bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward a molecular genetic classification of clear cell renal cell carcinoma.
Authors: Brugarolas James , Kapur Payal , Pena-Llopis Samuel , Christie Alana , Xie Xian-Jin 
Published: February 2017

341 Background: Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular underpinnings are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC and that BAP1 and PBRM1mutations are largely mutually exclusive. Herein, we investigate the clinicopathological significance of these molecular subtypes. Methods: Tumors from 145 patients with primary ccRCC were sequenced for PBRM1 and BAP1. Tumors were classified into BAP1-mutated and those exclusively mutated for PBRM1. Tumors were evaluated for pathologic features, gene expression and associated outcomes. A second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) was used for validation. Results: When compared to PBRM1-mutant tumors, BAP1-mutant tumors were associated with aggressive pathological features including high Fuhrman grade and tumor necrosis. BAP1-mutant and PBRM1-mutant tumors exhibited distinct gene expression signatures. The median overall survival (OS) was shorter for patients with BAP1-mutant tumors (4.6 years; 95% CI, 2.1-7.2), than for patients with PBRM1-mutant tumors (10.6 years; 95% CI, 9.8-11.5), corresponding to a hazard ratio (HR) of 2.7 (95% CI, 0.99-7.6, p = 0.044). A similar HR was observed in the independent dataset from the TCGA (2.8; 95% CI, 1.4-5.9; p = 0.004). The BAP1-mutant group could be further subdivided into tumors with mutations exclusively in BAP1 and those with mutations in both BAP1 and PBRM1. Double mutant tumors constituted a minority (n = 4; in TCGA), and were associated with the shortest OS (HR, 10; 95% CI, 3.2-33.6). Conclusions: Our findings reveal novel biological subgroups of ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular subclassification of ccRCC that could influence treatment decisions in the future.
Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.
Authors: Choueiri Toni K. , Je Youjin , Sonpavde Guru , Galsky Matt D. , Kaymakcalan Marina , Nguyen Paul Linh , Schutz Fabio , Heng Daniel Yick Chin , Richards Christopher J. 
Published: February 2017

347 Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.
Subgroup analyses of a phase III trial comparing tivozanib hydrochloride versus sorafenib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Hutson Thomas E. , Nosov Dmitry , Eisen Timothy , Lipatov Oleg N. , Tomczak Piotr , Alyasova Anna , Harza Mihai , Kogan Mikhail , Alexseev Boris Y. , Szczylik Cezary , Strahs Andrew Louis , Esteves Brooke , Berkenblit Anna , Motzer Robert John 
Published: February 2017

354 Background: Tivozanib hydrochloride (T) is a potent, selective, tyrosine kinase inhibitor of all 3 VEGF receptors with a long half-life. T has shown tolerability and has extended progression-free survival (PFS) compared with sorafenib (S; median 11.9 months vs. 9.1 months; p =0.042) in a phase III trial (TIVO-1) as initial targeted therapy for pts with mRCC. We report results of PFS subgroup analyses from TIVO-1. Methods: Pts with clear-cell mRCC, prior nephrectomy, and ≤1 prior treatment for mRCC were randomized to T (n=260) or S (n=257). Cox proportional hazards model was used to evaluate PFS. Results: Significant improvement in PFS by T vs. S was observed for the following prespecified subgroups: white, Eastern Cooperative Oncology Group (ECOG) performance status 0, ≥1 year since diagnosis, no prior treatment, ≥2 metastatic sites, North America/Western Europe, baseline systolic blood pressure (SBP) ≤140 mm Hg, and baseline diastolic BP (DBP) ≤90 mm Hg. Exploratory subgroup analysis showed a similar significant improvement by T vs. S in Memorial Sloan-Kettering Cancer Center (MSKCC) favorable prognostic group, and pts who developed hypertension on study had significantly longer PFS than pts with normal BP. The improvement in PFS by T vs S was more marked for the subgroups that developed hypertension (selected subgroups shown in the table). Conclusions: PFS subgroup analyses showed a consistent advantage with T vs. S for mRCC. Clinical trial information: NCT01030783. [Table: see text]
Validation of a genomic classifier that predicts metastatic disease progression in men with high-risk pathologic features postprostatectomy.
Authors: Ghadessi Mercedeh , Bergstralh Eric J. , Erho Nicholas , Crisan Anamaria , Davicioni Elai , Buerki Christine , Mitra Anirban Pradip , Thompson Darby J. S. , Carlson Rachel , Haddad Zaid , Zimmermann Benedikt , Ballman Karla V. , Kollmeyer Thomas M. , Sierocinski Thomas , Vergara Ismael A. , Triche Timothy J. , Black Peter C. , Thompson R. Houston , Karnes R. Jeffrey , Jenkins Robert B. 
Published: February 2017

