tocilizumab

tofacitinib

Comparative Efficacy of Novel DMARDs as Monotherapy and in Combination with Methotrexate in Rheumatoid Arthritis Patients with Inadequate Response to Conventional DMARDs: A Network Meta-Analysis. Given the availability of a number of alternative biologic treatment options and other novel disease-modifying antirheumatic drugs (DMARDs) for the treatment of patients with rheumatoid arthritis (RA), clinicians are faced with an increasingly challenging choice regarding optimal treatment. Biologics are usually combined with traditional DMARDs, primarily methotrexate (MTX), but some biologics and tofacitinib (together referred to in this article as novel DMARDs) have been shown to be efficacious as monotherapy as well. In real-world practice, approximately one-third of RA patients receiving biologics are on monotherapy, primarily because of intolerance of, or noncompliance with, MTX. Limited data, however, are available analyzing the effectiveness of monotherapy compared with combination therapy across novel DMARDs. ### objective To compare American College of Rheumatology (ACR) responses to approved novel DMARDs used as monotherapy or as combination therapy with methotrexate (MTX) at 24 weeks in RA patients who have shown inadequate response to conventional DMARDs (DMARD-IR). ### methods Through a systematic review of the literature, we identified randomized controlled trials that assessed approved novel DMARDs used as monotherapy or as combination therapy with MTX in DMARD-IR RA patients. Twenty-eight RCTs were identified that evaluated abatacept, anakinra, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib. ACR responses at 24 weeks were extracted and combined by means of Bayesian network meta-analyses. ### results With the exception of anakinra plus MTX, which was less efficacious, most novel DMARDs, when used in combination with MTX, demonstrated comparable ACR responses. When novel DMARDs were used as monotherapies , greater ACR20/50/70 responses were observed with tocilizumab than with anti-tumor necrosis factor agents ( aTNF ) or tofacitinib . Furthermore, ACR20/50/70 responses with tocilizumab plus MTX were similar to those with tocilizumab monotherapy (odds ratio [OR] for the indirect comparison = 1.08, 95% credible interval [CrI] = 0.40-2.84; OR = 1.24, CrI = 0.44-3.61; OR = 0.95, CrI = 0.33-2.72, respectively), whereas greater responses were observed with aTNF plus MTX than with aTNF monotherapy (OR = 2.41, CrI = 0.51-11.61; OR = 2.85, CrI = 0.51-17.67; OR = 1.28, CrI = 0.21-8.42, respectively). Relative efficacy estimates for the indirect comparison of tofacitinib plus MTX with tofacitinib monotherapy were very uncertain. ### conclusions Results suggest that in combination with MTX most of the available novel DMARDs have similar levels of efficacy in DMARD-IR patients. As monotherapy, however, tocilizumab displayed higher ACR responses than aTNF or tofacitinib. ACR responses with tocilizumab plus MTX were similar to those with tocilizumab as monotherapy, whereas aTNF in combination with MTX demonstrated greater ACR responses than aTNF as monotherapy.


Paclitaxel

fulvestrant

Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer. To investigate the prognostic role of the estrogen receptor (ER) in gastric cancer (GC) patients, tumor tissues from 932 patients with advanced GC were assessed for ER expression using immunohistochemistry, and their clinicopathologic features were evaluated. Forty patients (4.3%) had ER expression and they were more frequently associated with diffuse type gastric cancer and shorter disease free survival. Furthermore, we carried out in vitro analysis to evaluate the effect of ER modulation on the proliferation of GC cell lines. Estradiol enhanced proliferation of ER positive GC cells while it did not show any effect on ER negative GC cells. When ER was inhibited by fulvestrant and ER siRNA, estradiol-induced proliferation of ER positive GC cell was suppressed. Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant . Suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis.


ritodrine

lidocaine

phenylephrine

ephedrine

Ephedrine remains the vasopressor of choice for treatment of hypotension during ritodrine infusion and epidural anesthesia. Historically, ephedrine has been the vasopressor of choice for treatment of most cases of hypotension in obstetric patients. However, the choice of vasopressor in the parturient receiving a beta-adrenergic agent for tocolysis has not been evaluated extensively. The current study evaluated whether ephedrine or phenylephrine better restores uterine blood flow and fetal oxygenation during ritodrine infusion and epidural anesthesia-induced hypotension in gravid ewes. ### methods Fourteen chronically instrumented gravid ewes between 0.8 and 0.9 timed gestational age were used. On separate days, each animal underwent the experimental protocol with one of three agents: ephedrine, phenylephrine, and normal saline-control. The experimental protocol was as follows : ( 1 ) at time zero , intravenous infusion of ritodrine was begun ; ( 2 ) at 120 min , 2 % lidocaine was given epidurally to achieve a sensory level of at least T6 ; and ( 3 ) at 135 min , an intravenous bolus of either ephedrine , phenylephrine , or normal saline-control was given , followed by a continuous intravenous infusion of the same agent for 30 min . In the ephedrine and phenylephrine experiments, the rate of infusion was adjusted to maintain maternal mean arterial pressure close to baseline. ### results ritodrine infusion alone significantly increased maternal heart rate and cardiac output in all three groups. Epidural anesthesia during ritodrine infusion significantly decreased maternal mean arterial pressure, heart rate, cardiac output, uterine blood flow, and fetal arterial oxygen tension for each of the three groups. Both ephedrine and phenylephrine restored maternal mean arterial pressure to baseline, as designed. Ephedrine significantly increased uterine blood flow and fetal arterial oxygen tension when compared with normal saline--control, but phenylephrine did not. phenylephrine significantly increased uterine vascular resistance when compared with normal saline--control, but ephedrine did not. ### conclusions Although ephedrine and phenylephrine provided similar restoration of maternal mean arterial pressure, ephedrine was superior to phenylephrine in restoring uterine blood flow during ritodrine infusion and epidural anesthesia-induced hypotension in gravid ewes. Also, ephedrine, but not phenylephrine, significantly improved fetal oxygenation, when compared to normal saline--control.


busulfan

cyclophosphamide

compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia . busulfan plus cyclophosphamide (BuCy) is the traditional conditioning regimen for allogeneic stem cell transplant (allo-SCT) for young, fit patients with acute myeloid leukemia (AML). The thiotepa-busulfan-fludarabine (TBF) protocol has recently demonstrated promising outcome in cord blood and haploidentical SCT; however, there is limited evidence about this regimen in transplant from matched siblings (MSD) and unrelated donors (UD). We retrospectively compared outcomes of 2523 patients aged 18-50 with AML in remission, undergoing transplant from MSD or UD prepared with either TBF or BuCy conditioning. A 1:3 pair-matched analysis was performed: 146 patients receiving TBF were compared with 438 patients receiving BuCy. Relapse risk was significantly lower in the TBF when compared with BuCy group (HR 0.6, P = .02), while NRM did not differ. No significant difference was observed in LFS and OS between the two regimens. TBF was associated with a trend towards higher risk of grades III-IV aGVHD (HR 1.8, P = .06) and inferior cGVHD (HR 0.7, P = .04) when compared with BuCy. In patients undergoing transplant in first remission, the advantage for TBF in terms of relapse was more evident (HR 0.4, P = .02), leading to a trend for better LFS in favor of TBF (HR 0.7, P = .10), while OS did not differ between the two cohorts. In conclusion, TBF represents a valid myeloablative conditioning regimen providing significantly lower relapse and similar survival when compared with BuCy. Patients in first remission appear to gain the most from this protocol, as in this subgroup a tendency for better LFS was observed when compared with BuCy.


