doxorubicin

etoposide

Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide . In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.


efavirenz

etravirine

A computational study of CYP3A4 mediated drug interaction profiles for anti-HIV drugs. Molecular docking is a reliable method with which to identify the binding conformations of substrates, inducers and inhibitors of cytochrome P450 (CYP) enzymes. We used the docking method to explore possible binding modes of an entry inhibitor (maraviroc) and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and etravirine) to cytochrome P450 3A4 (CYP3A4). In addition, docking results were compared with the binding conformations of HIV protease drugs to infer the binding site residues and potential drug-drug interaction profiles for combination therapy in the treatment of AIDS. We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4 . Dosage adjustment is required for delavirdine and maraviroc when combined with HIV protease drugs. The present results are in good agreement with experimental data from drug interaction profiles. The information provided in this paper will be helpful in furthering our understanding the functions of CYP3A4, and could aid in the design of new drugs that would be metabolized easily without having any drug-drug interaction profile.


dexamethasone

vincristine

doxorubicin

The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia. KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL. ### Experimental Design First , we searched for the most synergistic combination of KPT-8602 with dexamethasone , vincristine , or doxorubicin ### results KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as ### conclusions Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients.


artesunate

artemether

The rational use of qinghaosu and its derivatives: what is the future of new compounds?  In Thailand , artesunate and artemether are the mainly used antimalarials for treatment of severe or multidrug resistant falciparum malaria . However, their availability (supply) and the registration requirements are the major limitations for their large-scale use. At Bangkok Hospital for Tropical Diseases, Thailand, we have studied the new artemisinin derivatives, dihydroartemisinin and arteether, and artesunate suppositories. We found that the three preparations are well tolerated, safe, and efficacious.


lidocaine

fentanyl

ropivacaine

fentanyl

Epidural analgesia during labor--0.5 % lidocaine with fentanyl vs. 0.08 % ropivacaine with fentanyl . Although lidocaine is a cheap and globally available local anesthetic, yet it is not a popular drug for labor analgesia. This is claimed to its higher intensity of motor block, possibility of transient neurological symptoms (TNS) and its placental transfer with probable drawbacks on fetal well-being. However, these effects could be concentration dependent and, the evidence linking them to lidocaine is still lacking. This study was designed to evaluate the efficacy and safety of 0.5% epidural lidocaine plus fentanyl during labor. ### methods One hundred and twenty healthy full term nulliparous women in early labor with a single fetus presented by the vertex were enrolled in this randomized, double-blind clinical trial. Parturient were assigned to receive epidural analgesia either with lidocaine 0.5% plus fentanyl 2 microg(-1 mL) (LF), or ropivacaine 0.08% plus fentanyl 2 microg(-1 ml) (RF) when their cervix was dilated to 4 centimeters. Analgesia was provided with 20 ml bolus of the study solution and maintained at 10 ml(-1) h. Upper level of sensory loss to cold, Visual Analogue Pain Score (VAPS), motor block (modified Bromage score), the duration of the first and second stages of labor, numbers of instrumental vaginal and cesarean deliveries, the neonatal apgar score, patient satisfaction and side effects, were recorded. ### results There were no significant differences in sensory level, pain scores, duration of the first and second stages of labor, numbers of instrumental and cesarean deliveries, the neonatal apgar scores, patient satisfaction or side effect between groups. Although motor block was significantly high in lidocaine group compared to ropivacaine group (p < 0.05), all parturient were moving satisfactorily in bed. ### conclusions Dilute epidural lidocaine (0.5%) with fentanyl effectively and safely initiates epidural analgesia clinically indistinguishable from 0.08% epidural ropivacaine with fentanyl. Although it induces significant motor block compared to ropivacaine, it still preserves maternal ability to move satisfactorily in bed. Whether further reduction in lidocaine concentration could trim down the motor block, remains to be investigated.


chloroquine

dexamethasone

methotrexate

vinblastine

The effect of immunosuppressive and anti-inflammatory drugs on monocyte function in vitro. MNL cellular chemotaxis, bacterial killing and phagocytosis, and Oil Red O phagocytosis were studied in vitro in the presence of eight anti-inflammatory or immunosuppressive drugs. Inhibition of Boyden Chamber migration of MNL 's in a MNL-lymphocyte mixture was achieved after 1/2 hr incubation by 10(-3 ) and 10(-4 ) mol/L. concentrations of chloroquine ( maximum inhibition 63 % + /- 2.8 ) , dexamethasone ( 58 % + /- 8.6 ) , 6-mercaptopurine ( 62 % + /- 4.2 ) , methotrexate ( 66 % + /- 6.4 ) , and vinblastine ( 100 % ) . Bacterial killing was not significantly affected by any of the drugs studied. Bacterial phagocytosis was improved by vinblastine at 10(-3) and 10(-4)M and by 6-mercaptopurine at 10(-5)M, but there was apparent interference with the assay at high drug concentrations. Modification of the Oil Red O technique showed inhibitions of MNL phagocytosis by vinblastine at 10(-3)M (69% +/- 2.8 inhibition), chloroquine at 10(-3)M (49% +/- 8.5), and mercaptopurine at 10(-3)M (32.5% +/- 0.7). cyclophosphamide, although reported to require hepatic conversion in vivo, may be partially activated in a lymphocyte-MNL mixture in vitro, producing a decrease in cell viability but no statistically significant impairment of MNL function. These results support direct inhibition of MNL cellular function as one of the mechanisms of the anti-inflammatory action of chloroquine, dexamethasone, methotrexate, 6-mercaptopurine, and vinblastine.


iloprost

bosentan

sildenafil

Severe pulmonary arterial hypertension secondary to lupus in the emergency department: proactive intense care associated with a better short-term survival. Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE) and could be an acute critical condition presenting to the emergency department (ED). Our previous retrospective study revealed that the ED-related mortality of such patients was over 50%. The aim of the current prospective study is to initiate a proactive intense care strategy on severe SLE-PAH patients in the emergency setting and evaluate its impact on the short-term survival. ### methods The proactive intense care strategy was applied , which includes : ( i ) an education and training course on the topic of SLE-PAH for ED physicians ; ( ii ) a SLE-PAH patient triage protocol with prompt specialist consultation and admission ; and ( iii ) intensive care with prompt initiation of combination PAH-targeted therapy , that is , at least two drugs from the three categories as represented by iloprost , bosentan and sildenafil . Consecutive SLE-PAH patients with WHO functional class III or IV who attended the ED were enrolled following the aforementioned protocol. A historical group of SLE-PAH patients in the ED (n = 11) was set up as a comparison, and 3-month short-term survival was calculated. ### results During October 2010 to December 2012, a total of 11 consecutive severe SLE-PAH patients were included in the present study. Compared with the historical group, an improved short-term survival can be appreciated over time (historical group vs. proactive group, 27.3% vs. 72.7%, P = 0.033). The application of PAH-targeted combination therapy apparently contributed to the better outcome (P = 0.0099). ### conclusions Proactive care and combination PAH-targeted treatment can improve short-term survival of severe SLE-PAH in the emergency setting.


sulbactam

piperacillin

sulbactam

In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data. We investigated the in vitro activity of various piperacillin and sulbactam combinations against Gram-negative bacterial isolates from Intensive Care Units (ICUs) in Taiwan. Antimicrobial susceptibility testing of 1030 bacterial isolates recovered from ICUs of nine major teaching hospitals was performed using the agar dilution method. sulbactam was added to piperacillin either at a fixed sulbactam concentration of 4 mg/L and 8 mg/L or at a piperacillin:sulbactam ratio of 2:1 and 4:1. piperacillin/sulbactam at a ratio of 2:1 or a fixed 8 mg/L concentration of sulbactam had better activities against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens than other piperacillin/sulbactam formulations. For Pseudomonas aeruginosa, piperacillin/sulbactam (2:1 or 4:1 ratios) had MIC(90) values (minimum inhibitory concentration for 90% of the organisms) of 64 mg/L (>90% susceptibility) compared with 64 mg/L for cefoperazone/sulbactam (68% susceptibility) and 128 mg/L for piperacillin/tazobactam (82% susceptibility). For Acinetobacter baumannii, both piperacillin/sulbactam (either 2:1 ratio or a fixed 8 mg/L sulbactam) and cefoperazone/sulbactam were the most potent agents. Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa ( 53 - 57 % in either 2:1 or 4:1 ratios ) and A. baumannii ( 38 - 46 % in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam ) isolates . Results of susceptibility tests with piperacillin/sulbactam are dependent on the method used. piperacillin/sulbactam combinations possessed better in vitro activities than piperacillin alone or piperacillin/tazobactam against P. aeruginosa and A. baumannii.


