 5 of the 10 patients experienced irAEs more severe than CTCAE grade 2. Three patients received steroid treatment for irAEs; all three experienced improvement in irAEs. Major clinical studies 1 , 2 , 3 , 4 have shown that irAEs of any grade occur in 19.4%‐69% of patients receiving chemotherapy, and 0.8%‐15% experience irAEs of CTCAE grades 3‐5. In this study, 50% of our patients experienced irAEs of any grade, and in 20%, irAEs were graded higher than 3. The rate of irAEs is slightly worse in this study than in previous studies. Because this study focused on older patients, however, ICI may not have been the cause of irAE. In particular, two patients who experienced diarrhea did not undergo colonoscopy because of their age; thus, they may have had diverticulitis or other conditions. The irAEs caused by ICIs were serious conditions (ulcerative colitis, myasthenia gravis, and interstitial lung disease); thus, irAEs that develop during ICI therapy must be investigated and treated accordingly.\n\nThe present study has an important limitation that it was a retrospective study and only had 10 patient’s data. We believe our real‐world data are nonetheless important. This study has used data from a single institution. However, the retrospective study of 10 patients older than 80 years who received ICIs for NSCLC at a single institution has been rarely reported. Moreover, our study includes 2 patients older than 90 years.\n\n5 CONCLUSIONS\n\nICI treatment may be effective in patients older than 80 years. ICIs may be key drugs for elderly patients with NSCLC if major irAEs can be managed without curtailing activities of daily living. However, in some cases, severe adverse effects occurred and had to be managed with steroids. Patients older than 80 years must be selected carefully for ICI treatment.\n\nCONFLICTS OF INTEREST\n\nNothing to disclose.\n\nAUTHOR CONTRIBUTIONS\n\nWriting of the paper: Chikaishi. Design of the study: Chikaishi and Inoue. Review of the study: Chikaishi. Data collection: Chikaishi, Kusanagi, Honda, and Yoshida. Review of medical records: Chikaishi, Kusanagi, Honda, and Yoshida. Statistical analysis: Chikaishi. Literature review: Inoue. Read and approved the final manuscript: Inoue and Tanaka. Initial statistical analysis: Yoshida.\n\nACKNOWLEDGMENT\n\nThe authors thank the Enago Group (https://www.enago.jp/) for editing a draft of this manuscript.\n==== Refs\nREFERENCES\n\n1 Brahmer J , Reckamp KL , Baas P , et al. Nivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer. N Engl J Med. 2015;9 (2 ):123‐135.\n2 Borghaei H , Paz‐Ares L , Horn L , et al. Nivolumab versus docetaxel in advanced nonsquamous non‐small‐cell lung cancer. N N Engl J Med. 2015;22 (17 ):1627‐1639.\n3 Garon EB , Rizvi NA , Hui R , et al. Pembrolizumab for the treatment of non‐small‐cell lung cancer. N Engl J Med. 2015;21 (21 ):2018‐2028.\n4 Rittmeyer A , Barlesi F , Waterkamp D , et al. Atezolizumab versus docetaxel in patients with previously treated non‐small‐cell lung cancer (OAK): a phase 3, open‐label, multicentre randomised controlled trial. Lancet. 2017;21 (10066 ):255‐265.\n5 Ichiki Y , Taira A , Chikaishi Y , et al. Prognostic factors of advanced or postoperative recurrent non‐small cell lung cancer targeted with immune check point inhibitors. J Thorac Dis. 2019;11 (4 ):1117‐1123.31179053\n6 Reck M , Rodríguez‐Abreu D , Robinson AG , et al. Pembrolizumab versus chemotherapy for PD‐L1‐positive non‐small‐cell lung cancer. N Engl J Med. 2016;10 (19 ):1823‐1833.\n7 Gandhi L , Rodríguez‐Abreu D , et al. Pembrolizumab plus chemotherapy in metastatic non‐small‐cell lung cancer. N Engl J Med. 2018;31 (22 ):2078‐2092.\n8 Socinski MA , Jotte RM , Cappuzzo F , et al. Atezolizumab for first‐line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;14 (24 ):2288‐2301.\n9 Hesketh PJ , Lilenbaum RC , Chansky K , et al. Chemotherapy in patients > or = 80 with advanced non‐small cell lung cancer: combined results from SWOG 0027 and LUN 6. J Thorac Oncol. 2007;2 (6 ):494‐498.17545843\n10 Abe T , Takeda K , Ohe Y , et al. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non‐small‐cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015;20 (6 ):575‐581.\n11 Quoix E , Zalcman G , Oster JP , et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non‐small‐cell lung cancer: IFCT‐0501 randomised, phase 3 trial. Lancet. 2011;17 (9796 ):1079‐1088.\n12 Okamoto I , Nokihara H , Yoh K , et al. Randomized phase III study comparing carboplatin plus pemetrexed followed by pemetrexed versus docetaxel in elderly patients with advanced non‐squamous non‐small‐cell lung cancer (JCOG1210/WJOG7813L). J Clin Oncol. 2019;37 (15_suppl ):9031.\n13 Eisenhauer EA , Therasse P , Bogaerts J , et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). J Eur J Cancer. 2009;45 :228‐247.\n14 NIH . Common Terminology Criteria for Adverse Events (CTCAE); 2017. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf\n15 Yamaguchi O , Imai H , Minemura H , et al. Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non‐small cell lung cancer. Cancer Chemother Pharmacol. 2020;85 (4 ):761‐7771.32193618\n16 Imai H , Wasamoto S , Yamaguchi O , et al. Efficacy and safety of first‐line pembrolizumab monotherapy in elderly patients (aged ≥ 75 years) with non‐small cell lung cancer. J Cancer Res Clin Oncol. 2020;146 (2 ):457‐466.31853661\n17 Kataoka N , Kunimatsu Y , Tachibana Y , et al. Atezolizumab in combination with carboplatin and etoposide for heavily treated small cell lung cancer. Thorac Cancer. 2020;11 (9 ):2740‐2742.32706170\n\n",
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"abstract": "Cutaneous cryptococcosis, an infectious disease resulting from Cryptococcus neoformans, primarily affects immunodeficient individuals. Here, we report a case of mediastinal small cell carcinoma (MSCC) complicated with multiple skin and soft tissue infections mimicking erysipelas and cellulitis. Antibiotics for bacteria were ineffective and a culture of pus from the infected areas revealed Cryptococcus neoformans in this patient. The absence of any evidence indicative of systemic cryptococcal infection leads to a final diagnosis of primary cutaneous cryptococcosis (PCC). Following two weeks of fluconazole at 400 mg/day and 200 mg/day for the subsequent three months, combined with incision, irrigation and drainage, the wound gradually healed. An analysis and discussion of the clinical features of this patient are presented. This case alerts clinicians as to the possibility of Cryptococcus neoformans in patients with advanced malignant tumors complicated with multiple skin and soft tissue infections. While a timely diagnosis and treatment of PCC in this patient resulted in a favorable outcome, the patient succumbed to the malignant tumor at six months post-discharge.",
"affiliations": "Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.;Department of Oral and Maxillofacial Surgery, Stomatology College of Dalian Medical University, Dalian, Liaoning, People's Republic of China.;Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.;Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.;Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.",
"authors": "Hu|Mengjie|M|0000-0002-3444-2160;Chai|Songling|S|;Lei|Wenyi|W|0000-0003-1642-6551;Liao|Kexin|K|;Zhang|Rongxin|R|",
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"fulltext": "\n==== Front\nInfect Drug Resist\nInfect Drug Resist\nidr\nidr\nInfection and Drug Resistance\n1178-6973\nDove\n\n325826\n10.2147/IDR.S325826\nCase Report\nMediastinal Small Cell Carcinoma with Primary Cutaneous Cryptococcosis: A Rare Case Report\nHu et al\nHu et al\nhttp://orcid.org/0000-0002-3444-2160\nHu Mengjie 1 *\nChai Songling 2 *\nhttp://orcid.org/0000-0003-1642-6551\nLei Wenyi 1\nLiao Kexin 1\nZhang Rongxin 1\n1 Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China\n2 Department of Oral and Maxillofacial Surgery, Stomatology College of Dalian Medical University, Dalian, Liaoning, People’s Republic of China\nCorrespondence: Rongxin Zhang Department of Dermatology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian, 116027, Liaoning, People’s Republic of ChinaTel +8617709873080Fax +86-411-84672130 Email zrx_1980@126.com\n* These authors contributed equally to this work\n\n09 9 2021\n2021\n14 36933697\n21 6 2021\n02 9 2021\n© 2021 Hu et al.\n2021\nHu et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ 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).\nAbstract\n\nCutaneous cryptococcosis, an infectious disease resulting from Cryptococcus neoformans, primarily affects immunodeficient individuals. Here, we report a case of mediastinal small cell carcinoma (MSCC) complicated with multiple skin and soft tissue infections mimicking erysipelas and cellulitis. Antibiotics for bacteria were ineffective and a culture of pus from the infected areas revealed Cryptococcus neoformans in this patient. The absence of any evidence indicative of systemic cryptococcal infection leads to a final diagnosis of primary cutaneous cryptococcosis (PCC). Following two weeks of fluconazole at 400 mg/day and 200 mg/day for the subsequent three months, combined with incision, irrigation and drainage, the wound gradually healed. An analysis and discussion of the clinical features of this patient are presented. This case alerts clinicians as to the possibility of Cryptococcus neoformans in patients with advanced malignant tumors complicated with multiple skin and soft tissue infections. While a timely diagnosis and treatment of PCC in this patient resulted in a favorable outcome, the patient succumbed to the malignant tumor at six months post-discharge.\n\nKeywords\n\nmediastinal small cell carcinoma\nprimary cutaneous cryptococcosis\nCryptococcus neoformans\nimmunodeficiency\ntherapy\nNatural Science Foundation of Liaoning Province, China This work was supported by the Natural Science Foundation of Liaoning Province, China [No.2020-MS-262, No.20180550028].\n==== Body\npmcIntroduction\n\nCryptococcosis is a chronic, subacute or even acute infection of the brain, meninges, lungs, skin or entire body resulting from Cryptococcus infection. Cryptococcus neoformans, an opportunistic pathogen mainly infecting immunocompromised hosts, invades the central nervous system and lungs.1–3 Cutaneous infections are the third most common clinical manifestation of cryptococcosis, and these patients can present with various skin aberrations such as, papules, nodules, tumors, ulcerations, ecchymoses, pustules, abscesses and granulomas.4–7 Early identification of polymorphic skin manifestations and treatment are essential for an effective prognosis of the infection. This condition can be divided into primary and secondary cutaneous cryptococcosis. Primary cutaneous cryptococcosis (PCC), which is rare, but life-threatening, was first recognized in 2003. It mainly results from direct infection of skin trauma with no apparent symptoms of systemic disease.8 Secondary cutaneous cryptococcosis, a more common type, mainly spreads from the brain, lung and other parts of the body. Immunodeficient individuals, as can result from AIDS, malignant tumors, organ transplantation and treatment with corticosteroids and immunosuppressive agents, represent the most susceptible cohort for cutaneous cryptococcosis.9\n\nMediastinal small cell carcinoma (MSCC), a rare tumor with a poor prognosis, is characterized by lesions located in the mediastinum. To the best of our knowledge, no more than 20 case reports of MSCC have been published in the literature.10 Here, we describe a rare, previously unreported case of PCC in a woman with MSCC.\n\nCase Presentation\n\nA 53-year-old female presented with multiple painful skin lesions on both thighs, without chills and fever. She had been treated with cephalosporin antibiotics prior to admission, however, her condition was not relieved and gradually aggravated. The patient had a history of MSCC for two years and received surgical treatment for this condition followed by four cycles of chemotherapy with irinotecan and cisplatin. Chemotherapy was eventually abandoned due to bone marrow suppression and, after one year, multiple metastases of the tumor were present throughout her entire body. She had no history of human immunodeficiency virus (HIV) infection and no contact with pigeons, poultry or other types of animals. Physical examination indicated painful skin lesions with erythema, swelling and abscesses on both thighs (Figure 1A–D). Laboratory assay results revealed that carbohydrate antigen 125 (CA125), CA199 and neuron-specific enolase (NSE) were substantially increased, while results of her computed tomography (CT) scan of the chest and abdomen showed multiple metastases of the tumor within the lung, liver, left adrenal gland, retroperitoneum, vertebral body and caput femoris (Figure 2A–D). Bacterial culture of the abscess puncture fluid was negative, but fungal culture and antifungal susceptibility tests revealed the growth of Cryptococcus and its sensitisation to fluconazole. Blood and cerebrospinal fluid (CSF) cultures, cryptococcal antigen and serological tests were negative. No abnormalities were observed for other test results, such as transthoracic echocardiography (TTE), electrocardiogram (ECG), CT of brain and HIV infection. The diagnosis was PCC based on these clinical features and results of the pus fungal culture. Treatment with fluconazole (400 mg/day) via intravenous infusion was then initiated and the abscess cavities were rinsed with fluconazole saline solution twice daily after local incision and drainage (Figure 3A and B). In addition, the patient received symptomatic and supportive treatment. After a week of this treatment, inflammation within the skin lesions was clearly improved (Figure 3C and D), but wound healing was very slow due to the cachexia resulting from the advanced stage of the tumor. The fluconazole dose was then changed to an oral administration of 200 mg/day for the following three months after the initial two-week intravenous infusion. Follow-up of the patient indicated no recurrence of the skin lesions. Unfortunately, she died six months post-discharge as a result of multiple organ failure from tumor metastases.Figure 1 Physical examination of the female patient diagnosed as mediastinal small cell carcinoma complicated with primary cutaneous cryptococcosis. Multiple painful skin lesions with erythema and swelling on both thighs (A and B). Abscesses on both thighs (C and D).\n\nFigure 2 Computed tomography (CT) scan of the chest and abdomen. Multiple metastases of the tumor were observed in the lung (A), liver, vertebral body (B), retroperitoneum (C), and caput femoris (D).\n\nFigure 3 Treatment with cutting the abscesses and lavaging the abscess cavities with fluconazole saline solution (A). A large amount of pus from the abscesses (B). Inflammation within the skin lesions was obviously improved after a week of treatment (C and D).\n\nDiscussion\n\nCryptococcus neoformans is an opportunistic pathogen found in soil, trees, decaying wood, fruit, vegetables and bird droppings.11 Compared with systemic diseases, PCC is recognized as a distinct clinical entity and rarely reported in patients with normal immune function. Clinical diagnosis of PCC is usually difficult due to its nonspecific skin manifestations characterized by infiltrative lesions confined to the skin and subcutaneous tissue. Culture and histology remain the gold standards for the diagnosis of cryptococcosis.12 While no definitive standard treatment protocol exists for PCC, fluconazole and itraconazole are commonly used to treat this condition, with their dose and treatment durations contingent on the patient’s immune status and degree of involvement.13,14 A treatment duration of 6–12 months is recommended by the Infectious Diseases Society of America (IDSA) for patients without dissemination and nervous system involvement.3\n\nThere are reports of PCC in patients with lymphoma, leukaemia and rectal adenocarcinoma combined with multiple metastases who were treated with targeted drugs, immunosuppressive agents or radiotherapy.15–17 However, to the best of our knowledge, the patient presented here represents the first reported case of PCC with MSCC. The presentation of multiple skin lesions limited to both thighs without systemic dissemination in this patient leads to an initial misdiagnosis of erysipelas, with the antibiotic therapy administered being ineffective. Culture of pus from the infected areas revealed Cryptococcus neoformans. The occurrence of PCC is mainly due to immunodepression as a result of MSCC metastases without treatment. Although the patient succumbed to the progression of the cancer six months after discharge, the topical treatment of fluconazole achieved a favorable outcome with no recurrence of skin lesions. Fluconazole is routinely used as a broad-spectrum antifungal agent in the treatment of cryptococcosis, usually administered orally or intravenously.18 In addition to this systemic antifungal agent treatment, the abscesses were incised and the abscess cavities were lavaged with fluconazole saline solution, to reduce the progression of the lesions. Although the patient had terminal cancer with multiple systemic metastases, presenting cachexia, hypoproteinemia and was immunocompromised, which increased her chances of being infected, there was no systemic dissemination due to the infection found at the time of admission. This case indicates that clinicians should be alerted to the possibility of Cryptococcus neoformans in patients with advanced malignant tumors complicated with multiple skin and soft tissue infections. Skin lesions that do not respond to antibiotics require additional tests to exclude other pathogens, such as fungi. Timely diagnosis and treatment are essential for the recovery of cryptococcosis.