cyclosporine

prednisone

A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study. Two novel preparatory regimens for conditioning of patients with leukemia for allogeneic bone marrow transplantation (BMT) from histocompatible sibling donors have been tested in a phase III trial under the auspices of the Southwest Oncology Group (SWOG 8612). These two regimens consisted either of fractionated total body irradiation and etoposide (FTBI/VP-16) or high-dose busulfan with cyclophosphamide (BU/CY). Only patients who had failed prior conventional management at least once were study eligible, ie, no patients with acute leukemia in first remission (CR) or in first chronic phase (CP) of chronic myelogenous leukemia (CML) participated. Patients were stratified according to the following risk criteria: "good-risk" patients were those who were in second CR of their acute leukemia or in accelerated phase (AP) of CML; "poor-risk" patients had further advanced stages of leukemia. During a 52-month period, 131 patients were registered of whom 122 (93%) were study eligible. Sixty-one eligible patients were randomized to the FTBI/VP-16 arm and 61 to the BU/CY regimen. Of these 122 patients, 114 (93%) proceeded to BMT according to protocol. Posttransplant immunosuppression to prevent graft-versus-host disease ( GVHD ) consisted of cyclosporine and prednisone ( CSA/PSE ) . Neither overall survival nor disease-free survival (DFS) differed significantly between the two treatment groups (P = .89 and .69, respectively). Estimated DFS for "good-risk" patients who had been prepared with the FTBI/VP-16 regimen was 55% +/- 11%, as compared with patients treated with BU/CY whose DFS figure was 34% +/- 10% (P = .30). For "poor-risk" candidates, the DFS rates at 24 months were 17% +/- 6% (for FTBI/VP-16) and 24% +/- 8% (for BU/CY), respectively (P = .81). These figures do not differ significantly, especially in view of the fact that the "good-risk" patients prepared with the FTBI/VP-16 regimen were younger than those treated with BU/CY. Both regimens were well tolerated with no regimen-related deaths encountered during the 6-week period after BMT. This study also confirmed the efficacy of the CSA/PSE combination in the prevention of GVHD with 23 of 113 (20%) of BMT recipients developing moderate to severe acute GVHD. The leading cause for treatment failure was leukemic relapse (45 of the 114 BMT recipients suffered a recurrence of their leukemia), whereas 38 patients died without evidence of relapse. Thirty-one patients are alive and in continued CR after marrow transplantation; four are alive in relapse.(ABSTRACT TRUNCATED AT 400 WORDS)


Tadalafil

sildenafil

A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. tadalafil is a phosphodiesterase 5 (PDE5) inhibitor approved in >30 countries for the treatment of erectile dysfunction (ED). It has been shown to improve erectile function compared with placebo in Phase III studies, but clinical experience comparing tadalafil with the PDE5 inhibitor sildenafil citrate is lacking. ### objective This study compared patient preference for tadalafil 20 mg or sildenafil 50 mg during initial treatment for ED. It also compared the tolerability of the 2 agents at these doses. ### methods This randomized, double-blind, fixed-dose, 2-period crossover trial took place at 13 sites in the United States and Germany. Patients were randomized 1:1 to receive 4 weeks of treatment with tadalafil 20 mg or sildenafil 50 mg, followed by the alternative treatment, to be taken as needed up to once daily before sexual activity. ### results The study enrolled 215 men with ED, 109 randomized to the tadalafil-sildenafil sequence and 106 to the sildenafil-tadalafil sequence. Their mean age was 49.8 years; 84.7% were sildenafil naive and 15.3% had undergone a previous inadequate trial of sildenafil. Most patients had moderate ED (60.5%) of >or=1 year's duration (74.9%). Of 190 evaluable patients, 126 (66.3%) preferred to initiate treatment with tadalafil, compared with 64 (33.7%) with sildenafil (P < 0.001). Patients' preference did not differ by age, duration of ED, treatment sequence, or previous sildenafil exposure. Both medications were well tolerated, with no significant differences in the incidence of treatment-emergent adverse events. Headache (11.2% tadalafil, 8.8% sildenafil), dyspepsia (6.0% and 4.2%, respectively), nasopharyngitis (4.7% and 2.8%), and flushing (2.8% and 4.7%) were the most common adverse events. The rate of ocular disturbances was low: 1 patient experienced intermittent bilateral reduction in visual acuity with tadalafil, and 2 exhibited conjunctival hyperemia or eyelid edema with sildenafil. ### conclusions Tadalafil 20 mg was preferred to sildenafil 50 mg for the initiation of ED therapy in this study population . Both medications were well tolerated.


heparin

enoxaparin

Heparin modulates the 99-loop of factor IXa: effects on reactivity with isolated Kunitz-type inhibitor domains.  Reactivity of factor IXa with basic pancreatic trypsin inhibitor is enhanced by low molecular weight heparin ( enoxaparin ) . Previous studies by us have suggested that this effect involves allosteric modulation of factor IXa. We examined the reactivity of factor IXa with several isolated Kunitz-type inhibitor domains: basic pancreatic trypsin inhibitor, the Kunitz inhibitor domain of protease Nexin-2, and the first two inhibitor domains of tissue factor pathway inhibitor. We find that enhancement of factor IXa reactivity by enoxaparin is greatest for basic pancreatic trypsin inhibitor (>10-fold), followed by the second tissue factor pathway inhibitor domain (1.7-fold) and the Kunitz inhibitor domain of protease Nexin-2 (1.4-fold). Modeling studies of factor IXa with basic pancreatic trypsin inhibitor suggest that binding of this inhibitor is sterically hindered by the 99-loop of factor IXa, specifically residue Lys(98). Slow-binding kinetic studies support the formation of a weak initial enzyme-inhibitor complex between factor IXa and basic pancreatic trypsin inhibitor that is facilitated by enoxaparin binding. Mutation of Lys(98) to Ala in factor IXa results in enhanced reactivity with all inhibitors examined, whereas almost completely abrogating the enhancing effects of enoxaparin. The results implicate Lys(98) and the 99-loop of factor IXa in defining enzyme inhibitor specificity. More importantly, these results demonstrate the ability of factor IXa to be allosterically modulated by occupation of the heparin-binding exosite.


leucovorin

levamisole

National Cancer Institute Clinical Trials Program in Colorectal Cancer. Colorectal cancer will be diagnosed in approximately 150,000 patients in the USA this year. Chemotherapy has recently been shown to improve survival when given as adjuvant therapy to surgery in patients with stage III colorectal cancer. Demonstration of this benefit required large, randomized controlled trials. Either 5-fluorouracil ( 5-FU ) and leucovorin for 6 months or 5-FU and levamisole for 12 months are currently considered standard adjuvant treatment for stage III colorectal cancer . However, current adjuvant trials are comparing continuous infusion and intravenous bolus 5-FU regimens and oral uracil/Ftorafur with intravenous 5-FU and leucovorin, as well as studying the timing of chemotherapy in the adjuvant setting. Subsequent adjuvant trials will examine newer regimens with activity in advanced colorectal cancer, as well as the efficacy of monoclonal antibodies. Other trials will study which type of surgery is optimal and whether adjuvant therapy is helpful in stage II colon cancer. Trials in metastatic disease will focus on combinations of newer agents which may improve survival in this patient group. Studies in rectal cancer will focus on determining which agents are optimal in combination with radiation therapy in the adjuvant setting. Molecular characteristics of tumor cells are being defined, which may guide therapy in the future. Careful, logically designed clinical trials will hopefully provide more efficacious therapy for this common cancer.


tamoxifen

letrozole

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. ### methods This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer , who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor , were randomly assigned ( 1:1 ) to receive 5 years of letrozole ( 2·5 mg orally per day ) or placebo . Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. ### findings Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). ### interpretation After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. ### funding National Cancer Institute, Korea Health Technology R&D Project, Novartis.


sorafenib

flavopiridol

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression. To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclin-dependent kinase (CDK) inhibition in therapy. ### Experimental Design The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenib-sensitive (Huh-7 and HepG2, IC50 5-6 μmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 μmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosis-related proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments . The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments. ### results Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect. ### conclusions The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. Clin Cancer Res; 22(10); 2555-64. ©2015 AACR.


sorafenib

curcumin

Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma . Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Herein, we first reported the codelivery of sorafenib and curcumin by directed self-assembled nanoparticles (SCN) to enhance the therapeutic effect on HCC. SCN was formed by employing the hydrophobic interactions among the lipophilic structure in sorafenib, curcumin, and similar hydrophobic segments of polyethylene glycol derivative of vitamin E succinate (PEG-VES), which comprised uniform spherical particles with particle size of 84.97 ± 6.03 nm. SCN presented superior effects over sorafenib, curcumin, and their physical mixture (Sora + Cur) on enhancing in vitro cytotoxicity and cell apoptosis in BEL-7402 cells and Hep G2 cells, and antiangiogenesis activities in tube formation and microvessel formation from aortic rings. Moreover, the tissue concentration of sorafenib and curcumin in gastrointestinal tract and major organs were significantly improved after their coassembly into SCN. In particular, in BEL-7402 cells induced tumor xenograft, SCN treatment displayed the obviously enhanced inhibitory effect on tumor progression over free drug monotherapy or their physical mixture, with significantly increased antiproliferation and antiangiogenesis capability. Thereby, the codelivered nanoassemblies of sorafenib and curcumin provided a promising strategy to enhance the combinational therapy of HCC.


