bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin use and outcome of sunitinib treatment in diabetic patients with metastatic renal cell carcinoma.
Authors: Keizman Daniel , Ish-Shalom Maya , Peer Avivit , Gottfried Maya , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Neiman Victoria , Rosenbaum Eli , Sarid David , Gez Eli , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Carducci Michael Anthony 
Published: February 2017

440 Background: Sunitinib (Su) is a standard treatment (tx) for metastatic renal cell carcinoma (mRCC). Pre-clinical and clinical studies in several cancer types suggest that the antidiabetic agent metformin (Met) has antitumor activity. Met may negatively regulate mTOR activity. Its effect on the outcome of targeted therapies in mRCC is poorly defined. We analyzed the effect of Met use on the outcome sunitinib tx in diabetic patients (pts) with mRCC. Methods: We performed a retrospective study of an unselected cohort of diabetic pts with mRCC, who were treated with Su in 7 centers across 2 countries. Pts were divided into 2 groups: (1) Met users and (2) Met naive. The effect of Met use on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from Cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and Met use, and outcome were performed using the entire pt cohort. Results: Between 2004-2014, 108 diabetic pts with mRCC were treated with sunitinib. There were 52 Met users (group 1) and 56 nonusers (group 2). The groups were balanced regarding the following clinicopathologic factors: age, gender, HENG risk, past nephrectomy, mRCC histology, ≥2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su-induced hypertension (HTN), and Su dose reduction/tx interruption. Clinical benefit (partial response + stable disease) in group 1 vs. group 2 was 96% vs. 84%, while 4% vs. 16% had disease progression within the first 3 months of tx (p=0.054). Median PFS was 15 vs. 11.5 months (p=0.1). Median OS was 32 vs. 21 months (p=0.001). In multivariate analyses of the entire pt cohort (n=108), factors associated with PFS were active smoking (HR=2.7, p<0.0001) and pre-tx NLR >3 (HR 1.8, p=0.012). Factors associated with OS were Met use (HR 0.2, p<0.0001), HENG risk (HR 3.3, p=0.008), active smoking (HR=2.9, p<0.0001), liver metastases (HR 1.8, p=0.004), and pre-tx NLR >3 (HR 3.3, p<0.0001). Conclusions: Met use may improve the OS of diabetic pts with mRCC that are treated with Su.
An alternative titration schedule of axitinib in metastatic renal cell carcinoma.
Authors: Alva Venur Vyshak , Wood Laura S. , Elson Paul , Martin Allison , Beach Jennifer , Garcia Jorge A. , Rini Brian I. 
Published: February 2017

444 Background: Titration of axitinib for metastatic renal cell carcinoma (mRCC) is currently based on tolerance with escalation from 10 mg/day to 14 mg/day and then to 20 mg/day. However, not all patients who can be titrated upward require a higher dose for response, nor do all patients tolerate the increased dose levels. An alternative titrating strategy was employed based on radiographic response, tolerance, and using intermediate dosing levels. Methods: In this retrospective analysis of mRCC, axitinib was initiated at 10 mg/day (5 mg BID). Response was assessed with CT scans at 6 weeks after each dosing change. Patients with response by MASS criteria and acceptable toxicity (<grade 2) were continued on the same dose. If the patient had no response and <grade 2 toxicity, axitinib was increased by 2 mg/day at each reassessment (e.g., initially to 6 mg BID), to a maximum of 20 mg/day. If the patient had >grade 2 toxicity the dose was reduced by 1 mg/day. Results: Twenty-eight patients were started on axitinib as per the above titration scheme between May 2013 and June 2014. Twenty four patients had clear cell, 3 had papillary and 1 had chromophobe mRCC, and all patients had received at least one prior systemic therapy. The final dose of axitinib ranged from 2 mg/day through 20 mg/day. Eleven patients did not change from the starting dose. Ten patients (36%) underwent dose escalation whereas 7 patients required dose reduction. Overall, for the 17 patients who had their dosage adjusted, the median time to final (current) dose was 9.9 weeks (range, 6.0-23.7), and the median time within a dose was 6.6 weeks (range, 1.1-10.0). Five of 10 patients who required dose escalation ended up on doses other than 14 mg/day or 20 mg/day (three at 12 mg/day and two at 16 mg/day). Among the dose-escalated patients, two patients had grade 1 diarrhea, one each had grade 3 diarrhea, grade 2 diarrhea, grade 1 nausea, grade 2 fatigue, grade 1 hypertension and grade 1 hand foot syndrome. The objective response rate was 17% with a median PFS of 7.4 months. Conclusions: Axitinib dose titration guided by radiographic response and toxicity is a feasible strategy with acceptable overall disease control and good tolerance. A prospective study is warranted.
Correlation between everolimus discontinuation or dose reduction induced by stomatitis or cutaneous toxicity and clinical outcome in patients with metastatic renal cell carcinoma.
Authors: Burgio Salvatore Luca , Santoni Matteo , Medri Matelda , Scarpi Emanuela , Burattini Luciano , Rossi Lorena , Savini Agnese , Berardi Rossana , Stanganelli Ignazio , Conteduca Vincenza , Cascinu Stefano , De Giorgi Ugo 
Published: February 2017