\n\nAbbreviations\n\nMSCC, mediastinal small cell carcinoma; PCC, Primary cutaneous cryptococcosis; HIV, human immunodeficiency virus; CA125, carbohydrate antigen 125; CA199, carbohydrate antigen 199; NSE, neuron-specific enolase; CT, computed tomography; CSF, cerebrospinal fluid; TTE, transthoracic echocardiography; ECG, electrocardiogram.\n\nEthical Approval\n\nThe patient’s informed consent for publication of the case details including the images was obtained and the study was approved by Ethics Committee of the Second Hospital of Dalian Medical University.\n\nAuthor Contributions\n\nAll authors have made significant contributions to the work reported, such as data acquisition, analysis, interpretation, drafting, revising, giving final approval of the version to be published, agreeing on the journal and to take responsibility and be accountable for the contents of the article.\n\nDisclosure\n\nThe authors declare no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. GaylordEA, ChoyHL, DoeringTL. Dangerous Liaisons: interactions of Cryptococcus neoformans with host phagocytes. Pathogens. 2020;9 (11 ):891. doi:10.3390/pathogens9110891\n2. GushikenAC, SahariaKK, BaddleyJW. Cryptococcosis. Infect Dis Clin North Am. 2021;35 (2 ):493–514. doi:10.1016/j.idc.2021.03.012 34016288\n3. PerfectJR, DismukesWE, DromerF, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50 (3 ):291–322. doi:10.1086/649858 20047480\n4. ChristiansonJC, EngberW, AndesD. Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts. Med Mycol. 2003;41 (3 ):177–188. doi:10.1080/1369378031000137224 12964709\n5. MarquesSA, BastaziniI, MartinsALGP, et al. Primary cutaneous cryptococcosis in Brazil: report of 11 cases in immunocompetent and immunosuppressed patients. Int J Dermatol. 2012;51 (7 ):780–784. doi:10.1111/j.1365-4632.2011.05298.x 22715820\n6. LonghitanoS, PeccerilloF, OdoriciG, BigiL, PellacaniG. An unusual presentation of primary cutaneous cryptococcosis. Dermatol Ther. 2019;32 (4 ):e12942. doi:10.1111/dth.12942 31012217\n7. ShalomG, HorevA. Primary Cutaneous Cryptococcosis: an Unusual Injection Site Infection. Case Rep Dermatol. 2020;12 (2 ):138–143. doi:10.1159/000508783 32999649\n8. NeuvilleS, DromerF, MorinO, et al. Primary cutaneous cryptococcosis: a distinct clinical entity. Clin Infect Dis. 2003;36 (3 ):337–347. doi:10.1086/345956 12539076\n9. NoguchiH, MatsumotoT, KimuraU, HirumaM, KusuharaM, IhnH. Cutaneous Cryptococcosis. Med Mycol J. 2019;60 (4 ):101–107. doi:10.3314/mmj.19.008 31787730\n10. DaiW, LiuM, ZhuangX, LiQ, WangD. Mediastinal small cell carcinoma: a unique clinical entity? Clin Transl Oncol. 2016;18 (5 ):515–520. doi:10.1007/s12094-015-1398-4 26329297\n11. YuCH, ChenY, DesjardinsCA, et al. Landscape of gene expression variation of natural isolates of Cryptococcus neoformans in response to biologically relevant stresses. Microb Genom. 2020;6 (1 ):e000319. doi:10.1099/mgen.0.000319\n12. DuL, YangY, GuJ, ChenJ, LiaoW, ZhuY. Systemic review of published reports on primary cutaneous cryptococcosis in immunocompetent patients. Mycopathologia. 2015;180 (1–2 ):19–25. doi:10.1007/s11046-015-9880-7 25736173\n13. SaagMS, GraybillRJ, LarsenRA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2000;30 (4 ):710–718. doi:10.1086/313757 10770733\n14. ChoiH, KimYI, NaCH, KimMS, ShinBS. Primary Cutaneous Cryptococcosis in an Older Immunocompetent Patient: a Case Report. Ann Geriatr Med Res. 2020;24 (2 ):148–151. doi:10.4235/agmr.20.0012 32743335\n15. PeriAM, RossioR, TafuriF, et al. Atypical primary cutaneous cryptococcosis during ibrutinib therapy for chronic lymphocytic leukemia. Ann Hematol. 2019;98 (12 ):2847–2849. doi:10.1007/s00277-019-03837-1 31741032\n16. RomanoC, TaddeucciP, DonatiD, MiraccoC, MassaiL. Primary cutaneous cryptococcosis due to Cryptococcus neoformans in a woman with non-Hodgkin’s lymphoma. Acta Derm Venereol. 2001;81 (3 ):220–221. doi:10.1080/000155501750376429 11558889\n17. PosadaC, de la TorreC, González-SixtoB, CrucesMJ. Primary cutaneous cryptococcosis presenting with a sporotrichoid pattern in a cancer patient. Actas Dermosifiliogr. 2009;100 (1 ):78–80. doi:10.1016/S0001-7310(09)70064-X 19268119\n18. IzumikawaK, KakeyaH, SakaiF, et al. Executive Summary of JSMM Clinical Practice Guidelines for Diagnosis and Treatment of Cryptococcosis. Med Mycol J. 2020;61 (4 ):61–89. doi:10.3314/mmj.20.001 33250505\n\n",
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},
{
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{
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "Hu M, Chai S, Lei W, Liao K, Zhang R. Mediastinal small cell carcinoma with primary cutaneous cryptococcosis: A rare case report. Infection and Drug Resistance. 2021;14:3693-7.",
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},
{
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{
"reactionmeddrapt": "Myelosuppression",
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}
],
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},
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"literaturereference": "Zhang, R.. Mediastinal small cell carcinoma with primary cutaneous cryptococcosis: A rare case report.. Infection and Drug Resistance. 2021;14:3693-7",
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] |
{
"abstract": "Steroid-refractory graft-versus-host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Alternative treatment options are often insufficient. Several studies have proven the efficacy of mesenchymal stromal cells (MSCs) in the treatment of therapy-refractory acute GvHD in adult and pediatric patients. Long-term data in pediatric patients are scarce. In this retrospective analysis, a total of 25 patients with a median age of 10.6 years (range 0.6-22.1 years) who received bone marrow-derived MSCs after alloHSCT for the treatment of steroid-refractory III and IV GvHD were analyzed. The median observation period of the surviving patients was 9.3 years (1.3-12.7 years) after HSCT. Among the 25 patients, 10 (40.0%) died [relapse (n = 3), multiorgan failure (n = 6), cardiorespiratory failure (n = 1)] at median 0.5 years (0.2-2.3 years) after HSCT. Partial response and complete remission (PR, CR) of the GvHD were achieved in 76.0% and 24.0% of the patients, respectively. Transplant-related mortality was 0% in the patients who achieved CR after MSC treatment and 26.3% for those with PR. A median improvement by one intestinal or liver GvHD stage (range 1-4) could be achieved after MSC application. No potentially MSC-related long-term adverse effects, for example, secondary malignancy, were identified. In conclusion, the intravenous application of allogeneic MSCs was safe and proved effective for the treatment of steroid-refractory GvHD. However, larger, prospective, and randomized trials are needed to evaluate these findings.",
"affiliations": "Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Experimental and Clinical Research Center, GMP-Facility for Cellular Therapies, Charité Universitätsmedizin Berlin, Campus Berlin Buch, Berlin, Germany.;Department of Pediatric Hematology and Oncology, University of Würzburg, Würzburg, Germany.;Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;University Hospital and Comprehensive Cancer Center Tübingen, Universitätsklinikum Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Division for Pediatric Stem Cell Transplantation and Immunology, Clinic for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Döring|Michaela|M|;Cabanillas Stanchi|Karin Melanie|KM|;Lenglinger|Katrin|K|;Treuner|Claudia|C|;Gieseke|Friederike|F|;Erbacher|Annika|A|;Mezger|Markus|M|;Vaegler|Martin|M|;Schlegel|Paul-Gerhardt|PG|;Greil|Johann|J|;Bettoni da Cunha Riehm|Claudia|C|;Faul|Christoph|C|;Schumm|Michael|M|;Lang|Peter|P|;Handgretinger|Rupert|R|;Müller|Ingo|I|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/scd.2020.0191",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-3287",
"issue": "30(5)",
"journal": "Stem cells and development",
"keywords": "graft-versus-host disease; hematopoietic stem cell transplantation; intestinal graft-versus-host disease; mesenchymal stem cells; mesenchymal stromal cells; pediatric patients",
"medline_ta": "Stem Cells Dev",
"mesh_terms": null,
"nlm_unique_id": "101197107",
"other_id": null,
"pages": "234-246",
"pmc": null,
"pmid": "33446053",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-Term Follow-Up After the Application of Mesenchymal Stromal Cells in Children and Adolescents with Steroid-Refractory Graft-Versus-Host Disease.",
"title_normalized": "long term follow up after the application of mesenchymal stromal cells in children and adolescents with steroid refractory graft versus host disease"
} | [
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"abstract": "BACKGROUND\nAngiotensin receptor blocker (ARB) can increase serum creatinine or potassium levels in patients with renal insufficiency, renal artery stenosis, heart failure or hypovolemia, but hardly cause severe kidney injury in patients without any risk factors. A case of severe acute interstitial nephritis (AIN) induced by valsartan was reported here.\nA 62-year-old female with nausea for 1 month and acute deterioration of kidney function for 2 weeks was admitted. She had a history of hypertension for 5 months and had taken valsartan 40 mg daily for 4 months. Although the valsartan had been stopped for 2 weeks, the serum creatinine continuously increased after admission. Kidney biopsy demonstrated the eosinophils infiltration in interstitium.\nAIN induced by valsartan.\n\n\nMETHODS\nThe patient was treated with glucocorticoid.\n\n\nRESULTS\nThe serum creatinine decreased gradually and got back to normal level 5 months later. Then therapy of glucocorticoid was stopped. Renal artery stenosis was excluded by computed tomography angiography (CTA).\n\n\nCONCLUSIONS\nAlthough valsartan-induced allergy has been reported previously, AIN was firstly recognized as a severe complication of this drug. We suggest when there is a ARB-associated continuous deterioration of kidney function for patients without renal insufficiency, renal artery stenosis, heart failure or hypovolemia, AIN should be thought of and therapy with glucocorticoid should be considered if necessary.",
"affiliations": "Department of Hematology, Tianjin Medical University General Hospital, Tianjin.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.",
"authors": "Chen|Tong|T|;Xu|Peng-Cheng|PC|;Hu|Shui-Yi|SY|;Yan|Tie-Kun|TK|;Jiang|Jian-Qing|JQ|;Jia|Jun-Ya|JY|;Wei|Li|L|;Shang|Wen-Ya|WY|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30732201MD-D-18-0757610.1097/MD.0000000000014428144285200Research ArticleClinical Case ReportSevere acute interstitial nephritis induced by valsartan A case reportChen Tong PhDaXu Peng-cheng PhDb∗Hu Shui-yi PhDbYan Tie-kun MScbJiang Jian-Qing MDbJia Jun-ya PhDbWei Li MScbShang Wen-ya MScbNA. a Department of Hematology, Tianjin Medical University General Hospital, Tianjinb Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.∗ Correspondence: Peng-cheng Xu, Department of Nephrology, Tianjin Medical University General Hospital, Tianjin 300052, China (e-mail: nkxpc@163.com).2 2019 08 2 2019 98 6 e1442818 10 2018 10 1 2019 15 1 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nAngiotensin receptor blocker (ARB) can increase serum creatinine or potassium levels in patients with renal insufficiency, renal artery stenosis, heart failure or hypovolemia, but hardly cause severe kidney injury in patients without any risk factors. A case of severe acute interstitial nephritis (AIN) induced by valsartan was reported here.\n\nPatient concerns:\nA 62-year-old female with nausea for 1 month and acute deterioration of kidney function for 2 weeks was admitted. She had a history of hypertension for 5 months and had taken valsartan 40 mg daily for 4 months. Although the valsartan had been stopped for 2 weeks, the serum creatinine continuously increased after admission. Kidney biopsy demonstrated the eosinophils infiltration in interstitium.\n\nDiagnoses:\nAIN induced by valsartan.\n\nInterventions:\nThe patient was treated with glucocorticoid.\n\nOutcomes:\nThe serum creatinine decreased gradually and got back to normal level 5 months later. Then therapy of glucocorticoid was stopped. Renal artery stenosis was excluded by computed tomography angiography (CTA).\n\nLessons:\nAlthough valsartan-induced allergy has been reported previously, AIN was firstly recognized as a severe complication of this drug. We suggest when there is a ARB-associated continuous deterioration of kidney function for patients without renal insufficiency, renal artery stenosis, heart failure or hypovolemia, AIN should be thought of and therapy with glucocorticoid should be considered if necessary.\n\nKeywords\nacute interstitial nephritiscase reportkidney biopsyvalsartanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAngiotensin receptor blocker (ARB) is one of renin angiotensin system (RAS) blockers and is commonly used as an antihypertensive drug. It can also reduce urinary protein and protect heart function. The ARB has some potential side effects of increasing serum creatinine and potassium due to its effect of reducing renal hemoperfusion.[1,2] According to the previous studies, these side effects mainly occur in patients with pre-existing kidney disfunction, renal artery stenosis, heart failure or hypovolemia. Therefore, ARB are generally safe for patients who do not have these risk factors.[3,4] However, like angiotensin-converting enzyme inhibitors (ACEI) which is an another RAS blocker,[5] ARB also cause allergic reactions in some patients.[6] Although ACEI such as captopril has been demonstrated to induce acute interstitial nephritis (AIN),[7] ARB-induced AIN has not been reported before. We reported a case of severe acute kidney injury after valsartan treatment. All risk factors were excluded by careful examination. Percutaneous kidney biopsy confirmed the renal failure was caused by AIN. Renal function returned to normal after treatment with corticosteroid. This case reminds us that we should closely monitor the renal function for all patients receiving ARB therapy.\n\n1.1 Ethics approval and consent to participate\nThe Ethics Committee of Tianjin Medical University General Hospital gave approval for the publication of this case report (IRB2018-002-01), and patient has provided informed consent for publication of the case.\n\n1.2 Case report\nA 62-year-old female with nausea for 1 month and increased serum creatinine for 2 weeks was admitted. She did not have a history of chronic kidney disease and the serum creatinine was 1.01 mg/dL when she did routine physical examination 13 months ago. She had a history of hypertension for 5 months and had taken valsartan dispersible tablets (Lunan pharmaceutical group, Shandong, China) 40 mg daily for 4 months. Two weeks before admission, she stopped the valsartan since serum creatinine showed as high as 4.29 mg/dL. Pertinent physical examination findings were normal except a hypertension of 160/100 mm Hg. Abdominal ultrasonography showed no obvious abnormality of 2 kidneys. Echocardiogram showed slight left ventricular hypertrophy with a normal ejection fraction 61%. Blood routine showed a mild anemia with hemoglobin 101 g/L, Total white blood cells counts and eosinophils counts were normal. Serum creatinine increased to 5.60 mg/dL. Urinalysis revealed glucosuria 2+ (Fasting blood glucose was 5.8 mmol/L), leukocyturia 1+ and proteinuria 1+. The 24 h urine protein excretion revealed 0.2596 grams (normal range was below 0.15 grams). Urine N-acetyl-beta-D-glucosamidase was increased (21.2 U/g creatinine, normal range was 1.1–12.0 U/g creatinine). Immunologic examinations were normal except a slight rise of C-reactive protein (0.89 mg/dL, normal range was below 0.8 mg/dL).\n\nSerum creatinine was reviewed 2 days later and the result showed as high as 5.75 mg/dL. Then kidney biopsy was performed immediately. Light microscopy showed no obvious abnormality of glomeruli (Fig. 1A), while there were obvious inflammatory changes in the interstitium with increased eosinophils infiltration. There were also mild interstitial fibrosis and tubular injury (Fig. 1B). Immunofluorescence showed no immune complex deposition. The AIN was diagnosed and the patient was given intravenous methylprednisolone 40 mg daily. One week later the serum creatinine decreased to be 5.67 mg/dL, then the patient was discharged with oral methylprednisolone 20 mg daily. Levamlodipine besylate 5 mg daily was given in order to control hypertension.