bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation signature to define cell ontogeny of renal cell carcinomas.
Authors: Malouf Gabriel G. , Su Xiaoping , Zhang Jianping , Ho Thai Huu , Lu Yue , Raynal Noel J-M , Karam Jose A , Tamboli Pheroze , Allanick Frederick , Mouawad Roger , Khayat David , Wood Christopher G. , Jelinek Jaroslav , Tannir Nizar M. 
Published: February 2017

536 Background: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype-phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron. Methods: We performed deep profiling of DNA methylation in diverse histopathological RCC subtypes and validated DNA methylation and transcriptome signatures in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets. Results: Our data provide the first mapping of methylome epi-signature and indicates that RCC subtypes can be grouped into two major epi-clusters: C1 which encompasses clear cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2 which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed three fold more hypermethylation as compared to C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC. Conclusions: Taken together, our data defines the epi-clusters that can discriminate between distinct RCC subtypes and for the first time, to our knowledge, define the epigenetic basis for proximal versus distal tubule derived kidney tumors.
Integrated genomic correlates of response to PD-1 inhibitor nivolumab in metastatic renal cell carcinoma (mRCC).
Authors: de Velasco Guillermo , Miao Diana , Shukla Sachet , Voss Martin Henner , Wu Catherine , Murray Bradley , Meyerson Matthew , Signoretti Sabina , Motzer Robert J. , Van Allen Eliezer Mendel , Choueiri Toni K. 
Published: February 2017

545 Background: Nivolumab (nivo) is a programmed death-1 (PD-1) inhibitor that has recently been shown to increase overall survival in patients with mRCC. The association between benefit from nivo with neoantigen load, mutation load and signatures of immune infiltration has yet to be explored in mRCC. Methods: Publicly available whole exomes (WES) and whole transcriptomes (RNA-seq) from over 300 clear-cell RCC patients in the Cancer Genome Atlas (TCGA) were analyzed for mutational load, neoantigen load and expression of immune-related genes. HLA types were inferred from WES with Polysolver and neoantigens were predicted from somatic nonsynonymous mutations with NetMHCpan3.2. The same analysis pipeline was applied to paired pre-treatment germline and metastatic tumor specimens from 9 patients who received nivo for mRCC: 3 responders (CR or PR by RECIST; R) and 6 non-responders (SD or PD by RECIST; NR), all with available pre-nivo fresh biopsies of metastatic lesions. Matched RNA-seq was available on a subset of these patient samples (3 R, 3 NR). Results: Across the TCGA and nivo-treated patients cohorts, RCC had relatively few nonsynonymous mutations and neoantigens. Among the nivo-treated patients, neoantigen load was significantly higher in NR compared to R (p = 0.048), but nonsynonymous mutation load was not. An exceptional R who experienced CR (PFS > 30 months) had outlying higher expression of selected immune-related genes compared to the 8 other patient samples (p < 0.05 for PD-L1, PD-L2; p < 0.01 for CTLA4, PD-1, PRF1; p < 0.001 for GZMA, BTLA, CD8A), and was in the top 1-5% of expression of these genes among all TCGA data. Bootstrapping analysis comparing mean expression in R vs NR compared to an empirical distribution of TCGA RNA-seq data showed significantly higher expression of PD-1, PD-L1, GZMA, LAG3, IDO1, ICOS, and BTLA in R vs. NR (p < 0.05). No genes were enriched for nonsynonymous mutations in R or NR. Conclusions: This analysis suggests that both DNA- and RNA-level data may be relevant for explaining clinical benefit from nivo in mRCC. In contrast with results from other tumor types, responders to nivo did not have more mutated tumors, though immune-related gene expression may be related to response.
Association between diabetes mellitus and the survival of sunitinib-treated patients with metastatic renal cell carcinoma.
Authors: Suyama Takahito , Fujimoto Ayumi , Kanesaka Manato , Hou Kyokushin , Araki Kazuhiro , Masuda Hiroshi , Kojima Satoko , Sazuka Tomokazu , Nakamura Kazuyoshi , Nihei Naoki , Ichikawa Tomohiko , Naya Yukio 
Published: February 2017