doxorubicin

cisplatin

etoposide

Occurrence of senescence-escaping cells in doxorubicin-induced senescence is enhanced by PD0332991, a cyclin-dependent kinase 4/6 inhibitor, in colon cancer HCT116 cells. Cancer treatment induces cellular senescence, and it is considered to be one of the factors that determines treatment outcome. Senescence can be efficiently induced in cultured cells by DNA-damaging drugs , including doxorubicin ( DOX ) , cisplatin and etoposide . Cells in senescence cease proliferation; however, it has been demonstrated that colonies that are formed from cells escaping senescence appear in drug-induced senescence; however, the conditions influencing the emergence of such senescence-escaping cells (SECs) remain unclear. The present study aimed to investigate the relevance of the cell cycle phase and colony formation in the DOX-induced senescence of human colon cancer HCT116 cells. After release from serum starvation in the presence of DOX, cells synchronously progressed through the cell cycle and were arrested in the G


oxaliplatin

leucovorin

Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer. Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy. ### Methods And Materials Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy ( 25 Gy to involved mesorectum , 20 Gy to elective nodes ) , followed by 4 cycles of FOLFOX [ 5-fluorouracil , oxaliplatin , leucovorin ] . Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls. ### results 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%). ### conclusion This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.


dapagliflozin

sulfonylurea

metformin

The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus . To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. ### methods Clinical inputs sourced from a head-to-head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. ### results The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of £1246 (95% CI: £613; £1637). This resulted in an ICER point estimate of £2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY. ### conclusions dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy.


latanoprost

timolol

brimonidine

dorzolamide

bimatoprost

travoprost

Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines. To evaluate efficacy and safety data of currently available ocular hypotensive medicines derived from 24-hour studies, of similar design, in patients with primary open-angle glaucoma (POAG), exfoliative glaucoma, or ocular hypertension (OH). ### design Meta-analysis of published articles evaluating patients with POAG, exfoliative glaucoma, or OH. ### methods We included articles that were randomized, prospective, single- or double-masked, comparative studies of ocular hypotensive therapies over 24 hours. Each article selected contained an untreated baseline, >or=4-week treatment period, >/=20 patients per treatment arm, and >or=6 time points not spaced >5 hours apart and used Goldmann applanation or Tonopen tonometry (supine measurements) to measure intraocular pressure (IOP). ### Main Outcome Measure Twenty-four-hour IOP efficacy. ### results This analysis included 864 separate 24-hour treatment curves from 386 patients in 28 treatment arms from 11 studies. A statistical difference in the mean diurnal pressure decrease existed between monotherapy treatments for POAG/OH patients, with bimatoprost (29%) and travoprost (27%) showing the greatest 24-hour reduction (P = 0.026). timolol 0.5% was less effective than latanoprost (24% vs. 19% reduction) but decreased the pressure at each night time point (P = 0.0003). dorzolamide showed a 19% 24-hour pressure reduction and brimonidine 0.2% a 14% one. In exfoliative glaucoma patients, latanoprost and travoprost showed higher baseline and treatment pressures, although the pressure reductions (29% and 31%, respectively) were greater generally than observed with POAG/OH. An evening-dosed latanoprost/timolol fixed combination reduced the pressure 33%, and the dorzolamide/timolol fixed combination (DTFC), 26%. However, the power to detect a difference for this specific comparison was probably low, due to the limited number of patients (n = 20) in the DTFC group. A statistical difference between evening-dosed (24%) and morning-dosed (18%) latanoprost (P<0.0001) was noted, but not between evening (27%) and morning (26%) travoprost (P = 0.074). The mean reduction of night time points was statistically lower than day time points for latanoprost (P = 0.031), timolol (P = 0.032), and brimonidine (P = 0.050), but not for dorzolamide. dorzolamide (P = 0.60), travoprost (P = 0.064), and bimatoprost (P = 0.057) did not demonstrate nighttime pressures lower than daytime ones. The mean reduction of night time points was statistically lower than that of day time points for latanoprost ( P = 0.031 ) , timolol ( P = 0.032 ) , and brimonidine ( P = 0.050 ) , but not for dorzolamide ( P = 0.60 ) , bimatoprost ( P = 0.057 ) , travoprost ( P = 0.064 ) . ### conclusions Similar relative efficacies generally exist in various classes of ocular hypotensive agents during night and day hours.


dronedarone

amiodarone

Emerging role of amiodarone and dronedarone, as antiarrhythmic drugs, in treatment of leishmaniasis. Leishmaniasis is a group of human and animal diseases causing 20,000-40,000 annual deaths and its etiological agents belong to the Leishmania genus. The most current treatment against leishmaniasis is chemotherapy. Pentavalent antimonials such as glucantime and pentostam have been administrated as the first-line drugs in treatment of various forms of leishmaniasis. The second-line drugs such as amphotericin B, liposomal amphotericin B, miltefosine, pentamidine, azole drugs and paromomycin are used in resistant cases to pentavalent antimonials. Because of drawbacks of the first-line and second-line drugs including adverse side effects on different organs, increasing resistance, high cost, need to hospitalization and long-term treatment, it is necessary to find an alternative drug for leishmaniasis treatment. Several investigations have reported the effectiveness of amiodarone, the most commonly used antiarrhythmic drug, against fungi, Trypanosomes and Leishmania spp. in vitro, in vivo and clinical conditions. Moreover , the beneficial effects of dronedarone , amiodarone analogues , against Trypanosoma cruzi and Leishmania mexicana have recently been demonstrated and such treatment regimens resulted in lower side effects . The anti- leishmanial and anti- trypanosomal effectiveness of amiodarone and dronedarone has been attributed to destabilization of intracellular Ca


iguratimod

methotrexate

Efficacy and safety evaluation of a combination of iguratimod and methotrexate therapy for active rheumatoid arthritis patients: a randomized controlled trial.  This study aimed to investigate the efficacy and safety of iguratimod ( T-614 ) in combination with methotrexate ( MTX ) for active rheumatoid arthritis ( RA ) patients . Sixty active RA patients were enrolled according to the 2010 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification criteria, and were randomized into MTX + T-614 group and MTX group. T-614 was orally administered at a dosage of 50 mg/day (25 mg twice daily) for 24 weeks. MTX was orally administered to RA patients at a stable weekly dosage of 10 mg/week for the first 4 weeks and subsequent 12.5 mg/week for the later 20 weeks. Clinical features at baseline and efficacy endpoints of the ACR 20 % response (ACR20), ACR50, ACR70, and adverse events at 24 weeks were evaluated, respectively. After 24 weeks of treatment, clinical features at baseline, including counts for tender joints and swelling joints, visual analog scale for pain, patient's and physician's global assessment, erythrocyte sedimentation rate, C-reactive protein, disease activity score 28, health assessment questionnaire, simplified disease activity index, and ACR50 in the MTX + T-614 group, showed statistically significant differences comparing with the MTX group (P < 0.05). There was no significant increase in adverse events in the MTX + T-614 group comparing with the MTX group (P > 0.05). The combination of MTX and T-614 therapy appeared to have a good efficacy and safety for active RA and was superior to MTX-alone therapy after 24 weeks of treatment.


Cyclophosphamide

doxorubicin

vincristine

prednisone

cyclophosphamide

vincristine

doxorubicin

etoposide

cytarabine

etoposide

prednisone

vincristine

cyclophosphamide

doxorubicin

methotrexate/ifosfamide

Plasmablastic Lymphoma: A Review of Current Knowledge and Future Directions. Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL), which frequently arises in the oral cavity of human immunodeficiency virus (HIV) infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM). PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide , vincristine , doxorubicin , high-dose methotrexate/ifosfamide , etoposide , high-dose cytarabine ( CODOX-M/IVAC ) , or dose-adjusted etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( DA-EPOCH ) are possible options . Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs) and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.


