docetaxel

paclitaxel

docetaxel

paclitaxel

Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study. To describe characteristics associated with neurotoxicity (NT) in advanced ovarian cancer patients treated on Gynecologic Oncology Group 218 and examine effect of substituting docetaxel for paclitaxel in these patients. ### methods The development of NT was defined as Common Toxicity Criteria grade (G)≥1. The association between substitution with docetaxel and NT improvement was explored with generalized estimating equations adjusting for treatment cycle and NT grading at previous cycle. ### results Of 1864 evaluable patients, 1329 (71%) developed G≥1 NT during the study. Nearly half appeared within the first two cycles of chemotherapy, with 31% experiencing G≥2. Older patients or those with worse quality of life (QoL) scores at baseline (p<0.05) were more likely to experience NT. One-hundred-six patients received docetaxel as substitute for paclitaxel. Of them , 47 patients started with docetaxel at cycle one due to reaction to paclitaxel ( n=32 ) , fear of NT ( n=4 ) , and other reasons ( n=11 ) , whereas 59 patients switched to docetaxel during cycle 2 - 6 due to NT ( n=32 ) , reaction to paclitaxel ( n=19 ) , and other reasons ( n=8 ) . Although the protocol instructed otherwise, the majority continued paclitaxel despite G≥2 NT symptoms. There was no evidence that substitution with docetaxel improved NT (Odds Ratio: 1.57; 95% CI 0.98-2.54; p>0.05). Of 59 patients who switched to docetaxel, only seven (12%) discontinued taxane prior to chemotherapy completion. A roughly equal chance of worsening NT was reported on paclitaxel (6%) as on docetaxel (5%). ### conclusions Age and worse QoL at baseline are associated with NT. Substitution of docetaxel did not improve NT symptoms.


prednisolone

cyclophosphamide

Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption , prednisolone and cyclophosphamide . Ten patients with rapidly progressive glomerulonephritis and acute renal failure were treated with extracorporeal immunoadsorption, prednisolone, and cyclophosphamide. Three patients had systemic lupus erythematosus, five had microscopic polyarteritis and two had Wegener's granulomatosis. All ten patients were dialysis-dependent prior to immunoadsorption. Nine of ten patients rapidly regained renal function and seven continue to have independent renal function between 9 and 30 months after immunoadsorption. Three patients at presentation were not dialysis dependent. Despite treatment with methylprednisolone, cyclophosphamide, and oral prednisolone, renal function continued to deteriorate and they required dialysis. Immunoadsorption was then started without alteration in baseline immunosuppression. Within a mean of 4.6 days, range 3-7 days, renal function improved and the patients no longer required dialysis. Antineutrophil cytoplasmic antibodies and double-stranded DNA antibodies were rapidly removed by immunoadsorption. Only one patient with systemic lupus erythematosus and two with microscopic polyarteritis had significant resynthesis of antibody at 1 month post-immunoadsorption. Renal biopsy before and after immunoadsorption and immunosuppressive therapy showed resolution of glomerular crescents and no evidence of active disease. Immunoadsorption coupled with prednisolone and cyclophosphamide may be of value in the treatment of rapidly progressive glomerulonephritis.


Doxifluridine

medroxyprogesterone

cyclophosphamide

[ Doxifluridine , medroxyprogesterone acetate and cyclophosphamide ( DMpC ) combination therapy is effective against recurrent triple negative breast cancer -- a case report ] . We report a postmenopausal recurrent breast cancer patient with triple negative disease who presented with right recurrent nerve palsy. Nine years previously, she had undergone a mastectomy. FDG-PET scan revealed neck lymph node metastases from the breast cancer. The recurrent nerve palsy was thus considered to have been caused by the lymph node metastases. The patient was orally administered DMpC (doxifluridine, medroxyprogesterone acetate and cyclophosphamide) combination therapy. This resulted in a remarkable response after five months, with the recurrent nerve palsy completely disappearing at six months. No side effects from the treatment were observed. The patient was well and the treatment was being continued without relapse at nine months. Oral anti-cancer treatments such as DMpC appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients with triple negative disease.


valganciclovir

ganciclovir

Pharmacokinetics of ganciclovir and valganciclovir in the adult horse. Equine herpes myeloencephalopathy, resulting from equine herpes virus type 1 (EHV-1) infection, is associated with substantial morbidity and mortality in the horse. As compared to other antiviral drugs, such as acyclovir, ganciclovir has enhanced potency against EHV-1. This study investigated the pharmacokinetics of ganciclovir and its oral prodrug, valganciclovir, in six adult horses in a randomized cross-over design. ganciclovir sodium was administered intravenously as a slow bolus at a dose of 2.5 mg/kg, and valganciclovir was administered orally at a dose of 1800 mg per horse. Intravenously administered ganciclovir disposition was best described by a three-compartment model with a prolonged terminal half-life of 72 ± 9 h. Following the oral administration of valganciclovir, the mean observed maximum serum ganciclovir concentration was 0.58 ± 0.37 μg/mL, and bioavailability of ganciclovir from oral valganciclovir was 41 ± 20%. Superposition predicted that oral dosing of 1800-mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir . However, superposition suggested that i.v. administration of ganciclovir at 2.5 mg/kg every 8 h for 24 h followed by maintenance dosing of 2.5 mg/kg every 12 h would maintain effective ganciclovir serum concentrations in most horses throughout the dosing interval.


paclitaxel

cyclophosphamide

cisplatin

Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Recent work has suggested a role for nuclear factor kappaB (NF-kappaB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-kappaB in ovarian cancer is unknown. The authors hypothesized that the NF-kappaB pathway is over activated in aggressive ovarian cancers. ### methods The levels of 3 NF-kappaB transcription factors , the activating inhibitors of NF-kappaB ( IkappaB ) kinases , and the NF-kappaB target matrix metalloproteinase 9 ( MMP9 ) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel , cisplatin , and cyclophosphamide . Associations were made between NF-kappaB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. ### results The presence of NF-kappaB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IkappaB kinase alpha, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-kappaB machinery suggested activity of NF-kappaB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. ### conclusions The deregulation of NF-kappaB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-kappaB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity.