546 Background: Diabetes mellitus is one of the major risk factor for renal cell carcinoma (RCC) development. Although, in various cancers, the relationship between diabetes mellitus and worse prognosis is pointed out, the association between RCC prognosis and diabetes mellitus is under discussion. We sought to determine the association between diabetes mellitus with outcome of sunitinib treatment in metastatic RCC (mRCC) patients. Methods: A retrospective study of sunitinib-treated mRCC patients was performed. 69 patients who had been treated with sunitinib in Japanese two institutions (Teikyo University Chiba Medical Center and Chiba University) were entered. Kaplan-Meier and the log-rank test were performed to investigate the association between the pretreatment status of diabetes mellitus and the outcome of the patients who received the treatment with sunitinib. Results: Between 2008 and 2015, 69 mRCC patients were treated with sunitinib. 53 (76.8%) patients received sunitinib treatment as the first line molecular target drug. 15 (21.7%) patients were diagnosed as diabetes mellitus at the time of sunitinib treatment. Median time to treatment failure (TTF) was 7.1 months, cancer specific survival (CSS) was 33.9 months for all patients. With regard to TTF, there was no difference between diabetic and non-diabetic patients, 9 months for diabetic patients and 7.1 months for non-diabetic patients respectively (P = 0.3271). CCS was significantly shorter for diabetic patients, 11 months for diabetic patients and 39.4 months for non-diabetic patients respectively (P = 0.0469). When focusing on HbA1c, CSS was significant longer for the patients with HbA1c under 6.5% than the patients with HbA1c was 6.5 or more, median CSS was 44.5 months and 11.3 months, respectively (P = 0.0055). Conclusions: Diabetes mellitus did not influence the TTF of sunitinib treatment for mRCC patients. Diabetes mellitus may negatively affect the CSS of sunitinib-treated mRCC. Clinicians should consider controlling patient’s HbA1c status at the initiation of sunitinib treatment for mRCC.
Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14-003.
Authors: Dudek Arkadiusz Z. , Sica R. Alejandro , Sidani Amer , Jha Gautam Gopalji , Xie Hui , Alva Ajjai Shivaram , Stein Mark N. , Singer Eric A. 
Published: February 2017

559 Background: Renal cell carcinoma (RCC) tumor vasculature is abnormal and does not provide nutritive blood flow, which results in regions of hypoxia. This hypoxia contributes to the immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma. In addition, tumor angiogenesis enhances activity of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that suppress innate anti-cancer immunity. It has been demonstrated in preclinical models that antiangiogenic therapy decreased the number of MDSCs and changed polarization of TAMs from an immunosuppressive (M2-like) to an immunostimulatory (M1-like) phenotype. We hypothesized that therapy with bevacizumab will normalize the tumor vasculature, promote M1-like phenotype of TAMs, and thus potentiate the immunotherapeutic activity of pembrolizumab. As a prerequisite to testing this hypothesis, the objective of this study was to establish the safe dose of bevacizumab when used in combination with pembrolizumab. Methods: Our subject population included males and females (age > 18 y) with metastatic clear cell RCC after failure of at least one systemic therapy. In this Phase Ib dose escalation study, pembrolizumab (200 mg fixed dose every 3 weeks) was given in combination with bevacizumab (either at 10 mg/kg or 15 mg/kg every 3 weeks). The primary endpoint was to establish the maximum safe dose. Results: 12 subjects have been enrolled: 10 males (ages 33-68 y, mean: 52.7, median: 54.5) and 2 females (ages 61 and 62 y). To date 3 patients have received 1 cycle; 2 patients have received 2, 3, and 4 cycles each; and there are single patients who have received 5, 6, and 7 cycles each. No dose-limiting toxicity or serious adverse events related to the study drug have been reported. There were no grade 3 or 4 drug-related toxicities noted, and the most common grade 1 and 2 toxicities were diarrhea, fatigue, fever, hypertension, nausea, rash, and rigors. Conclusions: The 200 mg fixed dose of pembrolizumab and 15 mg/kg dose of bevacizumab, both given every 3 weeks, was determined to be safe and recommended for a multicenter Phase 2 study that is ongoing. Clinical trial information: NCT02348008.
The role of metastasectomy in patients with renal cell carcinoma with sarcomatoid dedifferentiation: A matched controlled analysis.
Authors: Thomas Arun Z. , Adibi Mehrad , Slack Rebecca , Borregales Leonardo Daniel , Merrill Megan M. , Tamboli Pheroze , Sircar Kanishka , Jonasch Eric , Tannir Nizar M. , Matin Surena F. , Wood Christopher G. , Karam Jose A. 
Published: February 2017