36 Background: Following radical prostatectomy (RP), 30-40% of patients have adverse pathology and are deemed at high risk for metastatic progression. The objective of this study was to validate the ability of Decipher, a genomic classifier (GC), to improve prediction of metastatic disease progression compared with clinical variables in order to better identify candidates for therapy intensification. Methods: A previously developed 22-feature GC model was validated in a prospectively designed case-cohort study of a clinically high-risk population (i.e., with one or more adverse pathological features) of 1,010 RP patients treated at Mayo Clinic between 2000-2006. A random sample of 20% of the cohort was subjected to microarray analysis and GC scores were generated for 219 patients. The primary endpoint, the c-index for predicting metastatic disease progression (i.e., positive bone or CT scans) was evaluated in a blinded analysis. Cox modeling and decision curve analyses were used to compare the performance of GC to individual clinical variables and prediction models. Results: GC had a c-index 0.79 (95% CI 0.71-0.86) that was significantly better than any single clinical variable. Cumulative incidence curves in the cohort showed that 72% of patients had low GC scores with only 3% and 6% incidence of metastatic disease at 5 and 10 years post RP. In contrast, for the 28% of patients with high GC scores, the cumulative incidence was 17% and 25% at 5 and 10 years post RP. Decision curve analysis showed that the GC model had higher overall net benefit compared to clinical variables over a wide range of ‘decision-to-treat’ thresholds for risk of metastasis. In multivariable modeling with clinicopathologic variables, GC remained the only significant independent predictor of metastasis (HR=1.51, for each 0.1 unit increment, p<0.001). Conclusions: GC can better predict metastatic disease progression compared with clinical variables and may select among patients with adverse pathology a majority that is in fact at low risk for metastasis.
Efficacy and safety data from patients with advanced renal cell cancer treated with tivozanib hydrochloride after progression on sorafenib.
Authors: Motzer Robert John , Nosov Dmitry , Tomczak Piotr , Berkenblit Anna , Esteves Brooke , Strahs Andrew Louis , Hutson Thomas E. 
Published: February 2017

364 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life and has shown superior efficacy, measured as progression-free survival (PFS), as first-line, targeted therapy vs. sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (J Clin Oncol2012;30[suppl]:Abstract 4501). Patients who progressed (PD) on sorafenib could receive tivozanib in an open-label, prospective multicenter extension study of TIVO-1. We report preliminary efficacy and safety data for patients who had PD on sorafenib and subsequently received tivozanib in this extension study. Methods: Patients with PD on sorafenib, per RECIST version 1.0, were eligible to receive tivozanib dosed at 1.5 mg/day PO for 3 weeks followed by a 1-week rest, in repeated 4-week cycles, until PD or unacceptable toxicity. Patients were to have been no more than 4 weeks from last dose of sorafenib until initiation of tivozanib, and have an ECOG performance status of ≤2. Dose adjustments were performed as previously reported. Objectives included assessing objective response rate (ORR), duration of response, PFS for tivozanib following PD on sorafenib, and overall survival. Results: As of January 20, 2012, 127 patients (72.4% male) were evaluable for response. Median age was 59.0 years (range: 23–85 years). ORR was 7.9% (95% CI 3.8–14.0%; partial response [PR]=7.9%; stable disease [SD]=65.4%; PD=18.9%), and 71.3% of patients showed tumor shrinkage. Median duration of PR was 11.1 months (95% CI ≥7.5 months). Median duration of SD was 12.7 months (95% CI ≥7.4 months). Median PFS was 5.6 months (95% CI 5.4–9.1 months). Median OS was not yet reached. Most commonly reported treatment-emergent adverse events (all grades/Grade ≥3) were hypertension (22.4%/10.2%), asthenia (11.0%/3.1%), fatigue (11.0%/3.9%), palmar-plantar erythrodysesthesia (11.0%/1.6%), and diarrhea (10.2%/1.6%). Conclusions: Tivozanib has anti-tumor activity after PD on sorafenib. The adverse-event profile of tivozanib after sorafenib is similar to that observed in TIVO-1. Clinical trial information: NCT01076010.
Ten-year follow-up of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with interferon alfa-2b (IFN) as first-line therapy: Results from a randomized trial.
Authors: Conter Henry Jacob , Wood Christopher G. , Matin Surena F. , Tamboli Pheroze , Millikan Randall E. , Jonasch Eric , Tannir Nizar M. 
Published: February 2017