Irinotecan

oxaliplatin

oxaliplatin

irinotecan

Irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer: a meta-analysis. To compare clinical efficacy and toxicity of irinotecan combined with 5-fluorouracil and leucovorin with those of oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer. ### methods Literature search was performed by keywords "irinotecan", "oxaliplatin" and "colorectal cancer" on all randomized controlled trails reported on irinotecan versus oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer in MEDLINE, OVID, Springer, Cochrane Controlled Trials Register (CCTR) and CBMdisc (Chinese Biology and Medicine disc) before January 2010. Two authors drew the details of trial design, characteristics of patients, outcomes, and toxicity from the studies included. Data analysis was performed by RevMan 4.2. ### results According to the screening criteria, 7 clinical studies with 2095 participants of advanced colorectal cancer were included in this meta analysis. The baseline characteristics of irinotecan group were similar to those of oxaliplatin group. The response rate of oxaliplatin group was higher than that of irinotecan group (relative risk (RR) = 0.82, 95% confidence interval (95%CI) (0.70, 0.96), P = 0.01), and the median overall survival of oxaliplatin group was longer by 2.04 months than that of irinotecan group (95%CI (-3.54, -0.54), P = 0.008). In the comparison of grade 3 - 4 toxicity between the two groups, the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were higher than those in oxaliplatin group (RR = 1.94, 95%CI (1.22, 3.09), P = 0.005; 1.71, 95%CI (1.34, 2.18), P < 0.001; 14.56, 95%CI (4.11, 51.66), P < 0.0001), respectively. However, the incidence of neurotoxicity, neutropenia and thrombocytopenia in irinotecan group were lower than those in oxaliplatin group (RR = 0.06, 95%CI (0.03, 0.14), P < 0.00001; 0.70, 95%CI (0.55, 0.91), P = 0.006; 0.18, 95%CI (0.05, 0.61), P = 0.006), respectively. ### conclusions Both irinotecan and oxaliplatin combined with 5-fluorouracil and leucovorin were effective in the first-line therapy of advanced colorectal cancer. However, the combined regimen of oxaliplatin plus 5-fluorouracil and leucovorin is more excellent. Irinotecan tended to result in more gastrointestinal tract reactions than oxaliplatin did , but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen .


methylergometrine

oxytocin

[ Intraoperative anaphylactic shock induced by methylergometrine and oxytocin ] . We report a case of intraoperative anaphylactic shock in a 32-year-old multigravida woman undergoing elective cesarean section for partial placenta previa. Anesthesia was performed using combined spinal and epidural technique. After the baby was born, methylergometrine was administered i.v. simultaneously with oxytocin, the latter injected directly into the uterine muscle by an obstetrician. Several minutes later, she presented with dyspnea and became agitated. Because of the potential risk of pulmonary embolism, the patient was immediately intubated and mechanical ventilation was started. Her systolic blood pressure decreased to 50 mmHg and SpO2 to 87% under 100% oxygen administration. After catecholamine infusion, however, her respiratory condition soon improved. Postoperatively, her conjunctiva and vulva were not edematous. From the clinical course, it was considered that the patient was very likely to have suffered an anaphylactic reaction to oxytocin or methylergometrine. Forty days later, serological examinations as well as skin tests for those two drugs were carried out. While the serological tests were negative, the skin tests indicated the patient was allergic to both drugs. It is concluded that the endogenous peptide oxytocin can induce anaphylactic shock in multiparous women.


doxorubicin

etoposide

Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo. Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide . Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.


docetaxel

gemcitabine

pemetrexed

erlotinib

afatinib

osimertinib

crizotinib

alectinib

ceritinib

Second-Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological, and Molecular Aspects of Nintedanib. Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel , gemcitabine , pemetrexed , and erlotinib and for patients with target-specific oncogenes afatinib , osimertinib , crizotinib , alectinib , and ceritinib . In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC). nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor). Several preclinical and clinical studies have proven the usefulness of nintedanib as an anticancer agent for NSCLC. The most important study was the phase III LUME-Lung 1 trial, which investigated the combination of nintedanib with docetaxel for second-line treatment in advanced NSCLC patients. The significant improvement in overall survival and the manageable safety profile led to the approval of this new treatment in Europe. This review focuses on the preclinical and clinical studies with nintedanib in NSCLC.


formoterol

salmeterol

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.  an increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews . This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. ### objectives we set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment ### Search Strategy trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. ### Selection Criteria controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. ### Data Collection And Analysis two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. ### Main Results eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma. There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively. There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions. No studies were found in children. ### Authors Conclusions the seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children. Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.


cytarabine

etoposide

[ An elderly patient with myelodysplastic syndrome successfully treated with combination of granulocyte-colony stimulating factor and continuous-drip infusion of low-dose cytarabine and etoposide ] . A 73-year-old man was given a diagnosis of myelodysplastic syndrome in October 1997. He was treated with red blood cell transfusion and granulocyte-colony stimulating factor (G-CSF). In February 1998, he was admitted due to progression of pancytopenia. Bone marrow aspiration revealed refractory anemia with excess of blasts in transformation. The patient was treated with continuous-drip infusion of low-dose cytarabine and etoposide with G-CSF (AVG therapy). Complete remission (CR) was obtained after 2 courses of AVG therapy. Non-hematologic adverse effects were mild enough to be tolerated. CR has been maintained for 16 months with 1 course of consolidation therapy and 3 courses of intensification therapy using the AVG regimen.


cefoxitin

ampicillin

chloramphenicol

ceftizoxime

aztreonam

cefotaxime

imipenem

ceftazidime

gentamicin

tetracycline

ciprofloxacin

Prevalence of multiple antibiotic-resistant Gram-negative bacteria on bagged, ready-to-eat baby spinach. In this study, multiple antibiotic-resistant (MAR) Gram-negative bacteria (GNB) were isolated from triple-washed, bagged, ready-to-eat (RTE) baby spinach. Biochemical identification of randomly selected bacterial colonies showed the predominance of cytochrome oxidase-positive Pseudomonas species. Among the GNB , a higher prevalence of resistance was observed against cefoxitin ( 93.1 % ) followed by ampicillin ( 79.4 % ) , chloramphenicol ( 72.6 % ) , ceftizoxime ( 65.7 % ) , aztreonam ( 64.9 % ) , cefotaxime ( 53.6 % ) , imipenem ( 38.3 % ) , ceftazidime ( 33.5 % ) , gentamicin ( 32.6 % ) , tetracycline ( 22.2 % ) , and ciprofloxacin ( 19.8 % ) . Multiple antibiotic resistance (MAR) linked to two or more antibiotics was found in 95.3% of isolates, and resistance was transferable in the strains tested. These findings confirm the presence of MAR bacteria on RTE baby spinach and suggest that human consumption of this produce would amplify the MAR gene pool via conjugal transfer of MAR genes to commensal gut microflora and bacterial pathogens.


irinotecan

leucovorin

Phase II study of irinotecan, 5-fluorouracil, and leucovorin in relapsed or metastatic colorectal cancer as first-line therapy. The purpose of this study was to assess the efficacy and toxicity of biweekly irinotecan plus 5-fluorouracil (FU) and leucovorin (LV) in patients with relapsed or metastatic colorectal cancer. ### Materials And Methods Between March 2002 and May 2004, 24 patients with histologically confirmed relapsed or metastatic colorectal cancer were enrolled in this study. One chemotherapy cycle consisted of irinotecan 180 mg/m(2) on days 1 and 15; 5-FU 400 mg/m(2) bolus IV with 600 mg/m(2) by a 22 hour intravenous infusion on days 1, 2, 15 and 16; and leucovorin 20 mg/m(2) on days 1, 2, 15 and 16, every 4 weeks. ### results The median age of the 24 was 57.5 years (range, 38 approximately 69). Their metastatic sites included: the liver (62.5%), lung (20.8%), peritoneum (16.7%), lymph node (12.5%), ovary (8.3%) and pelvis/vagina (8.3%). Twenty-two patients were evaluable for a response. Six and 7 patients achieved partial responses and stable diseases, respectively. The overall response rate was 27.3% (95% Confidence interval; 10.3 approximately 44.5%). The median follow-up duration for surviving patients was 14.7 months (range, 1.7 approximately 26.5). Median overall survival (OS) and 1-year OS rates were 19 months and 86.3%, respectively. Median response duration and median progression free survival were 7.47 and 5.57 months, respectively. A total of 83 cycles (median 4 cycles) were administered. The main non-hematologic toxicities were nausea/vomiting (44.5%/18.1%) and diarrhea (8.4%). The most common hematologic toxicity was NCI grade I/II anemia (31.3%) and grade I/II neutropenia was 10.8%. There was no life-threatening toxicity. ### conclusion The results suggested that irinotecan , 5-FU and leucovorin combination chemotherapy in a biweekly schedule is a practical and tolerable treatment option in patients with advanced colorectal cancer .