closantel

albendazole

Efficacy of closantel plus albendazole liquid suspension against natural infection of gastrointestinal parasites in camels. Oral administration of closantel in a dose of 10 mg/kg plus albendazole in a dose of 5 mg/kg liquid suspension was studied in 75 camels naturally infected with various types of gastrointestinal parasites. The camels involved were 15 pregnant she-camels, 20 non-pregnant she-camels and 40 male camels of various ages. Each camel received a single oral dose of closantel (10 mg/kg) plus albendazole (5 mg/kg) orally. Two weeks later, 20 camels of this group were re-dosed again with the same dose of the anthelmintic. Fecal samples were collected per rectum from all camels at the time of treatment and again 14 and 42 days post treatment. Fecal egg counts and generic determination of third stage larvae was performed. Results indicated that six different species of gastrointestinal tract parasites were identified in camels. Single treatment of closantel plus albendazole mixture reduced egg counts in camels by 100 % , 100 % , 98 % and 77 % for Haemonchus longistipes , Ascaris spp . , Monezia expansa and Fasciola hepatica , respectively . However, administration of the drug twice on the base of 2 weeks apart significantly raised the efficacy of the drug for clearance of the parasites from 92.5% to 100% in camels infected with various parasites. Camels were not adversely affected by treatment.


lidocaine

tetracaine

A prospective, randomized, double-blind study comparing the efficacy of topical anesthetics in nasal endoscopy. Transnasal endoscopy is commonly performed in an outpatient otolaryngology setting. Patients are typically administered a topical anesthetic and decongestant prior to this procedure to alleviate discomfort and improve visualization. There is no consensus on which topical anesthetic is most effective in optimizing patient experience during the procedure. ### objective To determine whether there is a difference in the efficacy between atomized 2% tetracaine and 4% lidocaine as a topical anesthetic prior to transnasal endoscopy. ### Study Design Prospective, randomized, double-blind study. ### methods A total of 99 patients received oxymetazoline and were randomized to receive either 2% tetracaine or 4% lidocaine prior to transnasal endoscopy. Immediately following the procedure, participants completed a survey assessing level of discomfort and other adverse symptoms pertaining to the procedure using a 10-point visual analog scale (VAS). ### results There were no significant differences in VAS scores between the lidocaine and tetracaine groups. There were also no significant differences between genders in overall VAS scores and in the lidocaine and tetracaine subgroups. Older patients demonstrated significantly less discomfort or a sensation of bad taste overall. In contrast to patients receiving lidocaine , older patients receiving tetracaine experienced significantly less overall pain and discomfort , unpleasant taste , and dyspnea . ### conclusion In patients undergoing transnasal endoscopy, use of either 2% tetracaine or 4% lidocaine has similar effect. tetracaine may be a better choice in older patients, however.


bevacizumab

irinotecan

Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma. A 5-year-old boy with glioblastoma relapsed soon after postoperative irradiation in combination with temozolomide. Second-line chemotherapy was also ineffective ; therefore , the bevacizumab and irinotecan were given after a third gross-total resection of the tumor . Treatment was interrupted for 1 month due to development of posterior reversible encephalopathy syndrome, but was re-initiated at a lower dose of bevacizumab with prolonged intervals between treatments. The patient was alive and disease free 2 years after initial diagnosis. bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis.


nivolumab

pembrolizumab

Recent developments with immunotherapy for hepatocellular carcinoma. Immunotherapy is on the way to become the new standard of care for advanced hepatocellular carcinoma (HCC) worldwide. With higher rates of objective responses, and overall less side effects compared to tyrosine-kinase inhibitors (TKIs) immunotherapeutics will probably replace sorafenib from standard first-line treatment. ### Areas Covered This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC focusing on immunotherapy. ### Expert Opinion In unselected patients with advanced HCC immunotherapeutics , namely the programmed cell death-1 ( PD-1 ) antibodies , nivolumab and pembrolizumab have shown promising efficacy in therapy-naïve , as well as pre-treated patients with advanced HCC . However, only 10-20 percent of treated patients show an objective and durable response to the indicated therapeutics. Therefore, combination therapies including different immunotherapeutics, e.g. PD-1/programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, or combinations of immunotherapeutics and small molecules, or bifunctional antibodies will be needed to improve response rates. ### abbreviations HCC: hepatocellular carcinoma; TKI: tyrosine-kinase inhibitors; PD-1: programmed death receptor-1; PD-L1: programmed cell death 1 ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated Protein 4; CAR-T: chimeric T cell receptors; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; SBRT: stereotactic body radiation therapy; VEGF: vascular endothelial growth factor; MEK: mitogen-activated protein kinase kinase; NK cell: natural killer cell; TGFβ: transforming growth factor-β; OV: Oncolytic viruses; PFU: plaque-forming unit.


rapamycin

paclitaxel

Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Mammalian target of rapamycin (mTOR) inhibitors modulate signaling pathways involved in cell cycle progression, and recent phase II trials demonstrate activity in patients with endometrial cancer. Our objective was to examine the effects of combination therapy with rapamycin and paclitaxel in endometrial cancer cell lines. paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC(50) values of 0.1-0.5 nM and 1-5 nM for Ishikawa and ECC-1 cells, respectively. To assess synergy of paclitaxel and rapamycin, the combination index (CI) was calculated by the method of Chou and Talalay. Simultaneous exposure of cells to various doses of paclitaxel in combination with rapamycin (1 nM) resulted in a significant synergistic anti-proliferative effect (CI <1, range 0.131-0.920). rapamycin alone did not induce apoptosis, but combined treatment with paclitaxel increased apoptosis over that of paclitaxel alone. Treatment with rapamycin and paclitaxel resulted in decreased phosphorylation of S6 and 4E-BP1 , two critical downstream targets of the mTOR pathway . rapamycin decreased hTERT mRNA expression by real-time RT-PCR while paclitaxel alone had no effect on telomerase activity. paclitaxel increased polymerization and acetylation of tubulin, and rapamycin appeared to enhance this effect. Thus, in conclusion, we demonstrate that rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation, induction of apoptosis and potentially increased polymerization and acetylation of tubulin. This suggests that the combination of rapamycin and paclitaxel may be a promising effective targeted therapy for endometrial cancer.


atezolizumab

bevacizumab

sorafenib

Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma. Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver cancer worldwide, and the overall survival of patients with unresectable disease is poor. In the last five years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment scenario of several hematological and solid tumors, and these agents have been actively explored in unresectable HCC. Firstly, promising findings of phase I and II clinical studies reporting durable responses and a tolerable safety profile have led to the assessment of ICIs as single agents in phase III clinical studies; however, the latter have provided controversial results, and the activity of ICI monotherapy seems limited to a small subgroup of patients. Conversely , the IMbrave150 trial recently showed that , among patients with previously untreated unresectable HCC , treatment with atezolizumab plus bevacizumab resulted in significantly longer overall survival and progression-free survival compared to sorafenib monotherapy . In addition, the activity of several other ICIs is under investigation, as combination immunotherapy as well as combinations of immunotherapy with antiangiogenic agents. Nonetheless, there are currently no validated predictive biomarkers able to guide treatment choice in this setting, where the identification of specific predictors of response to ICIs represents a major challenge. In this review, we aim to provide a critical overview of recent evidence on biochemical predictors of response to ICIs in patients with unresectable HCC, especially focusing on PD-L1, TMB, MSI, and other emerging biomarkers.


tamoxifen

letrozole

Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer . The goals of this clinical trial involving postmenopausal women with metastatic breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM) pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and time to progression for the combination. Postmenopausal women with measurable or evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM], serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase inhibition, serum samples were obtained before treatment and at 6, 12, 18, and 24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding globulin. A total of 34 patients were entered on this trial, and 23 patients were still on study at week 24, 18 of whom had blood samples available at both week 6 and week 24. The 95% confidence interval for the mean difference between levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45 ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6 weeks of letrozole, which was maintained for an additional 12 weeks. Similar significant reductions were identified for E1. E1 sulfate levels increased after 6 weeks of TAM alone but then decreased significantly after the addition of letrozole. Sex hormone-binding globulin levels were significantly elevated after 6 weeks of TAM alone and remained elevated after the addition of letrozole. Six of the 34 patients (17.6%) achieved an objective response (95% confidence interval, 6.8-34.5%), with a median time to disease progression of 7.6 months. There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or 4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by letrozole was substantial despite the concomitant administration of TAM. The antitumor effect of TAM plus letrozole was less than expected.