365 Background: We previously reported on improved tolerability and maintained efficacy of low-dose IFN in pts with mRCC treated in the cytokine era (Tannir, et al. Cancer 2006). Although VEGFR targeted agents have supplanted cytokines for most pts, IFN, in combination with bevacizumab, is a standard front-line therapy for good-risk and intermediate-risk clear-cell RCC. Methods: Between March 2002 and December 2003, a total of 118 pts (59/arm) were randomized to receive IFN 0.5 million units (MU) twice/day [IFN1] or 5 MU/day [IFN5]. Patients who were progression-free and tolerating therapy well continued IFN for a total of 5 years. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), overall survival (OS), safety, and quality of life (QOL). Results of PFS, ORR, safety, and QOL were previously reported. We provide here updated OS and long-term outcome of complete responders (CR). Results: At 10 years of follow-up, >95% of participants have died. There was no significant difference in OS between the 2 arms (HR=1.32, 95% CI: 0.91-1.91), but favored IFN1 (median OS 2.1 years vs. 1.5 years, log-rank test p=0.14). Compared with IFN5, IFN1 was less toxic and was associated with better QOL. Two nephrectomised pts, 1 from each arm, 1 with multiple hepatic and lung metastases, and 1 with multiple lung and mediastinal metastases, performance status 1 and intermediate-risk clear-cell RCC, remain in unmaintained CR 10 years since starting IFN. Among pts who did not respond to IFN but remain alive, 1 patient received high-dose IL-2 and achieved durable CR; the other patient received multiple approved and investigational targeted agents sequentially. All responders to IFN had tumor regression as early as 8 wks, with PR or CR declared at 16 wks. Conclusions: IFN produces durable CRs and potential cure in about 2% of mRCC pts. Our data have implications for the front-line therapy of mRCC and suggest that IFN, like high-dose IL-2, can be discontinued after 16 wks, if a major response is not achieved. Our updated results are of interest, considering the paucity of durable CRs to VEGFR agents.
Development and internal validation of a prognostic nomogram for overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib (PAZ).
Authors: Kattan Michael W. , Chakrabarti Debasis , Bhatt Kamalnayan , Mehmud Faisal , Sternberg Cora N. , Motzer Robert John 
Published: February 2017

380 Background: PAZ, an oral multikinase inhibitor, demonstrated significant improvement in PFS over placebo in patients with aRCC in a randomized, phase III trial (J Clin Oncol 2009:29; 475). The purpose of this study was to develop and internally validate a prognostic nomogram based on the outcome data from phase III trial for predicting the probability of 12-month OS for treatment-naïve and cytokine-pretreated aRCC patients who received PAZ. Methods: Statistical modeling was performed on a dataset consisting of 281 patients from the PAZ arm of the phase III trial. Missing values were first imputed using multiple imputation with chained equations. A Cox proportional hazards regression model was fit using routinely available predictors thought to be prognostic based on clinical judgment. These predictors included the neutrophil count relative to ULN, platelet count relative to ULN, LDH relative to ULN, alkaline phosphatase relative to ULN, corrected calcium, albumin, hemoglobin, ECOG performance status, months from diagnosis to treatment, number of metastatic sites, and presence of lung, liver and bone metastases. Bootstrap-corrected estimates of discrimination and calibration in the small were calculated following 1,000 resamples. The Cox model was plotted as a nomogram. Results: A prognostic nomogram was developed and internally validated for predicting the probability of 12-month OS in aRCC patients based on a Cox regression model using 13 predictor variables. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of OS. The bootstrap-corrected concordance index, a measure of discrimination, was 0.70. When examining the nomogram, albumin appeared to have the greatest potential influence on predicted OS. Months from diagnosis to treatment and corrected calcium level seemed to be the next most potentially influential predictors. Conclusions: The nomogram predicts with reasonable accuracy and should facilitate treatment decision making for patients with advanced renal cell carcinoma. Validation in a separate dataset is planned.
Effect of targeted therapy on rapid progression and early death in renal cell carcinoma.
Authors: Wu Shenhong 
Published: February 2017

389 Background: Several targeted therapeutic agents have been approved for the treatment of advanced renal cell carcinoma (RCC) due to their efficacy in overall patient population. However, their effects have not been defined in patients with rapid progressive cancer, which is characterized by progression within three months and associated with poor prognosis. Therefore, we conducted a systematic review and meta-analysis of published randomized controlled clinical trials (RCTs) to assess the effect of targeted therapy on rapid progressive RCC. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October, 2012, were searched to identify relevant studies. Rapid progression was defined as progressive disease or death at three months after the initiation of clinical trial. Eligible studies included prospective RCTs in which a targeted therapy was compared to a control in RCC patients. Summary incidence of rapid progression or death, relative risk (RR), and 95% confidence interval (CI) were calculated based on the heterogeneity of included studies. Results: A total of 4,628 patients (targeted therapy: 2,461, control: 2,167) with RCC from 10 RCTs were included for analysis. The overall incidence of cancer rapid progression with the targeted therapy was 23.6% (95% CI: 19.2-28.6%). When compared to controls including interferon or placebo, the targeted therapy significantly reduced the overall risk of rapid progression (23.6% vs. 54.5%; overall RR=0.46, 95% CI: 0.38-0.54, p<0.001; versus IFN: RR=0.55, versus placebo: RR=0.38). The effect varied significantly among different agents (p<0.001), with the highest reduction seen in patients treated with pazopanib (RR=0.27; 95% CI: 0.21-0.35). There was no significant difference between mTOR and VEGF inhibitors (p=0.25). In addition, the targeted therapy significantly reduced the risk of mortality at 3 months (5.5% vs. 10.0%; RR=0.58, 95% CI: 0.41-0.81; p=0.002). Conclusions: The targeted therapeutic agents may significantly reduce the risk of rapid progression and early death in patients with renal cell cancer.
Analysis of molecular profiling of renal cell carcinoma: Identification of a 4-microRNA signature as a prognostic value in patients with stage I-II disease.
Authors: Castellano Daniel E. , Farfán Carlos A. , Angelo Gamez , Sepúlveda Juan M. , De Velasco Guillermo , Villacampa Felipe , Tejido Angel , Dominguez Mario , de la Rosa Federico , Fresno Juan A. 
Published: February 2017