clonidine

yohimbine

naloxone

The role of brain norepinephrine in clonidine suppression of isolation-induced distress in the domestic chick. Distress vocalizations (DV) induced by social isolation were measured in 1-day-old domestic chicks after intracerebroventricular injections of drugs believed to exert their effects through the noradrenergic system. The alpha-adrenoreceptor agonist clonidine reliably suppressed DV rates at doses low as 0.08 micrograms. When given alone, phentolamine, phenoxybenzamine, propranolol, sotalol, and yohimbine (adrenoreceptor antagonists) did not reliably alter DV rates at doses that were not toxic. The clonidine DV suppression was reliably reversed by yohimbine ( 1.75 micrograms ) , but by none of the other adrenoceptor antagonists or naloxone . 6-Hydroxydopamine at doses as high as 120 micrograms, which essentially eliminated forebrain norepinephrine, failed to suppress DV rates reliably when given alone and, when given in combination with clonidine (0.1 micrograms) or morphine (0.05 micrograms), failed to reverse the severe DV suppression imposed by these drugs. The results suggest that clonidine suppresses DV rates in or by some means other than prejunctional alpha 2-adrenoreceptor stimulation.


sunitinib

sorafenib

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy. To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. ### Patients And Methods We identified 118 patients with mRCC initiating first-line VEGF-targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed. ### results There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status ; the mean shrinkage was -17 % vs -25 % for sunitinib-treated patients with high vs low tumour CAIX expression , compared to -13 % vs + 9 % for sorafenib-treated patients ( P interaction , 0.05 ) . A higher tumour clear-cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02). ### conclusions Although CAIX expression had no prognostic value in patients with clear-cell mRCC treated with VEGF-targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear-cell component in their tumours are likely to have a superior clinical benefit from VEGF-targeted therapy.


Seribantumab

Erlotinib

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer . seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 ( ### Materials And Methods Patients with ### results One hundred twenty-nine patients received seribantumab + erlotinib ( ### conclusion The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). ### Implications For Practice The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.


Trabectedin

doxorubicin

Real-life experience using trabectedin plus pegylated liposomal doxorubicin combination to treat patients with relapsed ovarian cancer. The goal of recurrent ovarian cancer (ROC) treatment is no longer just palliation, but prolonging survival. This is usually through administering a new line of chemotherapy at each relapse. A novel treatment sequencing strategy to achieve this is through the intercalation of an effective non-platinum alternative, in between platinum-based therapies. Trabectedin in combination with pegylated liposomal doxorubicin ( PLD ) has been fully available privately in the UK since 2009 for treating patients with ROC . A single institution's experience with the trabectedin + PLD combination, as a non-platinum/non-taxane alternative, to intercalate between platinum-based therapies is reported here. To date 6 patients have been successfully treated with trabectedin + PLD at Broomfield Hospital, Chelmsford, Essex. Here we describe a new, practice-changing treatment approach in a real-life case study of a heavily-treated patient with advanced ROC treated with trabectedin + PLD at fourth-line and then subsequently rechallenged at seventh-line; with treatment continuing until disease progression.


lumefantrine

chloroquine

chloroquine

Update on the in vivo tolerance and in vitro reduced susceptibility to the antimalarial lumefantrine. Coartem(®), the combination of artemether (an artemisinin derivative) and lumefantrine, has been adopted as the first-line treatment for uncomplicated malaria in many countries. The emergence of resistance to artemisinin derivatives has now been proven in South-East Asia, and there is concern that this may spread to other endemic areas. Strategies to contain and control the spread of artemisinin resistance have been proposed. On the other hand, not much attention has been given to lumefantrine. Indeed, for more than 7 years, reports have been emerging that the use of Coartem(®) is associated with rapid selection of lumefantrine-tolerant parasites. These parasites can survive in the presence of sub-therapeutic lumefantrine concentrations, and, interestingly, this in vivo phenotype is translated in vitro into reduced susceptibility to lumefantrine. As a result, such parasites could form the setting in which lumefantrine resistance would emerge. Thus, identifying genetic markers that reflect this phenotype (both in vitro and in vivo) could yield information on the mechanisms of lumefantrine resistance. More interestingly , lumefantrine tolerance is associated with an increase in chloroquine susceptibility , raising the possibility of re-introducing chloroquine . In this work, we have reviewed the current knowledge, and we present existing challenges and gaps with regard to the mechanisms of in vivo tolerance and in vitro reduced susceptibility to lumefantrine. The re-introduction of chloroquine in areas of high lumefantrine resistance is also discussed.


Estramustine

vinblastine

Vinblastine and estramustine phosphate in metastatic renal cell carcinoma: a phase II trial of the Fox Chase Network. It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine . The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine. ### methods Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy. ### results Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks. ### conclusions Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC.