565 Background: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive tumor generally associated with a poor clinical course. Management of metastatic sRCC remains a therapeutic challenge with no standard treatment strategies. Our objective was to evaluate whether metastasectomy has any survival benefit in patients with synchronous or asynchronous metastatic sRCC treated with radical nephrectomy (RN). Methods: From an institutional database of 273 patients with sRCC treated with nephrectomy, we matched 80 patients with synchronous and asynchronous metastasis for age, ECOG performance status, histology and nodal status. Matched pairs were then retained only if patients who did not undergo metastasectomy were comparably alive at the time of metastasectomy in matched surgical patients to reduce the bias in survival outcomes. Overall survival (OS) from nephrectomy was studied using univariable and multivariable proportional hazards regression. Results: Median OS was 8.3 months (95%CI 6.5-10.5 months) and 18.5 months (95%CI 11.5-42.9 months) for patients with synchronous and asynchronous metastases, respectively. OS for patients undergoing metastasectomy for synchronous metastasis was comparable to non-surgical patients (8.4 and 8.0 months, respectively, p=0.35). Similarly, within the asynchronous cohort, median OS was 36.2 months (95%CI 7.6-Not Reached) in the metastasectomy group and 13.7 months (95%CI 8.8-41.6) in the non-metastasectomy group (p=0.29). On multivariable analysis, positive lymph node (LN) at nephrectomy was associated with increased risk of death in both synchronous and asynchronous patients groups; (HR=2.1 [95%CI 1.1-4.0] p=0.03) and (HR=3.3 [95%CI 1.2-9.2] p=0.02), respectively. Conclusions: Metastasectomy in patients with synchronous or asynchronous metastases after nephrectomy does not appear to confer significant survival benefit in patients with sRCC, particularly in patients with pathological LN positive disease at nephrectomy.
PD-1 expression and its impact on survival in localized clear cell renal cell carcinoma.
Authors: Sekar Rishi Robert , DiMarco Michelle A. , Patil Dattatraya , Osunkoya Adeboye O. , Pollack Brian P. , Sica Gabriel , Master Viraj A. 
Published: February 2017

