tbuckley/cabot-search huggingface dataset:
Risk of gastrointestinal and hepatic toxicities in patients with advanced breast cancer treated with everolimus: A meta- analysis of phase 3 randomized controlled trials.
Authors: Sriman Swarup, Kyaw Zin Thein, Anita Sultan, Saad Khan, Catherine Jones, Fred L. Hardwicke, Sanjay Awasthi
Journal: Journal of Clinical Oncology (2018)

e22215 Background: The introduction of everolimus (E), an mTOR inhibitor, was shown to improve clinical benefit in endocrine and trastuzumab resistant advanced breast cancer by mediating via the PI3K/AKT/mTOR signaling pathway with notable safety concerns. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Phase 3 RCTs that mention GI and hepatic toxicities as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Results: A total of 1992 patients with advanced breast cancer were eligible for analysis. Studies compared E+ paclitaxel(P) + Herceptin(H) vs P+H, E+ exemestane(Ex) vs Ex, E+ vinorelbine(V)+ H vs V+H. The RR of all-grade side effects were as follows: nausea, 0.96 (95% CI: 0.84-1.10, p = 0.60); vomiting, 1.11 (95% CI: 0.92-1.34, p = 0.27); diarrhea, 1.37 (95% CI: 1.08-1.73, p = 0.008); stomatitis, 2.79 (95% CI: 1.77-4.39, p < 0.001); mouth ulcer, 3.26 (95% CI: 1.49-7.11, p = 0.003); elevated aspartate aminotransferase (AST), 1.59 (95% CI: 1.20-2.10, p = 0.001); and elevated alanine aminotransferase (ALT), 1.65 (95% CI: 0.91-2.97, p = 0.09). The RR of high-grade side effects were as follows: nausea, 1.91 (95% CI: 0.80-4.54, p = 0.14); vomiting, 0.93 (95% CI: 0.30-2.88, p = 0.89); diarrhea, 2.65 (95% CI: 1.50-4.66, p = 0.001); stomatitis, 9.58 (95% CI: 4.90-18.75, p < 0.001); mouth ulcer, 5.64 (95% CI: 0.70-45.06, p = 0.10); elevated AST, 1.68 (95% CI: 0.77-3.67, p = 0.19); and elevated ALT, 1.30 (95% CI: 0.81-2.08, p = 0.27). Conclusions: Our study showed that patients on everolimus experienced a significant increase in all grades of stomatitis with a relative risk of 9.58 for grade 3 and 4 stomatitis. They also contributed to significant toxicity of all grades of diarrhea as well as any-grade elevated AST and mouth ulcer.
Quality of Care in the United Kingdom after Removal of Financial Incentives
Authors: Mark Minchin, Martin Roland, Judith Richardson, Shaun Rowark, Bruce Guthrie
Journal: New England Journal of Medicine (2018)

The benefits of pay-for-performance schemes in improving the quality of care remain uncertain. There is little information on the effect of removing incentives from existing pay-for-performance schemes.We conducted interrupted time-series analyses of electronic medical record (EMR) data from 2010 to 2017 for 12 quality-of-care indicators in the United Kingdom's Quality and Outcomes Framework for which financial incentives were removed in 2014 and 6 indicators for which incentives were maintained. We estimated the effects of removing incentives on changes in performance on quality-of-care measures.Complete longitudinal data were available for 2819 English primary care practices with more than 20 million registered patients. There were immediate reductions in documented quality of care for all 12 indicators in the first year after the removal of financial incentives. Reductions were greatest for indicators related to health advice, with a reduction of 62.3 percentage points (95% confidence interval [CI], -65.6 to -59.0) in EMR documentation of lifestyle counseling for patients with hypertension. Changes were smaller for indicators involving clinical actions that automatically update the EMR, such as laboratory testing, with a reduction of 10.7 percentage points (95% CI, -13.6 to -7.8) in control of cholesterol in patients with coronary heart disease and 12.1 percentage points (95% CI, -13.6 to -10.6) for thyroid-function testing in patients with hypothyroidism. There was little change in performance on the 6 quality measures for which incentives were maintained.Removal of financial incentives was associated with an immediate decline in performance on quality measures. In part, the decline probably reflected changes in EMR documentation, but declines on measures involving laboratory testing suggest that incentive removal also changed the care delivered.
Adverse effects of androgen deprivation therapy on cognitive impairment for men with prostate cancer: A meta-analysis.
Authors: Maxine Sun, Alexander P Cole, Nawar Hanna, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2017)