gemcitabine

carboplatin

RTOG 0017: a phase I trial of concurrent gemcitabine/carboplatin or gemcitabine/paclitaxel and radiation therapy ("ping-pong trial") followed by adjuvant chemotherapy for patients with favorable prognosis inoperable stage IIIA/B non-small cell lung cancer. The optimal dose of gemcitabine that can be used with concurrent radiation therapy for locally advanced non-small cell lung cancer has not been well defined. This trial addresses this question in an alternating sequence "ping-pong" design trial to find the maximum tolerated dose (MTD) for gemcitabine/carboplatin (Sequence A) or gemcitabine/paclitaxel (Sequence B) and thoracic radiation therapy followed by adjuvant gemcitabine/carboplatin chemotherapy. ### Patients And Methods Thirty-five patients with histologically confirmed Stage IIIA/B non-small cell lung cancer were entered into two separate sequences, each with multiple cohorts. A dose level was considered acceptable if, of the first six eligible patients on each cohort, fewer than three experienced dose limiting toxicities. ### results Sequence B of this 2 sequence "ping-pong" trial closed early due to toxicity in cohort 2 (gemcitabine 300 mg/m/wk and paclitaxel 30 mg/m/wk). On Sequence A, the MTD was the cohort 5 dose: gemcitabine 450 mg/m/wk and carboplatin 2 area under curve (AUC) concurrently with thoracic radiation. Cohort 7 ( gemcitabine 600 mg/m/wk and carboplatin 2 AUC ) showed 4 dose limiting toxicities : 2 grade 3 esophagitis ; one grade 3 febrile neutropenia ; and one grade 4 neutropenia . ### conclusion Concurrent gemcitabine/paclitaxel chemoradiation regimen followed by adjuvant gemcitabine/carboplatin produced excessive toxicity at the lowest tested dose combination and was not suitable for further study in this trial. Meanwhile, the MTD of concurrent gemcitabine/carboplatin chemoradiation was determined to be gemcitabine 450 mg/m and carboplatin AUC-2. This combination was found to be tolerable. Although not a primary end point, survival results are summarized as well.


bevacizumab

sunitinib

IFN-α

Immunotherapy for metastatic renal cell carcinoma. Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. ### objectives To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. ### Search Methods We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. ### Selection Criteria We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. ### Data Collection And Analysis We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. ### Main Results We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with IFN-α plus bevacizumab or standard targeted therapy ( sunitinib ) may lead to similar one-year overall mortality ( RR 0.37 , 95 % CI 0.13 to 1.08 ; 1 study ; 83 participants ; low-quality evidence ) and AEs of grade 3 or greater ( RR 1.18 , 95 % CI 0.85 to 1.62 ; 1 study ; 82 participants ; low-quality evidence ) . QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). ### Authors Conclusions Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.


selumetinib

trametinib

Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P = 0.130), and improved response rates (32% vs 14%, P = 0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. ### methods A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. ### results In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro , ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib . In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib. ### conclusions ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity. ### Clinical Trial Registration DOC-MEK (EudraCT no: 2009-018153-23).


sorafenib

sunitinib

Sorafenib, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma. Induction of regulatory T cells (Treg) is an important mechanism leading to tolerance against tumors. Increased levels of Treg have been described in renal cell carcinoma (RCC) patients and seem to correlate with an adverse outcome. Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC ( mRCC ) . Treg were analyzed by flow cytometry in the peripheral blood (PB) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). Blood samples were taken before treatment and during the first, second, and third months of therapy. Flow cytometric analysis of PB mononuclear cells was performed using fluorochrome-labeled antibodies against CD3, CD4, CD25, and FOXp3. During the first month of therapy, patients treated with sorafenib showed a significant increase in FOXp3CD3CD4CD25 Treg (13.5 vs. 36.3% of gated cells, P=0.02, or 0.35 vs. 0.49% of total cells) and the ratio FOXp3 T cells/FOXp3 T cells (0.16 vs. 0.56 of gated cells, P=0.02). These elevated levels persisted throughout the treatment period. There was no influence of sunitinib on the frequency of Treg in our cohort of patients. sorafenib, but not sunitinib, leads to an early and sustained increase in Treg in PB of mRCC patients. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. Our study suggests that sorafenib should be avoided in such a therapeutic setting.


Naloxone

atropine

Rhythmic oscillating complex: characterization, induction, and relationship to MMC in chickens. Migrating myoelectrical complexes (MMCs) and rhythmic oscillating complexes (ROCs) have been investigated in chickens prepared for electromyography. Animals were chronically implanted with electrodes in stomach, duodenum, jejunum, ileum, ceca, and rectum. MMCs showing phases I-III were found in the jejunum and ileum both in fed and fasted states. Repetitive spike bursts were recorded in the duodenum (0.5-1/h), disrupting the gastroduodenal coordination and preceding a phase III in the jejunum. ROCs appeared spontaneously in fasted animals and in 75% of the recordings during the dark period. Four consecutive intestinal myoelectrical patterns have been described during a ROC. Briefly, they consisted in series of high-speed propagated abroad contractions of great amplitude that progressively changed into others of orad direction. In relation to the MMC, the ROC pattern appeared just after a phase III reached the distal ileum, and a pattern of duodenal repetitive spike bursts, followed by a migrating phase III in the jejunum, started at the duodenum after a ROC. No myoelectrical changes were recorded in cecorectal activity during ROC. Vagotomized animals showed the ROC pattern. Neither apomorphine (5-100 micrograms/kg iv) nor cholecystokinin (10(-9) mol/kg iv) induced ROCs. Naloxone ( 5 x 10(-7 ) mol/kg iv ) and atropine ( 0.1 mg/kg iv ) induced isolated orad contractions . Myoelectrical and functional similarities can be found between retrograde giant contractions, described in mammals, and ROCs. However, they differ in their origin and mechanism of induction.


abiraterone

enzalutamide

Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial. abiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL). ### objective To assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide. ### Design Setting And Participants We randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357). ### intervention Patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment. ### Outcome Measurements And Statistical Analysis To compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test. ### Results And Limitations In the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model ( p=0.003 ) , with no difference in the < 75-yr model ( p>0.9 ) . A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating. ### conclusions Patient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup. ### Patient Summary In this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.


verapamil

doxorubicin

Doxorubicin in combination with verapamil in advanced colorectal cancer. A phase II trial.  The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy . The treatment started with oral verapamil, which was escalated up to the individual maximum tolerable dose (defined by prolongation of P-Q in ECG, fall in blood pressure, or dizziness). The median maximum tolerable dose was 600 mg (range 320-1,440 mg). During continued verapamil administration the patients then got weekly infusions of doxorubicin, 25 mg/m2. The median number of doxorubicin courses was 8 (range 2-22). Among 21 patients evaluable for response and toxicity two partial remissions occurred but no complete remission. The study did not indicate enhanced cardiac, hematological or non-hematological toxicity from the combined treatment.