famotidine

bismuth

Colloid bismuth versus famotidine in the treatment and prevention of duodenal ulcer relapse: results of a double-blind, double dummy randomized study.  Fifty-three consecutive patients with active duodenal ulcer ( DU ) were randomly included in a double-blind , double-dummy study to test the healing and relapsing rate of two treatment regimens : famotidine 40 mg nocte for 4 - 8 weeks , followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth ( CBS ) ( 240 mg bid ) for 4 - 8 weeks , followed by placebo maintenance treatment . The results of the short term period confirmed the efficacy of CBS in healing DU (24/25 in CBS group and 19/23 in famotidine group). However, the relapse rate in the CBS-treated group was higher (77.8% at 12 months) than in the famotidine group (35.7%) (p = 0.041). Only 7 patients (41.2%) were cleared from Helicobacter pylori (HP) after CBS treatment. In conclusion, the high relapse rate observed in CBS treated patients may be related to the high percentage of patients with HP infection in the tested group and support the hypothesis that lack of efficacy of CBS in preventing DU recurrence is related to its poor eradication of HP.


pembrolizumab

bevacizumab

Patient characteristics, treatment patterns, and clinical outcomes among patients with previously treated recurrent or metastatic cervical cancer: A community oncology-based analysis. There is no standard systemic treatment for recurrent or metastatic cervical cancer (r/mCC) after failure of first-line (1L) therapy. This study characterizes the patient experience, treatment patterns, and clinical outcomes of patients who initiated second-line (2L) therapy for r/mCC in a US community oncology setting. ### methods This is an observational study of cervical cancer patients who failed 1L systemic treatment for r/mCC and initiated 2L systemic therapy between 2014 and 2019 within the US Oncology Network (USON). USON's electronic health records were used to identify eligible patients and abstract data. Overall survival (OS), time to treatment discontinuation (TTD), and time to first subsequent treatment (TFST) were estimated using Kaplan-Meier methods. ### results A total of 130 patients were identified (mean age 53 years). Over 60% of patients had Eastern Cooperative Oncology Group score of 0-1. Cytotoxic monotherapy was the most frequently prescribed regimen ( N = 60 , 46 % ) in 2L , followed by combination therapies ( N = 45 , 35 % ) , pembrolizumab monotherapy ( N = 19 , 15 % ) , and bevacizumab monotherapy ( N = 6 , 5 % ) . Median OS was 9.1 months (95% CI: 7.2-12.2) after initiation of 2L therapy. Median TTD was 2.8 months (95% CI: 2.5-3.3), and median TFST was 4.9 months (95% CI: 4.2-5.7). No significant difference in outcomes was found when stratified by 2L treatments. ### conclusions The observed heterogeneity in 2L r/mCC therapy suggests no clear standard-of-care in this setting. Additionally, short duration of OS observed was consistent across 2L regimens. New, effective treatment options in this setting are needed.


Terlipressin

octreotide

terlipressin

Haemodynamic responses to a combination of terlipressin and octreotide in portal hypertensive rats. An enhancement of the haemodynamic effects of terlipressin by octreotide (and vice versa) may be useful in the treatment of portal hypertension. The aim of this study was to investigate the short-term effects of terlipressin, octreotide or a combination of these substances on splanchnic and systemic haemodynamics in rats with portal vein stenosis. ### methods Eight rats received an intravenous (i.v.) infusion of isotonic saline (10 microL/min for 15 min). Eight rats received terlipressin first (0.05 mg/kg) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min) 15 min later. Eight other rats first received an i.v. infusion of octreotide and then terlipressin 15 min later. Splanchnic and systemic haemodynamics (radioactive microsphere method) were measured after saline, after terlipressin or octreotide alone, and after the combined treatments. ### results terlipressin and octreotide alone significantly decreased portal pressure, portal tributary blood flow and cardiac index. terlipressin, but not octreotide, significantly increased heptocollateral vascular resistance and arterial pressure. octreotide administration in rats pre-treated with terlipressin did not change portal pressure, caused portal tributary blood flow to increase and decreased hepatocollateral vascular resistance; it also decreased arterial pressure but not cardiac index. Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure , portal tributary blood flow and increased hepatocollateral vascular resistance ; terlipressin increased arterial pressure and further decreased cardiac index . ### conclusions In rats with portal vein stenosis, octreotide decreased short-term splanchnic and systemic vasoconstriction due to terlipressin. In contrast, terlipressin enhanced the splanchnic and systemic vasoconstriction due to octreotide. Thus, the haemodynamic responses to the combination of octreotide and terlipressin depend on the order of administration of these substances.


alprazolam

imipramine

The effect of sympathetic antagonists on the antidepressant action of alprazolam. alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam-induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine . Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.


doxorubicin

etoposide

Towards a high throughput impedimetric screening of chemosensitivity of cancer cells suspended in hydrogel and cultured in a paper substrate. In order to achieve high predictive value of cell chemosensitivity test for clinical efficacy, cancer cells were suggested to be encapsulated and cultured in hydrogel to mimic the natural microenvironment of tumors. However, handling 3D cells/hydrogel culture construct is tedious and cellular response is difficult to be quantitatively analyzed. In the current study, a novel platform for conducting 3D cell culture and analyzing cell viability has been developed towards a high throughput drug screening. Cells encapsulated in the hydrogel were cultured in the microwells of a paper substrate. The substrate was then immersed in the culture medium containing drug for 2 days. At 24 and 48h during the culture course, the paper substrate was placed on the measurement electrodes for conducting the impedance measurement in order to quantify the cell viability in the hydrogel. Cell viability of two human hepatoma cell lines ( Huh7 and Hep-G2 ) was quantitatively investigated under the treatment of two drugs ( doxorubicin and etoposide ) . The results represented by IC


vasopressin

oxytocin

bradykinin

[The modulation of hemostatic reactions in vitro and in vivo by representatives of regulatory peptide families]. Data available in the literature and the author's own findings of the effects of regulatory peptide (RP) and their analogues are summarized. MIF , TRH , and its analog PR-546 , the paraopioid RP , leuenkephalin , dalargin , the ACTH analogue Semax , tafcin , thymosine , interleukin-1 , vasopressin , oxytocin , bradykinin , defencin , and some proline-containing oligopeptides , such as Pro-Gly , Gly-Pro , Trp-Pro , Pro-Gly-Pro , Gly-Pro-Gly-Gly were studied . A complex of in vitro and in vivo tests identified three groups of RP: 1) neutral ones as to the hemostatic reactions studied; 2) stimulants of hypercoagulation and fibrin polymerization; 3) inhibitors of blood coagulation, increased fibrinolysis, and fibrin demopolymerization. The fibrinolytic and antithrombotic effects of Semax (in vivo), the procoagulative action of defencin, and the enhanced anticoagulant effects in the combinations of Semax-heparin and tafcin (in vivo) attract particular attention. Semax alone and in combination with heparin is recommended for clinical studies in respective hemostatic abnormalities.