e16506 Background: Use of androgen deprivation therapy (ADT) may confer a higher risk of cognitive impairment. Published results are variable and lack consensus. Our objective was to perform meta-analysis of the risk of overall cognitive impairment in men receiving ADT for prostate cancer. Methods: Relevant studies were identified through the search of English language articles indexed in PubMed Medline, PsycINFO, Cochrane Library and Web of Knowledge/Science until December 21 st 2016. Articles were included if they were published in English, reported on original research with adult male subjects undergoing treatment for prostate cancer, incorporated longitudinal comparisons, and included a control group. Controlled intervention studies were required to assess an established cognitive-related endpoint that was measured by a validated instrument, and measure cognitive impairment based on the International Cognition and Cancer Task Force (ICCTF) criteria. The effect of ADT on cognitive impairment was pooled using a random-effects model for controlled intervention and case-control studies separately. Results: Of 221 abstracts, 25 were selected for full-text review, and 8 studies, with 2 controlled studies and 6 case-control studies were identified. Overall cognitive impairment was not significantly different when the results of the 2 prospective studies were pooled (OR: 1.57, 95% CI: 0.50–4.92, P= 0.44), with significant heterogeneity between estimates ( I 2 : 83%). In retrospective data, the odds of developing any cognitive impairment were significantly higher in men treated with ADT (HR: 1.37, 95% CI: 1.06–1.77, P= 0.02), with considerable heterogeneity ( I 2 : 84%). Conclusions: The relationship between overall cognitive impairment and use of ADT defined according to the ICCTF criteria in a pooled-analysis of two prospective studies was inconclusive. Although retrospective studies suggest a higher risk of overall cognitive impairment after ADT, we caution readers not to over-interpret this finding given the limitations of retrospective data. Better well-designed prospective studies are needed to assess the effect of ADT on cognitive impairment with long-term follow-up.
Phase I dose-escalation and pharmacokinetic (PK) study of regorafenib in pediatric patients with recurrent or refractory solid malignancies.
Authors: Birgit Geoerger, Bruce Morland, Irene Jimenez, Didier Frappaz, Andrew DJ Pearson, Gilles Vassal, Patricia Maeda, Jasmine Kincaide, Udo Mueller, Sarah Schlief, Adriaan Cleton, Andrea Chassot-Agostinho, Lynley V Marshall
Journal: Journal of Clinical Oncology (2016)

10542 Background: Regorafenib, a multikinase inhibitor targeting VEGFR1-3, PDGFR, TIE-2, RET, c-KIT, is approved for the treatment of adults with advanced CRC and GIST. This study assessed its safety, PK, maximum tolerated/recommended phase 2 dose (MTD/RP2D) in pediatric patients. The study was run in ITCC sites. Methods: Patients 6 months to < 18 years with histologically confirmed recurrent/refractory solid tumors received tablets or granulates QD for the first 21 days of each 28-day cycle. Starting dose of 60 mg/m2 was based on a physiology-based PK (PBPK) model developed in adults and scaled to children 2–18 years, and estimated to 80% of the adult exposure of total regorafenib after multiple dosing. Doses of 60, 72, 82, and 93 mg/m2/day were assessed by a rolling-6 design. The PBPK model was updated in real time to support dose escalation decisions. Results: 41 patients, median 13 years (3–17), 20 with central nervous system tumors, 11 with sarcomas, received a median of 2 cycles (1–16). Dose-limiting toxicities were thrombocytopenia at 60 mg/m2, rash at 72 mg/m2, pyrexia at 82 mg/m2, hypertension and exfoliative dermatitis at 93 mg/m2. MTD was defined as 82 mg/m2 but due to a higher rate of grade 3/4 hematologic events in heavily pretreated patients than in adults, RP2D was determined as 72 mg/m2. 98% of patients had at least one adverse event considered drug related, the majority grades 1 or 2, most frequent being skin and subcutaneous disorders (76%), hyperbilirubinemia (42%), thrombocytopenia (37%), AST increase (34%), and fatigue, nausea, ALT increase (32% each). The observed exposure of regorafenib and its metabolites at all dose levels was similar to the adult exposure in 80–160 mg dose range. One partial response was seen in a patient with rhabdomyosarcoma, with stable disease of at least 15 weeks in 8 patients, including 31 and 56+ weeks in 2 anaplastic ependymomas. Conclusions: The toxicity of regorafenib in pediatric patients was tolerable and consistent with the known adult profile, although increased hematologic toxicity was observed in heavily pretreated patients. The RP2D was 72 mg/m2, estimated to be 100% of adult exposure after multiple dosing based on the PBPK model. Clinical trial information: NCT02085148.
Combinatorial genomic and pathological indices for integrated stratification of unfavorable intermediate-risk prostate cancer.
Authors: Melvin Chua, Jure Murgic, Melania Pintilie, Emilie Lalonde, Alejandro Berlin, Julie Livingstone, Alan Dal Pra, Alice Meng, Junyan Zhang, Yves Fradet, Bernard Têtu, Neil Eric Fleshner, Michael Fraser, Paul Boutros, Theodorus van der Kwast, Robert G. Bristow
Journal: Journal of Clinical Oncology (2016)