vinorelbine

paclitaxel

Phase II study of paclitaxel combined with vinorelbine in patients with advanced breast cancer. paclitaxel and vinorelbine are two drugs active against breast cancer. A phase II study was initiated with the aim of assessing the efficacy and feasibility of the combination. Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine ( 20 mg/m2 on D1 , D15 ) , followed by paclitaxel ( 175 mg/m2 on D1 ) , every 3 weeks . A 48% (95% CI: 35-61) response rate was obtained in the 23 patients evaluable for response. vinorelbine was administered on D15, as scheduled, in 72% of cycles. The main toxicity observed was grade III to IV neutropenia in 73% of patients. Febrile neutropenia was reported in three patients. Disease-free survival was 118 days, and overall median survival was 361 days. This combination of paclitaxel and vinorelbine is feasible and effective in patients with early relapse or previously treated with first-line chemotherapy for metastatic disease.


docetaxel

pemetrexed

Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer. In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. ### background Although monotherapy with cytotoxic agents , including docetaxel and pemetrexed , is recommended for patients with previously treated advanced non-small cell lung cancer ( NSCLC ) , its outcomes are unsatisfactory . S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. ### methods Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m ### results Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. ### conclusion This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.


verapamil

nifedipine

diltiazem

Combination therapy with diltiazem and propranolol: precipitation of congestive heart failure.  Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine , it has not previously been reported for combination therapy that includes diltiazem . The following case documents the occurrence of clinical congestive failure in a patient with baseline left ventricular dysfunction and severe angina pectoris. Although the patients had tolerated propranolol therapy for years without difficulty, and high-dose diltiazem monotherapy with an excellent clinical response, the combination of diltiazem and propranolol resulted in the development of congestive heart failure. Thus, although generally well tolerated, given the suitable scenario of reduced left ventricular function, the combination of diltiazem and a beta blocker may adversely affect left ventricular performance.


digoxin

verapamil

diltiazem

Relationships between heart rate , exercise tolerance and cardiac output in atrial fibrillation : the effects of treatment with digoxin , verapamil and diltiazem . Six patients with chronic atrial fibrillation (AF) took single doses of digoxin, verapamil and diltiazem, alone and in combination. Three hours after dosing, resting and post-exercise heart rate, exercise tolerance and resting and post-exercise cardiac output were measured. Post-exercise heart rates ranged from 167 bpm (after placebo) to 122 bpm (after digoxin plus diltiazem) (P less than 0.05). However, the lower ventricular rates seen after treatment with the calcium antagonists were not associated with improved exercise tolerance, which did not differ significantly between the various treatments. Reduction of the ventricular rate was associated with a small increase in stroke volume but the benefits of this were offset by a rate related reduction in cardiac output. Further reduction of the rapid ventricular rates seen in digitalized patients with AF does not appear to be of benefit in terms of improving either exercise tolerance or cardiac output.


Oxaliplatin

leucovorin

Scheduled prospective tri-weekly modified FOLFOX6 maintenance chemotherapy in the treatment of metastatic colorectal cancer.  Oxaliplatin , which is effective for colorectal cancer ( CRC ) in combination with 5-fluorouracil ( 5-FU ) and leucovorin ( LV ) , is widely used for metastatic CRC . With the increasing use of oxaliplatin, however, serious adverse events have been experienced, including hematologic and neurologic toxicities. The aim of this study was to evaluate whether tri-weekly modified FOLFOX6 (mFOLFOX6) maintenance chemotherapy is associated with a low incidence of severe hematologic and neurologic toxicities in the treatment of patients with metastatic CRC. ### methodology We developed a new treatment regimen with mFOLFOX6 biweekly for 8-10 consecutive cycles (induction phase) followed by a 3-week rest period, after which treatment was resumed with cycles of tri-weekly mFOLFOX6 at standard doses (maintenance phase). Validity and complications were investigated retrospectively. ### results Twenty-nine patients were enrolled in this study. The median progression-free survival (PFS) and overall survival (OS) times were 9.4 months and 23 months, respectively. All patients had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 2 patients (6.9%). ### conclusions mFOLFOX6 maintenance chemotherapy was associated with a very low incidence of grade 3 hematologic and neurologic toxicities. The toxicities associated with PFS and OS were comparable to those reported in the treatment of patients with metastatic CRC. A tri-weekly mFOLFOX maintenance strategy of alternative treatment with a less-toxic regimen may reduce toxicity and maintain efficacy.


paclitaxel

docetaxel

vinorelbine

The effect of combining antitubulin agents on differentiated and undifferentiated human colon cancer cells.  The cytotoxicity of sequential combinations of a taxoid [ paclitaxel ( TAX ) or docetaxel ( TXT ) ] with a vinca alkaloid [ vinorelbine ( NVB ) ] was compared in differentiated and undifferentiated HT29-D4 cells . Agents were titrated from low doses inducing no modification of microtubule network to high doses corresponding to the clinically relevant concentrations that block mitosis. For undifferentiated cells, the sequential combination NVB/TAX was more efficient than TAX/NVB (22% cell survival versus 37% for 5 nM TAX and NVB). Surprisingly, we successively obtained synergism for low doses of both compounds [NVB (1-5 nM) and TAX (1-15 nM)], then additivity and finally antagonism when one of the compounds was at the concentration inducing mitotic block. The three patterns of results were also obtained with NVB/TXT combinations. For the synergistic combinations at the lowest concentrations, cytotoxicity occurred by apoptosis following mitosis. For differentiated cells, the most cytotoxic combinations were 1 microM TAX or TXT for 3 days followed by 1 microM NVB for 3 days, and 0.75 nM TAX or TXT for 9 days followed by 1 microM NVB for 3 days, the latter producing synergistic effects. Cytotoxicity occurred by apoptosis for the two states of differentiation. Major differences depending on cell phenotype were demonstrated: low sensitivity of differentiated cells to antitubulin agents and the difference in apoptotic pathways since mitosis is not involved in differentiated cells.