pazopanib

sunitinib

Persistence and compliance among U.S. patients receiving pazopanib or sunitinib as first-line therapy for advanced renal cell carcinoma: a retrospective claims analysis. For first-line therapy options for advanced renal cell carcinoma (RCC), clinical trials have demonstrated similar efficacy for pazopanib and sunitinib as well as differing side-effect profiles, which may affect patient persistence in self-administration of these oral medications. However, the treatment patterns of each drug in real-world clinical practice, as opposed to the controlled environment of a trial, have not been directly compared. ### objective To compare persistence and compliance (adherence) with pazopanib versus sunitinib in a real-world setting. ### methods This was a retrospective claims analysis using 2 databases: Optum Research Database and Impact National Benchmark Database. Eligible patients included adult patients (aged ≥ 18 years) with ≥ 2 RCC diagnoses and evidence of first-line therapy with ≥ 1 subsequent pharmacy claim for pazopanib or sunitinib between October 2009 and July 2012. The date of the first pazopanib or sunitinib claim was defined as the index date. Additional requirements included continuous enrollment in the health plan for 2 months prior (baseline period) through 6 months after (follow-up period) the index date and no cancers other than those associated with RCC. Propensity score matching was used to minimize selection bias. Persistence with the index drug was compared using days to discontinuation, estimated level of persistence (ELPT) at 180 days, and proportion of days covered (PDC). PDC was defined by dividing the number of days covered with the index drug by the number of follow-up days. Compliance was estimated using medication possession ratio (MPR). For matched cohort pairs with > 1 fill, MPR was defined by dividing the number of days covered with the index drug by the number of days between the first and last index medication fill. ### results We identified 84 matched pairs among 97 patients prescribed pazopanib and 349 prescribed sunitinib. Among the matched population, mean comorbidity index score was 5.8 (95% CI = 1.8-6.0) for pazopanib, and 6.1 (95% CI =1.8-6.0) for sunitinib (P = 0.133). Evidence of any radiation therapy during the baseline period was significantly higher among the sunitinib cohort prior to matching (9% vs. 18%, P = 0.043), and evidence of surgery was higher in the pazopanib cohort after matching (12% vs. 7%, P = 0.046). Cohorts were balanced according to demographic and clinical characteristics with mean (SD) age of 63.0 (9.0) years and 77.4% male. During the 6-month period after drug initiation, there was no significant difference (P > 0.05) by drug cohort in the duration of index drug therapy or the percentage of patients who discontinued their index drugs. The mean (SD) time to discontinuation was 133.4 (62.8) days and 139.9 (55.6) days among the matched pazopanib and sunitinib cohorts, respectively (P = 0.445). In both cohorts , more than 40 % of patients discontinued their index drugs ( 46.4 % pazopanib and 44.1 % sunitinib , P = 0.732 ) . In addition, there was no significant difference by drug cohort in the ELPT at any time examined between 30 and 180 days after initiation of therapy. PDC with the index drug during the fixed 6-month follow-up was also examined. Although the mean PDC was significantly higher among the sunitinib cohort (0.77 vs. 0.68 for pazopanib, P = 0.037), there was no difference by cohort in the percentage of patients with high PDC (defined as ≥ 80%): 52.4% versus 56.0% for pazopanib and sunitinib, respectively (P = 0.622). Mean MPR among matched pairs with at least 2 fills for the index drug was significantly higher among the sunitinib cohort, although there was no difference by cohort in the percentage of patients with high MPR (defined as ≥ 80%): 81.4% versus 93.2% for pazopanib and sunitinib, respectively (P > 0.071). ### conclusions In the first 6 months of treatment, persistence and compliance to pazopanib and sunitinib were similar. Future studies are needed, including those assessing larger cohorts and longer follow-up periods.


pretreated

paclitaxel

docetaxel

capecitabine

vinorelbine

mitomycin

Efficacy of S-1 in heavily pretreated patients with metastatic breast cancer: cross-resistance to capecitabine. It is not clear what the optimal treatment of chemotherapy is for patients with heavily treated metastatic breast cancer (MBC). We have retrospectively examined the efficacy and safety of S-1 in patients with MBC who had been previously treated with anthracycline, taxane, and capecitabine. ### methods Patients with MBC who had been administered S-1, an oral modulated compound containing a fluoropyrimidine derivative, between November 2001 and June 2003 at the Cancer Institute Hospital were retrospectively reviewed. S-1 at a standard dose of 50 mg/body was administered twice daily for four weeks, followed by a two-week rest period. This was repeated every six weeks until disease progression or unacceptable toxicity. ### results Thirty-five patients were assessed. The patients were heavily pretreated with anthracycline ( 100 % ) , taxane ( paclitaxel or docetaxel ) ( 100 % ) , capecitabine ( 100 % ) , vinorelbine ( 71 % ) , and mitomycin ( 69 % ) . Median follow-up time of patients was 9.6 months (range, 1.2-26.6). ORR was 3% (95% confidence interval: 0-9%), and CBR was 20% (95% confidence interval: 6-33%). Time to treatment failure was 2.8 months. Overall survival was 21.4 months. Grade 1 or 2 adverse events were observed in 17% and 13%, respectively. Grade 3 events occurred as anorexia (9%), nausea (9%), vomiting (9%), diarrhea (14%), fatigue (3%), and elevation of AST/ALT (3%). No grade 3 was seen as hand-foot syndrome. Neither grade 3 nor 4 was observed in bone marrow suppression. ### conclusions S-1 was fairly well tolerated, but demonstrated very limited activity in capecitabine-pretreated patients who had already been exposed to anthracycline and taxane. It was suggested that S-1 clinically exhibited cross-resistance to capecitabine.


amphotericin

rifampin

Aspergillus osteomyelitis. Report of a case and review of the literature. Aspergillus is a ubiquitous saprophytic fungus seldom pathogenic for normal hosts. Aspergillus osteomyelitis occurs infrequently and is typically limited to patients with predisposing factors, including leukocyte dysfunction, malignancy with neutropenia, steroid or antibiotic therapy, pulmonary aspergillosis, and surgical manipulation. The spine is most frequently affected, and the clinical presentation is nonspecific (50% afebrile). Diagnosis requires demonstration of characteristic, acutely branching, broad, septate hyphae in biopsy material, and culture of Aspergillus. Therapy includes debridement of necrotic bone and loculated purulence combined with amphotericin B and possibly 5-fluorocytosine or rifampin .


Docetaxel

cisplatin

capecitabine

Induction chemotherapy with docetaxel, cisplatin and capecitabine, followed by combined cetuximab and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck: a phase I-II study. To replace 5-fluorouracil with capecitabine within a trial of induction chemotherapy followed by cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). Also, to replace cisplatin with cetuximab after induction chemotherapy. ### methods Docetaxel and cisplatin were given at 75 mg/m(2 ) , while capecitabine was initially given at 500 mg/m(2 ) twice a day and subsequently escalated . The maximum tolerated dose was used for the phase II study. ### results Seven patients were enrolled. At dose level 1, two dose-limiting toxicities were observed in the first 4 patients (grade 4 neutropenia and grade 3 diarrhea). In both patients, capecitabine was withdrawn and toxicities resolved. Dose escalation was halted and a lower capecitabine dose (750 mg/m(2) daily) was selected. Two complete responses and five partial responses were observed after induction chemotherapy. Four patients were evaluable for response after cetuximab-RT (3 complete response and 1 partial response). ### conclusion Combined chemoradiotherapy is still the gold standard in LA SCCHN and no studies currently support the use of early induction chemotherapy. Our study did not contribute toward addressing this issue since it was discontinued early because of toxicity.