5051 Background: Men with intermediate-risk prostate cancer represent a clinically heterogeneous group with varying prognoses. High tumor copy number alteration as measured by percent genome aberration (PGA), intraductal carcinoma (IDC), and cribriform architecture (CA) are novel genomic and pathological indices that are associated with aggressive prostate cancer. Our primary endpoint was to test a combinatorial model integrating tumor genomics and pathology in predicting biochemical relapse in patients with intermediate-risk disease. Methods: IDC/CA, PGA, and clinical indices of T-category, PSA, and Gleason score (GS) were tested in a cohort of 531 men with NCCN-defined intermediate-risk prostate cancer, who were treated with radical prostatectomy (N = 173) or radiotherapy (N = 358). Pathological review was centrally performed by two expert pathologists. PGA was calculated using data from SNP array profiling (Affymetrix Oncoscan). Clinical end-points included biochemical relapse-free rate (bRFR), 18-month bRFR, and metastasis-free rate (mFR). Results: Biochemical relapse was independently associated with high PGA and presence of IDC/CA on univariable and multivariable analyses (HR high vs low PGA defined by median = 1.61 [95% CI = 1.04-2.49], Wald’s p = 0.033; HR IDC/CA present vs absent = 1.63 [1.04-2.54], p = 0.033). Early biochemical relapse and distant metastasis rates were higher in the patient subgroup of high PGA and IDC/CA present than in the low PGA and IDC/CA absent subgroup (HR 18-month bRFR = 2.55 [1.49-4.39], p < 0.001; mFR = 2.96 [0.83-10.63], p = 0.096), even for a sub-cohort with unfavorable clinical indices (PSA > 10 ng/ml, and T2b/c or GS 4+3). Inclusion of PGA to IDC/CA yielded the strongest model for predicting early biochemical relapse (AUC = 0.649 [0.476-0.776] for T-category, PSA, IDC/CA, with PGA vs 0.580 [0.456-0.675] without PGA). Conclusions: We developed a risk stratification model integrating novel pathological and genomic indices to identify patients with unfavorable intermediate-risk prostate cancer who are at risk of relapse. These patients may benefit from systemic intensification added to definitive local treatment.
CD8 and PD-L1 determination in lung tumor tissue as prognostic biomarker and a predictive marker of anti PD-1 efficacy.
Authors: Jean-David Fumet, Corentin Richard, Fanny Ledys, Quentin Klopfenstein, Caroline Truntzer, Bruno P. Coudert, Laurent Arnould, Laure Favier, Aurelie Lagrange, Sylvain Ladoire, Pierre Saintigny, Sandra Ortiz-Cuaran, Maurice Perol, Pascal Foucher, Paul Hofman, Marius Ilie, Sandy Chevrier, Romain Boidot, Valentin Derangere, FranÃ§ois Ghiringhelli
Journal: Journal of Clinical Oncology (2018)