448 Background: Patients (pts) presenting with persistent moderate to severe stomatitis or cutaneous toxicity during everolimus may need of treatment discontinuation or a dose reduction. We assessed the correlation between stomatitis or cutaneous toxicity associated with either everolimus discontinuation or dose reduction and clinical outcome pts with metastatic renal cell cancer (mRCC). Methods: We retrospectively reviewed the clinical data of pts with mRCC treated with everolimus in two Italian Centers. Clinical evidence of stomatitis or cutaneous toxicity toxicity inducing a treatment discontinuation or a dose reduction were considered stomatitis-cutaneous toxicity events (SCTE). SCTE were evaluated and corresponding clinical data were reviewed for response and clinical outcome. Response was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Results: Seventy-nine mRCC pts treated with everolimus (57 male, 22 female; median age 69 years, range 44–88) were evaluated. Fifty-two pts (66%) received everolimus as second-line therapy, while 27 (34%) as third-line. SCTE were observed in 20/79 pts (25%) at a median of 30.5 days on everolimus treatment (range 10–270 days). Tumor response was evaluable in 77 of 79 patients (19 of 20 SCTE pts and 58 of 59 non-SCTE). Partial response or stable disease was achieved in 15 of 19 pts with SCTE (79%) compared to 28 of 58 (48%) with no SCTE (p=0.03). After a median follow up of 19 months (range, 1 to 39), the median progression-free survival (PFS) was 5.5 months (95% CI 3.4-7.7) and the median overall survival (OS) was 17.2 months (95% CI 13.2-24.4). A significant difference was found in the median PFS equal to 7.5 months (95% CI 3.4-24.4) in SCTE pts vs. 3.7 months (95% CI 2.7-7.5) in non-SCTE, p = 0.047, and in the median OS equal to 30.6 months (95% CI 14.8-not reached) in SCTE pts vs. 14.0 months (95% CI 9.9-17.7) in non-SCTE, p=0.004. Conclusions: These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC pts treated with everolimus.
High-dose interleukin-2 (HD IL-2) for metastatic renal Cell carcinoma (mRCC): Contemporary utilization trends in the United States.
Authors: Allard Christopher B. , Gelpi-Hammerschmidt Francisco , Harshman Lauren Christine , Faiena Izak , Modi Parth K , Chung Benjamin I. , Singer Eric A. , Chang Steven L. 
Published: February 2017

449 Background: Targeted therapies (TT) have revolutionized treatment of mRCC with broad based efficacy and tolerability but ultimately all patients progress. While HD IL-2, the prior standard of care treatment, is associated with significant toxicities, it remains the only agent proven to elicit durable complete responses albeit rarely. This study evaluated trends in HD IL-2 use for patients with mRCC during the TT era. Methods: Our study cohort was comprised of a weighted sample of 2,351 patients with mRCC undergoing HDIL-2 treatment from 2004-2012, from the Premier Hospital Database (Premier Inc., Charlotte, NC), a nationally representative hospital discharge database. We employed descriptive statistics and fitted multivariable regression models, accounting for clustering and weighting, to identify predictors of treatment toxicity and tolerability. Results: We found a progressive decrease in the use of HD IL-2 from 2004 to 2008 with a general upward trend thereafter. HD IL-2 was increasingly concentrated at academic centers representing the site of treatment for 24% of patients in 2004 versus 90% of patients in 2012. Most patients were men (75.3%), Caucasian (70.7%) and aged <60 (59.6%) with lung metastases (60.9%) and otherwise healthy (64.72%, Charlson comorbidity index=0). Our adjusted analysis showed that severe hypotension was associated with patients <50 years (odds ratio [OR]: 1.35, p=0.045), while the likelihood of receiving ≥2 cycles of HDIL-2 was associated with good health (CCI=0, OR: 1.72, p=0.004) and having >1 metastatic site (OR: 4.32, p<0.001). Conclusions: Over the past decade, the use of HD IL-2 initially diminished coinciding with the widespread availability of TT but has remerged potentially due to renewed enthusiasm for immunotherapies showing promising efficacy with novel immune checkpoint inhibitors in mRCC. HD IL-2 has increasingly been limited to academic centers and our analysis suggests a strong selection bias for younger, healthier patients who can better tolerate the toxicities and those with a greater burden of metastatic disease. Future studies are warranted to determine the optimal role of HDIL-2 in the contemporary treatment of mRCC.
A first catch, non-DRE urine exosome gene signature to predict Gleason 7 prostate cancer on an initial prostate needle biopsy.
Authors: Donovan Michael J. , Noerholm Mikkel , Bentink Stefan , Belzer Susan , Skog Johan , Brown Gordon Andrew , Cochran James S. , O'Neill Vince 
Published: February 2017