curcumin

irinotecan

Proteomic analysis identifies proteins associated with curcumin-enhancing efficacy of irinotecan-induced apoptosis of colorectal cancer LOVO cell. We wish to implement a proteomics-based approach to pick and identify the proteins associated with curcumin enhancing efficacy of irinotecan inducing apoptosis of colorectal cancer LOVO cells, and further explore their synergy mechanism by bioinformatics. ### methods A colorectal cancer cell line ( LOVO cell ) treated by curcumin combined with irinotecan in different ways respectively was used as our comparative model . Protein spots were analyzed through MALDI-TOF/TOF. The location and function of differential protein spots were analyzed through UniProt database. Protein-protein interactions were examined through String software. ### results A total of 54 protein spots differentially expressed with 1.5-fold difference were picked, 11 of which were repeated. They mainly were involved in intracellular calcium pathways, cellular respiratory chain pathway and intracellular redox reaction pathways of LOVO cell. According to the function of various protein points, combining with varying curves of protein points in each treatment groups, we selected five interesting protein spots, 4 of which exists Protein-protein interactions, and they were close to the formation and reduction of disulfides in intracellular endoplasmic reticulum (ER). ### conclusion We selected preliminary but comprehensive data about differential expression protein spots of LOVO cell. Among these, the five interesting differential expression protein spots identified in this study may provide new insight into LOVO cell therapeutic biomarkers. curcumin may suppress GSTM5 expression to enhance the lethal effect of irinotecan on LOVO cells, and maybe their combination via the affection of PDI and PRDX4 to disturb the formation and reduction of disulfides results in inducing apoptosis of LOVO cell.


ceftriaxone

doxycycline

plus

Effectiveness of ceftriaxone plus doxycycline in the treatment of patients hospitalized with community-acquired pneumonia. Limited data exist on the effectiveness of ceftriaxone plus doxycycline in the treatment of patients hospitalized with community-acquired pneumonia (CAP). ### methods We performed a retrospective cohort study of all adults hospitalized for pneumonia between January 1999 and July 2001 at an academic medical center. Outcomes were compared for patients with CAP treated with ceftriaxone plus doxycycline versus other appropriate initial empiric antibiotic therapies. Outcomes were adjusted with the use of a propensity score to account for differences in patient characteristics and illness severity between groups. ### results A total of 216 patients were treated with ceftriaxone plus doxycycline and 125 received other appropriate initial empiric antibiotic therapies. After adjustment, use of ceftriaxone plus doxycycline was associated with reduced inpatient mortality (OR = 0.26, 95% CI: 0.08-0.81) and 30-day mortality (OR = 0.37, 95% CI: 0.17-0.81), but not with length of stay or readmission rates. Analysis of a subset of the sample that excluded patients admitted from nursing homes, patients admitted to the ICU, and patients diagnosed with aspiration also showed reduced inpatient mortality with the use of ceftriaxone plus doxycycline. ### conclusions The use of ceftriaxone plus doxycycline as an initial empiric therapy for patients hospitalized with CAP appears safe and effective , and its potential superiority should be evaluated prospectively .


Metformin

genistein

genistein

metformin

Genistein enhances the secretion of glucagon-like peptide-1 (GLP-1) via downregulation of inflammatory responses. Glucagon-like peptide-1 (GLP-1) an incretin hormone, is known to regulate the glucose-mediated insulin secretion. However, reduction in the level of GLP-1 is considered to be a major cause for the reduction of GLP-1-dependent insulin secretory response. genistein an isoflavone, is an important polyphenol and has wide range of therapeutic potentials, but its therapeutic effects alone and/or in combination with metformin on GLP-1 secretion have not been investigated yet. Hence, we aimed to investigate the stimulatory action of genistein in combination with metformin on GLP-1 via downregulation of inflammatory mediators, hyperlipidemia and hyperglycemia in alloxan-induced diabetic rats. Diabetes was induced in experimental rats by single administration of alloxan intraperitoneally. Metformin ( 50 mg/kg/day ) , genistein ( 20 mg/kg/day ) and combination of genistein and metformin was administered in alloxan-induced diabetic rats . We found that genistein alone and/or in combination with metformin significantly increased the serum level (P < 0.01) and tissue content (P < 0.05) of GLP-1 in intestine when compared with that of metformin-treated animals. Similarly, genistein alone and/or in combination with metformin also resulted in normoglycemia (P < 0.001), glucose tolerance (P < 0.01), insulin sensitivity (P < 0.0001), hyperlipidemia (P < 0.01), liver and kidney function biomarkers (P < 0.01) as compared to that of metformin-treated experimental animals. Moreover, genistein alone and/or in combination with metformin also downregulated the inflammatory responses by decreasing the levels of interleuin-6, tumor necrosis factor-α and C-reactive protein in serum (P < 0.05) and intestine (P < 0.001) more efficiently as compared to that of metformin-treated experimental animals. The downregulation of inflammatory responses in intestine, was positively associated with increased secretion of GLP-1 from intestine. Histopathology of pancreas and intestine also showed that genistein significantly improved the deleterious effects of alloxan on pancreas and intestine. Hence, our work provides new insights on the synergistic effects of genistein and metformin on GLP-1 secretion. This may significantly improve the perception for proposing new GLP-1-based synergistic approaches for the treatment of diabetes mellitus.


sirolimus

tacrolimus

Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. ### methods Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 ( intron 3 ) and MDR1 ( exons 12 , 21 , 26 ) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus . ### results There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. ### conclusions Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.


ibritumomab tiuxetan

carmustine

etoposide

cytarabine

melphalan

Autologous transplantation for transformed non-Hodgkin lymphoma using an yttrium-90 ibritumomab tiuxetan conditioning regimen. Transformation from indolent non-Hodgkin lymphoma (NHL) to diffuse large B cell lymphoma (DLBCL) has historically been associated with a poor prognosis. A small series of autologous stem cell transplantation (ASCT) studies using conventional conditioning regimens has demonstrated durable progression-free survival (PFS) rates ranging from 25% to 47%, but data in the rituximab era are lacking. Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen , which combines yttrium-90-labeled ibritumomab tiuxetan ( Zevalin ) with high-dose BEAM ( carmustine , etoposide , cytarabine , melphalan ) chemotherapy . Sixty-three patients from 4 institutions were treated between 2003 and 2011. Histological confirmation of transformation was required and defined as a diagnosis of DLBCL in patients with either a prior history or concomitant diagnosis of low-grade B cell NHL. Median patient age at ASCT was 59.5 years, median number of prior regimens was 2, and all patients were exposed to rituximab. Disease status at ASCT was as follows: first complete remission (CR) (n = 30), first partial remission (n = 11), first relapse (n = 14), and at least second CR (n = 8). The median time from diagnosis of histological transformation to ASCT was 7.5 months (range, 2.8 to 116). Two-year nonrelapse mortality was 0%. Median follow-up for living patients was 28 months (range, 5 to 103). Two-year PFS was 68% (95% confidence interval, 58% to 75%), and overall survival was 90% (95% confidence interval, 80% to 95%). In conclusion, the Z-BEAM conditioning regimen for ASCT is well tolerated by patients with transformed lymphoma and demonstrates encouraging clinical outcomes.


Palbociclib

fulvestrant

Real-World Palbociclib Use in HR+/HER2- Advanced Breast Cancer in Canada: The IRIS Study.  Palbociclib is a selective cyclin-dependent kinase ( CDK ) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive ( HR+ ) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer ( ABC/MBC ) . palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2- ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study (NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. ### methods This retrospective chart review included women with HR+/HER2- ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan-Meier analysis. ### results Thirty-three physicians examined medical records for 247 patients (P+L, ### conclusions Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.


irinotecan

oxaliplatin

Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer : a dose-finding and phase II study . A weekly administration of alternating irinotecan or oxaliplatin associated to 5-fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).


daptomycin

vancomycin

Wax moth larva (Galleria mellonella): an in vivo model for assessing the efficacy of antistaphylococcal agents. To investigate whether the wax moth larva, Galleria mellonella, is a suitable host for assessing the in vivo efficacy of antistaphylococcal agents against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infections. ### methods Wax moth larvae were infected with increasing doses of S. aureus to investigate the effect of inoculum size on larval survival. In addition, infected wax moth larvae were treated with daptomycin, penicillin or vancomycin to examine whether these agents were effective against S. aureus and MRSA infections in vivo. ### results Increasing inoculum doses of live S. aureus cells resulted in greater larval mortality, but heat-killed bacteria and cell-free culture filtrates had no detrimental effects on survival. Larval mortality rate also depended on the post-inoculation incubation temperature. After larvae were infected with S. aureus , larval survival was enhanced by administering the antistaphylococcal antibiotics daptomycin or vancomycin . Larval survival increased with increasing doses of the antibiotics. Moreover, penicillin improved survival of larvae infected with a penicillin-susceptible methicillin-susceptible S. aureus (MSSA) strain, but it was ineffective at similar doses in larvae infected with MRSA (penicillin resistant). daptomycin and vancomycin were also effective when administered to the larvae prior to infection with bacteria. ### conclusions This is the first report to demonstrate that antibiotics are effective in the wax moth larva model for the treatment of infections caused by Gram-positive bacteria. The new wax moth larva model is a useful preliminary model for assessing the in vivo efficacy of candidate antistaphylococcal agents before proceeding to mammalian studies, which may reduce animal experimentation and expense.