\n\nFigure 1 Manifestations of kidney biopsy. (A) No obvious injury of glomerulus was found. (B)There were lymphocytes and eosinophils infiltration (arrows). There were also slight tubular atrophy and fibrosis in interstitium (H&E stain ×400).\n\nDuring follow-up for 5 months, the serum creatinine decreased gradually and the glucocorticoid was tapered (Fig. 2). Her serum creatinine had recovered to normal before the follow-up on August 4th 2018. To exclude renal artery stenosis, computed tomography angiography (CTA) was done. The results showed no abnormality for bilateral renal arteries (Fig. 3).\n\nFigure 2 The clinical course of the patient. Since the kidney function recovered, CTA was done to excluded renal artery stenosis. The glucocorticoid was stopped before the examination of CTA. CTA = computed tomography angiography.\n\nFigure 3 The CTA examination for renal artery. Iohexol was used as contrast. No stenosis was found for bilateral renal arteries. CTA = computed tomography angiography.\n\n2 Discussion\nUntil now, the pathogenic mechanism of anaphylaxis caused by ARB has remained unclear. Losartan, which is the 1st marketed ARB, has been reported to cause lymphoid hyperplasia,[8] vasculitis,[9] and angioneurotic edema[10] in literature. Valsartan-associated allergy is similar to losartan including drug eruption,[11–14] angioedema[15–20] and mucocutaneous bullous pemphigoid[21] (Table 1). Drug eruption of valsartan is relatively common in clinic and usually start after weeks to 1 month of therapy. To our knowledge, this is the 1st case of AIN caused by valsartan (The Naranjo score is 5). The AIN mainly injure the tubules and interstitium and causes acute to subacute deterioration of kidney function. The pathophysiology of AIN is induced by a hypersensitive allergic reaction to an offending agent with the activation of eosinophils causing inflammatory infiltrates in the interstitium of kidney. Most AIN is due to non-steroidal anti-inflammatory drugs and antibiotics. A kidney biopsy is required to confirm the diagnosis of AIN. Supportive findings including eosinophils in urine or blood in laboratory testing can help to diagnose. None of the preceding clinical findings is sensitive or specific to AIN. In the present study, when the patient was admitted, the possibility of AIN was considered because the serum creatinine increased rapidly and valsartan was the only drug used before admission. However, the diagnose of AIN could not be confirmed for our patient until the kidney biopsy demonstrated the infiltration of eosinophils in the interstitium.\n\nTable 1 Anaphylaxis induced by valsartan in reported cases.\n\nSince ARB could cause severe increase of serum creatinine in patients with pre-existing kidney disfunction, renal artery stenosis, heart failure or hypovolemia, all these risk factors were carefully checked for our patient. After reviewing the history and doing echocardiogram examination, the pre-existing kidney disfunction, heart failure and hypovolemia were easily excluded. However, the exclusion of the renal artery stenosis was difficult because the patient had a new-onset hypertension and the high level of serum creatinine did not allow doing imaging examination which needed contrast. Fortunately, the patient got complete recovery of kidney function 5 months later and a CTA excluded the renal artery stenosis at last.\n\nThe AIN is a dose-independent allergic reaction. The time from exposure to appearance of symptoms is widely variable and can be from a few days to years.[22,23] In the current study, the patient only took valsartan 40 mg daily. We thought the low dose of drug postponed the occurrence of AIN. The patient felt nausea after 2 months of valsartan therapy, but she did not test kidney function at that time. Generally speaking, mild increase of serum creatinine does not cause nausea. So we speculated the appearance of AIN should be earlier than the appearance of nausea.\n\nControversy exists about whether corticosteroid therapy is necessary in the treatment of drug-induced AIN. Some studies have reported corticosteroid induced a more rapid and complete recovery of kidney function, while the others have failed to confirm the results.[24–27] In a recent research, Quinto LR et al made a systemic review of 8 retrospective studies comparing the effects of corticosteroid therapy versus non-corticosteroid therapy in the treatment of drug induced AIN.[28] Four studies showed no difference in serum creatinine between corticosteroid and non-corticosteroid therapy, while 4 studies found a benefit of corticosteroid therapy. Regretfully, a meta-analysis was not performed due to considerable heterogeneity. The authors proposed larger well-designed trials are needed to draw a conclusion. In the present study, the deterioration of kidney function did not cease although valsartan had been discontinued for 2 weeks. In order to accelerate the recovery of kidney function, glucocorticoid was administrated after kidney biopsy. Although the serum creatinine decreased slowly, the patient got complete kidney recovery after treatment for 5 months.\n\n3 Conclusion\nThis is the 1st case of valsartan-induced AIN. We suggest when there is a ARB-associated continuous deterioration of kidney function for patients without renal insufficiency, renal artery stenosis, heart failure or hypovolemia, AIN should be considered and kidney biopsy should be done when necessary. Besides, close monitoring of the renal function for all patients receiving ARB therapy is recommended.\n\nAuthor contributions\nConceptualization: Peng-cheng Xu.\n\nData curation: Jian-Qing Jiang.\n\nProject administration: Li Wei, Wen-ya Shang.\n\nSupervision: Tie-kun Yan.\n\nVisualization: Shui-yi Hu.\n\nWriting – original draft: Tong Chen.\n\nWriting – review & editing: Jun-ya Jia.\n\nAbbreviations: AIN = acute interstitial nephritis, ARB = angiotensin receptor blocker, CTA = computed tomography angiography.\n\nFunding: This study is supported by 3 grants of National Natural Science Fund (No. 81200534, No. 81570630 and No. 81600554), 2 grants of Tianjin Research Program of Application Foundation and Advanced Technology (No. 15JCQNJC10700 and 17JCQNJC10200) and a grant of China Postdoctoral Science Foundation funded project (No. 2014M560191). The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Gao F Yao M Cao Y \nValsartan ameliorates podocyte loss in diabetic mice through the Notch pathway . Int J Mol Med \n2016 ;37 :1328–36 .26985716 \n[2] Schmidt M Mansfield KE Bhaskaran K \nSerum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study . BMJ \n2017 ;356 :j791.28279964 \n[3] Bandak G Sang Y Gasparini A \nHyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) Project . J Am Heart Assoc \n2017 ;6 :e005428.28724651 \n[4] Mathieson L Severn A Guthrie B \nMonitoring and adverse events in relation to ACE inhibitor/angiotensin receptor blocker initiation in people with diabetes in general practice: a population database study . Scott Med J \n2013 ;58 :69–76 .23728750 \n[5] Brown T Gonzalez J Monteleone C \nAngiotensin-converting enzyme inhibitor-induced angioedema: a review of the literature . J Clin Hypertens (Greenwich) \n2017 ;19 :1377–82 .28994183 \n[6] Thalanayar MP Fajt ML Birnie KM \nAngiotensin receptor blocker-induced visceral angioedema . J Investig Allergol Clin Immunol \n2015 ;25 :63–4 .\n[7] Smith WR Neill J Cushman WC \nCaptopril-associated acute interstitial nephritis . Am J Nephrol \n1989 ;9 :230–5 .2527007 \n[8] Viraben R Lamant L Brousset P \nLosartan-associated atypical cutaneous lymphoid hyperplasia . Lancet \n1997 ;350 :1366.\n[9] Piérard Franchimont C1 Henry F Piérard GE \nSevere pustular and polymorphous vasculitis caused by losartan . Ann Dermatol Venereol \n2001 ;128 :1040–2 .11907966 \n[10] Kazim SF Shahid M \nLosartan associated anaphylaxis and angioneurotic oedema . J Pak Med Assoc \n2010 ;60 :685–6 .20726206 \n[11] Mustasim DF \nLymphomatoid drug eruption mimicking digitate dermatosiscross reactivity between two drugs that suppress angiotensin II function . Am J Dermatopathol \n2003 ;25 :331–4 .12876491 \n[12] Gencoglan G Ceylan C Kazandi AC \nLinear lichenoid drug eruption induced by valsartan . Clin Exp Dermatol \n2009 ;34 :e334–5 .19456765 \n[13] Sawada Y Yoshiki R Kawakami C \nValsartan-induced drug eruption followed by CD30+ pseudolymphomatous eruption . Acta Derm Venereol \n2010 ;90 :521–2 .20814632 \n[14] Ozturk G Turk BG Senturk B \nExanthematous drug eruption due to valsartan . Cutan Ocul Toxicol \n2012 ;31 :335–7 .22257082 \n[15] Frye CB Pettigrew TJ \nAngioedema and photosensitive rash induced by valsartan . Pharmacotherapy \n1998 ;18 :866–8 .9692664 \n[16] de la Serna Higuera C \nAngioedema and urticarial reaction induced by valsartan . Med Clin \n2000 ;114 :599.\n[17] Martínez Alonso JC Domínguez Ortega FJ Méndez Alcalde J \nAngioedema due to valsartan . Allergy \n2003 ;58 :367.\n[18] Irons BK Kumar A \nValsartan-induced angioedema . Ann Pharmacother \n2003 ;37 :1024–7 .12841812 \n[19] Shino M Takahashi K Murata T \nAngiotensin II receptor blocker-induced angioedema in the oral floor and epiglottis . Am J Otolaryngol \n2011 ;32 :624–6 .21324549 \n[20] Kalra A Cooley C Palaniswamy C \nValsartan-induced angioedema in a patient on angiotensin-converting enzyme inhibitor for years: case report and literature review . Am J Ther \n2012 ;19 :e189–92 .20838200 \n[21] Femiano F \nMucocutaneous bullous pemphigoid induced by valsartan. A clinical case . Minerva Stomatol \n2003 ;52 :187–90 .12874527 \n[22] Chamarthi G Kamboj M Olaoye OA \nAcute interstitial nephritis: a multifaceted disease . Clin Case Rep \n2018 ;6 :946–7 .29744094 \n[23] Raghavan R Shawar S \nMechanisms of drug-induced interstitial nephritis . Adv Chronic Kidney Dis \n2017 ;24 :64–71 .28284381 \n[24] Fernandez-Juarez G Perez JV Caravaca-Fontán F \nDuration of treatment with corticosteroids and recovery of kidney function in acute interstitial nephritis . Clin J Am Soc Nephrol \n2018 ;13 :1851–8 .30397027 \n[25] Chowdry AM Azad H Mir I \nDrug-induced acute interstitial nephritis: prospective randomized trial comparing oral steroids and high-dose intravenous pulse steroid therapy in guiding the treatment of this condition . Saudi J Kidney Dis Transpl \n2018 ;29 :598–607 .29970736 \n[26] Nast CC \nMedication-induced interstitial nephritis in the 21st Century . Adv Chronic Kidney Dis \n2017 ;24 :72–9 .28284382 \n[27] Moledina DG Perazella MA \nTreatment of drug-induced acute tubulointerstitial nephritis: the search for better evidence . Clin J Am Soc Nephrol \n2018 ;13 :1785–7 .30397028 \n[28] Quinto LR Sukkar L Gallagher M \nThe effectiveness of corticosteroid compared to non-corticosteroid therapy for the treatment of drug-induced acute interstitial nephritis: a systematic review . Intern Med J \n2018 ;[Epub ahead of print] .\n\n",
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{
"abstract": "BACKGROUND Methemoglobinemia due to the administration of sulfamethoxazole/trimethoprim has been documented in a series of case reports. However, all of these reports are on adult patients, and all patients received at least daily administration of sulfamethoxazole/trimethoprim for the treatment of active or suspected infection. CASE REPORT Herein we report the development of methemoglobinemia in a pediatric patient receiving sulfamethoxazole/trimethoprim three times weekly for the prophylaxis of opportunistic infections. CONCLUSIONS The clinician should always consider sulfamethoxazole/trimethoprim, even when administered for opportunistic infection prophylaxis at reduced doses and intervals, as a possible cause of methemoglobinemia.",
"affiliations": "Department of Pediatrics, Section of Critical Care, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.;, Independent Researcher, Oklahoma City, OK, USA.",
"authors": "Carroll|Timothy G|TG|;Carroll|Megan G|MG|",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.897820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile; D008297:Male; D008708:Methemoglobinemia; D009894:Opportunistic Infections; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "499-502",
"pmc": null,
"pmid": "27424851",
"pubdate": "2016-07-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23903510;7073040;15342970;15514101;9606476;16986127;10503695;4013630;2392131;24834764;26134197;22892375;6848863;17900210;15182104",
"title": "Methemoglobinemia in a Pediatric Oncology Patient Receiving Sulfamethoxazole/Trimethoprim Prophylaxis.",
"title_normalized": "methemoglobinemia in a pediatric oncology patient receiving sulfamethoxazole trimethoprim prophylaxis"
} | [
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"abstract": "The widespread use of multiplex molecular diagnostics has led to a significant increase in the detection of respiratory viruses in patients undergoing cytotoxic chemotherapy and hematopoietic cell transplantation (HCT). Respiratory viruses initially infect the upper respiratory tract and then progress to lower respiratory tract disease in a subset of patients. Lower respiratory tract disease can manifest itself as airflow obstruction or viral pneumonia, which can be fatal. Infection in HCT candidates may require delay of transplantation. The risk of progression differs between viruses and immunosuppressive regimens. Risk factors for progression and severity scores have been described, which may allow targeting treatment to high-risk patients. Ribavirin is the only antiviral treatment option for noninfluenza respiratory viruses; however, high-quality data demonstrating its efficacy and relative advantages of the aerosolized versus oral form are lacking. There are significant unmet needs, including data defining the virologic characteristics and clinical significance of human rhinoviruses, human coronaviruses, human metapneumovirus, and human bocavirus, as well as the need for new treatment and preventative options.",
"affiliations": "University of Washington, Seattle, WA; Seattle Children's Hospital, Seattle, WA; and Fred Hutchinson Cancer Research Center, Seattle, WA.;University of Washington, Seattle, WA; Seattle Children's Hospital, Seattle, WA; and.;University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA.",
"authors": "Waghmare|Alpana|A|0000-0003-2268-9470;Englund|Janet A|JA|0000-0003-1134-4178;Boeckh|Michael|M|0000-0003-1538-7984",
"chemical_list": "D012254:Ribavirin",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2016-01-634873",
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"issn_linking": "0006-4971",
"issue": "127(22)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D064591:Allografts; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D011024:Pneumonia, Viral; D018108:Respirovirus; D010253:Respirovirus Infections; D012254:Ribavirin; D012307:Risk Factors",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2682-92",
"pmc": null,
"pmid": "26968533",
"pubdate": "2016-06-02",
"publication_types": "D016428:Journal Article; D016454:Review; D052061:Research Support, N.I.H., Extramural",
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"title": "How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation.",
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
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"activesubstancename": "CYCLOSPORINE"
},
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
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"activesubstance": {
"activesubstancename": "TREOSULFAN"
},
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}
],
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"reactionmeddrapt": "Rhinovirus infection",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pulmonary oedema",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Nasal congestion",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acute left ventricular failure",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Respiratory distress",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BOECKH M, WAGHMARE A, ENGLUND JA. HOW I TREAT RESPIRATORY VIRAL INFECTIONS IN THE SETTING OF INTENSIVE CHEMOTHERAPY OR HEMATOPOIETIC CELL TRANSPLANTATION. BLOOD. 2016;127(22):2682-92",
"literaturereference_normalized": "how i treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
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"receivedate": "20160607",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12445060,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160815"
},
{
"companynumb": "US-SA-2016SA118327",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
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"drugadministrationroute": "065",
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"medicinalproduct": "CYCLOSPORINE."
},
{
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},
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"medicinalproduct": "TREOSULFAN"
},
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"actiondrug": null,
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"activesubstancename": "FLUDARABINE PHOSPHATE"
},
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"medicinalproduct": "FLUDARABINE PHOSPHATE."