nilotinib

ponatinib

Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML. In chronic myelogenous leukemia (CML), leukemic stem cells (LSC) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel relevant markers of CML LSCs. ### Experimental Design CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25(+)CML cell line KU812. ### results In contrast to normal hematopoietic stem cells, CD34(+)/CD38(-)CML LSCs expressed the IL-2 receptor alpha chain, IL-2RA (CD25). STAT5 was found to induce expression of CD25 in Lin(-)/Sca-1(+)/Kit(+)stem cells in C57Bl/6 mice. Correspondingly, shRNA-induced STAT5 depletion resulted in decreased CD25 expression in KU812 cells. Moreover , the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs . A CD25-targeting shRNA was found to augment proliferation of KU812 cellsin vitroand their engraftmentin vivoin NOD/SCID-IL-2Rγ(-/-)mice. In drug-screening experiments, the PI3K/mTOR blocker BEZ235 promoted the expression of STAT5 and CD25 in CML cells. Finally, we found that BEZ235 produces synergistic antineoplastic effects on CML cells when applied in combination with nilotinib or ponatinib. ### conclusions CD25 is a novel STAT5-dependent marker of CML LSCs and may be useful for LSC detection and LSC isolation in clinical practice and basic science. Moreover, CD25 serves as a growth regulator of CML LSCs, which may have biologic and clinical implications and may pave the way for the development of new more effective LSC-eradicating treatment strategies in CML.


somatostatin

everolimus

Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study. Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials. ### Materials And Methods This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression). ### results Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS. ### conclusion The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting. ### Implications For Practice The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting .


trastuzumab

paclitaxel

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer.  Synergism between anti-HER2 monoclonal antibody ( trastuzumab ) and paclitaxel has been shown in vitro and in vivo . In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.


basiliximab

cyclosporine

Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. cyclosporine (CsA) is frequently initiated as induction therapy in patients undergoing orthotopic heart transplantation, but our experience has identified a significant rate of post-operative renal dysfunction. We therefore devised a renal-sparing cyclosporine-free induction regimen consisting of the early administration basiliximab, an interleukin-2 receptor monoclonal antibody, followed by the late initiation of cyclosporine on post-operative Day 4. ### methods Between September 1998 and December 1999 , we treated 25 patients at risk for post-operative renal dysfunction ( high-risk basiliximab group ) with the new induction regimen and another 33 patients not at risk ( low-risk CsA group ) for renal dysfunction with our standard cyclosporine protocol . We identified a historical control group (1996 through 1998) of 32 patients at risk for renal dysfunction (high-risk CsA group) who had received our standard cyclosporine protocol. ### results The increase in serum creatinine levels after transplantation was less in the high-risk basiliximab group (-0.1 +/- 0.7) than in the high-risk CsA group (0.5 +/- 1.0, p < 0.02) and comparable to the low-risk CsA group (0.03 +/- 0.6). The basiliximab protocol did not increase rejection; the percentage of rejection episodes was high-risk basiliximab, 0; high-risk CsA, 13; and low-risk CsA, 3 (p = .13). ### conclusion basiliximab induction therapy allows delayed initiation of cyclosporine after cardiac transplantation without an increase in rejection and reduces the risk of post-operative renal dysfunction.


posaconazole

posaconazole

voriconazole

Long QT Syndrome Leading to Multiple Cardiac Arrests After Posaconazole Administration in an Immune-Compromised Patient with Sepsis: An Unusual Case Report. We present the case of a septic patient with severe immunodeficiency, who developed QT interval prolongation followed by episodes of lethal cardiac arrhythmia. Cardiac events occurred after posaconazole administration , incriminating posaconazole use , alone or in combination with voriconazole , as the culpable agent . ### Case Report A 26-year-old female patient underwent orthopedic surgery to remove ectopic calcifications in her left hip joint. On the first post-operative day she became septic due to a surgical wound infection. Despite being treated according to the therapeutic protocols for sepsis, no clinical improvement was noticed and further assessment revealed an underlying immunodeficiency. Considering the underlying immunodeficiency and to that point poor clinical response, an antifungal agent was added to the antibiotic regiment. Following discontinuation of multiple antifungal agents due to adverse effects, posaconazole was administered. posaconazole oral intake was followed by episodes of bradycardia and QT interval prolongation. The patient suffered continuous incidents of cardiac arrest due to polymorphic ventricular tachycardia (torsades des pointes) that degenerated to lethal ventricular fibrillation. posaconazole was immediately discontinued and a temporary pacemaker was installed. The patient finally recovered without any neurological deficit, and was discharged in a good clinical status. ### conclusions Close cardiac monitoring is recommended in cases where posaconazole administration is combined with coexisting risk factors, as they may lead to severe ECG abnormalities and cardiac arrhythmias such as long QT interval syndrome and torsades de pointes. posaconazole interactions with medications metabolized via the CYP3A4 pathway should be considered an additional risk factor for lethal cardiac incidents.


paclitaxel

capecitabine

Prognostic value of expression of Kit67 , p53 , TopoIIa and GSTP1 for curatively resected advanced gastric cancer patients receiving adjuvant paclitaxel plus capecitabine chemotherapy . To investigate the role of Kit67, p53, topoisomerase II (TopoII) and glutathione S-transferase P1 (GSTP1) in predicting clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel chemotherapy. ### methodology The clinical data and tissue samples from 136 curatively resected advanced gastric cancer patients receiving capecitabine plus paclitaxel in the third affiliated hospital of Kunming medical university from January 2005 to December 2007 were retrospectively collected and analyzed for Kit67, p53, TopoIIa and GSTP1 expressions by immunohistochemistry. The relationships between expressions of the biomarkers and survival were analyzed. ### results p53 expression were associated with the significantly shorter disease-free survival (DFS) (p<0.001) and overall survival (OS) (p=0.012) in the curatively resected advanced gastric cancer patients receiving capecitabine plus paclitaxel. Kit67, TopoIIa and GSTP1 expressions were not related to DFS and OS. ### conclusions p53 expression positive might predict prognosis in gastric cancer patients who underwent curative surgery followed by adjuvant capecitabine plus paclitaxel chemotherapy. A favorable effect of capecitabine plus paclitaxel might therefore be expected in patients that do not express p53.


fluorouracil

leucovorin

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.  The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin ( FL ) . oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. ### methods We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. ### results A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). ### conclusions Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.


propranolol

phenylephrine

Alteration of left ventricular endocardial function by intracavitary high-power ultrasound interacts with volume, inotropic state, and alpha 1-adrenergic stimulation. High-power intracavitary ultrasound abbreviates left ventricular (LV) ejection duration, thereby decreasing mechanical LV performance, presumably by selective impairment of endocardial endothelial function. ### Methods And Results Effects of ultrasound were evaluated in the ejecting LV of anesthetized, open-chest dogs under different conditions of LV volume and contractile state and after mild selective alpha 1-adrenergic stimulation. LV pressures, left atrial pressures, and regional segment lengths were measured in anterior and posterior midwall. A cylindrical ultrasound probe (0.9 MHz, 25 W) mounted on a catheter was inserted into the LV cavity through the apex and was activated for 4 minutes in each condition. In protocol A (n = 7), LV volume was altered with caval vein occlusion and intravenous dextran infusion. The ultrasound probe was activated at low (4.1 +/- 0.9 mm Hg), mid (10.6 +/- 1.5 mm Hg), and high (17.9 +/- 1.8 mm Hg) LV end-diastolic pressure (EDP). Effects of ultrasound were less pronounced at higher EDP. For example, the time interval from end-diastole to peak (-)dP/dt decreased by 7.5 +/- 2.3% at low, 4.4 +/- 2.2% at mid, and 1.9 +/- 1.6% at high LVEDP (p < 0.001). In protocol B (n = 7), LV inotropic state was altered by slow intravenous infusion of low-dose calcium. The ultrasound probe was activated before and after calcium. Effects of ultrasound were less pronounced after calcium. Time from end-diastole to peak (-)dP/dt decreased by 8.4 +/- 3.1% at baseline and by 3.5 +/- 2.1% after calcium (p < 0.001). In protocol C (n = 7), activation of the ultrasound probe was performed at baseline and after mild selective alpha 1-adrenergic stimulation (propranolol plus phenylephrine). Effects of ultrasound were similar at baseline and after propranolol but increased after phenylephrine . Time from end-diastole to peak (-)dP/dt decreased by 5.2 +/- 2.4% at baseline, by 5.3 +/- 1.9% after propranolol, and by 8.9 +/- 3.2% after phenylephrine (p < 0.05). ### conclusions Effects of intracavitary ultrasound, which are presumably mediated through modulation of endocardial endothelial function, were more important at low volume, lower calcium, and under mild selective alpha 1-adrenergic stimulation.