395 Background: Renal-cell carcinoma (RCC) accounts for 3% of all cancers and produces over 12,000 deaths every year in the EE.UU. Currently, there is a need to identify stage I/II RCC patients with high risk of relapse following nephrectomy, given that these patients do not receive adjuvant treatment and ≈ 25% of them relapse. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNA and playing an important role as regulators of gene expression during tumorigenesis. Our willing is to define a miRNA expression profile associated with a high risk of relapse in early RCC. Methods: We analyzed 113 pts. with RCC stage I-II of a local data-base who had undergone nephrectomy from 2000 to 2008. RNA was extracted from FFPE samples using RecoverAll (Ambion). RNA samples were hybridized to Human miRNA Microarray Release 14.0, 8x15K (Agilent Technologies. Data were normalized using Quantile Normalization. Only 396 miRNAs with detectable signal in at least 10% of the hybridized samples were considered for further analysis. Identification of miRNAs related with recurrence risk and subsequent developing and validation of miRNA expression-based prediction models of recurrence risk were performed in BRB-ArrayTools v4.2.1. Results: We identified a 4-miRNA expression signature that distinguishes early stage RCC patients with low and high recurrence risk (p value = 0.0013; HR = 4.68 [1.82-12.0]). Distant recurrence free survival rate at five years was 97.4 and 81.2 for the low and high recurrence risk groups respectively. High levels of miR-424 were related with a high recurrence risk (p = 0.023). Conclusions: The TNM staging system lacks accuracy to identify prognostic markers of survival in early RCC. Our results suggest that specific miRNAs are involved in the recurrence of early disease. We have found a miRNA expression signature that identifies patients with high risk of developing distant metastasis using the FFPE sample of primary tumors. High expression levels of miR-424 were related with a high recurrence risk. MiR-424 is a hypoxia induced miRNA whose expression has been related with HIF-1α and HIF-2α stabilization and angiogenesis induction.
Metabolic complications with the use of mTOR inhibitors for cancer therapy: A systematic review and meta-analysis.
Authors: Sivendran Shanthi , Ying Jian , Gartrell Benjamin Adam , Agarwal Neeraj , Boucher Kenneth M. , Choueiri Toni K. , Sonpavde Guru , Oh William K. , Galsky Matt D. 
Published: February 2017

398 Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). The risk of metabolic complications with these agents is not well characterized. Methods: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. 16 eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia were extracted. Incidence rates and incident rate ratios were calculated. Results: In total, 24 trials (including 4,261 patients) were included. The average incidence rate of any grade metabolic adverse events and grade 3-4 metabolic adverse events was 0.70 per patient and 0.11 (95% CI, 0.08, 0.15) per patient respectively. Analysis of the 3,317 patients across 8 RCT’s revealed that the log incidence rate ratio (IRR) of any grade metabolic adverse events with mTOR inhibitor therapy compared with control was 1.08 (95% CI, 0.84, 1.31) using a random-effects model. The risk of grade 3-4 adverse events was also increased with an IRR of 1.52 (95% CI, 1.05, 1.99). The IRR of all grade hyperglycemia was 1.08 (95% CI, 0.76, 1.40) and of grade 3-4 hyperglycemia was 1.66 (95% CI, 1.12, 2.20). The IRR of all grade hypertriglyceridemia was 0.91 (95% CI, 0.56, 1.26) and of grade 3-4 hypertriglyceridemia was 0.70 (95% CI,- 0.43, 1.83). The IRR of all grade hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65) and of grade 3-4 hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. Conclusions: The risk of all grade and grade 3-4 metabolic adverse events are increased in patients treated with mTOR inhibitors compared with control. However, grade 3-4 metabolic adverse events remain relatively uncommon.