},
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"actiondrug": "5",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
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"drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": "3",
"patientonsetage": "10",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pulmonary oedema",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Rhinovirus infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Respiratory distress",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acute left ventricular failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Nasal congestion",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WAGHMARE A, ENGLUND JA, BOECKH M. HOW I TREAT RESPIRATORY VIRAL INFECTIONS IN THE SETTING OF INTENSIVE CHEMOTHERAPY OR HEMATOPOIETIC CELL TRANSPLANTATION. BLOOD 2016 JUN 02;127(22):2682-92. DOI: 10.1182/BLOOD-2016-01-634873. ACCESSED: 2016 MAR 11.",
"literaturereference_normalized": "how i treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160826",
"receivedate": "20160630",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12519430,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
}
] |
{
"abstract": "OBJECTIVE\nWe evaluated the effect of oral and other hormonal contraceptive (HC) use on venous thromboembolism risk among African American women and investigated whether the association was modified by the sickle cell trait.\n\n\nMETHODS\nWe report the findings of a case-control study that included 60 African American women with an idiopathic, first episode of venous thromboembolism and 196 African American controls.\n\n\nRESULTS\nThe odds of current HC use compared with noncurrent use contrasting cases and controls is 3.8 (95% confidence interval [CI], 1.7-8.1; P < .001). Among subjects with sickle cell trait, the odds ratio is higher (odds ratio [OR], 6.7; 95% CI, 1.0-43) than the odds ratio among subjects without sickle cell trait (OR, 2.6; 95% CI, 1.1-6.2), but the difference is not statistically significant.\n\n\nCONCLUSIONS\nThis study provides persuasive evidence that hormonal contraceptive use increases venous thromboembolism risk among African American women and that the increase in risk may be larger among women with sickle cell trait.",
"affiliations": "Rollins School of Public Health, Emory University, Atlanta, GA, USA.",
"authors": "Austin|Harland|H|;Lally|Cathy|C|;Benson|Jane M|JM|;Whitsett|Carolyn|C|;Hooper|W Craig|WC|;Key|Nigel S|NS|",
"chemical_list": "D003271:Contraceptive Agents, Female; D003278:Contraceptives, Oral, Hormonal",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajog.2009.01.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "200(6)",
"journal": "American journal of obstetrics and gynecology",
"keywords": null,
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001741:African Americans; D016022:Case-Control Studies; D003271:Contraceptive Agents, Female; D003278:Contraceptives, Oral, Hormonal; D005260:Female; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D012805:Sickle Cell Trait; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "620.e1-3",
"pmc": null,
"pmid": "19306959",
"pubdate": "2009-06",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Hormonal contraception, sickle cell trait, and risk for venous thromboembolism among African American women.",
"title_normalized": "hormonal contraception sickle cell trait and risk for venous thromboembolism among african american women"
} | [
{
"companynumb": "US-JNJFOC-20121207438",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DESOGESTREL\\ETHINYL ESTRADIOL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "020301",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLETS",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CONTRACEPTION",
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"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "DESOGESTREL/ETHINYL ESTRADIOL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETHINYL ESTRADIOL\\NORGESTIMATE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "019653",
"drugbatchnumb": null,
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"drugdosageform": "TABLETS",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CONTRACEPTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "NORGESTIMATE/ETHINYL ESTRADIOL"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Embolism venous",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "AUSTIN H, LALLY C, BENSON JM, WHITSETT C, HOOPER WC, KEY NS. HORMONAL CONTRACEPTION, SICKLE CELL TRAIT, AND RISK FOR VENOUS THROMBOEMBOLISM AMONG AFRICAN AMERICAN WOMEN. AMERICAN JOURNAL OF OBSTETRICS + GYNECOLOGY 2009;6.",
"literaturereference_normalized": "hormonal contraception sickle cell trait and risk for venous thromboembolism among african american women",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150525",
"receivedate": "20150412",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "One of the most used cephalosporins in clinical practice is cefuroxime axetil. Anaphylaxis due to the administration of cefuroxime is considered a rare event. We report a case of anaphylactic reaction after the administration of cefuroxime in a child who had tolerated the drug in past exposures. Diagnostic workup is recommended for all patients with at least a moderate anaphylactic reaction (hypotension, tachycardia, bronchial hyperreactivity). This should include a detailed history of the event, previous allergies, and underlying conditions. Unfortunately, all currently available diagnostic approaches (IgE, skin-prick-test, tryptase) leave a significant percentage of non-diagnostic results and false positive or negative outcomes.",
"affiliations": "Department of Paediatrics. Segovia General Hospital, Segovia, Spain pablitovg@hotmail.com.;Department of Paediatrics. Segovia General Hospital, Segovia, Spain.;Department of Paediatrics. Segovia General Hospital, Segovia, Spain.;Department of Paediatrics. Segovia General Hospital, Segovia, Spain.",
"authors": "Del Villar-Guerra|Pablo|P|;Moreno Vicente-Arche|Blanca|B|;Castrillo Bustamante|Sara|S|;Santana Rodríguez|Carlos|C|",
"chemical_list": "D002511:Cephalosporins; D002444:Cefuroxime; C040738:cefuroxime axetil",
"country": "England",
"delete": false,
"doi": "10.1177/0394632016664529",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0394-6320",
"issue": "29(4)",
"journal": "International journal of immunopathology and pharmacology",
"keywords": "anaphylactic reaction; anaphylaxis; antibiotic; cephalosporins",
"medline_ta": "Int J Immunopathol Pharmacol",
"mesh_terms": "D000707:Anaphylaxis; D002444:Cefuroxime; D002511:Cephalosporins; D002648:Child; D005260:Female; D006801:Humans; D012882:Skin Tests",
"nlm_unique_id": "8911335",
"other_id": null,
"pages": "731-733",
"pmc": null,
"pmid": "27531605",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "11260156;18159398;20934625;11556301;17017928;15238790;12144556;15805383",
"title": "Anaphylactic reaction due to cefuroxime axetil: A rare cause of anaphylaxis.",
"title_normalized": "anaphylactic reaction due to cefuroxime axetil a rare cause of anaphylaxis"
} | [
{
"companynumb": "ES-TEVA-766682ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "064035",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CEFUROXIME."
}
],
"patientagegroup": null,
"patientonsetage": "12",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Loss of consciousness",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DEL VILLAR-GUERRA P. ANAPHYLACTIC REACTION DUE TO CEFUROXIME AXETIL: A RARE CAUSE OF ANAPHYLAXIS. INT-J-IMMUNOPATHOL-PHARMACOL. 2016 JAN 01;29(4):731-733.",
"literaturereference_normalized": "anaphylactic reaction due to cefuroxime axetil a rare cause of anaphylaxis",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20170515",
"receivedate": "20170515",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13544878,
"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": "BACKGROUND\nNeurobiological work has demonstrated that expression of mitogen-activated protein kinases (MAPK) is upregulated on neurones and glial cells after nerve damage. Furthermore, the epidermal growth factor receptor (EGFR) has been identified as having a key role in this process and subsequent interruption of this using EGFR-Inhibitors (EGFR-I), may improve neuropathic pain. The aim of this report was to explore if EGFR-I attenuated neuropathic pain in humans.\n\n\nMETHODS\nA selection of patients with neuropathic pain were treated off-label with one of four EGFR-Is, approved for the treatment of cancer. All patients had chronic and severe neuropathic pain (as defined by diagnostic criteria). Pain intensity, interference with function, and adverse events were prospectively registered.\n\n\nRESULTS\nTwenty patients were treated. Eighteen patients experienced clinically significant pain relief after treatment with EGFR-I. Median observed pain reduction for all patients was 8.5 (IQR=5-9.5) points on a 0-10 numeric rating scale. Neuropathic pain spike duration and frequency also improved. Pain relief was most often achieved within 24 h and was more rapid in cases of i.v. than oral administration. All four EGFR-I that were tested were of equal efficacy. The duration of pain relief was consistent with the individual drugs' half-lives. No cases of drug-tolerance were observed. Side-effects were predominantly skin reactions. One grade 3 adverse event was registered. Median follow-up for responders was 7 months (Range 1-37).\n\n\nCONCLUSIONS\nEGFR-I improves neuropathic pain and this is in keeping with basic science work. Controlled clinical trials are now eagerly awaited to assess this further.",
"affiliations": "Center for Cancer Treatment, Sørlandet Hospital, Pb 416, Kristiansand 4604, Norway christian.kersten@sshf.no.;Center for Cancer Treatment, Sørlandet Hospital, Pb 416, Kristiansand 4604, Norway.;Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XR, UK European Palliative Care Research Centre, NTNU, Trondheim, Norway.;Center for Cancer Treatment, Sørlandet Hospital, Pb 416, Kristiansand 4604, Norway.",
"authors": "Kersten|C|C|;Cameron|M G|MG|;Laird|B|B|;Mjåland|S|S|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000911:Antibodies, Monoclonal; D011799:Quinazolines; D000077544:Panitumumab; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D000077156:Gefitinib",
"country": "England",
"delete": false,
"doi": "10.1093/bja/aev326",
"fulltext": null,
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"issn_linking": "0007-0912",
"issue": "115(5)",
"journal": "British journal of anaesthesia",
"keywords": "analgesics; epidermal growth factor; neuralgia; pain, radiating; receptor",
"medline_ta": "Br J Anaesth",
"mesh_terms": "D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic; D000911:Antibodies, Monoclonal; D000068818:Cetuximab; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009437:Neuralgia; D010147:Pain Measurement; D000077544:Panitumumab; D011446:Prospective Studies; D011799:Quinazolines; D012008:Recurrence; D055815:Young Adult",
"nlm_unique_id": "0372541",
"other_id": null,
"pages": "761-7",
"pmc": null,
"pmid": "26475804",
"pubdate": "2015-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Epidermal growth factor receptor-inhibition (EGFR-I) in the treatment of neuropathic pain.",
"title_normalized": "epidermal growth factor receptor inhibition egfr i in the treatment of neuropathic pain"
} | [
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{
"abstract": "The importance of nosocomial infections caused by coagulase-negative staphylococci is constantly growing. The threat primarily affects immunocompromised patients, the elderly and neonates, particularly after invasive surgery. The problem is fundamentally exacerbated by expanding antibacterial drug resistance. A case report is presented of an 86-year-old patient who underwent a ruptured abdominal aortic aneurysm surgery and developed septicaemia upon surgical wound infection. The causal agent was likely a carbapenem-resistant Klebsiella pneumoniae, however, daptomycin-resistant Staphylococcus pettenkoferi was identified in blood cultures in the absence of daptomycin treatment. To the authors' knowledge, the case study presented is the first published episode of daptomycin-resistant S. pettenkoferi strain.",
"affiliations": "Clinical Microbiology and Virology, Spirito Santo Hospital, Pescara, Italy.;Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.;LGC Ltd, Newmarket Rd, Fordham, Cambridgeshire, United Kingdom.;Clinical Microbiology and Virology, Spirito Santo Hospital, Pescara, Italy.;Clinical Microbiology and Virology, Spirito Santo Hospital, Pescara, Italy.;Epidemiological Office, Spirito Santo Hospital, Pescara, Italy.;Clinical Microbiology and Virology, Spirito Santo Hospital, Pescara, Italy.;Laboratory of Microbiology, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.;Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.;Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.",
"authors": "Savini|Vincenzo|V|;Kosecka|Maja|M|;Siegwart|Ed|E|;Marrollo|Roberta|R|;Polilli|Ennio|E|;Palmieri|Dalia|D|;Fazii|Paolo|P|;Carretto|Edoardo|E|;Międzobrodzki|Jacek|J|;Bukowski|Michal|M|",
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"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0001-527X",
"issue": "63(2)",
"journal": "Acta biochimica Polonica",
"keywords": null,
"medline_ta": "Acta Biochim Pol",
"mesh_terms": "D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D024881:Drug Resistance, Bacterial; D017809:Fatal Outcome; D005798:Genes, Bacterial; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D012150:Polymorphism, Restriction Fragment Length; D012772:Shock, Septic; D013203:Staphylococcal Infections; D013210:Staphylococcus",
"nlm_unique_id": "14520300R",
"other_id": null,
"pages": "297-301",
"pmc": null,
"pmid": "26730410",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Daptomycin-resistant Staphylococcus pettenkoferi of human origin.",
"title_normalized": "daptomycin resistant staphylococcus pettenkoferi of human origin"
} | [
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"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
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{
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"reactionmeddraversionpt": "20.0",
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}
],
"summary": {
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}
},
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{
"abstract": "OBJECTIVE\nOur purpose was to quantitate the risk of perinatal thyroid dysfunction and other amiodarone-induced adverse effects among infants exposed in utero to amiodarone.\n\n\nMETHODS\nA historic cohort study of gestational exposure to amiodarone was conducted by contacting Canadian cardiac electrophysiologists.\n\n\nRESULTS\nTwelve cases were identified. Of six with first-trimester exposure, one child had congenital nystagmus with synchronous head titubation. There was one case each of transient neonatal hypothyroidism (9%) and hyperthyroidism (9%). A fourth child, exposed to amiodarone from 20 weeks' gestation, had developmental delay, hypotonia, hypertelorism, and micrognathia. Four small-for-gestational-age infants were also exposed to beta-blockers, which in addition to maternal cardiac disease, have been recognized to cause growth restriction. beta-Blockers may also have contributed to bradycardia in one of the three fetuses in whom this was observed.\n\n\nCONCLUSIONS\nGestational exposure to amiodarone may be complicated by perinatal hypothyroidism or hyperthyroidism and possibly neurologic abnormalities, intrauterine growth retardation or fetal bradycardia. Concomitant beta-blocker therapy should probably be avoided. Full neonatal thyroid function tests and developmental follow-up are recommended.",
"affiliations": "Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.",
"authors": "Magee|L A|LA|;Downar|E|E|;Sermer|M|M|;Boulton|B C|BC|;Allen|L C|LC|;Koren|G|G|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1016/0002-9378(95)91498-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "172(4 Pt 1)",
"journal": "American journal of obstetrics and gynecology",
"keywords": null,
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000328:Adult; D000638:Amiodarone; D001145:Arrhythmias, Cardiac; D001919:Bradycardia; D002170:Canada; D015331:Cohort Studies; D005260:Female; D005315:Fetal Diseases; D005317:Fetal Growth Retardation; D006801:Humans; D006980:Hyperthyroidism; D007037:Hypothyroidism; D007231:Infant, Newborn; D009422:Nervous System Diseases; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "1307-11",
"pmc": null,
"pmid": "7726275",
"pubdate": "1995-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy outcome after gestational exposure to amiodarone in Canada.",
"title_normalized": "pregnancy outcome after gestational exposure to amiodarone in canada"
} | [
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"medicinalproduct": "PROPRANOLOL"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Learning disability",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cognitive disorder",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
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},
{
"reactionmeddrapt": "Congenital nystagmus",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MAGEE, L.. PREGNANCY OUTCOME AFTER GESTATIONAL EXPOSURE TO AMIODARONE IN CANADA. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. 1995?172 (4 PART 1):1307?1311",
"literaturereference_normalized": "pregnancy outcome after gestational exposure to amiodarone in canada",
"qualification": "1",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20180911",
"receivedate": "20170724",
"receiver": {
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},
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"safetyreportid": 13783294,
"safetyreportversion": 6,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20181010"
}
] |
{
"abstract": "BACKGROUND\nPreconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses.\n\n\nMETHODS\nIn this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18-40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Participants were stratified by eligibility criteria--the original stratum was restricted to women with one loss at less than 20 weeks' gestation during the previous year, whereas the expanded stratum included women with one to two previous losses, with no restrictions on gestational age or time of loss. Women were block-randomised by centre and eligibility stratum in a 1:1 ratio. Preconception-initiated daily low-dose aspirin (81 mg per day) plus folic acid was compared with placebo plus folic acid for up to six menstrual cycles; for women who conceived, study treatment continued until 36 weeks' gestation. Participants, trial staff, and investigators were masked to the assigned treatment. The primary outcome was livebirth rate, which was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00467363.\n\n\nRESULTS\nOverall, 1228 women were recruited and randomly assigned between June 15, 2007, and July 15, 2011, 1078 of whom completed the trial and were included in the analysis (535 in the low-dose aspirin group and 543 in the placebo group). 309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p=0·0984; absolute difference in livebirth rate 5·09% [95% CI -0·84 to 11·02]). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p=0·7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p=0·0446; absolute difference in livebirth rate 9·20% [0·51 to 17·89]). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p=0·7406; absolute difference in livebirth rate 1·71% [-6·37 to 9·79]). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss.\n\n\nCONCLUSIONS\nPreconception-initiated low-dose aspirin was not significantly associated with livebirth or pregnancy loss in women with one to two previous losses. However, higher livebirth rates were seen in women with a single documented loss at less than 20 weeks' gestation during the previous year. Low-dose aspirin is not recommended for the prevention of pregnancy loss.\n\n\nBACKGROUND\nEunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health).",
"affiliations": "Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA. Electronic address: schistee@mail.nih.gov.;Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, School of Medicine, Salt Lake City, UT, USA.;Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, School of Medicine, Salt Lake City, UT, USA.;Department of Statistics, University of Haifa, Haifa, Israel.;Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY, USA.;Department of Family, Community and Rural Health, Commonwealth Medical College, Scranton, PA, USA.;Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA.;Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.;Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.;Department of Statistics, University of Haifa, Haifa, Israel.",
"authors": "Schisterman|Enrique F|EF|;Silver|Robert M|RM|;Lesher|Laurie L|LL|;Faraggi|David|D|;Wactawski-Wende|Jean|J|;Townsend|Janet M|JM|;Lynch|Anne M|AM|;Perkins|Neil J|NJ|;Mumford|Sunni L|SL|;Galai|Noya|N|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D005492:Folic Acid; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "384(9937)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D001724:Birth Weight; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005492:Folic Acid; D005865:Gestational Age; D006801:Humans; D050498:Live Birth; D016742:Preconception Care; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "29-36",
"pmc": null,
"pmid": "24702835",
"pubdate": "2014-07-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "22900525;19965971;16507806;3273482;14739212;20335572;12919986;10796208;10548638;11159655;21422062;12220757;21833951;19160241;11777524;20237316;14592543;10231040;7906809;9262298;15846729;19208560;19559568;24118062;10362823;11006203;15846641",
"title": "Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.",
"title_normalized": "preconception low dose aspirin and pregnancy outcomes results from the eager randomised trial"
} | [
{
"companynumb": "US-BAYER-2014-059818",
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{
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"activesubstancename": "ASPIRIN"
},
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},
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"medicinalproduct": "FOLIC ACID."