paclitaxel

vinorelbine

A phase II study of non-platinum based chemotherapy with paclitaxel and vinorelbine in non-small cell lung cancer. paclitaxel and vinorelbine combination in previous untreated patients with stage IIIb-IV non-small cell lung cancer (NSCLC) as a phase II study. ### Patients And Methods Thirty-four patients ( 4 patients with stage IIIb , 30 patients in stage IV ) , with median age 66 and performance status 0 - 1 , were administered paclitaxel , 175 mg/m(2 ) in a 3-h infusion rate on day 1 and vinorelbine , 25 mg/m(2 ) in a 10-min infusion rate on days 1 , and 8 with G-CSF and EPO support . ### results Among our 33 evaluable patients for toxicity 16 patients (48.4%) presented leukopenia and 15 patients (45.4%) presented anemia despite G-CSF and EPO administration. Two patients (6%) presented Grade III-IV peripheral neuropathy. The overall response rate was 67.7%; 5 patients (16.1%) showed complete response (2 patients stage IIIb) and 16 patients (51.6%) showed partial response (1 patient stage IIIb). The overall median survival time was 10 months (range 3-18 months) and the median disease-free survival was 9 months (range 3-15 months) with an 1-year survival time of 45.1% (14 patients). ### conclusion The results of the combination as 1st line treatment for patients with non-operable NSCLC are promising and should be further investigated.


decitabine

valproic

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia . To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML). ### Patients And Methods Twenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21). ### results The OBD of decitabine was 20 mg/m(2)/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P < or = .05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% (11 of 25). Of 21 assessable patients, 11 (52%) responded: four with morphologic and cytogenetic complete remission (CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA. ### conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m(2)/d for 10 days) alone or with an alternative deacetylating agent are warranted.


clopidogrel

aspirin

clopidogrel

Low risk of rebound events after a short course of clopidogrel in acute TIA or minor stroke. The combination of aspirin and clopidogrel is indicated after acute coronary events and possibly for a short period after TIA or minor ischemic stroke. Early discontinuation of clopidogrel results in a transient rebound increase in risk of recurrence in acute coronary syndromes , but there are no published data on any similar rebound effect in patients with TIA or stroke that might inform the design of clinical trials of aspirin and clopidogrel in the acute phase . ### methods A 30-day course of aspirin and clopidogrel (both 75 mg daily) was given to high-risk patients with TIA or minor ischemic stroke seen acutely in the EXPRESS study clinic from April 1, 2002, to March 31, 2009. clopidogrel was stopped after 30 days and aspirin continued. Recurrent events were ascertained at face-to-face follow-up. ### results A total of 320 patients were prescribed a 30-day course of aspirin and clopidogrel acutely after TIA or minor stroke. There were 5 recurrent ischemic strokes and 7 TIAs during the aspirin and clopidogrel treatment period, but no strokes and 4 TIAs during the 30 days after stopping clopidogrel. A similar temporal trend in stroke risk was seen in the 487 patients prescribed aspirin alone in the acute phase, with 12 and 5 strokes in the equivalent time periods. The upper 95% confidence intervals of the observed 0% risk of stroke during the 30 days after stopping clopidogrel was 1.15% overall. ### conclusion Although larger studies are required, our findings suggest there is unlikely to be a large rebound effect after discontinuation of a 30-day course of clopidogrel in acute TIA and minor ischemic stroke. However, planned trials of aspirin and clopidogrel in the acute phase after TIA or stroke should still follow-up beyond the cessation of clopidogrel treatment.


docetaxel

irinotecan

Docetaxel and irinotecan in recurrent or metastatic head and neck cancer: a phase 2 trial of the Eastern Cooperative Oncology Group. docetaxel and irinotecan have single-agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN. ### methods Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m(2 ) and irinotecan 60 mg/m(2 ) , intravenously , on Days 1 and 8 , every 21 days , until disease progression . The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase-2 and VEGF in baseline tumor tissue. ### results Fifty-two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel-exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression-free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085). ### conclusions docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum-based regimens.


paclitaxel

carboplatin

Gemcitabine and carboplatin in second-line ovarian cancer.  Most patients with advanced ovarian cancer achieve a clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel plus carboplatin . However, a majority of these patients will ultimately recur, and second-line treatment for this group of patients is an important aspect of management of this disease as well as an area of active clinical investigation. Until recently, for patients with platinum-sensitive ovarian cancer (more than 6-month disease-free interval), chemotherapy with single-agent carboplatin was frequently recommended. However, two recent prospective randomized trials have shown that combination chemotherapy produces higher response rates and improvement in progression-free survival compared with treatment with single-agent carboplatin. One trial compared treatment with paclitaxel plus a platinum compound with re-treatment with platinum, and a second trial compared carboplatin plus gemcitabine re-treatment against carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Both trials showed a 3-month improvement in progression-free survival in patients treated with the combination, as well as acceptable toxicity. In the absence of a prospective randomized trial comparing these two regimens in patients with platinum-sensitive recurrent ovarian cancer, the choice of which combination to use may depend on toxicity considerations.


oxaliplatin

docetaxel

Low-dosed docetaxel showed equivalent efficacy but improved tolerability compared with oxaliplatin in the S-1-based first-line chemotherapy regimen for metastatic or recurrent gastric adenocarcinoma. Platinum-fluoropyrimidine combinations are the preferred first-line options for advanced gastric cancer (AGC) in East Asia. On the other hand, docetaxel-containing regimens without platinum have demonstrated promising activity in AGC. However, dose-related toxicity of docetaxel has limited its clinical adoption. This study compared the efficacy and safety of a modified low-dosed docetaxel plus S-1 (mDS) with oxaliplatin plus S-1 (SOX) in Chinese patients with AGC. Patients were assigned to receive either oxaliplatin ( 100 mg/m(2 ) ) in the SOX arm or docetaxel ( 40 mg/m(2 ) ) in the mDS arm on day 1 of every 3-week cycle . S-1 80-120 mg/day was administered orally on days 1-14 in the 3-week cycle in both groups. One hundred and eighty-eight patients (mDS regimen 101; SOX 87) showed similar overall survival (OS; 13.1 vs 12.8 months, P = 0.878), progression-free survival (PFS; 5.8 vs 5.5 months, P = 0.924), and overall response rate (39.7 vs 44.2%, P = 0.569) in the mDS and SOX arms, respectively. mDS was associated with significantly less grade 3/4 toxicities in thrombocytopenia (5.9 vs 16.1%) and gastrointestinal disturbances (1.0 vs 8.0%). Furthermore, in patients who had ever received oxaliplatin-based adjuvant chemotherapy (N = 40), mDS resulted in significantly superior OS (17.8 vs 9.5 months, P = 0.015) and PFS (7.0 vs 4.2 months, P = 0.008) compared with SOX. In conclusion, mDS was as effective as SOX in Chinese patients with AGC, but it resulted in a significantly improved tolerability. In patients who received oxaliplatin-based adjuvant chemotherapy before, mDS was associated with improved efficacy in the first-line setting.


luspatercept

venetoclax

Recent advances in the cellular and molecular understanding of myelodysplastic syndromes: implications for new therapeutic approaches. It has been more than 10 years since any new disease-modifying therapies have received regulatory approval for indications related to myelodysplastic syndromes (MDS). Advances in our collective biological understanding of MDS in the last decade, however, have made it possible to hope that effective therapeutics can be designed to improve MDS-associated cytopenias and patients' quality of life, and perhaps even delay clonal progression and extend survival. Classes of MDS-associated mutations and disordered biological pathways targeted by developmental therapeutics include the following: aberrant messenger RNA splicing, neomorphic enzymes in the citric acid cycle with oncogenic activity, overactivated tyrosine and serine-threonine kinases, epigenetic and chromatin remodeling alterations, abnormal telomere dynamics, and failed protection of DNA integrity. At present, treatments for MDS are usually administered as sequential monotherapy, but there is a trend toward clinical trials of combination therapies-in which new agents are added to a DNA hypomethylating agent backbone-for both upfront treatment and the treatment of relapsed/refractory disease. Agents in clinical trials for subsets of MDS include luspatercept , antibodies targeting CD33 , isocitrate dehydrogenase inhibitors , deacetylase inhibitors , venetoclax , and immunotherapies designed to overcome immune checkpoint inhibition . These biologically based therapeutics, as well as the encouraging precedent of 7 new approvals by the US Food and Drug Administration in 2017 for the treatment of acute leukemia, offer the prospect that 10 more years will not elapse before another new therapy is approved for MDS.