axitinib

sorafenib

pazopanib

Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis. A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib. ### methods Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI). ### results Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival ( PFS ) , axitinib was superior compared with placebo ( HR = 0.25 , 95 % CrI : 0.17 - 0.38 ) , sorafenib ( HR = 0.46 , 95 % CrI : 0.32 - 0.68 ) and pazopanib ( HR = 0.47 , 95 % CrI : 0.26 - 0.85 ) . An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib. ### conclusion Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy.


paclitaxel

gemcitabine

Combination versus sequential paclitaxel plus gemcitabine as first-line chemotherapy for women with metastatic breast cancer: a prospective randomized phase II study. paclitaxel (T) plus gemcitabine (G) is an active concomitant combination for the treatment of metastatic breast cancer (MBC). However, the efficacy of sequential administration of these two drugs is unclear. This randomized phase II study was conducted to evaluate the efficacy of T and G administered either as a concomitant or as a sequential regimen in patients with MBC. ### methods Patients with MBC (n=66) were randomized to either receive 6 cycles of concomitant T and G or 4 cycles of T followed by 4 cycles of G, as first line chemotherapy. With no progression, the arms would switch to maintenance with paclitaxel. Progression free survival (PFS) was defined as the primary endpoint; secondary endpoints were the overall response rate (ORR), overall survival (OS), and toxicity. In total, 33 patients were randomized to the concomitant or sequential arms. Patient characteristics were well balanced. The median number of chemotherapy cycles was 6 for the concomitant arm and 8 for the sequential arm. ### results No significant difference was observed in terms of PFS, ORR, and OS. Only 13 (39.4%) patients progressed in the sequential arm. Although there was no significant difference between the two arms (p=0.056),the sequential arm had a remarkable trend of longer PFS than the concomitant arm. Toxicities were manageable and similar in both arms.The incidence of neutropenia was significantly higher in the concomitant arm (90.9%) than in the sequential arm (60.6%). Grade 3 or 4 neutropenia was not significantly different between the two arms. ### conclusions Concomitant and sequential treatment with paclitaxel and gemcitabine had no significant difference in terms of PFS .


Margetuximab

Trastuzumab

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer : A Phase 3 Randomized Clinical Trial . ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. ### objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. ### Design Setting And Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. ### interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. ### Main Outcomes And Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. ### results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. ### Conclusions And Relevance In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. ### Trial Registration ClinicalTrials.gov Identifier: NCT02492711.


cyclophosphamide

vincristine

prednisolone

Combined Modality Management of Sinonasal Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma in a Young Adult-Report of a Rare Case. Sinonasal anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) without nodal involvement is extremely rare and the rarity of this tumor often leads to diagnostic dilemma. It has been predominantly reported in pediatric, adolescent and young adult patients, mostly of Asian origin. A 21-year-old female patient presented with history of epistaxis for 1 year. On clinical and radiological examination, there was a 5 cm mass in the right nasal cavity, ethmoid, and frontal sinus. Biopsy at a local center had shown moderately differentiated squamous cell carcinoma. Rebiopsy at our center showed possibility of a hematolymphoid malignancy(pancytokeratin-, CD45+, CD3-, CD20-) and further immunohistochemistry studies(CD4+, CD43+, CD30+, ALK+) revealed ALK-positive ALCL. Rest of the lymphoma work-up was essentially normal and she had stage IE disease. She was treated with a combination of four cycles of cyclophosphamide , hydroxydaunorubicin , vincristine , and prednisolone ( CHOP ) regimen followed by local radiotherapy ( 36 Gray/20 fractions/4 weeks ) by three-dimensional conformal technique . She tolerated the treatment well without any severe toxicity and had complete clinical and radiological response. At last follow-up visit, 40 months from the initial diagnosis, she was alive and disease free. Sinonasal ALK-positive ALCL is a rare tumor, which can be effectively treated with a combination of multiagent CHOP/CHOP-like regimen and local conformal radiotherapy.


docetaxel

prednisone

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease . ### methods From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. ### results As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. ### conclusions When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.


vasopressin

oxytocin

Simultaneous detection of neuropeptides and messenger RNA in the magnocellular hypothalamo-neurohypophysial system by a combination of non-radioactive in situ hybridization histochemistry and immunohistochemistry. A protocol was developed combining non-radioactive in situ hybridization histochemistry with enzyme based immunohistochemistry, detect the expression of mRNA in phenotypically defined neurons. Free-floating brain sections were hybridized with the oligonucleotide probes which have been 3'-end labelled with biotin-11-dUTP. The hybridized probe was visualized by a combined avidin-biotin bridge method, anti-avidin immunohistochemistry, and horseradish peroxidase detection using diaminobenzidine as a substrate. The in situ hybridization step yielded a very stable reaction product enabling subsequent immunohistochemical reactions using horseradish peroxidase and benzidine dihydrochloride as a chromogen. Magnocellular neurons of the hypothalamo-neurophypophysial system synthesize either vasopressin or oxytocin ; water deprivation and chronic saline ingestion are potent stimuli for the expression of both of the genes encoding these neuropeptides . A number of other neuropeptides with putative transmitter action are synthesized in magnocellular neurons during such stimulation. Experiments were performed to explore whether neuropeptide y immunoreactivity is present within magnocellular vasopressin mRNA-expressing neurons of the hypothalamo-neurophypophysial system. The results clearly demonstrated that neuropeptide y-immunoreactive elements were present within a number of magnocellular vasopressin mRNA-containing cells. In addition, immunohistochemical detection of the neuropeptides ocytocin and cholecystokinin was carried out on sections hybridized non-radioactively for vasopressin; as expected vasopressin mRNA did not co-exist with cholecystokinin, whereas a few oxytocin immunoreactive neurons in osmotically stimulated animals also contained vasopressin mRNA. The developed method makes possible the immunohistochemical detection of intracellular antigens with concomitant detection of intracellular mRNA.


fluorouracil

irinotecan

fluorouracil

Update on chemotherapy for advanced colorectal cancer. Efforts to improve the length and quality of life, as well as to expand treatment options, for patients with metastatic colorectal cancer have only recently become more successful. With maximization of dose and schedule schemes for fluoropyrimidine therapy, new drugs such as irinotecan (CPT-11, Camptosar) and oxaliplatin have also become part of the standard therapy for patients. Combination chemotherapy has been established to have superior response rates and progression-free survival and -- in some instances , for fluorouracil and irinotecan combinations -- improved overall survival compared to fluorouracil alone . There is still much to be learned about the optimal management of patients with colorectal cancer, including the role of second- and third-line chemotherapy in the overall survival outcome, and the role of salvage therapy in patients with limited metastatic disease. Most importantly, the development of a biological marker of prognosis and response should help to select appropriate chemotherapy programs for patients on a rational and individual basis, not only in the setting of metastatic disease, but also in the adjuvant population.


bevacizumab

fluorouracil

leucovorin

irinotecan

Phase IV study of bevacizumab in combination with infusional fluorouracil , leucovorin and irinotecan ( FOLFIRI ) in first-line metastatic colorectal cancer . bevacizumab (Avastin) significantly improves overall survival (OS) and progression-free survival (PFS) when combined with first-line irinotecan (IFL) plus bolus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer (CRC). This open-label, phase IV trial evaluated the efficacy and safety of first-line bevacizumab in combination with IFL and infusional 5-FU/LV (FOLFIRI). ### methods Two-hundred and nine treatment-naïve metastatic CRC patients were enrolled and received bevacizumab and FOLFIRI every 2 weeks. Treatment was continued until disease progression. The primary objective was PFS, with additional determinations of OS, response and toxicity. ### results Median PFS was 11.1 months and is comparable to that observed in published phase III and community-based trials using first-line bevacizumab plus FOLFIRI, and to phase III trials using bevacizumab in combination with bolus 5-FU/LV plus IFL. Median OS was 22.2 months. Overall response rate was 53.1% and the disease control rate 85.6%. Most adverse events were grade 1/2 and were manageable. The most common grade 3/4 adverse events (> or =10%) were neutropenia, venous thromboembolic events, diarrhea, and fatigue. ### conclusion bevacizumab combined with first-line FOLFIRI is an effective and well-tolerated therapy option for patients with metastatic CRC.