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"medicinalproduct": "FOLIC ACID."
}
],
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"reaction": [
{
"reactionmeddrapt": "Cleft lip",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Cleft palate",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SCHISTERMAN EF, SILVER RM, LESHER LL, FARAGGI D, WACTAWSKI-WENDE J, TOWNSEND JM, LYNCH AM, PERKINS NJ, MUMFORD SL, GALAI N. PRECONCEPTION LOW-DOSE ASPIRIN AND PREGNANCY OUTCOMES: RESULTS FROM THE EAGER RANDOMISED TRIAL. LANCET, 2014. 2014?XX:1-8",
"literaturereference_normalized": "preconception low dose aspirin and pregnancy outcomes results from the eager randomised trial",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160325",
"receivedate": "20140429",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 10137410,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160525"
}
] |
{
"abstract": "BACKGROUND\nPatients with severe viral pneumonia are likely to receive high-dose immunomodulatory drugs to prevent clinical worsening. Aspergillus species have been described as frequent secondary pneumonia agents in severely ill influenza patients receiving steroids. COVID-19 patients admitted to Intensive Care Unit (ICU) are receiving steroids as part of their treatment and they share clinical characteristics with other patients with severe viral pneumonias. COVID-19 patients receiving steroids should be considered a putative risk group of invasive aspergillosis.\n\n\nMETHODS\nWe are reporting a SARS-CoV-2/Aspergillus section Fumigati coinfection in an elderly intubated patient with a history of pulmonary embolism treated with corticosteroids. The diagnosis was made following the ad hoc definitions described for patients admitted to ICU with severe influenza, including clinical criteria (fever for 3 days refractory to the appropriate antibiotic therapy, dyspnea, pleural friction rub, worsening of respiratory status despite antibiotic therapy and need of ventilator support), a radiological criterion (pulmonary infiltrate) and a mycological criterion (several positive galactomannan tests on serum with ratio ≥0.5). In addition, Aspergillus section Fumigati DNA was found in serum and blood samples. These tests were positive 4 weeks after the patient was admitted to the ICU. The patient received voriconazole and after two month in ICU his respiratory status improved; he was discharged after 6 weeks of antifungal treatment.\n\n\nCONCLUSIONS\nSeverely ill COVID-19 patients would be considered a new aspergillosis risk group. Galactomannan and Aspergillus DNA detection would be useful methods for Aspergillus infection diagnosis as they allow avoiding the biosafety issues related to these patients.",
"affiliations": "Laboratorio de Micología y Diagnóstico Molecular, Cátedra de Parasitología y Micología, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas, Santa Fe, Argentina.;Sanatorio Adventista del Plata, Libertador San Martín, Entre Ríos, Argentina; Facultad de Ciencias de la Salud, Universidad Adventista del Plata, Libertador San Martín, Entre Ríos, Argentina.;Sanatorio Adventista del Plata, Libertador San Martín, Entre Ríos, Argentina; Facultad de Ciencias de la Salud, Universidad Adventista del Plata, Libertador San Martín, Entre Ríos, Argentina.;Sanatorio Adventista del Plata, Libertador San Martín, Entre Ríos, Argentina.;Laboratorio de Micología y Diagnóstico Molecular, Cátedra de Parasitología y Micología, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas, Santa Fe, Argentina.;Laboratorio de Micología y Diagnóstico Molecular, Cátedra de Parasitología y Micología, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas, Santa Fe, Argentina. Electronic address: ggarcia@unl.edu.ar.",
"authors": "Sasoni|Natalia|N|;Rodriguez Müller|Milton|M|;Posse|Graciela|G|;González|Jorge|J|;Leonardelli|Florencia|F|;Garcia-Effron|Guillermo|G|",
"chemical_list": "D000890:Anti-Infective Agents; D017984:Enoxaparin; D007166:Immunosuppressive Agents; D008351:Mannans; C012990:galactomannan; D000082:Acetaminophen; D006886:Hydroxychloroquine; D005690:Galactose; D008775:Methylprednisolone",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.riam.2020.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-1406",
"issue": "38(1)",
"journal": "Revista iberoamericana de micologia",
"keywords": "Coinfección SARS-COV-2/Aspergillus; Diagnosis; Diagnóstico; Galactomananos; Galactomannans; SARS-COV-2/Aspergillus coinfection",
"medline_ta": "Rev Iberoam Micol",
"mesh_terms": "D000082:Acetaminophen; D000368:Aged; D000890:Anti-Infective Agents; D001232:Aspergillus fumigatus; D001992:Bronchoalveolar Lavage Fluid; D000086382:COVID-19; D000087123:COVID-19 Nucleic Acid Testing; D060085:Coinfection; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D017984:Enoxaparin; D005690:Galactose; D006801:Humans; D006886:Hydroxychloroquine; D007121:Immunocompetence; D007166:Immunosuppressive Agents; D007442:Intubation, Intratracheal; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D008351:Mannans; D008775:Methylprednisolone; D009305:Nasopharynx; D011019:Pneumonia, Mycoplasma; D011550:Pseudomonas aeruginosa; D060888:Real-Time Polymerase Chain Reaction; D012121:Respiration, Artificial; D000086402:SARS-CoV-2; D013211:Staphylococcus aureus; D014132:Trachea",
"nlm_unique_id": "9425531",
"other_id": null,
"pages": "16-18",
"pmc": null,
"pmid": "33500209",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32835328;32339350;31802125;30076119;10921948;32192578;21865184;32091533;15272286",
"title": "SARS-CoV-2 and Aspergillus section Fumigati coinfection in an immunocompetent patient treated with corticosteroids.",
"title_normalized": "sars cov 2 and aspergillus section fumigati coinfection in an immunocompetent patient treated with corticosteroids"
} | [
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},
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"literaturereference": "SASONI N, RODRIGUEZ MULLER M, POSSE G, GONZALEZ J, LEONARDELLI F, GARCIA?EFFRON G. SARS?COV?2 AND ASPERGILLUS SECTION FUMIGATI COINFECTION IN AN IMMUNOCOMPETENT PATIENT TREATED WITH CORTICOSTEROIDS. REV IBEROAM MICOL. 2021 JAN?MAR?38(1):16?18. DOI: 10.1016/J.RIAM.2020.11.001. EPUB 2020 NOV 28. PMID: 33500209? PMCID: PMC7700005.",
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"abstract": "Intrathecal baclofen (ITB) therapy is an effective way to manage spasticity in numerous conditions, including multiple sclerosis, stroke, and cerebral palsy. While pump failure is a common complication of ITB, improvements in device design have led to reduction of complications. In particular, the Ascenda catheter from Medtronic, Inc. was designed to resist kinking and associated complications; indeed, no incidences of catheter twisting or occlusion have been reported in literature prior to this case.\nWe report a case of a 32-year old gentleman who presented to the clinic with symptoms of baclofen withdrawal 19 months after he had a programmable pump implanted for spasticity. During the diagnostic evaluation it was discovered that the patients pump had flipped in his abdominal pocket. He was taken to surgery to reorient the pump, during which time it was noted the catheter was tightly coiled on itself occluding flow. The twisted catheter was excised and replaced with a new segment.His symptoms subsequently resolved.\nAlthough catheter occlusions have subsided since the approval of the Ascenda catheter, pump twiddler's syndrome remains a risk factor for this complication. This is the first report describing this syndrome in a patient with the Ascenda catheter.",
"affiliations": "Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH.;Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio.;Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio.;Mellen Center, Cleveland Clinic, Cleveland, OH.;Mellen Center, Cleveland Clinic, Cleveland, OH.;Mellen Center, Cleveland Clinic, Cleveland, OH.;Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio.",
"authors": "Shao|Jianning|J|;Frizon|Leonardo|L|;Machado|Andre G|AG|;McKee|Keith|K|;Bethoux|Francois|F|;Hartman|Jennifer|J|;Nagel|Sean J|SJ|",
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"doi": "10.5812/aapm.65312",
"fulltext": "\n==== Front\nAnesth Pain MedAnesth Pain Med10.5812/aapmKowsarAnesthesiology and Pain Medicine2228-75232228-7531Kowsar 10.5812/aapm.65312Case ReportOcclusion of the Ascenda Catheter in a Patient with Pump Twiddler’s Sydrome: A Case Report Shao Jianning 1*shaoj2@ccf.orgFrizon Leonardo 2frizona@ccf.orgMachado Andre G. 23McKee Keith 4mckeek@ccf.orgBethoux Francois 4bethouf@ccf.orgHartman Jennifer 4Nagel Sean J. 231 Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH2 Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio3 Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, OH4 Mellen Center, Cleveland Clinic, Cleveland, OH* Corresponding author: Jianning Shao, B.A., Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 44195, 9980 Carnegie Ave, Cleveland, OH. Tel: +1-8474360396, Fax: +1-216444.1015, E-mail: shaoj2@ccf.org28 4 2018 4 2018 8 2 e6531218 12 2017 05 2 2018 22 4 2018 Copyright © 2018, Anesthesiology and Pain Medicine2018This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly citedIntroduction\nIntrathecal baclofen (ITB) therapy is an effective way to manage spasticity in numerous conditions, including multiple sclerosis, stroke, and cerebral palsy. While pump failure is a common complication of ITB, improvements in device design have led to reduction of complications. In particular, the Ascenda catheter from Medtronic, Inc. was designed to resist kinking and associated complications; indeed, no incidences of catheter twisting or occlusion have been reported in literature prior to this case.\n\nCase Report\nWe report a case of a 32-year old gentleman who presented to the clinic with symptoms of baclofen withdrawal 19 months after he had a programmable pump implanted for spasticity. During the diagnostic evaluation it was discovered that the patients pump had flipped in his abdominal pocket. He was taken to surgery to reorient the pump, during which time it was noted the catheter was tightly coiled on itself occluding flow. The twisted catheter was excised and replaced with a new segment.His symptoms subsequently resolved.\n\nConclusions\nAlthough catheter occlusions have subsided since the approval of the Ascenda catheter, pump twiddler’s syndrome remains a risk factor for this complication. This is the first report describing this syndrome in a patient with the Ascenda catheter.\n\nAscenda CatheterIntrathecal Baclofen Therapy (ITB)Baclofen, Twiddler’s Syndrome\n==== Body\n1. Introduction\nIntrathecal (IT) baclofen therapy is a well-established treatment option for patients with refractory spasticity secondary to multiple sclerosis, stroke, traumatic brain injury, cerebral palsy, and spinal cord injury (1, 2). Patients with these conditions are implanted with a programmable pump that delivers a preset dose tailored to each patient’s symptoms (1-3). However, a recent study revealed that the pump failure/complication rate was approximately 35% over 12 years with many of these events related to catheter performance (4). Incremental improvements in the design of these devices and refinements in the implant technique have consistently increased catheter and pump survival (4-6). The introduction of the Ascenda (Medtronic, Inc.) catheter to the market is one such example (6). Approved for use in 2011 by the FDA, it was initially associated with a reduction of major complications in comparison to silicone catheters (6). Although the elasticity modulus for this reinforced catheter is improved, it can still be susceptible to extreme shear and strain forces generated in patients.\n\nKinking of the catheter and migration of the pump are recognized risk factors for catheter occlusion with previous generation of catheters (4, 5, 7-10). Other adverse effects associated with intrathecal drug delivery include spinal headache, as reported by Kurnutala et al. in 2015 (11). The twisting and occlusion of the catheter in ITB systems can also be described as Twidder’s syndrome; first coined in 1968, Twiddler’s syndrome described the malfunction of a pacemaker secondary to manipulation of the pulse generator by the patient (12). Specifically, voluntary or involuntary patient movement dislodges and tangles the leads around the generator stimulating the ipsilateral phrenic nerve (12). This is associated with diaphragamic pacing, abdominal pulsations, and cessation of ventricular pacing (12). The same principle of Twiddler’s syndrome can also been applied to other devices including programmable pumps where catheter occlusion obstructs outflow (4, 9, 13). In this report, we describe the first documented case of Twiddler’s syndrome in a patient with an Ascenda catheter resulting in acute baclofen withdrawal.\n\n2. Case Presentation\nA 32-year-old, man, with a medical history significant for severe spasticity secondary to spinal cord injury presented to the ED with signs and symptoms consistent with baclofen withdrawal 19 months after insertion of a programmable pump.Prior to intrathecal therapy, he was managed with oral baclofen, tizanidine and botulinum toxin injections. Despite involvement with physical therapy and stretching daily, he continued to experience severe spasms exacerbated with ambulation or when recumbent. A 37.5 mcg test injection of IT baclofen reduced his spasms and improved his range of motion. He consented for implantation of a permanent programmable pump that could deliver IT baclofen continuously. A tunneled Ascenda catheter was deployed into the IT space with the tip positioned over the T9 - T10 interspace under fluoroscopy. A 40 mL Synchomed II pump was fitted into the suprafascial right abdominal wall, anchored and connected to the pump segment that was secured to the catheter. There were no perioperative complications.\n\nThe patient reported marked relief in his spasticity until he presented 19 months later in baclofen withdrawal. Axial CT revealed that the pump had flipped within the abdominal pocket (Figure 1). He was taken to the OR for urgent pump revision. The incision was reopened and the scar tissue was cut until the pump was exposed and explanted from the pocket. The coiled catheter was dissected free (Figure 2).\n\nFigure 1. Axial CT showing flipping of pump in abdominal pocket\nFigure 2. Intraoperative image acquired immediately after the programmable pump was freed from the right abdominal wall pocket. The Ascenda catheter is twisted on itself just proximal to its insertion at the catheter port.\nThe catheter was unwound and the side-port aspirated. CSF flowed easily. Careful examination of the catheter disclosed significant damage. It was decided to replace the pump segment. After the pump segment was secured, the side-port was aspirated again to verify flow. The incision was closed and the patient was awoken from anesthesia and discharged uneventfully. At follow-up, the patient reported resolution of his symptoms.\n\n3. Discussion\nTo our knowledge, this is the first reported case of an Ascenda catheter occlusion in a patient with Twiddler’s sydrome. Prior to introduction of this device, catheter complications may have been more frequent. A review of previously reported cases of ITB system malfunction consistently identifies the catheter as the most vulnerable component of the ITB system (5, 9, 14). For example, a systematic review performed by Stetkarova et al. in 2010 reported that of the 558 complications in 1,362 pump implantations, 66% were related to catheter malfunctions (10).\n\nModern series suggest that the catheter related complications have subsided (3). Motta and Antonello reported only 1 patient out of 92 with a catheter related complication when the Ascenda was chosen (6). In patients implanted with a silicon catheter, 120 out of 416 experienced a complication. In a recent report from the implantable systems performance registry (ISPR), device survival probability for the SynchroMed II pump (used by our patient) is 99.9% at one year (4). By comparison, the Ascenda catheter has a 90% survival probability over one year (4). Long term survival data of the Ascenda included in this registry are not yet available (4). A pump that is continuously flipped in its pocket, which causes the catheter to wind on itself and obstruct flow (as is the case in the present patient), is cited as a very uncommon complication (9, 10, 13).