3021 Background: With recent approval of mAb targeting PD-1 and PD-L1 for non–small cell lung cancer (NSCLC), extensive efforts are under way to develop predictive biomarkers for anti PD-1/PD-L1 response. PD-L1 expression upon histology is currently the only clinically available biomarker, but mRNA immune signatures are also emerging. While the efficacy of these drugs is dependent on CD8 T-cells, no study has evaluated both CD8 and PD-L1 as biomarkers. Methods: CD8 and PD-L1 expression was studied by RNA sequencing and immunohistochemistry (IHC). We used RNA sequencing data from The Cancer Genome Atlas (TCGA) lung cancer samples as a prognostic cohort. We validated the results obtained from the transcriptomic data with IHC data using another prognostic cohort of 34 metastatic NSCLC tumor samples untreated by immunotherapy and stained using CD8 and PD-L1. A predictive study was conducted on 85 NSCLC patients treated with nivolumab, for whom outcome was known. To evaluate our signature, we used IFN and Immune Expanded Signature (IES), previously described as gold standards. Data were externally validated using public data (GSE93157). Results: In the prognostic TCGA mRNA cohort, we observed that high CD8 expression is associated with better overall survival, while PD-L1 expression is associated with poor prognosis. CD8 and PD-L1 determined upon IHC also had prognostic value in the prognostic cohort. In the predictive cohort, CD8 and PD-L1 expression evaluated using mRNA or IHC are associated with better progression-free survival in patients treated with nivolumab. Use of mRNA improved discrimination when compared with histological measures. A combination of both CD8 and PDL1 variables was highly predictive of outcome and remained significant after adjustment for usual clinical variables (age, sex, histology performance status). This 2-gene signature using CD8 and PD-L1 outperformed both IFN and EIG signatures, even with IHC data. Similar results were obtained in the external validation cohort (GSE93157). Conclusions: CD8 and PD-L1 mRNA or IHC could be used to address NSCLC outcomes for patients treated with nivolumab.
A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemictabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
Authors: Linda R. Duska, Jubilee Brown, Danijela Jelovac, Kathleen N. Moore, William P. McGuire, Christopher Darus, Lisa Marie Barroilhet, Angeles Alvarez Secord
Journal: Journal of Clinical Oncology (2017)

5532 Background: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib (paz) is a potent angiogenic small molecular inhibitor of the tyrosine kinases VEGRF-1, -2, -3, PDGFR, c-kit and has shown activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent, advanced ovarian cancer. Methods: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive ovarian cancer with up to 3 prior lines of chemotherapy, and measurable or evaluable disease. Patients were randomly assigned (1:1) to receive weekly gem 1000 mg/m 2 with or without paz 800 mg QD and stratified according to platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. Intent-to-treat was defined as all eligible patients who receive any protocol treatment with analysis based on randomized arm. Results: As of 3/2017, we randomized 148 and treated 146 patients (target sample size 148 eligible patients who receive any protocol treatment). 75 (46 platinum resistant, 61%) were randomly assigned to receive gem/paz and 71 (41 platinum resistant, 58%) to receive gem only. 110 patients (75%) had received 2 or 3 prior lines. There were no unexpected toxicities or deaths. Adverse events were more common in the gem/paz group. The most common grade 3–4 AEs (gem/paz vs gem) were: neutropenia (25 [33%] vs 15 [21%]), fatigue (7 [10%] vs 1 [2%]), hypertension (11 [15%] vs 1 [1%]), elevated alanine aminotransferase (8 [11%] vs 0), thrombocytopenia (9 [12%] vs 12[3%]) and anemia (7 [9%] vs 2 [3%]). There were 2 GI perforations in the paz arm. Median time on therapy was 12 weeks (range 1-55 weeks). Of the 138 patients off study to date, 30 (22%) were for AE’s (23 on gem/paz arm). Conclusions: The gem/paz combination is tolerable in this population, with patients tolerating multiple cycles with manageable toxicity. Median follow-up and PFS data will be presented after 122 events (progression or death) have occurred per protocol (currently 117 events). Clinical trial information: NCT01610206.
A pilot study of Irinotecan plus raltitrexed as second-line treatment for advanced colorectal cancer.
Authors: Xiujuan Qu, Zhenhai Wu, Shuo Wang, Jinglei Qu, Lingyun Zhang, Jing Liu, Jing Shi, Jingdong Zhang, Yunpeng Liu
Journal: Journal of Clinical Oncology (2017)