45 Background: There is a critical need to reduce initial prostate biopsies (PB) in the PSA ‘gray zone’ of 2-10 ng/mL. Non-invasive screening tools that add predictive value for identifying high-grade, Gleason score (GS) ≥7 should impact on the current diagnostic paradigm. We have developed standardized processes to isolate exosomal-RNA from first-catch urine specimens and sought to identify a gene signature that reliably differentiates GS7+ from GS6 and benign disease. Methods: First-catch non-DRE urine specimens were collected at six sites in standard collection vessels without preservative, stored at 2-8C (up to two weeks) and shipped on ice to a central laboratory (Exosome Diagnostics, St. Paul, MN). Upon receipt, samples were filtered (0.8um), and exosome isolation and RNA extraction performed. RT-qPCR RNA copy numbers of ERG and PCA3, normalized to SPDEF, were measured to generate a three-gene signature, defined to yield a score S between 0 and 30, where S>10 predicts GS7+ vs. GS6 and benign lesions with optimal NPV, Sensitivity and Specificity. Results: Urine samples from 170 men (PSA 2-10 ng/mL, first biopsy,40 mL; median age 62 years, median PSA 5.1 ng/mL, 70% negative DRE, 77%, no family history, 82% Caucasian) of 453 total, with comparable demographics, were evaluated. With 46% and 21% prevalence of positive biopsy for any cancer or GS7+ disease, respectively, a dichotomous gene signature demonstrated good clinical performance in predicting biopsy result. For GS7+, the NPV and PPV were 98.6% and 34.7%, respectively. A continuous score alone had an AUC of 0.76 for discriminating GS7+ from GS6 and benign disease and the results were significantly better than the prostate cancer prevention trial risk calculator (PCPTRC), AUC 0.60. Conclusions: A novel, non-invasive urine exosome gene signature demonstrated independent, negative predictive value for the diagnosis of GS7+ from first biopsy patients with ‘gray zone’ serum PSA. Its use in the biopsy decision process could result in fewer prostate biopsies once validated on an expanded prospective cohort.
Association between primary tumor protein expression and response to sunitinib in patients with metastatic renal cell carcinoma.
Authors: Ornstein Moshe Chaim , Knezevic Vlado , Rini Brian I. , Vaishampayan Ulka N. 
Published: February 2017

450 Background: Sunitinib is FDA-approved and widely used as frontline treatment for metastatic renal cell carcinoma (mRCC), but there is a large degree of variability in patient (pt) response to therapy. The association of baseline primary tumor expression of multiple proteins and objective response to sunitinib was investigated. Methods: Primary tumor samples from clear cell mRCC pts treated with sunitinib as frontline therapy at two academic institutions were retrieved. Layered immunohistochemical (LIHC) assay which allow the detection of multiple biomarkers in a single tissue section was used to evaluate the expression of 8 proteins (VEGFR1, VEGFR2, p-mTOR, p-4E-BP1 S65, VEGF A, 4E-BP1, PDGFRb, CAIX) on tumor cells. Pts were characterized as Responders (Complete Responders (CR), Partial Responders (PR) and Stable diseases (SD)) or Non-Responders (NR) based on investigator-assessment. The 8 proteins were tested separately and the area under the receiver operator characteristic (ROC) curve (AUC) analysis was used to compare the predictive power of each biomarker and their combinations. Results: 38 pts were eligible for evaluation; 29 responders and 9 non-responders. Of the 8 biomarkers tested individually, only PDGFRb and CAIX were statistically significant in providing a predictive value for response to sunitinib. Of the different possible biomarker combinations, the combination of increased levels of CAIX expression and decreased 4E-BP1 expression provided the highest ROC AUC (0.9) for predicting response. When stable disease cases were removed from the responders group, in addition to CAIX and 4E-BP1, increased levels of PDGFRb expression predicted response (AUC was 0.889). Conclusions: Baseline primary tumor expression of CAIX and 4E-BP1 is associated with an objective response to sunitinib in pts with mRCC.
Identification of actionable targets in chromophobe renal cell carcinoma detected by multiplatform molecular analysis.
Authors: Abbosh Philip , Geynisman Daniel M. , Doll Nancy , Hauben ADAM , Reddy Sandeep K. , Millis Sherri Z. , Uzzo Robert G. 
Published: February 2017