enalapril

captopril

Possible differences between enalapril and captopril . Inhibitors of angiotensin converting enzyme block the conversion of angiotensin I to angiotensin II, the active hormone of the renin-angiotensin system. This inhibition leads to a reduction in angiotensin-mediated vasoconstriction and aldosterone production. Although converting enzyme inhibitors have other potential metabolic effects, their beneficial effects in hypertension and congestive heart failure appear to be, in large part, related to their ability to reduce angiotensin II. This causes an increase in plasma renin levels and a fall in plasma and urine aldosterone, which can be sustained for many years. As a consequence, converting enzyme inhibitors produce mild natriuresis and positive potassium balance. At conventionally used doses, enalapril more completely prevents posture-induced increases in aldosterone than does captopril, probably reflecting more complete inhibition of angiotensin II formation in vivo.


imipenem

imipenem

amphotericin

Effects of antibiotics on the endothelium of fresh and cryopreserved canine saphenous veins. To determine if antibiotic solutions for potential use in antimicrobial treatment of tissues were detrimental to cell viability, canine saphenous veins were exposed to three different antibiotic solutions at 37 degrees C for 12 h. Viability was determined by tissue culture, utilizing a limiting dilution assay. The antibiotic series included two formulations currently used for the preservation of heart valves and a new formulation containing imipenem, a broad spectrum beta-lactam. Currently used antibiotic regimes and imipenem with gentamicin resulted in a decrease of 30 to 50% of the viable endothelial cells within 12 h. Exposure of the saphenous veins to imipenem or imipenem combined with amphotericin B had no adverse effects on the viability of the endothelial cells with 12 h exposure . However, veins exposed to amphotericin B were more susceptible to subsequent damage during freezing and thawing than veins frozen after incubation with either imipenem alone or imipenem combined with flucytosine. These studies indicate that imipenem combined with flucytosine is suitable for use with vein grafts.


rituximab

cyclophosphamide

doxorubicin

vincristine

prednisolone

[Primary testicular non-Hodgkin's lymphoma: clinical analysis of 21 cases]. To explore the clinical characteristics and prognosis of patients with primary testicular non-Hodgkin's lymphoma. ### methods The clinical profiles and prognostic factors of 21 cases newly diagnosed as primary testicular non-Hodgkin's lymphoma at Peking University Cancer Hospital from January 2005 to December 2012 were retrospectively analyzed. ### results Their median age was 59 (34-86) years. And they were classified as Ann Arbor stage I (n = 8), stage II (n = 2) and stage IV (n = 11). There were B symptoms (n = 4), extranodal involvement outside testis (n = 12) and elevated lactate dehydrogenase (LDH) at diagnosis (n = 6). The scores of international prognostic index (IPI) were 0-1 point (n = 10), 3 points (n = 10) and 4 points (n = 1). The regimens included orchidectomy as the initial treatment (n = 15), chemotherapy followed by radiotherapy (n = 7) and CNS prophylaxis during treatment (n = 15). All patients were pathologically diagnosed as diffuse large B-cell lymphoma. And 11 cases belonged to the non-germinal center B cell-like subgroup. First-line chemotherapy was either R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine and prednisolone ) or CHOP-like-based regimen . Complete response was achieved in 85.7% of patients. The median follow-up period was 18 (6-58) months. The 1, 2 and 3-year survival rates were 100%, 80% and 60% respectively. Statistical analysis showed that the first-line chemotherapy with rituximab was a prognostic factor (P = 0.038).Other factors included stage (P = 0.275), LDH level (P = 0.179) , β2-microglobulin level (P = 0.229) and IPI (P = 0.275) . ### conclusions The prognosis of primary testicular non-Hodgkin's lymphoma is usually poor. The first-line chemotherapy with rituximab is a prognostic factor.


rituximab

vincristine

cyclophosphamide

Immunochemotherapy with rituximab, vincristine and 5-day cyclophosphamide for heavily pretreated follicular lymphoma. Therapeutic options for relapsed or refractory follicular lymphoma include combination chemotherapy, immunotherapy and, for selected patients, autotransplant. Because of the different mechanisms of action and non-overlapping toxicities, combination of rituximab with chemotherapy is a rational approach. ### methods 30 patients with follicular non-Hodgkin's lymphoma with advanced-stage disease were treated with four cycles of immunochemotherapy with rituximab 375 mg/m2 on day 1, vincristine 2 mg i.v. on day 2 and cyclophosphamide 400 mg/m2 i.v. from days 2 to 6, repeated at 3-week intervals. All patients had received multiple lines of therapy (median 3); 9 (30%) had relapses (2 after high-dose therapy with autologous transplant), and 21 (70%) were in relapse and refractory to salvage treatment (with an anthracycline-containing regimen in 19). ### results Of 29 patients evaluable for response, 16 (55 %) obtained a complete response (CR) and 3 (10%) a partial response (PR), with an overall response rate of 65% (19/29); 10 patients (35%) achieved less than PR. The median event-free survival was 16.1 months for all patients, being 22.8 months for responders. After a median follow-up of 2 years from the start of therapy (range 6 months to 3.8 years), of 16 patients who achieved CR, 10 remain free of disease. ### conclusion The combination of rituximab with vincristine and 5-day cyclophosphamide is able to produce CR in patients with advanced follicular lymphoma , even in patients resistant to third-generation regimens . The regimen designed on the basis of pharmacokinetics of the chimeric antibody seemed important for the clinical efficacy of the combination.


lamotrigine

carbamazepine

Effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemical epileptogenesis in rats. The present study assessed the effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemically induced epileptogenesis in rats. Epileptogenesis was induced by administration of pentylenetetrazole (30 mg/kg, s.c.) on alternate days (three times/week) for 9-11 weeks or until stage 4 of seizure score was achieved. The neurobehavioural parameters used for cognitive assessment were step-down latency in continuous avoidance apparatus and transfer latency in elevated plus maze test paradigm. carbamazepine and lamotrigine were administered intraperitoneally in doses of 60 mg/kg and 25 mg/kg, respectively, according to the groups, once a day for 11 weeks. Oxidative stress was assessed in isolated homogenized whole brain samples and estimated for the levels of malondialdehyde, reduced glutathione, catalase and superoxide dismutase. The results showed that lamotrigine did not produce any change in cognitive function , while carbamazepine produced cognitive dysfunction . Cognitive decline seen in the carbamazepine-treated pentylenetetrazole-kindled group was also associated with increased oxidative stress. lamotrigine treatment had no effect on oxidative stress parameters alone, while it significantly decreased oxidative stress in the pentylenetetrazole-kindled group as compared to the pentylenetetrazole-kindled carbamazepine-treated group.


decitabine

carboplatin

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma. Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma. ### methods To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction. ### results Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin. ### conclusions Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma .


vinblastine

bleomycin

cis-platinum

[ Rhabdomyosarcoma of the urinary bladder : complete remission induced by vinblastine , cis-platinum , and bleomycin ] . Combination therapy consisting of vincristine, actinomycin-D, and cyclophosphamide with or without adriamycin is the most common chemotherapy for rhabdomyosarcoma in childhood. But the effective chemotherapy for rhabdomyosarcoma resistant to these four drugs has not been established. We report a case with rhabdomyosarcoma, which was resistant to these four drugs but responded completely to three drug combination chemotherapy consisting of vinblastine, cis-platinum, and bleomycin (VPB therapy). A 11-months-old boy was referred to us because of giant abdominal tumor. Postoperative diagnosis was Group III embryonal rhabdomyosarcoma of the urinary bladder. Partial resection was followed by vincristine, actinomycin-D, cyclophosphamide, and adriamycin, but his residual tumor was growing. Then VPB therapy was administered and the first course of the chemotherapy reduced the size of tumor. After three courses of VPB therapy the second-look operation was performed. At operation no residual tumor was found and a complete remission was confirmed. During the course of VPB therapy no severe adverse effect was detectable.