568 Background: Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have been shown to have activity in advanced renal cell carcinoma (RCC), prompting research into PD-1 as a potential biomarker. In this study, we evaluate tumor PD-1 expression and its prognostic value in patients with localized clear cell RCC. Methods: Patients that underwent nephrectomy for localized clear cell RCC (T1-T3) with >4 years of follow-up were queried from our nephrectomy database. Tissue blocks with tumor and adjacent benign renal parenchyma were selected for analysis. Immunohistochemical staining for PD-1 was performed on tumor specimens using anti-PD-1 clone NAT105 (Abcam). Focusing on immune cells, PD-1 positivity was defined as >1% expression and graded in 10% increments. The relationship between PD-1 positivity, FNG, and TNM stage was evaluated using Pearson’s chi-square test. The impact of PD-1 positivity on overall and recurrence-free survival was evaluated using the Kaplan-Meir method. Results: Fifty-three patients were included in the study. The distribution of PD-1 expression in 10% increments can be seen in Table. No statistically significant correlation was found between PD-1 positivity, TNM stage and FNG (chi-square test; p=0.15, p=0.62, respectively). No statistically significant differences in overall or recurrence-free survival were found between positive and negative PD-1 expression groups (log-rank; p=0.32, p=0.43, respectively). Conclusions: Our data show that primary tumor PD-1 expression varies widely in patients with clear cell RCC and that PD-1 positivity does not correlate with commonly reported histopathological features such as TNM stage and FNG. Further, PD-1 positivity does not have a significant impact on overall and recurrence-free survival. These findings contrast with previous studies of PD-1 expression in RCC, suggesting that further research into the role of PD-1 in tumor progression as well as methods of case/tissue block selection and PD-1 quantification is needed. [Table: see text]
Pilot study of dovitinib in patients with VHL disease.
Authors: Pilie Patrick Glen , Matin Surena F. , Woodson Ashley Henriksen , Marcott Valerie D. , Bird Shelly , Slack Rebecca , Fuller Greg , McCutcheon Ian E. , Jonasch Eric 
Published: February 2017

587 Background: Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease occurring in 1 in 35,000 births. Individuals with germline mutations in the VHL gene may phenotypically express a variety of lesions including hemangioblastomas (HBs), pancreatic cysts, renal cysts, and renal cell carcinomas (RCC). Previous studies have shown differentially increased FGFR3 levels in HBs compared to RCC. In this pilot trial, we investigated the safety and efficacy profile of TKI 258 (dovitinib), a tyrosine kinase inhibitor of VEGF and FGF receptors, in VHL related lesions, focusing on HBs. Methods: A MDACC IRB-approved protocol planned to enroll 25 subjects who had genetically confirmed VHL disease or clinical diagnosis of VHL, and measurable HBs with no immediate risk of needing intervention. Dovitinib 500mg/day was given in a 4 week cycle on 5 day on/2 day off schedule. In the absence of adverse events (AE), treatment lasted 6 cycles or until disease progression. Evaluation of response to treatment was done every 8 weeks including imaging, laboratory, and clinical evaluation. The trial design used a continuous Bayesian stopping rule based on toxicities that resulted in discontinuation of dovitinib and another for lack of efficacy. Signed informed consent completed on all patients enrolled. Results: Trial stopped after six patients enrolled due to toxicity stopping rule. Patients’ ages ranged 18-61 with 5/6 being male. With regards to safety, 6/6 subjects had at least one AE with the most common AEs being rash, diarrhea, and fatigue including a grade 3 AE (severe rash) in one patient. 1/6 was stopped due to noncompliance, 1/6 stopped due to progression, 3/6 stopped due to side effects despite dose reduction, and 1/6 completed full six cycles at full dose. Best response in 6/6 subjects was stable disease (SD) in HBs. Conclusions: This pilot study of dovitinib in patients with VHL disease with measureable HBs did not show a favorable safety or efficacy profile for this dose and schedule. Half of the patients discontinued the drug due to AEs before study completion, and the best achieved response was SD. Further investigation into alternative scheduling and other FGFR inhibitors in the treatment of HBs is warranted given the strong pre-clinical data. Clinical trial information: NCT01266070.
The relationship between preoperative c-reactive protein and Fuhrman nuclear grade in stage T1 renal cell carcinoma.
Authors: Sekar Rishi Robert , Patil Dattatraya , Pearl Jeff , Baum Yoram , Alemozaffar Mehrdad , Filson Christopher Paul , Ogan Kenneth , Master Viraj A. 
Published: February 2017