nivolumab

ipilimumab

Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). ### aim To evaluate patient-reported outcomes (PROs) in this population. ### methods Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. ### results In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures . ### conclusion First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. ### Clinical Trial Registration NCT02477826.


atorvastatin

celecoxib

tipifarnib

Effects of atorvastatin in combination with celecoxib and tipifarnib on proliferation and apoptosis in pancreatic cancer sphere-forming cells. Cancer stem cell (CSC) plays an important role in pancreatic cancer pathogenesis and treatment failure. CSCs are characterized by their ability to form tumor spheres in serum-free medium and expression of CSC related markers. In the present study , we investigated the effect atorvastatin , celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells . The sphere-forming cells were isolated from Panc-1 cells by sphere-forming method. These sphere-forming cells showed CSC properties. The levels of CD44, CD133 and ALDH1A1 in the sphere-forming cells were increased. Moreover, Panc-1 sphere-forming cells were resistant to chemotherapeutic drug gemcitabine. Combined atorvastatin with celecoxib and tipifarnib synergistically decreased the sphere forming ability of Panc-1 cells and the drug combination also strongly inhibited cell proliferation and promoted apoptosis in the sphere-forming cells. The effects of the drug combination on the Panc-1 sphere-forming cells were associated with decreases in the levels of CD44, CD133 and ALDH1A1, and suppression of Akt and NF-κB activation. Results of the present study indicate that the combination of atorvastatin, celecoxib and tipifarnib may represent an effective approach for inhibiting pancreatic CSCs.


donepezil

galantamine

rivastigmine

memantine

[The Use of Symptomatic Drugs for Dementia]. The treatment of Alzheimer's disease (AD) can be roughly divided into Disease-modifying Drugs (DMD) and Symptomatic Drugs (SD). Major strategies of DMD are the amyloid vaccine therapy and β/γ-secretase inhibitors, which have been developed with high expectations as fundamental treatments for AD. As SD , donepezil , galantamine , rivastigmine , and memantine are now usable . While memantine is an NMDA receptor inhibitor, the remaining three agents are cholinesterase inhibitors. The inhibitory mechanisms of the four agents exhibit some differ- ences. Although they may offer tips for proper use, the SD guidelines have so far stated that there are no significant differences among SD. The guidelines also state that no SD can stop the progression of AD and that their use for MCI should not be encouraged. There are some criticisms about the use of SD because they are not root treatments. In contrast, there are some reports that SD delay AD progression, preserve ADL, reduce the care burden and have an effect on BPSD. Therefore, in proper combination with non-drug treat- ments, the use of SD is considered to be valuable.


Raloxifene

tamoxifen

The pharmacokinetics of raloxifene and its interaction with apigenin in rat.  Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen . As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin. ### methods The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the pharmacokinetic profiles of raloxifene administered alone and in combination with apigenin were compared. ### results Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the C(max) and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the C(max) and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and C(max) of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug. ### conclusions The results showed that apigenin decreased the first-pass metabolism of raloxifene but did not increase its absorption from the gastrointestinal tract.


bosentan

ramipril

bosentan

ramipril

Effects of blockade of the renin-angiotensin and endothelin systems on experimental bronchiolitis obliterans. Blockade of the renin-angiotensin and the endothelin (ET) systems ameliorates fibrous airway obliteration in rat tracheal allografts. The aim of this study was to test which of these pharmacologic interventions attenuates the process more effectively, and whether combination therapy confers additional benefit. ### methods Rat tracheas were heterotopically transplanted from Brown-Norway donors into Lewis recipients. Recipients received the dual endothelin-1 ( ET-1 ) receptor blocker , bosentan ( 100 mg/kg ) , the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril ( 5 mg/kg ) , bosentan plus ramipril ( doses as just noted ) or vehicle . Grafts were harvested at Days 7 and 21 for morphometric studies and molecular analysis by real-time polymerase chain reaction (PCR). ### results At Day 21, bosentan and ramipril treatment reduced the percentage of luminal occlusion compared with vehicle to a similar extent. In animals that received the combined treatment, luminal obliteration was further reduced compared with the respective monotherapies. Furthermore, rats treated with bosentan plus ramipril showed a lower percent of epithelial necrosis. The beneficial effects of bosentan and ramipril, alone or in combination, were associated with reduced mRNA levels of transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF)-A in the tracheal allografts. ### conclusions Our data suggest that ET receptor blockade prevents fibrous airway obliteration to a similar extent as ACE inhibition in this model. Interruption of both pathways provides superior graft protection as compared with single-system blockade.


carboplatin

paclitaxel

[Weekly paclitaxel administration and intraabdominal CBDCA injection possibly beneficial treatment for recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation--a case report]. A 46-year-old woman who had received mastectomy for breast cancer 6 years earlier complained of abdominal distension. Computed tomography and ultrasonography revealed massive ascites and ovarian swelling of both sides. She was diagnosed as having primary ovarian cancer and peritoneal dissemination, and underwent a total hysterectomy as well as ovarectomy on both sides. After surgery , she received a sequential chemotherapy , ie , intraabdominal injection of carboplatin ( CBDCA 300 mg/m2 ) and div administration of paclitaxel ( PTX 180 mg/m2 ) as a standard regimen for advanced ovarian cancer . However, detailed histological examinations showed that the ovarian cancer had metastasized from her breast cancer. It is well-known that breast cancer easily metastasizes to the bone, liver, pleura and lymph node, but rarely to the ovarium or peritoneum when chemotherapy is conducted. Therefore, no standard therapy has been established for breast cancer metastasizing to the ovarium. Our patient received 4 cycles of weekly administration of PTX (PTX 80 mg/m2, 3 consecutive weeks, 1-week break), followed by oral administration of doxifluridine+anastrozole on an outpatient basis. No evidence of recurrence of breast cancer has been noted 1 year after surgery. This result suggests that weekly administration of PTX and intraabdominal injection of CBDCA might be beneficial in the treatment of recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation.