451 Background: Chromophobe renal cell carcinoma (chRCC) is a rare kidney cancer subtype that infrequently metastasizes or recurs after definitive local therapy. Limited biomarker data exists to prognosticate outcome or predict response to therapy. We explored the utility of multiplatform tumor profiling, which uses immunohistochemistry (IHC) and targeted next generation sequencing (tNGS) to identify druggable targets, with the intent of developing targeted therapy protocols in patients with (chRCC). Because of the non-aggressive nature of small chRCCs, we excluded T1a tumors. Methods: Cases were identified from 65,000+ tumors submitted for commercial testing at Caris Life Sciences. All tissues were internally reviewed by a dedicated genitourinary pathologist to confirm diagnosis. Markers were analyzed on tumor tissue removed during partial or radical nephrectomy. IHC was performed on 19 proteins. FISH was performed on EGFR, HER2, and TOP2A. tNGS was performed on 47 genes. Results: Twelve patients with chRCC were profiled. Five patients had metastatic disease. Median age was 54 years old; 50% of patients were male. One patient had a T1b tumor, two patients had T2 tumors, 8 patients had T3 tumors, and one had a T4 tumor. Thymidylate synthase (TS), ribonucleotide reductase M1 (RRM1), and O-6-methylguanine-DNA methyltransferase (MGMT) expression was absent in 12/12, 11/12 and 11/12 tumors, respectively. PTEN expression was absent in 7/12 of tumors. cKIT and PDGFR was expressed in 6/9 and 0/4 tumors, respectively. Lastly, point mutations in APC and TP53 were detected in 1/7 and 3/7 tumors, respectively. No mutations were identified in the other 45 genes tested and no changes in copy number were identified. Conclusions: Biomarker analysis showed that advanced chRCC might be amenable to chemotherapy with 5-fluorouracil, gemcitabine, or temozolamide because of absent TS, RRM1, and MGMT expression, respectively. Such rationale has been used successfully in targeted treatment of other cancers. In addition, sunitinib or imatinib but not sorafenib might be preferred tyrosine kinase inhibitors, as cKIT but not PDGFR was detected.
Robustness of the 16-gene signature for prediction of recurrence-free interval in localized clear cell renal cell carcinoma.
Authors: Escudier Bernard J. , Koscielny Serge , Maddala Tara , Svedman Christer , Verkarre Virginie , Radulescu Camelia , Neuzillet Yann , Timsit Marc Olivier , Hemmerlé Isabelle , Tsiatis Athanasios C. , Bonham Michael , Knezevic Dejan , Martini Jean-Francois , Williams James Andrew , Lebret Thierry , Goddard Audrey D. , Mejean Arnaud 
Published: February 2017

455 Background: The Renal Cancer assay is a clinically validated RT-PCR assay developed to estimate the risk of recurrence in stage I-III clear cell renal cell carcinoma (ccRCC) patients (pts) treated with nephrectomy. The assay measures expression of 16 genes that are combined to calculate the Recurrence Score result (RS). The RS is associated with recurrence, renal cancer-specific survival and overall survival (all p<0.001) (Escudier, ASCO 2014). The performance of the RS in clinically relevant subgroups, compared to the Leibovich score, and its within-patient variability was examined. Methods: The algorithm, endpoints, methods, and analysis plan were pre-specified prior to merging clinical and molecular data. RT-PCR of RNA from fixed paraffin-embedded ccRCC tissue was performed without knowledge of clinical data. Recurrence-free internval (RFI) was analyzed using Cox regression stratified by stage with data censored at 5 years, and Kaplan-Meier methods. Multivariable models incorporating the Leibovich score were used to assess the additional contribution of the RS to prediction of recurrence. Within- and between-tumor block reproducibility was assessed in an independent study using two separate tumor blocks from 8 pts, where each block was analyzed at 3 depths. Results: RS was generated in 626/645 pts (97%): 398 stage I, 54 stage II, 174 stage III. Median follow up was 5.5 yrs. The RS was significantly associated with risk of recurrence after adjustment for the Leibovich score (HR=4.20, p<0.001). Additionally, the performance of RS was similar across age groups (<60, 60-70 or ≥70), gender, nephrectomy type, tumor size (≤4, 4-7 or >7cm), grade, and presence/absence of invasion (all interaction p>0.29). Within-patient variability in the score (std. dev. of 1.73 and 4.74 RS units for within- and between-tumor block, respectively) was lower than patient-to-patient variability (std. dev. of 15.6 in validation study). Conclusions: The 16-gene signature remains strongly associated with risk of recurrence after adjustment for the Leibovich score and performs consistently across clinically relevant subgroups. Examination of within-patient and between-patient variability indicates that the score is robust to tumor heterogeneity.
Correlation of endothelial angiopoietin-2 expression with tumor angiogenesis and response to sunitinib in metastatic renal cell carcinoma.
Authors: Rautiola Juhana , Lampinen Anita , Ristimäki Ari , Mirtti Tuomas , Joensuu Heikki , Bono Petri , Saharinen Pipsa 
Published: February 2017