\n\nIn this case, it is likely the fixation failed because the pump was not able to be adequately secured to the fascial wall due to depth limits related to excess adipose tissue. This, coupled with his ambulatory status compounded the risk of this event. Obese patients should be cautioned about this risk. Surgical technique modification, pump location or the continuous use of abdominal binders could mitigate the occurrence of this complication.\n\nConflicts of Interests:Dr. Andre Machado receives fellowship support from Medtronic, Inc. and has distribution rights for Enspire and Cardionomics. He is also a consultant for St. Jude.\n==== Refs\n1 Bottros MM Christo PJ Current perspectives on intrathecal drug delivery. J Pain Res. 2014 7 615 26 10.2147/JPR.S37591 25395870 \n2 Petropoulou KB Panourias IG Rapidi CA Sakas DE The phenomenon of spasticity: a pathophysiological and clinical introduction to neuromodulation therapies. Acta Neurochir Suppl. 2007 97 Pt 1 137 44 17691369 \n3 Lance JW The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology. 1980 30 12 1303 13 7192811 \n4 Konrad PE Huffman JM Stearns LM Plunkett RJ Grigsby EJ Stromberg EK et al. Intrathecal Drug Delivery Systems (IDDS): The Implantable Systems Performance Registry (ISPR). Neuromodulation. 2016 19 8 848 56 10.1111/ner.12524 27730704 \n5 Fluckiger B Knecht H Grossmann S Felleiter P Device-related complications of long-term intrathecal drug therapy via implanted pumps. Spinal Cord. 2008 46 9 639 43 10.1038/sc.2008.24 18332884 \n6 Motta F Antonello CE Comparison between an Ascenda and a silicone catheter in intrathecal baclofen therapy in pediatric patients: analysis of complications. J Neurosurg Pediatr. 2016 18 4 493 8 10.3171/2016.4.PEDS15646 27341610 \n7 Kovanda TJ Pestereva E Lee A Intrathecal Baclofen Pump Migration Into the Peritoneal Cavity: A Case Report. Anesth Pain Med. 2016 6 3 e33031 10.5812/aapm.33031 27642571 \n8 Li TC Chen MH Huang JS Chan JY Liu YK Chen MH Catheter migration after implantation of an intrathecal baclofen infusion pump for severe spasticity: a case report. Kaohsiung J Med Sci. 2008 24 9 492 7 19073382 \n9 Russell LJ leRoux AA Wheelock WB Twisted catheter causing baclofen pump malfunction: a case report. Can J Neurol Sci. 2012 39 6 838 9 23230615 \n10 Stetkarova I Yablon SA Kofler M Stokic DS Procedure- and device-related complications of intrathecal baclofen administration for management of adult muscle hypertonia: a review. Neurorehabil Neural Repair. 2010 24 7 609 19 10.1177/1545968310363585 20233964 \n11 Kurnutala LN Kim D Sayeed H Sibai N Persistent Spinal Headache After Removal of Intrathecal Drug Delivery System: A Case Report and Review of Literature. Anesth Pain Med. 2015 5 5 e29786 10.5812/aapm.29786 26587409 \n12 Nicholson WJ Tuohy KA Tilkemeier P Twiddler's Syndrome. N Engl J Med. 2003 348 17 1726 7 10.1056/NEJM200304243481722 12711756 \n13 Dickerman RD Stevens QE Schneider SJ The role of surgical placement and pump orientation in intrathecal pump system failure: a technical report. Pediatr Neurosurg. 2003 38 2 107 9 10.1159/000068047 12566846 \n14 Fukuhara T Tanaka T Namba Y Kuyama H Tangled catheter as a rare cause of baclofen pump malfunction. Surg Neurol. 2009 72 1 80 2 discussion 82 10.1016/j.surneu.2008.01.043 18440622\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2228-7523",
"issue": "8(2)",
"journal": "Anesthesiology and pain medicine",
"keywords": "Ascenda Catheter; Baclofen, Twiddler’s Syndrome; Intrathecal Baclofen Therapy (ITB)",
"medline_ta": "Anesth Pain Med",
"mesh_terms": null,
"nlm_unique_id": "101585412",
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"pages": "e65312",
"pmc": null,
"pmid": "30027067",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports",
"references": "19073382;23230615;27341610;26587409;18440622;25395870;12566846;7192811;27730704;18332884;27642571;12711756;20233964;17691369",
"title": "Occlusion of the Ascenda Catheter in a Patient with Pump Twiddler's Sydrome: A Case Report.",
"title_normalized": "occlusion of the ascenda catheter in a patient with pump twiddler s sydrome a case report"
} | [
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{
"abstract": "The prevalence of epilepsy and psychosis in 22q11.2 deletion syndrome (22q11.2DS) is higher than in the general population. Recent study on adults with 22q11.2DS reported that the most common trigger for provoked seizures was the use of antipsychotics and antidepressants. In this paper, blonaserin was used because aripiprazole, quetiapine, paliperidone were not effective. The patient had convulsion on the fourth day of taking blonaserin. Neurological and cardiac examination was carried out, and lamotrigine was added at the advice of neurologist. Than the patient didn't have any convulsions and the symptoms gradually improved. When treating patients with 22q11.2DS, the medicine should be chosen carefully, and the patient should be observed closely, paying attention to the possibility of convulsions.",
"affiliations": "Department of Psychiatry, Inha University Hospital, Incheon, Korea.;Department of Psychiatry, Inha University Hospital, Incheon, Korea.;Department of Psychiatry, Inha University Hospital, Incheon, Korea.;Department of Psychiatry, Inha University Hospital, Incheon, Korea.;Department of Psychiatry, Inha University Hospital, Incheon, Korea.;Department of Psychiatry, Inha University Hospital, Incheon, Korea.;Department of Psychiatry, Inha University Hospital, Incheon, Korea.",
"authors": "Choi|Seo-Hyun|SH|https://orcid.org/0000-0002-2726-5610;Kang|Sang-Gu|SG|https://orcid.org/0000-0003-0824-9022;Kim|Hee-Yeon|HY|https://orcid.org/0000-0002-6766-5969;Kim|Hye-Young|HY|https://orcid.org/0000-0002-2313-8892;Bae|Jae-Nam|JN|https://orcid.org/0000-0002-5024-6231;Lee|Jung-Sub|JS|https://orcid.org/0000-0001-5585-0334;Kim|Won-Hyoung|WH|https://orcid.org/0000-0002-6650-3685",
"chemical_list": null,
"country": "Korea (South)",
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"fulltext": "\n==== Front\nClin Psychopharmacol Neurosci\nClin Psychopharmacol Neurosci\nClinical Psychopharmacology and Neuroscience\n1738-1088 2093-4327 Korean College of Neuropsychopharmacology \n\n32702225\n10.9758/cpn.2020.18.3.454\nCPN-18-454\nCase Report\nImportant Consideration in Choosing Antipsychotics in the Treatment of Patients with 22q11.2 Deletion Syndrome: Risk of Convulsion\nhttps://orcid.org/0000-0002-2726-5610Choi Seo-Hyun https://orcid.org/0000-0003-0824-9022Kang Sang-Gu https://orcid.org/0000-0002-6766-5969Kim Hee-Yeon https://orcid.org/0000-0002-2313-8892Kim Hye-Young https://orcid.org/0000-0002-5024-6231Bae Jae-Nam https://orcid.org/0000-0001-5585-0334Lee Jung-Sub https://orcid.org/0000-0002-6650-3685Kim Won-Hyoung \n1 Department of Psychiatry, Inha University Hospital, Incheon, Korea\n\nAddress for correspondence: Won-Hyoung Kim Department of Psychiatry, Inha University Hospital, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea E-mail: ckgodman@hanmail.net ORCID: https://orcid.org/0000-0002-6650-3685\n31 8 2020 \n31 8 2020 \n18 3 454 457\n7 9 2018 6 12 2018 21 12 2018 Copyright © 2020, Korean College of Neuropsychopharmacology2020This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://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.The prevalence of epilepsy and psychosis in 22q11.2 deletion syndrome (22q11.2DS) is higher than in the general population. Recent study on adults with 22q11.2DS reported that the most common trigger for provoked seizures was the use of antipsychotics and antidepressants. In this paper, blonaserin was used because aripiprazole, quetiapine, paliperidone were not effective. The patient had convulsion on the fourth day of taking blonaserin. Neurological and cardiac examination was carried out, and lamotrigine was added at the advice of neurologist. Than the patient didn’t have any convulsions and the symptoms gradually improved. When treating patients with 22q11.2DS, the medicine should be chosen carefully, and the patient should be observed closely, paying attention to the possibility of convulsions.\n\nDiGeorge syndromePschotic disorderSeizureAantipsychotic agents\n==== Body\nINTRODUCTION\nA 22q11.2 deletion syndrome (22q11.2DS) is the most common deletion syndrome in humans with an estimated frequency of 1:2,000 to 1:4,000 of live births [1]. More than 180 clinical features have been described, such as cardiovascular malformations, palatal anomalies, immune deficiency, and dysmorphic facial features [2-4]. Neuropsychiatric disorders have frequently been reported [5,6]. Some reports have highlighted the high frequency of schizophrenia among individuals with the 22q11.2 deletion compared to the general population [7,8].\n\nAlthough psychosis and epilepsy may coexist in adult patients with 22q11.2DS, few reports have discussed the interrelation between schizophrenia and seizure. This paper reports a case of 22q11.2DS in an adult patient, who had a seizure during the treatment of schizophrenia.\n\nCASE\nA 25-year-old woman was admitted to hospital for her first episode of psychosis. The patient was born via a normal vaginal delivery after an uncomplicated full-term pregnancy. The tetralogy of Fallot was diagnosed at 9 months and treated surgically at the age of 1 and 3 years. She had no seizure history until admission and no family history of epilepsy or psychiatric disorders.\n\nAt the time of admission, she had swollen eyelids, short palpebral fissures, flat cheeks, a bulbous nose tip, broad nasal root, and low-set ears. Her vital signs were stable and the medical and neurological examination revealed no abnormalities. A mental status examination revealed a psychotic state including paranoid delusions, a delusion of reference, and thought control. In addition, she stated that she heard unfamiliar voices trying to communicate with her continuously. She presented with psychomotor agitation, and a lack of insight. Her Positive and Negative Syndrome Scale (PANSS) score was 96 based on these symptoms.\n\nThe neuropsychological assessment revealed a full-scale intelligence quotient of 66 on the Korean Wechsler Adult Intelligence Scale. Her blood count was normal without any signs of infection. The serum calcium level and serum phosphorous level were normal. The thyroid function tests and intact parathyroid hormone were normal. An electrocardiogram revealed a normal sinus rhythm but possible right ventricular hypertrophy. Electroencephalography (EEG) showed generalized fast activities but within the normal limits. The 22q11.2DS deletion was confirmed using a fluorescence in situhybridization probe. Based on these findings, the patient was diagnosed with 22q11.2DS, mild mental retardation, and schizophrenia.\n\nThirty milligrams of aripiprazole and 800 mg of quetiapine was tried at first and then switched to 30 mg of olanzapine and 400 mg of amisulpride but the symptoms didn’t improve. The psychiatrist used olanzapine 30 mg and paliperidone 9 mg for 2 weeks, but the symptoms persisted. Therefore, paliperidone was changed to 8 mg of blonaserin.\n\nOn the fourth day that blonaserin was administered, the patient fell to the ground with generalized shaking of her extremities for 20 seconds. At that time, blonaserin was discontinued, and cardiology and neurology consultations were requested. The ECGs performed after the events revealed an incomplete right bundle branch block and prolonged QTc (483 mc). A sleep deprived EEG indicated localized cerebral dysfunction and bilateral temporal areas. The magnetic resonance imaging revealed multiple iso and high signal intense lesions in the bilateral periventricular white matter and subcortical white matter. The neurologist recommended the addition of lamotrigine to reduce the likelihood of seizure activity and the careful prescription of antipsychotics. She had three more absence-like seizures on five days after the first seizure. The neurologist recommended that lamotrigine be increased to 75 mg twice a day. After lamotrigine was increased, there were no more seizures, and the psychotic symptoms improved. The patient was discharged 10 days after remaining seizure-free on olanzapine 30 mg and lamotrigine 150 mg daily.\n\nDISCUSSION\nThe effectiveness and safety of antipsychotics in the treatment of psychosis associated with 22q11.2DS are not well established. 22q11.2DS is relatively unresponsive to currently used antipsychotic drugs [9]. Quetiapine and olanzapine appear to be efficacious in 22q11.2DS patients with schizophrenia because they are in idiopathic schizophrenia, whereas risperidone may be less effective [10-12]. Clozapine has been shown to reduce schizophrenia symptoms and hospitalizations as effectively in 22q11.2DS patients as it does in idiopathic schizophrenia, and at a lower average dose. On the other hand, neurological side effects with antipsychotic therapy tend to increase in 22q11.2DS patients and with clozapine in particular. These include generalized tonic-clonic seizures, focal seizures, myoclonus, rigidity, and tremors, with seizure being the most severe and most common [13,14].\n\nThe prevalence of epilepsy and acute symptomatic seizures in adults with 22q11.2DS is higher than in the general population [7,15]. A recent study on adults with this condition reported that the most common trigger for provoked seizures was the use of antipsychotics and antidepressants, even though a history of hypocalcemia was also common [16]. The incidence of seizure reported from US Food and Drug Administration approval trials was highest with clozapine, olanzapine, and quetiapine compared to a placebo. Only a slight increase was observed with ziprasidone, aripiprazole and risperidone [17]. In epileptic patients, risperidone has a low risk of inducing seizure activity [18]. In this case, it is presumed the convulsion occurred by adding blonaserin to the high capacity of antipsychotics. Although recent studies have shown that blonaserin prevents convulsion, but in this case blonaserin increases the potency of antipsychotics, and did not prevent convulsion [19]. After the convulsion was stopped, the previously used olanzapine was again used as 30 mg, but seizure did not occur again and the psychotic symptom also improved. Careful observation is always needed because high doses of psychotic drugs are risk factors for convulsion in 22q11.2DS [17].\n\nFor the seizure risk, a detailed history, full neurological examination and neurologist consultation to assist in the selection of the most appropriate anticonvulsant or augmentation agent is recommended in 22q11.2DS [18]. After seizure events, antipsychotics should be switched to others or stopped. Previous papers have reported similar cases. Additional monitoring, such as ECG or EEG, should be repeated at consecutive intervals during treatment in the 22q11.2DS [20].\n\nWhen treating schizophrenia patients with 22q11.2DS, the high dose of antipsychotic drugs should be chosen carefully, and the patients should be observed closely, paying attention to the possibility of convulsions. This is important for preventing potential adverse neurological events.\n\nAcknowledgments\nThis work was supported by an Inha University Research Grant.\n\n\nConflicts of Interest\n\n\nNo potential conflict of interest relevant to this article was reported.\n\n\nAuthor Contributions\n\n\nConceptualization: Won-Hyoung Kim, Seo-Hyun Choi. Investigation: Seo-Hyun Choi, Sang-Gu Kang. Resources: Won-Hyoung Kim, Seo-Hyun Choi. Supervision: Hee-Yun Kim, Hye-Young Kim, Jae-Nam Bae, and Jung-Sub Lee. Writing−original draft: Seo-Hyun Choi. Writing−review & editing: Won-Hyoung Kim.