ranolazine

ivabradine

Pharmacodynamic effects in the cardiovascular system: the modeller's view. Cardiovascular disease, and the cardiovascular side effects of drugs, are essentially multifactorial problems involving interactions between many proteins, dependent on highly organized cell, tissue and organ structures. This is one reason why the side effects of drugs are often unanticipated. It is impossible to unravel such problems without using a systems approach, i.e. focussing on processes, not just molecular components. This inevitably involves modelling as the interactions require quantitative analysis. Modelling is a tool of analysis aimed at understanding, first, and predicting, eventually. We illustrate these principles using modelling of the heart. Models of the cardiac myocyte have benefited from several decades of interaction between experimentation and simulation. They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine . With the help of cardiac modelling, we have also been able to unravel the mechanisms underlying the beneficial effect of sodium calcium exchange block for long QT syndrome (LQTS) 2 and LQTS3 patients. Detailed models of the interaction between ion channels and blocking agents provide the basis for modelling drug action from basic principles and predict changes in the inhomogeneous tissue of the heart. We demonstrate that mathematical models are beneficial for unravelling the complex interactions of pharmacodynamics in the heart. Embedding these detailed biophysical cellular scale models into anatomically correct models of the ventricle geometry will enable reconstructions of Torsades de Pointes arrhythmias and of fibrillation, providing a mechanism for linking detailed cellular scale experimental data to clinical applications.


pseudoephedrine

andrographolide

chloroquine

abacavir

thalidomide

Network bioinformatics analysis provides insight into drug repurposing for COVID-19. The COVID-19 disease caused by the SARS-CoV-2 virus is a health crisis worldwide. While developing novel drugs and vaccines is long, repurposing existing drugs against COVID-19 can yield treatments with known preclinical, pharmacokinetic, pharmacodynamic, and toxicity profiles, which can rapidly enter clinical trials. In this study, we present a novel network-based drug repurposing platform to identify candidates for the treatment of COVID-19. At the time of the initial outbreak, knowledge about SARS-CoV-2 was lacking, but based on its similarity with other viruses, we sought to identify repurposing candidates to be tested rapidly at the clinical or preclinical levels. We first analyzed the genome sequence of SARS-CoV-2 and confirmed SARS as the closest virus by genome similarity, followed by MERS and other human coronaviruses. Using text mining and database searches, we obtained 34 COVID-19-related genes to seed the construction of a molecular network where our module detection and drug prioritization algorithms identified 24 disease-related human pathways, five modules, and 78 drugs to repurpose. Based on clinical knowledge , we re-prioritized 30 potentially repurposable drugs against COVID-19 ( including pseudoephedrine , andrographolide , chloroquine , abacavir , and thalidomide ) . Our work shows how in silico repurposing analyses can yield testable candidates to accelerate the response to novel disease outbreaks.


cefuroxime

tobramycin

Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release.  To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein ( PBP ) 3-specific beta-lactam antibiotic cefuroxime , the aminoglycoside tobramycin , and a combination of the two , and to test the relationship between bacterial killing rate and endotoxin release . ### methods A clinical isolate of Escherichia coli in logarithmic phase was exposed to 0.1, 2, 10, and 50 x minimum inhibitory concentration (MIC) of cefuroxime, tobramycin, and a combination of the two. Samples for viable counts and endotoxin analysis were drawn immediately before and after the addition of the antibiotics and at 1, 2, 4, 6, and 24 h. All experiments were performed in triplicate. For the analysis of endotoxin, a chromogenic limulus amoebocyte lysate assay was used. ### results Endotoxin liberation was found to be proportional to the number of killed bacteria for each antibiotic regimen at each concentration level justifying the endotoxin-liberating potential to be expressed as release of endotoxin per killed bacterium, an expression that was independent of the inoculum size. At all concentration levels there was a statistically significant difference between the treatments, with the highest release of endotoxin per killed bacterium for cefuroxime, lower for tobramycin and the lowest for the combination of the two drugs (P < 0.001). With increasing doses, there was a significant reduction (P < 0.001) in the propensity to release endotoxin. When the bacterial killing rate was correlated to the propensity to release endotoxin in bacteria exposed to tobramycin or the combination of tobramycin and cefuroxime, a significant negative correlation was found (P < 0.01). This reduction in endotoxin release was not caused by an unspecific endotoxin binding of tobramycin. ### conclusions Addition of tobramycin reduced the cefuroxime-induced endotoxin release per killed bacterium to a level which was even lower than that of tobramycin alone in spite of an increased killing rate. Increasing concentrations of tobramycin led to reduction in endotoxin release, which may be of benefit when dosing aminoglycosides once daily.


ponatinib

lapatinib

CDK7 inhibitor

Combination therapy with the CDK7 inhibitor and the tyrosine kinase inhibitor exerts synergistic anticancer effects against MYCN-amplified neuroblastoma. Patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression have very poor prognosis. The cyclin-dependent kinase 7 (CDK7)/super-enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase phosphatase 1 nuclear targeting subunit (PNUTS) has recently been shown to interact with c-Myc protein and suppresses c-Myc protein degradation. Here we screened the U.S. Food and Drug Administration-Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN-amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, while having little effects in normal nonmalignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. Reverse transcription polymerase chain reaction and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N-Myc protein but not N-Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N-Myc protein but not mRNA expression and decreased MYCN-amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients , our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients .


epirubicin

paclitaxel

[Feasibility of breast conservation surgery after neoadjuvant chemotherapy for breast cancer]. To investigate the efficacy of neoadjuvant chemotherapy (NCT) and the feasibility of conservative breast surgery after reducing the size of a primary tumor by NCT in patients with operable breast cancer. ### methods Thirty patients with stage IIB and IIIA breast cancer underwent NCT including epirubicin 60 mg/m(2) by intravenous injection on day 1 and paclitaxel 150 mg/m(2) by 3-hour continuous infusion on day 2 with 21 days as a cycle from July 2001 to April 2003. All patients received 3 - 4 cycles of NCT. Breast conservation treatment or modified mastectomy was performed after the tumor was reduced to less than 3 cm in diameter. The nonresponders received modified mastectomy. ### results The overall response rate (ORR) was 93% (28/30) for the primary tumors of breast, Fifteen patients (50%) obtained clinical complete response (cCR), including 7 cases (23%) with pathologic complete response (pCR). Thirteen cases (43%) achieved clinical partial response (cPR), and 2 (7%) no change (NC). No case showed progression of disease. Twenty-six (87%) cases were downstaged according to the TNM system classification. The median initial tumor size was 4 cm (3 - 10 cm) before NCT and was reduced to 0.8 cm (0 - 6 cm) after NCT. All 30 patients received operation. Eighteen (60%) of them were candidates for breast conserving therapy, and actually only 11 (37%) selected such surgery. ### conclusion An effective treatment for operable breast cancer , NCT with epirubicin plus paclitaxel results in significant downstaging or eliminating of primary tumors in breast cancer , thus expanding the indication of breast conservation therapy .


Carboplatin

etoposide

Carboplatin and etoposide for recurrent malignant glioma following surgical and radiotherapy failure : A clinical study conducted at the Northern Israel Oncology Center . We conducted a phase II study using carboplatin and etoposide on patients with recurrent malignant glioma to investigate tumor response. ### methods From January 1995 to March 1997, 21 patients with recurrent malignant glioma were treated with a carboplatin (300 mg/m(2), day 1)/etoposide (100 mg/m(2), days 1-3) regimen every 3-4 weeks. The following radiologic parameters were evaluated: tumor size, central lucency, degree of contrast enhancement, and mass effect. No patient had received chemotherapy previously. Dose escalation corresponded to hematologic tolerance and to general and neurologic performance status. Most patients were treated postoperatively with involved field radiotherapy followed by a boost to the tumor area, as defined on the presurgery computed tomography scan or on magnetic resonance imaging. Mean interval to introduction of chemotherapy was 8.8 months (range, 7-36 months). Patients received a mean of four cycles [range, 2-8 cycles]. ### results Only 2 patients showed moderate radiological response, while 12 patients died of progressive disease. Mean time to progression following discontinuation of chemotherapy was 5.8 months (range, 1-11 months). The other patients survived with persistent disease and are being treated palliatively. Toxicity was manageable (1, neutropenic sepsis; 1, thrombocytopenia (45,000/mm(3)); 2, temporarily elevated transaminase level; 2, steroid-induced erosive gastritis). ### conclusions This phase II regimen proved to be ineffective in recurrent malignant glioma. Further studies incorporating innovative drug regimens and schedules are warranted. J. Surg. Oncol., 1999;71:167-170.


dexamethasone

dasatinib

ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma. An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). ### objective To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. ### methods The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. ### results Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). ### conclusion ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib , resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27 M mutant DIPG .


prednisone

mitoxantrone

Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. A combination of mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL). ### Patients And Methods Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain . HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module-Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients. ### results At 6 weeks, both groups showed improvement in several HQL domains, and only physical functioning and pain were better in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life (P =.009), four functioning domains, and nine symptoms (.001 < P <. 01), and the improvement (> 10 units on a scale of 0 to100) lasted longer than in the prednisone-alone group (.004 < P <.05). The addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life (.001 < P <.003). ### conclusion Treatment with mitoxantrone plus prednisone was associated with greater and longer-lasting improvement in several HQL domains and symptoms than treatment with prednisone alone.


imatinib

cytarabine

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase . In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response.


gemcitabine

capecitabine

Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine : a multicenter , phase II trial of the Swiss Group for Clinical Cancer Research . To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. ### Patients And Methods Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. ### results Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. ### conclusion Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.


doxorubicin/cisplatin

ifosfamide

methotrexate

Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan. From 1997 to 2003, 40 patients (all <40 years of age) with non-metastatic osteosarcoma of the extremities were treated with OOS-D and definitive surgery. Two cycles of doxorubicin 90 mg/m(2) plus cisplatin 120 mg/m(2) and ifosfamide 15 g/m(2) were given as neoadjuvant chemotherapy , and two cycles of doxorubicin/cisplatin and ifosfamide , and two cycles of high-dose methotrexate ( 10 - 12 g/m(2 ) ) were given post-operatively . All patients underwent limb salvage surgeries, and 66% showed good response to neoadjuvant chemotherapy.  With a median follow-up period of 117 months, 31 of the evaluable 40 patients were continuously disease-free, 7 were currently alive with no evidence of disease, and 2 died of disease. There was no local recurrence. The 5-year event-free and overall survival rates were 83 and 98%, respectively.  The 10-year event-free and overall survival rates were 80 and 95%, respectively. The major form of toxicity was haematological one.


rituximab

lamivudine

tenofovir

[Viral hepatitis B in a patient with follicular lymphoma treated with biological therapy]. Reactivation, recurrence or acute infection with hepatitis B virus (HBV) represent severe complications of biological therapy. Reported is a case of a 58-year-old female treated in the past with cytostatics and rituximab for follicular lymphoma , in whom HBV infection was detected during a follow-up of the contacts of her partner diagnosed with acute viral hepatitis B. At the beginning , the patient had a very high serum level of HBV DNA ( 4.3 × 108 IU/mL ) and therefore she was treated with combined antiviral therapy ( lamivudine and tenofovir ) . After 10 months, the serum level of HBV DNA decreased significantly (3,100 IU/mL) and the combined antiviral therapy was switched to monotherapy with tenofovir. Another 5 months later, the serum level of HBV DNA was only 950 IU/mL. This case demonstrates important clinical problems connected with HBV infection in immunocompromised persons.


fluorouracil-

oxaliplatin-

irinotecan-based

panitumumab

irinotecan

panitumumab

cetuximab

irinotecan

cetuximab

Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G). cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. ### Patients And Methods Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil- , oxaliplatin- and irinotecan-based chemotherapies were randomised ( 1:1 ) to either panitumumab plus irinotecan ( panitumumab arm ) or cetuximab plus irinotecan ( cetuximab arm ) . The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety. ### results From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). ### conclusion panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.