vincristine

etoposide

doxorubicin

Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Chemoresistance is a major obstacle in chemotherapy of laryngeal carcinoma. Recently, studies indicate that cancer stem cells are responsible for chemotherapy failure. In addition, microRNAs play important roles in tumor initiation, development and multidrug resistance. In the present study, we found that the expression of microRNA-125a was decreased in laryngeal carcinoma tissues and Hep-2 laryngeal cancer stem cells (Hep-2-CSCs). MicroRNA-125a gain-of-function significantly increased the sensitivity of Hep-2-CSCs to cisplatin in vitro and in vivo. Combination with microRNA-125a mimics can decrease the half maximal inhibitory concentration of Hep-2-CSCs to cisplatin. Mechanically, we found that microRNA-125a reverses cisplatin resistance in Hep-2-CSCs by targeting Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1). Inhibition of HAX-1 by microRNA-125a significantly promotes the cisplatin-induced apoptosis in Hep-2-CSCs through mitochondrial pathway. In addition , multidrug resistance of Hep-2-CSCs to vincristine , etoposide and doxorubicin was greatly improved after the cells were transfected with microRNA-125a mimics . These dates strongly suggested the promotion of microRNA-125a/HAX-1 axis on chemotherapy of laryngeal carcinoma.


cisplatin

etoposide

cyclophosphamide

doxorubicin

vincristine

cyclophosphamide

etoposide

vincristine

etoposide

Resolution of superior vena cava obstruction in small cell lung cancer patients treated with chemotherapy. Small cell lung cancer is a highly chemo-sensitive malignancy. As it often presents with a central lesion, superior vena cava obstruction (SVCO) is not an uncommon manifestation. From January 1990 to December 1993, 161 patients with small cell lung carcinoma were seen at our institution. Twenty (12.4%) of these patients presented with symptoms and signs of SVCO. Initial therapy consisted of radiotherapy in 4 patients and chemotherapy in 16 patients. Of those treated with chemotherapy, patient characteristics included 13 males, median age of 62.5 years (range 51 to 78 years), Eastern Co-operative Oncology Group (ECOG) performance status of 3 to 4 in 7 patients; 1 to 2 in 9 patients, and limited stage disease in 8 patients. The median period of follow-up was 5 months. Nine patients received a combination of cisplatin and etoposide ( EP ) , 5 had cyclophosphamide , doxorubicin and vincristine , 1 had cyclophosphamide , etoposide and vincristine and 1 had monotherapy with oral etoposide . Overall response to chemotherapy was 81% (with 31% complete responses). All responders had resolution of SVCO. Only 3 patients did not respond (1 patient defaulted, 1 patient died of neutropenic sepsis at week one and 1 patient had stable disease). Resolution of SVCO was noted within the first 2 weeks after the first cycle; the earliest being 3 days. The only patient given single-agent oral etoposide responded within 10 days after initiation of treatment. Of the 7 patients with poor performance status (ECOG 3 to 4), 3 died from treatment-related complications. Chemotherapy is highly effective as a primary treatment of small cell lung carcinoma despite presentation with SVCO. However, caution is advised in the use of combination chemotherapy for those presenting with poor performance status. Initial therapy with oral etoposide or radiotherapy should be considered as possible alternatives for these patients.


Tetracycline

chlortetracycline

Sorption of tetracycline and chlortetracycline on K- and Ca-saturated soil clays, humic substances, and clay-humic complexes.  Tetracycline ( TC ) and chlortetracycline ( CTC ) are used extensively for growth promotion and therapeutic purposes in livestock production . The sorption of TC and CTC on clays, humic substances (HS), and clay-humic complexes (clay-HC) derived from two agricultural soils was quantified using dilute CaCl2 (Ca) and KCI (K) as background solutions. In all systems, the soil components sorbed > 96% of added tetracyclines. Strongest sorption was observed for clays, followed by HS, and then clay-HC. Greater sorption by the Ca systems than the K systems and decreased sorption with increasing pH suggests that cation bridging and cation exchange contribute to sorption. X-ray diffraction analysis showed that TC and CTC were sorbed in the interlayers of smectites and that the presence of HS reduced interlayer sorption of tetracyclines by smectites in clay-HC. The results indicate that tetracyclines are dominantly sorbed on soil clays and that HS in clay-HC either mask sorption sites on clay surfaces or inhibit interlayer diffusion of tetracyclines.


nalidixic acid

metronidazole

metronidazole

Efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. To determine the efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. ### methods In this double-blind field trial, 156 children aged 4-36 months with persistent diarrhoea not associated with Giardia lamblia infestation seeking treatment in a community outpatient clinic, were randomized to receive a combination of nalidixic acid and metronidazole, metronidazole alone, or placebo for 7 days. ### results In comparison with placebo, metronidazole treatment did not result in a significant reduction in the mean post-enrollment diarrhoeal duration and stool frequency, increase in the proportion of patients recovered by days 3, 5 and 7 of treatment, and increase in weight gain at days 7 and 14. Comparing the combination of nalidixic acid and metronidazole with metronidazole alone , 17.5 % more children treated with the combination recovered by day 3 of treatment ( p = 0.08 ) and the mean stool frequency ascertained on day 7 for the previous 24 h was 26.8 % less in them ( p = 0.05 ) . The weight gains at days 7 and 14 were similar in the two groups. ### conclusions These findings indicate that metronidazole offers no therapeutic benefit in persistent diarrhoea not associated with Giardia lamblia and nalidixic acid has only a modest clinical benefit, which is not substantial enough to warrant its routine use.


propranolol

primidone

Topiramate for essential tremor. Essential tremor (ET) is one of the most common movement disorders. The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy . However, these treatments can be ineffective in 25% to 55% of people and are frequently associated with serious adverse events (AEs). For these reasons, it is worthwhile evaluating other treatments for ET. topiramate has been suggested as a potentially useful agent for the treatment of ET but there is uncertainty about its efficacy and safety. ### objectives To assess the efficacy and safety of topiramate in the treatment of ET. ### Search Methods We carried out a systematic search without language restrictions to identify all relevant trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to January 2017), Embase (January 1988 to January 2017), National Institute for Health and Care Excellence (1999 to January 2017), ClinicalTrials.gov (1997 to January 2017) and World Health Organization International Clinical Trials Registry Platform (ICTRP; 2004 to January 2017). We searched BIOSIS Citation Index (2000 to January 2017) for conference proceedings. We handsearched grey literature and the reference lists of identified studies and reviews. ### Selection Criteria We included all randomised controlled trials (RCTs) of topiramate versus placebo/open control or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in people presenting with secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. ### Data Collection And Analysis Two review authors independently collected and extracted data using a data collection form. We assessed the risk of bias and the quality of evidence. We used a fixed-effect meta-analysis for data synthesis. ### Main Results This review included three trials comparing topiramate to placebo (309 participants). They were all at high overall risk of bias. The quality of evidence ranged from very low to low. Compared to placebo, participants treated with topiramate showed a significant improvement in functional disability and an increased risk of withdrawal (risk ratio (RR) 1.78, 95% confidence interval (CI) 1.23 to 2.60). There were more AEs for topiramate-treated participants, particularly paraesthesia, weight loss, appetite decrease and memory difficulty. ### Authors Conclusions This systematic review highlighted the presence of limited data and very low to low quality evidence to support the apparent efficacy and the occurrence of treatment-limiting AEs in people with ET treated with topiramate. Further research to assess topiramate efficacy and safety on ET is needed.