\n==== Refs\nREFERENCES\nHoeffding LK Trabjerg BB Olsen L Mazin W Sparsø T Vangkilde A 2017 Risk of psychiatric disorders among individuals with the 22q11.2 deletion or duplication: a danish nationwide, register-based study JAMA Psychiatry 74 282 290 10.1001/jamapsychiatry.2016.3939 28114601 \nShprintzen RJ 2000 Velo-cardio-facial syndrome: a distinctive behavioral phenotype Ment Retard Dev Disabil Res Rev 6 142 147 10.1002/1098-2779(2000)6:2<142::AID-MRDD9>3.0.CO;2-H 10899808 \nShprintzen RJ Higgins AM Antshel K Fremont W Roizen N Kates W 2005 Velo-cardio-facial syndrome Curr Opin Pediatr 17 725 730 10.1097/01.mop.0000184465.73833.0b 16282778 \nShprintzen RJ 2008 Velo-cardio-facial syndrome: 30 Years of study Dev Disabil Res Rev 14 3 10 10.1002/ddrr.2 18636631 \nKim SY Um YH Lim SC Jeong JH 2018 Limbic encephalitis manifesting as selective amnesia and seizure-like activity: a case report Clin Psychopharmacol Neurosci 16 109 113 10.9758/cpn.2018.16.1.109 29397673 \nAytuluk HG Simsek T Yilmaz M Turan AZ Saracoglu KT 2019 Can propofol lead to an increase in seizure threshold over the course of electroconvulsive therapy? Clin Psychopharmacol Neurosci 17 523 530 10.9758/cpn.2019.17.4.523 31671490 \nSchneider M Debbané M Bassett AS Chow EW Fung WL van den Bree M 2014 Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome Am J Psychiatry 171 627 639 10.1176/appi.ajp.2013.13070864 24577245 \nJolin EM Weller RA Jessani NR Zackai EH McDonald-McGinn DM Weller EB 2009 Affective disorders and other psychiatric diagnoses in children and adolescents with 22q11.2 Deletion Syndrome J Affect Disord 119 177 180 10.1016/j.jad.2009.02.016 19269692 \nVogels A Verhoeven WM Tuinier S DeVriendt K Swillen A Curfs LM 2002 The psychopathological phenotype of velo-cardio-facial syndrome Ann Genet 45 89 95 10.1016/S0003-3995(02)01114-0 12119217 \nMüller UJ Fellgiebel A 2008 Successful treatment of long-lasting psychosis in a case of 22q11.2 deletion syndrome Pharmacopsychiatry 41 158 159 10.1055/s-2008-1062700 18651346 \nVerhoeven WM Egger JI 2015 Atypical antipsychotics and relapsing psychoses in 22q11.2 deletion syndrome: a long-term evaluation of 28 patients Pharmacopsychiatry 48 104 110 10.1055/s-0034-1398612 25654302 \nDori N Green T Weizman A Gothelf D 2017 The effectiveness and safety of antipsychotic and antidepressant medications in individuals with 22q11.2 deletion syndrome J Child Adolesc Psychopharmacol 27 83 90 10.1089/cap.2014.0075 26131914 \nGladston S Clarke DJ 2005 Clozapine treatment of psychosis associated with velo-cardio-facial syndrome: benefits and risks J Intellect Disabil Res 49 567 570 10.1111/j.1365-2788.2005.00708.x 15966965 \nYacoub A Aybar M 2007 Response to clozapine in psychosis associated with velo-cardio-facial syndrome Psychiatry (Edgmont) 4 14 \nRyan AK Goodship JA Wilson DI Philip N Levy A Seidel H 1997 Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study J Med Genet 34 798 804 10.1136/jmg.34.10.798 9350810 \nWither RG Borlot F MacDonald A Butcher NJ Chow EWC Bassett AS 2017 Bassett AS, et al. 22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy Epilepsia 58 1095 1101 10.1111/epi.13748 28448680 \nAlper K Schwartz KA Kolts RL Khan A 2007 Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports Biol Psychiatry 62 345 354 10.1016/j.biopsych.2006.09.023 17223086 \nHulvershorn LA Madou MR Weis JR Coffey B 2009 First-episode psychosis in an adolescent with seizure disorder and tetralogy of Fallot J Child Adolesc Psychopharmacol 19 307 311 10.1089/cap.2009.19302 19519268 \nYokota K Tatebayashi H Matsuo T Shoge T Motomura H Matsuno T 2002 The effects of neuroleptics on the GABA-induced Cl- current in rat dorsal root ganglion neurons: differences between some neuroleptics Br J Pharmacol 135 1547 1555 10.1038/sj.bjp.0704608 11906969 \nCorrell CU Penzner JB Parikh UH Mughal T Javed T Carbon M 2006 Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents Child Adolesc Psychiatr Clin N Am 15 177 206 10.1016/j.chc.2005.08.007 16321730\n\n",
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"abstract": "Reactivation of hepatitis B virus replication is a known complication of immunosuppressive therapy, which can lead to hepatocellular injury, liver failure, and death. In this report, we describe the case of a 44-year-old man with chronic hepatitis B and a dilated cardiomyopathy status after a heart transplant. Reactivation of the patient 's hepatitis B virus occurred 4 months after the heart transplant. Despite prompt administration of antiviral therapy, he developed fulminant hepatitis with hepatic encephalopathy. A successful living-related liver transplant was performed 7 months after the heart transplant. The patient was followed up for 1 year, and during that time was free of hepatitis B virus. We suggest that routine antiviral therapy should be administered to patients with chronic hepatitis B receiving immunosuppressive therapy.",
"affiliations": "Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.",
"authors": "Yang|Po-Chih|PC|;Ho|Cheng-Maw|CM|;Chou|Nai-Kuan|NK|;Wang|Shoei-Shen|SS|;Wu|Yao-Ming|YM|;Ho|Ming-Chih|MC|;Hu|Rey-Heng|RH|;Lee|Po-Huang|PH|",
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"title_normalized": "successful living donor liver transplant for fulminant hepatitis in a heart recipient"
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],
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},
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},
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},
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"sendertype": "2"
},
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"transmissiondate": "20151125"
},
{
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},
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"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "44",
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"reaction": [
{
"reactionmeddrapt": "Hepatic failure",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatitis B",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic encephalopathy",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "YANG P-C, HO C-M, CHOU N-K, WANG S-S, WU Y-M, HO M-C, ET AL. SUCCESSFUL LIVING-DONOR LIVER TRANSPLANT FOR FULMINANT HEPATITIS IN A HEART RECIPIENT. EXP-CLIN-TRANSPLANT. 2015;13(4):369-370",
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"qualification": "3",
"reportercountry": "TW"
},
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"receiptdate": "20150921",
"receivedate": "20150921",
"receiver": {
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},
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},
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}
] |
{
"abstract": "A 59-year-old man presented to the ED with a chief complaint of shortness of breath. His past medical history was significant for end-stage renal disease secondary to lithium toxicity, immunosuppression subsequent to cadaveric renal transplantation, bipolar disorder, and hypertension. His shortness of breath had begun 6 months previously and was initially intermittent; it then progressed to constant shortness of breath over the few weeks before presentation. He had no fever, hemoptysis, or chest pain. The patient was admitted to hospital for further evaluation.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Rush University Medical Center, Chicago, IL. Electronic address: patrick_m_duncan@rush.edu.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Rush University Medical Center, Chicago, IL.;Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, IL.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Rush University Medical Center, Chicago, IL.",
"authors": "Duncan|Patrick|P|;Cull|Stephanie|S|;Shah|Palmi|P|;Gamino|Amie|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2019.08.1918",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "157(1)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D002114:Calcinosis; D003937:Diagnosis, Differential; D018450:Disease Progression; D004417:Dyspnea; D006801:Humans; D016030:Kidney Transplantation; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e9-e12",
"pmc": null,
"pmid": "31916972",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 59-Year-Old Man With Chronic Kidney Disease After Kidney Transplantation Presents With Chronic Dyspnea.",
"title_normalized": "a 59 year old man with chronic kidney disease after kidney transplantation presents with chronic dyspnea"
} | [
{
"companynumb": "US-RISING PHARMACEUTICALS, INC.-2019RIS00653",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "LITHIUM CARBONATE"
},
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}
],
"patientagegroup": null,
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"patientonsetageunit": "801",
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"reaction": [
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"reactionmeddrapt": "End stage renal disease",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DUNCAN P., CULL S., SHAH P., AND GAMINO A. A 59-YEAR-OLD MAN WITH CHRONIC KIDNEY DISEASE AFTER KIDNEY TRANSPLANTATION PRESENTS WITH CHRONIC DYSPNEA. CHEST. 2020?157(1):E9-E12",
"literaturereference_normalized": "a 59 year old man with chronic kidney disease after kidney transplantation presents with chronic dyspnea",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200109",
"receivedate": "20200109",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 17253417,
"safetyreportversion": 1,
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
},
{
"companynumb": "US-HETERO-HET2020US00043",
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{
"actiondrug": "5",
"activesubstance": {
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},
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"medicinalproduct": "LITHIUM."
}
],
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "End stage renal disease",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DUNCAN P, CULL S, SHAH P, GAMINO A. A 59-YEAR-OLD MAN WITH CHRONIC KIDNEY DISEASE AFTER KIDNEY TRANSPLANTATION PRESENTS WITH CHRONIC DYSPNEA. CHEST. 2020?157(1):E9-E12",
"literaturereference_normalized": "a 59 year old man with chronic kidney disease after kidney transplantation presents with chronic dyspnea",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200120",
"receivedate": "20200120",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17287299,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "BACKGROUND\nPosttransplant lymphoproliferative disorder (PTLD) is a rare condition occurring after organ transplantation. PTLD comprises 4 subtypes, of which Hodgkin lymphoma (HL) type and HL-like type (currently included in polymorphic type) account for only about 1%-3% of cases. Primary central nervous system PTLD is also rare; most cases are Epstein-Barr virus-positive, B-cell PTLD. To our knowledge, no case of HL-like PTLD has been documented.\n\n\nMETHODS\nA 43-year-old woman who underwent kidney transplantation for IgA nephropathy 14 years previously presented to the emergency department with seizure. Gadolinium-enhanced T1-weighted magnetic resonance imaging showed a ring-enhancing mass in the left temporal lobe. Gross total removal of the tumor was performed, and pathologic examination revealed findings consistent with HL-like PTLD. The patient's immunosuppressants were subsequently reduced, and she received postoperative systemic therapy with rituximab and radiation therapy. Follow-up magnetic resonance imaging showed no signs of relapse.\n\n\nCONCLUSIONS\nThis represents an extremely rare case of a patient with HL-like PTLD occurring as a primary central nervous system lesion.",
"affiliations": "Department of Neurological Surgery, National Hospital Organization Okayama Medical Center, Okayama, Japan. Electronic address: ys-hori@umin.ac.jp.;Department of Pathology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurological Surgery, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurological Surgery, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurological Surgery, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Pathology, National Hospital Organization Okayama Medical Center, Okayama, Japan.",
"authors": "Hori|Yusuke S|YS|;Nagakita|Keina|K|;Ebisudani|Yuki|Y|;Aoi|Mizuho|M|;Fukuhara|Toru|T|;Shinno|Yoko|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.03.153",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "114()",
"journal": "World neurosurgery",
"keywords": "B-cell lymphoma; Hodgkin lymphoma; Posttransplant lymphoproliferative disorder; Primary central nervous system lymphoma",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D016543:Central Nervous System Neoplasms; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D011183:Postoperative Complications",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "230-234",
"pmc": null,
"pmid": "29609086",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Central Nervous System Hodgkin Lymphoma-Like Posttransplant Lymphoproliferative Disorder.",
"title_normalized": "primary central nervous system hodgkin lymphoma like posttransplant lymphoproliferative disorder"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-02971",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
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},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
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"drugcharacterization": "1",
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"drugdosagetext": "4 MG, UNK",
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"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
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"medicinalproduct": "METHYLPREDNISOLONE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": "091249",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IRBESARTAN"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugcharacterization": "2",
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"drugdosagetext": "50 MG, UNK",
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"medicinalproduct": "IRBESARTAN."
}
],
"patientagegroup": null,
"patientonsetage": "43",
"patientonsetageunit": "801",
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Post transplant lymphoproliferative disorder",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Epstein-Barr virus associated lymphoproliferative disorder",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hodgkin^s disease",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HORI YS, NAGAKITA K, EBISUDANI Y, AOI M, ET AL.. PRIMARY CENTRAL NERVOUS SYSTEM HODGKIN LYMPHOMA-LIKE POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER. WORLD NEUROSURGERY.. 2018?114:230-234",
"literaturereference_normalized": "primary central nervous system hodgkin lymphoma like posttransplant lymphoproliferative disorder",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180516",
"receivedate": "20180516",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14900082,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Drug-induced crystalline nephropathies are secondary to abnormal accumulation of crystals leading to parenchymal renal injuries. Methotrexate, used to treat a wide range of malignancies, is one of the various drugs accountable in this particular condition. We report a case of acute renal injury during the course of high-dose methotrexate therapy in a patient presenting primary cerebral diffuse large B-cell lymphoma. Interestingly, the kidney biopsy revealed intratubular methotrexate crystal formations. We also summarize the distinctive characteristics of main crystalline nephropathies in order to guide pathologists toward the many types of crystals encountered on renal biopsy.",
"affiliations": "Service d'anatomie et cytologie pathologiques, centre hospitalier universitaire de Besançon, 3, boulevard Alexandre-Fleming, 25030 Besançon cedex, France. Electronic address: pcolpart@chu-besancon.fr.;Service d'anatomie et cytologie pathologiques, centre hospitalier universitaire de Besançon, 3, boulevard Alexandre-Fleming, 25030 Besançon cedex, France. Electronic address: sadrianfelix@chu-besancon.fr.",
"authors": "Colpart|Prudence|P|;Félix|Sophie|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate",
"country": "France",
"delete": false,
"doi": "10.1016/j.annpat.2018.08.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0242-6498",
"issue": "39(1)",
"journal": "Annales de pathologie",
"keywords": "Acute kidney injury; Biopsie rénale; Crystalline nephropathies; Insuffisance rénale aiguë; Kidney biopsy; Methotrexate; Méthotrexate; Nephrotoxicity; Néphropathies cristallines; Néphrotoxicité",
"medline_ta": "Ann Pathol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001706:Biopsy; D003460:Crystallization; D006801:Humans; D007668:Kidney; D008297:Male; D008727:Methotrexate",
"nlm_unique_id": "8106337",
"other_id": null,
"pages": "18-23",
"pmc": null,
"pmid": "30554834",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methotrexate induced crystalline nephropathy: A rare histological finding on renal biopsy.",
"title_normalized": "methotrexate induced crystalline nephropathy a rare histological finding on renal biopsy"
} | [
{
"companynumb": "FR-TEVA-2019-FR-1019822",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
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"medicinalproduct": "METHOTREXATE."