461 Background: The endothelial growth factor angiopoietin-2 (Ang2) is a target for novel anti-angiogenic therapies, but its potential as a biomarker remains unknown. Methods: We evaluated Ang2, CD31 and Ki67 expression in tumors of 136 patients with metastatic RCC (mRCC) treated with first-line sunitinib from tumor samples. Results: Ang2 was exclusively expressed in the endothelial cells of tumor blood vessels. Using a cutoff of ≥50 Ang2+ vessels/microscopic field, 38% of the samples had high Ang2 expression. High Ang2 expression correlated with high CD31+ vessel density (p=0.002). 91% of patients with high Ang2 expression had partial response (PR) or stable disease (SD) as best response to sunitinib compared to 76% of those with low Ang2 expression (p=0.033). High CD31+ vessel density correlated with high clinical benefit rate (p=0.015), and with low levels of Ki-67+ tumor cells (p=0.018). Combined high expression of both Ang2 and CD31 predicted a better clinical benefit rate with 100% of the patients with high Ang2 and CD31 expression (n=25) achieving PR/SD compared to 77% among the rest of the patients (n=101; p=0.007). Only one (8%, n=12) patient with papillary RCC had high Ang2 expression, whereas 49 (41%, n = 120) patients with clear cell RCC had high Ang2 expression (p=0.03). Conclusions: In this first study to investigate Ang2 expression and outcome in mRCC patients treated with an angiogenesis inhibitor, high Ang2 expression in the tumor vasculature was predictive for sunitinib efficacy.
Exploring the effect of medication features in renal cell carcinoma: A patient preference study.
Authors: Srinivas Sandy , Mansfield Carol , Sandin Rickard , Hauber A. Brett , Hariharan Subramanian , Matczak Ewa , Pugh Amy , Chen Connie 
Published: February 2017

463 Background: Limited information exists about patient preference (PP) for renal cell carcinoma (RCC) medication profiles, especially related to uncertainty in outcomes, potential correlation between toxicity and efficacy, and dosing schedules. Methods: RCC patients in the United States and Canada completed an online survey with questions that examined PP for medication profiles by varying efficacy (progression free survival [PFS]), tolerability (fatigue, hand-foot syndrome, hypertension, diarrhea) and dosing schedules (with or without 2 week break). A discrete-choice experiment (DCE) survey tested the impact of information on correlation between PFS and toxicity on medication choice, with half of the sample randomly assigned to receive the information. Separate exploratory questions assessed patient tradeoff between higher toxicity during treatment vs. the chance of longer PFS (2+ years) and type of dosing schedules, respectively. Results: The interim survey results included 343 RCC patients (172 metastatic (mRCC), 96 currently on treatment). In the exploratory questions, 50% of mRCC patients and 51% of patients receiving treatment selected the option with higher toxicity and a 5% higher chance of longer PFS. Patients who received information on a potential correlation between tolerability and PFS were more likely to say they would tolerate worse toxicity for a 5% higher chance of longer PFS than those who did not receive the information (49% vs. 31%). A majority of RCC patients preferred a treatment with a 2-week break in the dosing schedule compared to continuous treatment (59% vs. 25%). When told side effects were worse during the treatment period for the medication with the break vs. the continuous treatment (moderate vs. mild), 42% of RCC patient, 50% of mRCC patients, and 55% patients on treatment still preferred a break. Additional DCE analysis is underway and will provide more results on patient preferences for medication profiles, including the importance of information received. Conclusions: Patients have heterogeneous preferences over medicine features and outcomes. Physicians need to provide patients with comprehensive information about medication features and efficacy to provide a personalized and optimal approach to treatment.