Epirubicin

oxaliplatin

capecitabine

panitumumab

Epirubicin , oxaliplatin , and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer ( REAL3 ): EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. ### methods In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. ### findings Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). ### interpretation Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. ### funding Amgen, UK National Institute for Health Research Biomedical Research Centre.


letrozole

tamoxifen

letrozole

tamoxifen

letrozole

tamoxifen

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. ### methods BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005 , after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen , a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone ; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting ( IPCW ) are used to account for selective crossover to letrozole of patients ( n=619 ) in the tamoxifen arm . Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. ### findings 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. ### interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. ### funding Novartis, United States National Cancer Institute, International Breast Cancer Study Group.


FOLFIRI

cetuximab

bevacizumab

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab ( FIRE-3 trial ) . To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. ### Patients And Methods CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. ### results Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. ### conclusion In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. ### Clinical Trials Number NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.


Tamoxifen

Exemestane

Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). ### methods The Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) phase 3 trial was conducted in hospitals in nine countries . Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. ### findings 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. ### interpretation Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. ### funding Pfizer.


formoterol

terbutaline

Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma. The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 ( range 0.0 - 6.3 ) formoterol and 2.34 ( range 0.1 - 7.5 ) terbutaline relief inhalations x day(-1 ) . No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.


leucovorin

oxaliplatin

docetaxel

Advances in the treatment of gastric cancer: 2019. The aim of this study was to review studies published within the past year regarding management of gastric cancer. ### Recent Findings Laparoscopic gastrectomy achieves equivalent survival compared with open gastrectomy in early stage and locally advanced gastric cancer. Adjuvant chemotherapy with 6 months of S-1 and oxaliplatin was superior to 12 months of S-1, and the addition of postoperative radiation therapy did not improve survival. The FLOT regimen is the new standard for preoperative chemotherapy. In metastatic gastric cancer, the addition of docetaxel to S-1 and cisplatin failed to improve overall survival over two-drug chemotherapy. The addition of the immune checkpoint inhibitor pembrolizumab to chemotherapy failed to improve overall survival compared with chemotherapy alone. ### summary Laparoscopic gastrectomy is acceptable in early and locally advanced gastric cancer. Combination adjuvant chemotherapy is superior to S-1 monotherapy. Adjuvant radiation therapy after D2 gastrectomy for node-positive gastric cancer does not improve survival. Preoperative chemotherapy with FLOT ( 5-FU , leucovorin , oxaliplatin and docetaxel ) without radiation therapy is the standard treatment in the West . Two-drug chemotherapy is the optimal initial treatment in metastatic disease. Adding pembrolizumab to front-line chemotherapy did not improve survival, with use of immune checkpoint inhibitors reserved to treat chemotherapy refractory metastatic disease.


anastrozole

exemestane

letrozole

tamoxifen

Switching from tamoxifen to aromatase inhibitors for adjuvant endocrine therapy in postmenopausal patients with early breast cancer.  The third-generation aromatase inhibitors ( AIs ) , including anastrozole , exemestane and letrozole , have demonstrated improved efficacy versus tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer . AIs can be used in several adjuvant endocrine settings: as upfront therapy, switch to an AI after 2-3years of tamoxifen or extended therapy following 5years of tamoxifen. In the switch setting, two different types of study designs have been utilized. One is a late randomization design which randomizes patients who are disease-free after 2-3years of tamoxifen to receive an AI versus continuation of tamoxifen. In contrast, an early randomization design randomizes all patients immediately after primary treatment and prior to starting tamoxifen. Efficacy benefits with AIs have been shown in several trials evaluating the late randomization strategy, including the Intergroup exemestane Study, the Italian tamoxifen anastrozole trial and the anastrozole-Nolvadex 95 trial. Similarly, early randomization studies, including the Austrian Breast and Colorectal Cancer Study Group-8 and the Breast International Group (BIG) 1-98 trial, have demonstrated the effectiveness of receiving an AI after tamoxifen. Two trials are assessing an early switch strategy versus upfront AI therapy: the BIG 1-98 trial and the ongoing tamoxifen exemestane Adjuvant Multicentre trial are assessing switching from tamoxifen to an AI after 2-3years versus upfront AI therapy. This paper reviews studies that have investigated a switch strategy with AIs and considers the implications of these data on treatment choice for postmenopausal patients with hormone receptor-positive breast cancer.


Digoxin

gemcitabine

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway . Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.


rapamycin

oxaliplatin

Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1. The mTOR-inhibitor rapamycin has shown antitumor activity in various tumors. Bedside observations have suggested that rapamycin may be effective as a treatment for colorectal carcinomatosis. ### methods We established an orthotopic syngenic model by transplanting CT26 peritoneal tumors in Balb/C mice and an orthotopic xenograft model by transplanting SW620 peritoneal tumors in nu/nu mice. Expression levels of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by enzyme-linked immunosorbent assay. ### results rapamycin significantly suppressed growth of syngenic and xenografted peritoneal tumors. The effect was similar with intraperitoneal or oral rapamycin administration. Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin . The combination treatment showed no acute toxicity. TIMP-1 serum levels correlated well (CC = 0.75; P < 0.01) with rapamycin treatment. ### conclusions rapamycin suppressed advanced stage colorectal cancer, even with oral administration. Combining rapamycin with current chemotherapy regimens significantly increased antitumor efficacy without apparent toxicity. The treatment efficacy correlated with serum TIMP-1 levels, suggesting its potential as a surrogate marker in future clinical trials.


econazole

fluconazole

metyrapone

How do azoles inhibit cytochrome P450 enzymes? A density functional study. To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles , such as econazole , fluconazole , and metyrapone . The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH(2) distance of approximately 3.0 A, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.