},
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"activesubstancename": "PREDNISONE"
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"abstract": "OBJECTIVE\nThe phase II TACTIC trial prospectively selected patients with KRAS wild-type advanced biliary tract cancer for first-line treatment with panitumumab and combination chemotherapy.\n\n\nMETHODS\nOf 78 patients screened, 85 % had KRAS wild-type tumours and 48 were enrolled. Participants received cisplatin 25 mg/m(2) and gemcitabine 1000 mg/m(2) on day 1 and day 8 of each 21-day cycle and panitumumab 9 mg/kg on day 1 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or request to discontinue. The primary endpoint was the clinical benefit rate (CBR) at 12 weeks (complete response, partial response, or stable disease). CBR of 70 % was considered to be of clinical interest. Secondary outcomes were progression-free survival, time to treatment failure, overall survival, CA19.9 response and safety.\n\n\nRESULTS\nThirty-four patients had a clinical benefit at 12 weeks, an actuarial rate of 80 % (95 % CI 65-89 %). 46 % had a complete or partial response. Median progression-free survival was 8.0 months (95 % CI 5.1-9.9) and median overall survival 11.9 months (95 % CI 7.4-15.8). Infection accounted for 27 % of the grade 3 or 4 toxicity, with rash (13 %), fatigue (13 %), and hypomagnesemia (10 %) among the more common grade 3 or 4 non-haematological toxicities.\n\n\nCONCLUSIONS\nA marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.",
"affiliations": "National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.;Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.;National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.;Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.;National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.;Austin Health, Melbourne, VIC, Australia.;Chris O'Brien Lifehouse, Sydney, NSW, Australia.;St Vincents Hospital, Melbourne, VIC, Australia.;Western Health, Melbourne, VIC, Australia.;Haematology and Oncology Clinics of Australasia, Wesley Medical Centre, Brisbane, QLD, Australia.;National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.;National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.;Nambour General Hospital, Nambour, QLD, Australia.;Sir Charles Gairdner Hospital, Nedlands, WA, Australia.;Flinders University, Adelaide, SA, Australia.;Department of Medical Oncology, Nepean Cancer Care Centre, PO Box 63, Penrith, Sydney, NSW, 2751, Australia. Jenny.Shannon@health.nsw.gov.au.",
"authors": "Ferraro|D|D|;Goldstein|D|D|;O'Connell|R L|RL|;Zalcberg|J R|JR|;Sjoquist|K M|KM|;Tebbutt|N C|NC|;Grimison|P|P|;McLachlan|S|S|;Lipton|L L|LL|;Vasey|P|P|;Gebski|V J|VJ|;Aiken|C|C|;Cronk|M|M|;Ng|S|S|;Karapetis|C S|CS|;Shannon|J|J|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D018395:CA-19-9 Antigen; C117307:KRAS protein, human; D003841:Deoxycytidine; D000077544:Panitumumab; C056507:gemcitabine; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-3089-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "78(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Biliary tract cancer; Cancer antigen 19.9; Chemotherapy; KRAS; Panitumumab; Phase II trial",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D001661:Biliary Tract Neoplasms; D018395:CA-19-9 Antigen; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077544:Panitumumab; D018579:Patient Selection; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "361-7",
"pmc": null,
"pmid": "27335026",
"pubdate": "2016-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer.",
"title_normalized": "tactic a multicentre open label single arm phase ii trial of panitumumab cisplatin and gemcitabine in biliary tract cancer"
} | [
{
"companynumb": "AU-AMGEN-AUSCT2016113205",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125147",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN FORMULATION",
"drugdosagetext": "9 MG/KG, ON DAY 1 OF EACH CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BILE DUCT CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugseparatedosagenumb": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "9",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PANITUMUMAB"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "25 MG/M2, ON DAY AND DAY 8 OF EACH 21-DAY CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BILE DUCT CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "25",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1000 MG/M2 ON DAY 1 AND DAY 8 OF EACH 21-DAY CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BILE DUCT CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GEMCITABINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "R.L O^CONNELL. TACTIC: A MULTICENTRE, OPEN-LABEL, SINGLE-ARM PHASE II TRIAL OF PANITUMUMAB, CISPLATIN, AND GEMCITABINE IN BILIARY TRACT CANCER.. CANCER CHEMOTHER PHARMACOL.. 2016;78:361-367",
"literaturereference_normalized": "tactic a multicentre open label single arm phase ii trial of panitumumab cisplatin and gemcitabine in biliary tract cancer",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20160901",
"receivedate": "20160901",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12705387,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
}
] |
{
"abstract": "BACKGROUND\nNon-vitamin K antagonist oral anticoagulant (NOAC) use has significantly reduced intracerebral hemorrhagic (ICH) risk compared with standard anticoagulant treatment. Hematoma expansion (HE) is a known predictor of mortality in warfarin-associated ICH. Little is known about HE in patients using NOACs.\n\n\nMETHODS\nWe conducted a retrospective chart review of patients with ICH admitted to Cedars-Sinai Medical Center from October 2010 to June 2016. We identified patients with concomitant administration of an oral anticoagulant and collected data including evidence of HE on imaging and modified Rankin Scale (mRS) at discharge. We defined HE as relative (≥33% increase) or absolute expansion (≥12 mL). We compared outcomes of patients with and without HE.\n\n\nRESULTS\nOut of 814 patients with ICH who were admitted, we identified 9 patients with recent NOAC use and 18 intentionally matched controls on warfarin. We found no significant differences in National Institutes of Health Stroke Scale or ICH score on presentation (median [interquartile range] 15 [5,21] versus 7 [1.25,19.5] [P = .41] and 2 [1,4] versus 1 [1,3] [P = .33]) between patients on NOACs and those on warfarin. Four out of the 9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated HE, with no significant difference (P = .42). There were no significant differences in mRS on discharge between groups (P = .52).\n\n\nCONCLUSIONS\nIn our coagulopathic NOAC patient population, HE occurs within 6 hours in 44% of patients. This case series did not have sufficient statistical power to detect significant differences between the groups. To our knowledge, this is one of the largest case series reporting on HE with concomitant NOAC use.",
"affiliations": "Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: Kara.Melmed@cshs.org.;Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California.;Department of Radiology, Cedars-Sinai Medical Center, Los Angeles, California.;Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California.",
"authors": "Melmed|Kara R|KR|;Lyden|Patrick|P|;Gellada|Norman|N|;Moheet|Asma|A|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2017.04.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "26(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Critical care; hematoma expansion; intracerebral hemorrhage; novel oral anticoagulants; stroke",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D002543:Cerebral Hemorrhage; D004185:Disability Evaluation; D005260:Female; D006406:Hematoma; D006801:Humans; D015141:Los Angeles; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "1874-1882",
"pmc": null,
"pmid": "28647419",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intracerebral Hemorrhagic Expansion Occurs in Patients Using Non-Vitamin K Antagonist Oral Anticoagulants Comparable with Patients Using Warfarin.",
"title_normalized": "intracerebral hemorrhagic expansion occurs in patients using non vitamin k antagonist oral anticoagulants comparable with patients using warfarin"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2017-066076",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "009218",
"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": "WARFARIN SODIUM."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MELMED KR, LYDEN P, GELLADA N, MOHEET A. INTRACEREBRAL HEMORRHAGIC EXPANSION OCCURS IN PATIENTS USING NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS COMPARABLE WITH PATIENTS USING WARFARIN. JOURNAL OF STROKE AND CEREBROVASCULAR DISEASES. 2017?26(8):1874-82",
"literaturereference_normalized": "intracerebral hemorrhagic expansion occurs in patients using non vitamin k antagonist oral anticoagulants comparable with patients using warfarin",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201029",
"receivedate": "20170727",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13802815,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210113"
}
] |
{
"abstract": "Cladophialophora bantiana, a dematiaceous neurotropic mold causes rare and lethal brain abscess, commonly in immunocompetent hosts. We report a rare and probably a case of disseminated infection with this black mold in an immunosuppressed individual from India. A 55-year-old diabetic male presented with severe headache, blurred-vision, behavioural abnormalities, eye-pain and ear-discharge. He was undergoing treatment for hypertension, prostatomegaly and obstructive pulmonary disease. He was on steroids for the past six years for uveitis. Haematology reports indicated elevated WBC and platelet count. He was negative for HIV, hepatitis, autoimmune antibodies and tumour markers. CD4 count was within normal limits. Brain magnetic resonance imaging revealed multiple ring-enhancing lesions and oedema in the left tempero-parietal region. Chest X-ray showed irregular consolidations in right paracardiac region and confluence in both lungs. Positron Emission Tomography of whole body revealed multiple lesions in brain, lungs, lymph nodes and C3-vertebrae. Histopathology of the lung lesion showed non-tuberculous infectious pathology and brain lesions showed necrosis with occurrence of pigmented hyphal fungi. The pus aspirated during surgical excision of brain lesions grew black mold, identified as C. bantiana. Although patient was started on intravenous Voriconazole, he succumbed to the infection after 7 days. The lesion was initially suspected to be of tuberculous etiology, and the lesions in lungs were also suggestive of malignancy, which was however ruled out by histopathological examination. Such diagnostic dilemmas are common in the infection caused by Cladophialophora, which can cause treatment delay and death. Early diagnosis is therefore mandatory for the rapid treatment and survival of patients.",
"affiliations": "Department of neuromicrobiology, National institute of mental health and neuro sciences (NIMHANS), Bangalore, India.;Department of neuropathology, NIMHANS, Bangalore, India.;Department of neuromicrobiology, National institute of mental health and neuro sciences (NIMHANS), Bangalore, India.;Department of neuroimaging & interventional radiology, NIMHANS, Bangalore, India.;Department of neurosurgery, NIMHANS, Bangalore, India.;Department of neuromicrobiology, National institute of mental health and neuro sciences (NIMHANS), Bangalore, India.;Department of neuromicrobiology, National institute of mental health and neuro sciences (NIMHANS), Bangalore, India. Electronic address: nagarathnachandrashekar@gmail.com.",
"authors": "Lahiri Mukhopadhyay|S|S|;Mahadevan|A|A|;Bahubali|V H|VH|;Dawn Bharath|R|R|;Prabhuraj|A R|AR|;Maji|S|S|;Siddaiah|N|N|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2017.04.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "27(3)",
"journal": "Journal de mycologie medicale",
"keywords": "Brain abscess; Cladophialophora bantiana; Dematiaceous fungi; Disseminated infection; Histopathology; Immunosuppressed; Multiple lesions; Non-tuberculous; Surgical excision",
"medline_ta": "J Mycol Med",
"mesh_terms": "D001203:Ascomycota; D001922:Brain Abscess; D020314:Central Nervous System Fungal Infections; D006801:Humans; D016867:Immunocompromised Host; D007194:India; D008297:Male; D008875:Middle Aged; D060446:Phaeohyphomycosis",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "391-395",
"pmc": null,
"pmid": "28478966",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare case of multiple brain abscess and probably disseminated phaeohyphomycosis due to Cladophialophora bantiana in an immunosuppressed individual from India.",
"title_normalized": "a rare case of multiple brain abscess and probably disseminated phaeohyphomycosis due to cladophialophora bantiana in an immunosuppressed individual from india"
} | [
{
"companynumb": "IN-PFIZER INC-2017211555",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "019950",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "400 MG, 2X/DAY (GRADUALLY INCREASING)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUCONAZOLE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "019950",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "40 MG, UNK (INITIALLY)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIFUNGAL TREATMENT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "40",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUCONAZOLE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "021267",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POWDER FOR SOLUTION FOR INFUSION",
"drugdosagetext": "UNK, (20 MG TO 200 MG/DAY)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIFUNGAL TREATMENT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VORICONAZOLE."
}
],
"patientagegroup": null,
"patientonsetage": "55",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Fungal infection",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Brain abscess",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MUKHOPADHYAY, S.. A RARE CASE OF MULTIPLE BRAIN ABSCESS AND PROBABLY DISSEMINATED PHAEOHYPHOMYCOSIS DUE TO CLADOPHIALOPHORA BANTIANA IN AN IMMUNOSUPPRESSED INDIVIDUAL FROM INDIA. JOURNAL DE MYCOLOGIE MEDICALE. 2017;27(3):391-395",
"literaturereference_normalized": "a rare case of multiple brain abscess and probably disseminated phaeohyphomycosis due to cladophialophora bantiana in an immunosuppressed individual from india",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20170925",
"receivedate": "20170515",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13546373,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20171127"
}
] |
{
"abstract": "OBJECTIVE\nTo report two cases of cat-scratch fever with atypical posterior segment manifestations.\n\n\nMETHODS\nTwo cases were retrospectively reviewed.\n\n\nRESULTS\nA 27-year-old woman presented with painless blurring of central vision in her left eye. Clinical examination revealed a small focal area of retinitis within the macula associated with a subtle macular star. Spectral-domain optical coherence tomography showed a hyper-reflective inner retinal lesion in addition to subretinal and intraretinal fluid as well as hyperreflective foci within the outer plexiform layer. Serology was positive for anti-B. henselae IgM (titer 1:32). A 34-year-old woman presented with painless loss of vision in both eyes associated with headaches and pain with extraocular movement. Spectral-domain optical coherence tomography depicted subretinal fluid, intraretinal fluid, and hyperreflective deposits within the outer plexiform layer. A focal collection of vitreous cell was observed overlying the optic nerve in the left eye. Bilateral disk leakage was identified on fluorescein angiography. Serology revealed high-titer anti-B. henselae antibodies (IgM titers 1:32, IgG titers 1:256).\n\n\nCONCLUSIONS\nOur cases highlight the necessity of recognizing more unusual posterior segment presentations of ocular bartonellosis. Multimodal retinal imaging including spectral-domain optical coherence tomography may help better characterize lesions.",
"affiliations": "Casey Eye Institute, Oregon Health and Science University, Portland, Oregon.;Casey Eye Institute, Oregon Health and Science University, Portland, Oregon.;Casey Eye Institute, Oregon Health and Science University, Portland, Oregon.",
"authors": "Michel|Zachary|Z|;Redd|Travis|T|;Bhavsar|Kavita V|KV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000893",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31348120",
"pubdate": "2019-07-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "MULTIMODAL IMAGING OF TWO UNCONVENTIONAL CASES OF BARTONELLA NEURORETINITIS.",
"title_normalized": "multimodal imaging of two unconventional cases of bartonella neuroretinitis"
} | [
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] |
{
"abstract": "OBJECTIVE\nVitamin D receptor activation by vitamin D sterols and calcium-sensing receptor stimulation by cinacalcet are the most powerful treatments of secondary hyperparathyroidism. This study was aimed to assess a possible association between histopathologic changes of parathyroid tissue and treatment modality.\n\n\nMETHODS\nStudies were performed on 82 parathyroids of 22 adult white hemodialysis patients undergoing first parathyroidectomy. The type of hyperplasia and the distribution of chief and oxyphil cells, expressed as oxyphil/chief cell ratio, were assessed. Three groups could be studied according to treatment modality: group A consisted of 6 patients who were treated with cinacalcet, intravenous calcitriol, and phosphate binders; group B consisted of 6 patients who were treated with intravenous calcitriol and phosphate binders, and group C consisted of 10 patients who were treated with phosphate binders alone.\n\n\nRESULTS\nSixty-eight (82.9%) out of 82 glands removed showed nodular hyperplasia. It was more frequent in groups A and B than in group C. A stepwise forward logistic regression model showed that the probability of nodular hyperplasia was higher in patients who were on calcitriol and/or cinacalcet therapy, in female gender and in patients with a higher body mass index. Oxyphil/chief cell ratio also was significantly different among the three groups. Cinacalcet treatment was the only predictor of this ratio.\n\n\nCONCLUSIONS\nAn association was found between calcitriol and/or cinacalcet therapy and a high prevalence of nodular hyperplasia, and between cinacalcet therapy and high oxyphil/chief cell ratio. The meaning of the observed associations remains uncertain.",
"affiliations": "Division of Nephrology, Miulli General Hospital, Acquaviva delle Fonti, Manduria, Italy.",
"authors": "Lomonte|Carlo|C|;Vernaglione|Luigi|L|;Chimienti|Domenico|D|;Bruno|Andrea|A|;Cocola|Savino|S|;Teutonico|Annalisa|A|;Cazzato|Francesco|F|;Basile|Carlo|C|",
"chemical_list": "D009281:Naphthalenes; D010710:Phosphates; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D014815:Vitamins; D002117:Calcitriol; D000069449:Cinacalcet",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.04150907",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "3(3)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": null,
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002117:Calcitriol; D000069449:Cinacalcet; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D006965:Hyperplasia; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes; D024862:Oxyphil Cells; D010280:Parathyroid Glands; D016105:Parathyroidectomy; D010710:Phosphates; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D006435:Renal Dialysis; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D017211:Treatment Failure; D014511:Uremia; D014815:Vitamins",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "794-9",
"pmc": null,
"pmid": "18322048",
"pubdate": "2008-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "17449495;15772929;16326747;17706605;15794735;15507543;15951480;15956063;15563573;15188026;10820180;11813867;14633156;11373348;9893121;8255296;11152759;14733419;17449493",
"title": "Does vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism?",
"title_normalized": "does vitamin d receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021175401",
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{
"actiondrug": "5",
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"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
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"drugdosageform": "Unknown formulation",
"drugdosagetext": "UNK UNK, QD",
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"drugindication": "Hyperparathyroidism secondary",
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"medicinalproduct": "CINACALCET HYDROCHLORIDE"
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{
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"medicinalproduct": "CALCITRIOL"
}
],
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"reaction": [
{
"reactionmeddrapt": "Parathyroid hyperplasia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Basile C.; Lomonte C.; Vernaglione L. et al.. Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?. Clinical journal of the American Society of Nephrology: CJASN. 2008;3:794-799",
"literaturereference_normalized": "does vitamin d receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism",
"qualification": "1",
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},
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}
] |
{
"abstract": "Adverse drug reactions and interactions are among the major causes of death in the United States. Antidepressants have been reported as causing suicide and homicide and share the class attribute of frequently producing akathisia, a state of severe restlessness associated with thoughts of death and violence. Medical examiners can now identify some pharmacogenetic interactions that cause drugs, deemed safe for most, to be lethal to others. Such deaths do not yet include medication-induced, akathisia-related suicides and homicides. An extrapyramidal side effect, akathisia is a manifestation of drug toxicity whose causes lie, inter alia, in drugs, doses, and co-prescribed medications that inhibit and compete for metabolizing enzymes, which may themselves be defective. In this paper, we report our investigation into adverse drug reactions/interactions in three persons who committed homicide, two also intending suicide, while on antidepressants prescribed for stressful life events. Their histories of medication use, adverse reactions and reasons for changes in medications are presented. DNA samples were screened for variants in the cytochrome P450 gene family; that produce drug metabolizing enzymes. All three cases exhibit genotype-based diminished metabolic capability that, in combination with their enzyme inhibiting/competing medications, decreased metabolism further and are the likely cause of these catastrophic events.",
"affiliations": "Independent Forensic Services LLC, 32796 Edward Drive, Conifer, CO, 80433, USA. Electronic address: s.eikelenboom@ifscolorado.com.;Forensic Psychiatrist, Pharmacogeneticist, Suite 310, Level 3 203-223 New South Head Road, Point Piper, NSW, 2027, Australia. Electronic address: lucire@ozemail.com.au.;Department of Biological Sciences, University of Denver, Denver, CO, 80208, USA. Electronic address: fogleman@du.edu.",
"authors": "Eikelenboom-Schieveld|Selma J M|SJ|;Lucire|Yolande|Y|;Fogleman|James C|JC|",
"chemical_list": "D000928:Antidepressive Agents; D003577:Cytochrome P-450 Enzyme System",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-928X",
"issue": "41()",
"journal": "Journal of forensic and legal medicine",
"keywords": "Akathisia; Antidepressants; Cytochrome P450 (CYP450); Forensic pharmacogenetics; Homicide; Suicide",
"medline_ta": "J Forensic Leg Med",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D000928:Antidepressive Agents; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D005554:Forensic Medicine; D006708:Homicide; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013405:Suicide",
"nlm_unique_id": "101300022",
"other_id": null,
"pages": "65-71",
"pmc": null,
"pmid": "27138119",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The relevance of cytochrome P450 polymorphism in forensic medicine and akathisia-related violence and suicide.",
"title_normalized": "the relevance of cytochrome p450 polymorphism in forensic medicine and akathisia related violence and suicide"
} | [
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"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
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"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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],
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"literaturereference": "EIKELENBOOM-SCHIEVELD S, LUCIRE Y, FOGLEMAN J. THE RELEVANCE OF CYTOCHROME P450 POLYMORPHISM IN FORENSIC MEDICINE AND AKATHISIA-RELATED VIOLENCE AND SUICIDE. J FORENSIC LEG MED. 2016;41:65-71.",
"literaturereference_normalized": "the relevance of cytochrome p450 polymorphism in forensic medicine and akathisia related violence and suicide",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
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}
] |