e15024 Background: This pilot study is aimed to evaluated the efficacy and safety of irinotecan plus raltitrexed as second-line treatment for advanced colorectal cancer patients. Methods: A pilot study was made among patients with advanced, previously treated colorectal cancer from June 2013 to April 2016 in the First Hospital, China Medical University,. A total of 13 patients eligible were enrolled to receive irinotecan at a dose of 180mg/m2 d1, plus raltitrexed at a dose of 3mg/m2 d1, every 3 weeks, until disease progression or un-tolerable adverse events. All statistical analyses were performed using the SPSS (21.0) software program. Kaplan–Meier analysis and Log-rank test were used for survival analysis. P &lt; 0.05 was considered as statistically significant. The primary end point was time to progression (TTP) and objective response rate (ORR), the secondary end point was safety. Results:The median follow-up time was 10.1 months at data cut-off on Dec1, 2016. 11 patients were defined progression of disease (PD) based on the criteria of RECIST 1.1 and 6 patients died. The median TTP of second-line was 4.0 months. The rate of disease control rate (DCR) was 46.2% (6patients stable disease). In univariate analysis, sex (3.2months of 12male patients versus 4.6months of 1female patient, P = 0.926), body mass index (BMI) (3.2months of 5 patients BMI &lt; = 24 versus 4.0months of 8 patients BMI &gt; 24, P = 0.311), site of tumor (4.0months of left versus 3.2months of right, P = 0.555) were not associated with TTP. Safety was assessed within 10 patients including nausea (70%), vomiting (30%), diarrhea (60%), constipation (10%), fatigue (90%), fever (20%), hand foot syndrome (20%), rash (40%), alopecia (40%), palpitations (20%), oral mucositis (10%), neurotoxicity (50%). 2 of 9 patients (22.2%) had hematologic toxic. Liver injury occurred in 3 of 8 patients (37.5%) and no kidney injury was reported. Conclusions: In advanced colorectal cancer patients, irinotecan plus raltitrexed as second-line treatment showed encouraging clinical activity and a tolerable safety profile.
Microbiome 101: Studying, Analyzing, and Interpreting Gut Microbiome Data for Clinicians
Authors: Celeste Allaband, Daniel McDonald, Yoshiki Vázquez-Baeza, Jeremiah J. Minich, Anupriya Tripathi, David A. Brenner, Rohit Loomba, Larry Smarr, William J. Sandborn, Bernd Schnabl, Pieter Dorrestein, Amir Zarrinpar, Rob Knight
Journal: Clinical Gastroenterology and Hepatology (2018)
Statins improve outcomes of non-surgical curative treatments in hepatocellular carcinoma patients: cohort study from Taiwan cancer registry.
Authors: Chia lun Chang, Szu-Yuan Wu
Journal: Journal of Clinical Oncology (2016)

e15627 Background: Statins are associated with a reduced risk of hepatocellular carcinoma (HCC) and have the potential to be an adjuvant agent for HCC. In this study, we examined whether statin use is associated with additional benefits among patients who received curative treatments (CTs) such as surgery, percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA). Methods: We conducted a cohort study using the Taiwan National Health Insurance Research Data linked to the Taiwan Cancer Registry in 2001~2012. The patient cohort consisted of those who received different treatments, and we compared patients who received statins with those who did not. Statin users were defined as patients who received > 28 cumulative defined daily doses after their HCC diagnosis. We used a time-dependent Cox proportional method to model the time from the HCC diagnosis to any death and HCC death between men who received statins and those who did not after adjusting for confounders. Data on statin prescriptions were collected every 6 months to define the user status. Results: In total, 18,892 patients were included, and the mean follow-up duration was 1.74 years. The adjusted hazard ratio (aHR) of all-cause deaths increased in HCC patients who received RFA/PEI compared to those who received surgery (p < 0.0001 and p < 0.05, with aHRs of 1.81 and 1.16, respectively, for hepatitis B virus (HBV) or non-HBV HCC). However, with the addition of statin use to RFA or PEI, the overall survival was statistically equal. Conclusions: Surgical resection is still superior over other therapies. If HCC patients cannot meet the criteria for surgery, the addition of statin use to RFA or PEI might improve HCC survival.