atenolol

metoprolol

acebutolol

oxprenolol

nadolol

timolol

propranolol

Use of beta-adrenoceptor blocking drugs in hyperthyroidism. There is an increasing use and variety of beta-adrenoceptor blocking agents (beta-blockers) available for the treatment of hyperthyroidism. Recent comparative studies suggest that atenolol ( 200 mg daily ) , metoprolol ( 200 mg daily ) ; acebutolol ( 400 mg daily ) , oxprenolol ( 160 mg daily ) , nadolol ( 80 mg daily ) and timolol ( 20 mg daily ) produce a beneficial clinical response equal to that seen with propranolol ( 160 mg daily ) . Most beta-blockers reduce resting heart rate by approximately 25 to 30 beats/min, although a lesser reduction is seen with those possessing intrinsic sympathomimetic activity such as oxprenolol and pindolol. While earlier studies employing large doses of intravenous propranolol concluded that beta-blockade reduced myocardial contractility, more recent non-invasive studies suggest that the predominant cardiac effect is on heart rate. In patients with cardiac failure, beta-blockers may, however, produce a profound fall in cardiac output. Nevertheless, in combination with digoxin they may be useful in controlling the atrial fibrillation of thyrocardiac disease. beta-Blockers improve nervousness and tremor (although to a lesser extent with cardioselective agents) and severe myopathy, and they also reduce the frequency of paralysis in patients with thyrotoxic periodic paralysis. There is often subjective improvement in sweating but usually no major effect on eye signs. Recent studies show a 10% reduction in oxygen consumption/basal metabolic rate with long term oral use of selective or nonselective beta-blockers. In addition, many agents (propranolol, metoprolol, nadolol and sotalol but not acebutolol, atenolol or oxprenolol) reduce circulating tri-iodothyronine (T3) concentration by between 10 and 40%, although the clinical significance of this effect (if any) is not established. beta-Blockers may also have endocrinological effects on gastrin, cyclic AMP, catecholamines and other hormone levels. Given in adequate dosage, propranolol has been shown to control thyrotoxic hypercalcaemia. Minor side effects (nausea, headaches, tiredness, etc.) are quite common but overall beta-blockers are well tolerated by the thyrotoxic patient. The major use of these drugs is in symptomatic control while awaiting definitive diagnosis or treatment. As an adjunct to antithyroid drugs or radioactive iodine, beta-blockers will produce a satisfactory clinical response in the weeks to months before these forms of therapy produce a euthyroid state. beta-Blockers are more convenient than antithyroid drugs in the control of patients receiving therapeutic radioiodine, in that continuous therapy and assessment of biochemical response is possible.(ABSTRACT TRUNCATED AT 400 WORDS)


raloxifene

nimesulide

Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor. The chemopreventive efficacies of raloxifene and nimesulide, an anti-estrogen but with anti-androgen action and a cyclooxygenase-2 (COX-2) selective inhibitor, respectively, were evaluated in probasin/SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 p.p.m. in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 p.p.m.), and raloxifene (10 mg/kg/day) plus nimesulide (400 p.p.m.). Animals were killed at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure the testosterone levels. All the animals in the placebo group had tumors in each lobe compared with only 43 % each in the dorsolateral ( DLP ) and anterior prostate ( AP ) of the animals treated with raloxifene ( 10 mg/kg/day ) plus nimesulide . The total prostate weights and adenocarcinoma portions were significantly reduced in the three raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between the nimesulide alone and placebo groups or between the raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide group, suggesting a lack of cancer preventive effects of the COX-2 inhibitor in this animal model. PCNA positive rates in ventral prostate (VP) and DLP, and androgen receptor (AR) levels in VP were significantly reduced in the three raloxifene-treated groups. Furthermore, circulating testosterone was decreased after raloxifene (10 mg/kg/day) plus nimesulide treatment. These results demonstrate that raloxifene, but not nimesulide, inhibits prostate carcinogenesis in SV40 Tag TG rats associated with a decline in circulating testosterone levels and a loss of AR expression, as well as an inhibition of cell proliferation.


dolutegravir

tenofovir

Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient . A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay®) and tenofovir disaproxil fumarate/emtricitabine (Truvada®) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments.


Abiraterone

prednisone

Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer : a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes . The aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes. ### methods This was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- ### results Overall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) ⩾ 10 ng/ml ( ### conclusions Median PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series.


Nivolumab

ipilimumab

Increased serum CCL26 level is a potential biomarker for the effectiveness of anti-PD1 antibodies in patients with advanced melanoma.  Nivolumab plus ipilimumab combined therapy is among the most effective therapies for advanced melanoma . However, this therapy is also associated with a high frequency of immune-related adverse events (irAEs). To avoid such severe irAEs caused by additional administration of anti-CTLA4 antibodies, biomarkers to distinguish responders from non-responders among patients treated with anti-PD1 antibodies are important. The purpose of this study is to evaluate the increased serum levels of CCL11, CCL24, and CCL26 as a predictive biomarker for the efficacy of anti-PD1 antibodies in advanced cutaneous melanoma patients. This study analyzed increased serum levels of CCL11, CCL24, and CCL26 in 46 cases of advanced cutaneous melanoma treated with anti-PD1 antibodies. Serum levels on day 42 were compared to baseline (day 0) and analyzed statistically. Receiver operating characteristic curves were established to evaluate the correlation between serum levels of CCL11, CCL24, and CCL26 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 correlated significantly with the efficacy of anti-PD1 antibodies. In contrast, no significant correlations were seen between increased serum levels of CCL11 and CCL24 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 may be a useful biomarker for identifying those patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.


rapamycin

topotecan

topotecan

Rapamycin-topotecan combination exhibited enhanced antitumor efficacy compared to topotecan used alone in cisplatin-resistant ovarian cancer cells. The present study aimed to investigate the antitumor efficacy of combination of topotecan with rapamycin, a mTOR inhibitor, in cisplatin-resistant ovarian cancer cells A2780cis and COC1/DDP. Expressions of mTOR and its target molecules p70S6K and 4E-BP1 were determined in A2780cis and COC1/DDP and the parental cells A2780 and COC1 that are sensitive to cisplatin using Western blotting. Cell proliferation was examined using MTT assay in vitro and a nude mouse model in vivo, respectively. Cell apoptosis and the relevant proteins were determined by flow cytometry and Western blotting. We found that the levels of phosphorylated mTOR, p70S6K, and 4E-BP1 were obviously higher in A2780cis and COC1/DDP cells than that in A2780 and COC1 cells. Pretreatment with rapamycin significantly enhanced the effects of topotecan in suppressing cell proliferation and soliciting cell apoptosis in A2780cis and COC1/DDP cells. Cells that were sequentially exposed to rapamycin and topotecan had significantly higher levels of cleaved caspase-8 , -3 , and PARP compared to those treated with topotecan alone . Mice co-administered rapamycin and topotecan had significantly decreased terminal tumor burden without additional loss of bodyweight compared to the mice received topotecan alone. The results suggested that rapamycin sensitized A2780cis and COC1/DDP cells to topotecan-induced apoptosis and rapamycin-topotecan combination might have a value in treatment of cisplatin-resistant ovarian cancer.


doxorubicin

methotrexate

cisplatin

4-Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a promising new candidate for chemotherapeutic treatment of osteosarcoma patients. The effectiveness of the alkycycline 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548, ladirubicin), a new drug with high antitumour activity against a broad range of neoplasms, was evaluated by using a panel of 32 human osteosarcoma cell lines, including cell lines resistant to doxorubicin, methotrexate, or cisplatin. PNU-159548 resulted to be highly active in all cell lines. No cross-resistance was found with conventional drugs , being PNU-159548 active also in cells resistant to doxorubicin and with a multidrug resistance phenotype ( associated with MDR1 gene/P-glycoprotein overexpression ) , as well as in cells resistant to methotrexate or to cisplatin . Analysis of drug-drug interactions showed that PNU-159548 could be successfully used in combination with all the most important drugs currently used in OS chemotherapy. In fact, the simultaneous administration of PNU-159548 and doxorubicin, methotrexate, or cisplatin produced mostly additive or synergistic effects. Sequential exposure to PNU-159548 followed immediately by doxorubicin, methotrexate, or cisplatin was the most effective sequence of administration, invariably resulting in additive or synergistic effects in both drug-sensitive and drug-resistant osteosarcoma cell lines. In conclusion, the high in vitro effectiveness, the absence of cross-resistance with doxorubicin, methotrexate, or cisplatin and the possibility to be successfully used in combination with these drugs indicate PNU-159548 as a promising candidate to be considered for planning new therapeutic regimens for osteosarcoma patients, who show a decreased response to conventional chemotherapy.


human tumor necrosis factor

Etoposide

Doxorubicin

Synergistic cytotoxic effects of recombinant human tumor necrosis factor and Etoposide ( VP16 ) or Doxorubicin on A2774 human epithelial ovarian cancer cell line . Recombinant human tumor necrosis factor (rHuTNF) is a cytokine, with some antitumor activity, released by stimulated monocytes-macrophages. In vivo and in vitro cytotoxicity studies testing the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents have been carried out. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone or in combination with etoposide (VP16) or doxorubicin (Doxo), some topoisomerase II (Topo II) targeted drugs, or in combination with cisplatin (CDDP), a not Topo II interactive drug. Our results suggest that rHuTNF is directly cytotoxic and that it is also able to induce a potentiation of VP16- or Doxo-cytotoxicity, but it is unable to potentiate CDDP-cytotoxicity. These data represent a reasonable basis for combining rHuTNF with Topo II inhibitors within phase I studies. The combination regimen could be tested in ovarian cancer patients.


gentamicin

nalidixic

ciprofloxacin

Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia. The purpose of this study was to investigate extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilities, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC)-typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin ( p ＜ 0.0001 ) and the quinolones nalidixic acid ( p＝0.004 ) and ciprofloxacin ( p ＜ 0.0001 ) than non-producers . In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL-producing E. coli ST617 appear to have spread to Indonesia.


topotecan

amlodipine

Effect of stealthy liposomal topotecan plus amlodipine on the multidrug-resistant leukaemia cells in vitro and xenograft in mice. Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy as the over-expressed MDR protein acts as an efflux pump, which leads to a reduction in the uptake of the anticancer agent by tumour cells. We combined topotecan and amlodipine together into the stealthy liposomes, in which amlodipine was applied as a MDR reversing agent to overcome the resistance. ### Materials And Methods Cytotoxicity, apoptosis and the signalling pathway assays were performed on human chronic myelogenous leukaemia K562, promyelocytic leukaemia HL-60 and MDR HL-60 cells, respectively. Pharmacokinetics and antitumour activity studies were performed on normal Kunming mice and female BALB/c nude mice with MDR HL-60 xenografts, respectively. ### results topotecan alone was effective in inhibiting the growth of non-resistant leukaemia cells, K562 and HL-60 cells but not the growth of MDR HL-60 cells. The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine . Moreover, amlodipine enhanced the apoptosis-inducing effect of topotecan synergistically. Apoptosis was through activating caspases in a cascade: first, the initiator caspase 8 and then effectors caspase 3/7 (total activity of caspases 3 and 7) were activated. Being encapsulated into the stealthy liposomes with an acidic internal medium, topotecan existed dominantly in an active lactone species, which was reversibly changed from an inactive carboxylate form via a pH-dependent reaction. After administration of stealthy liposomes to mice, the blood exposure of the lactone form was evidently increased and extended. The antitumour effects in the MDR HL-60 xenografted tumour were stealthy liposomal topotecan (SLT) plus amlodipine > SLT > un-encapsulated topotecan > blank control. ### conclusions The enhanced antitumour activity in the MDR HL-60 cells by the SLT plus amlodipine could be owing to multiple reasons: (a) synergistic apoptosis inducing effect, (b) reversing MDR by amlodipine and (c) increasing the availability of active lactone of topotecan by the stealthy liposomes. The apoptosis induced by amlodipine is through caspase 8 and then the 3/7 signalling pathway.


loratadine

terfenadine

promethazine

diphenhydramine

Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea-pigs. Sedation limits the clinical utility of classical H1 antihistamines, while newer antihistamines such as loratadine and terfenadine are non-sedating. However, clinical use of the terfenadine has been associated with rare but severe cardiac arrhythmias, in particular torsades de pointes. ### objective To establish a quantitative experimental model for assessing the sedating and cardiotoxicity potential of non-sedating and sedating antihistamines. ### methods Drugs were administered intravenously and the integrated amplitude of the cortical electroencephalogram (EEG) signal was recorded. The threshold dose that depressed EEG activity was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by 10 micrograms/kg i.v., of histamine. In separate studies , the electrocardiogram ( ECG ) and cardiovascular effects of loratadine ( 30 and 100 mg/kg , i.v . ) , terfenadine ( 10 mg/kg , i.v . ) , promethazine ( 5 mg/kg , i.v . ) and diphenhydramine ( 20 mg/kg , i.v . ) were evaluated . ### results The sedating antihistamines, diphenhydramine and promethazine, depressed the integrated EEG at doses between 0.6 and 2.0 times their peripheral antihistamine doses. loratadine had no EEG depressant activity at 100 mg/kg, i.v., a dose more than 170 times its ED50 (0.58 mg/kg, i.v.) against histamine bronchospasm. We were unable to evaluate the EEG effects of terfenadine, because it produced cardiovascular collapse at 10 mg/kg, i.v. loratadine and promethazine did not produce adverse cardiovascular effects, nor did they alter normal ECG activity. diphenhydramine produced bradycardia followed by a transient hypertensive phase without affecting the QTc interval. In contrast, terfenadine elicited hypotension, bradycardia and significant arrhythmogenic activity, causing a prolongation of the QTc interval and a torsades de pointes--like ventricular arrhythmia. Pharmacokinetic studies after i.v. administration of loratadine (30 and 100 mg/kg) demonstrated plasma levels of loratadine and its major metabolite descarboethoxyloratadine to be several orders of magnitude greater than levels found in humans at the clinical dose of 10 mg. ### conclusion The CNS depressant effects of H1 antihistamines are promethazine approximately diphenhydramine >> loratadine = placebo. Of the non-sedating antihistamines, loratadine was devoid of adverse cardiovascular effects whereas terfenadine caused a pronounced disruption of the normal ECG, characterized by a torsades de pointes-like effect.


epirubicin

paclitaxel

[ Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer -- comparative study of treatment with 2 and 4 cycles ] . Neoadjuvant chemotherapy of epirubicin plus paclitaxel was administered to 75 patients (including a 2-cycle group of 39 patients and a 4-cycle group of 36 patients) with locally advanced breast cancer (35 cases of stage IIb, 28 of stage IIIa, 12 of stage IIIb) to compare efficacy and toxicity of 2 cycle and 4 cycle regimens. All patients were female. They were treated with epirubicin 60 mg/m2, on day 1, by i.v., followed by paclitaxel 150 mg/m2, by 3 hour continuous infusion on day 2 repeated every 3 weeks. Premedication with dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteritic and allergic reactions before chemotherapy. Thirty-nine patients were given 2 cycles and thirty-six were given 4 cycles of this regimen. One of 39 patients had complete response, 28 had partial response and 10 had no change in the 2-cycle group. In addition, 21 of 36 patients had complete response (including 9 who had pathologic complete response), 13 had partial response and 2 had no change. The response rates were 74% (29/39) in the 2-cycle group and 94% (34/36) in the 4-cycle group. There were no progressive disease in these 2 groups. However a higher proportion of PR was observed in stage II patients than in stage III patients. Twelve of 36 patients underwent breast conserving surgery, as tumor size had become smaller and down-staging was realized after neoadjuvant chemotherapy. In addition, axillary lymph nodes were palpable in all 75 patients before neoadjuvant chemotherapy with the ET regimen. But 46% (18/39) in the 2-cycle group and 75% (27/36) in the 4-cycle group became impalpable. Conversely, major toxicities (including leukopenia and gastroenteric reactions) were similar in both groups, but myalgia, arthralgia, neurotoxicity and alopecia were more severe in the 4-cycle group than in the 2-cycle group. In the present study, neoadjuvant chemotherapy with a 4-cycle ET regimen was more effective than with a 2-cycle regimen in down staging locally advanced breast cancer. Although major toxicities were more severe in the 4-cycle group than in the 2-cycle group, the regimen was tolerable and safe.


pemetrexed

carboplatin

A phase I study of pemetrexed, carboplatin, and concurrent radiotherapy in patients with locally advanced or metastatic non-small cell lung or esophageal cancer. The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. ### Experimental Design Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m(2)); regimen 2 was pemetrexed (500 mg/m(2)) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). ### results Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m(2)). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m(2); AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached , further dose escalation was discontinued , and a phase II dose-range was established ( pemetrexed 500 mg/m(2 ) and carboplatin AUC = 5 - 6 ) . ### conclusions The combination of pemetrexed (500 mg/m(2)) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.