593 Background: In an era of active surveillance for small renal masses (SRMs), non-invasive predictors of tumor aggressiveness may be helpful in identifying high-risk patients for surgical intervention. In this study, we evaluate the predictive value of preoperative C-reactive protein (CRP) on Furhman Nuclear Grade (FNG) in patients with stage T1 renal cell carcinoma (RCC). Methods: Patients who underwent nephrectomy for stage T1 RCC with documented preoperative CRP within 15 days of surgery were included in the study. Surgical pathology reports were used to determine TNM stage and FNG. Receiver operating characteristic (ROC) analysis, sensitivity-specificity analysis, and Youden index were used to determine the optimal threshold of preoperative CRP in predicting FNG 4 disease versus FNG 1-3 disease. Logistic regression analysis was then performed to assess the significance and independence of preoperative CRP in predicting FNG 4 disease. Results: 351 patients were included in the study. On ROC analysis, area under the curve (AUC) was 0.7576. The optimal threshold of preoperative CRP was determined to be 4.8 mg/dL. On univariate and multivariate analysis, CRP ≥ 4.8 mg/dL was found to be a significant and independent predictor of FNG 4 disease (log-rank, p=0.014, p=0.006, respectively). Conclusions: Our data show that preoperative CRP ≥ 4.8 mg/dL is a significant and independent predictor of FNG 4 disease in patients with stage T1 RCC. These findings suggest that a standardized and cost-effective preoperative laboratory value can provide crucial prognostic information in patients undergoing active surveillance for SRMs, allowing for improved patient selection for definitive surgical therapy. [Table: see text]
Long-term response to sunitinib treatment in metastatic renal cell carcinoma (mRCC).
Authors: Tannir Nizar M. , Figlin Robert A. , Gore Martin Eric , Michaelson Dror , Motzer Robert J. , Porta Camillo , Rini Brian I. , Hoang Caroline J. , Lin Xun , Escudier Bernard 
Published: February 2017

598 Background: A subset of patients (pts) with mRCC treated with sunitinib achieves a long-term response. This study aimed to characterize the duration of treatment and clinical outcomes of pts with mRCC who were long-term responders (LTRs), defined as pts who had progression-free survival (PFS) > 2 years, while on sunitinib therapy. Methods: A retrospective analysis of data from 5714 pts with mRCC treated with sunitinib in 8 phase II or III clinical trials and pts treated in the expanded access program (EAP). Data on treatment duration and response to treatment were compared between LTRs and pts who had PFS ≤ 2 years (others). Results: A total of 529 (9.3%) pts achieved a long-term response, 5162 (90.3%) achieved other response, and data were missing for 23 (0.4%) pts. Overall, 309 (5.4%) pts achieved PFS between >2 and ≤3 years, 125 (2.2%) pts achieved PFS between >3 and ≤4 years, 62 (1.1%) pts achieved PFS between >4 and ≤5 years, and 33 (0.6%) pts achieved PFS between >5 and ≤6 years. The median (range) duration of sunitinib treatment was 36.7 (23.4–71.7) months for LTRs versus 6.5 (0–69.8) months for others. Response rates comparing LTRs versus others are presented in Table. Conclusions: With over 500 pts with mRCC achieving PFS >2 years and 33 achieving PFS >5 years, this analysis of sunitinib LTRs is the largest published to date. Additional analyses are being conducted to describe the clinical characteristics of these LTRs and identify risk factors that may predict long-term response. [Table: see text]
Initial compared to deferred cytoreductive nephrectomy for metastatic kidney cancer and its association with improved survival in the targeted therapy era.
Authors: Macleod Liam Connor , Tykodi Scott S. , Holt Sarah , Gore John L. 
Published: February 2017

607 Background: Since 2005 seven new agents were approved for metastatic renal cell carcinoma (mRCC), demarcating a transition from the cytokine to the targeted therapy era. Trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) pre-2005. However, upfront versus delayed CN relative to targeted therapy has not been reported in the trial arena. We hypothesized that upfront CN confers a survival benefit in the targeted therapy era. We analyze survival in a population based cohort exposed to targeted therapies with upfront CN compared to deferred CN. Methods: Patients from SEER registries (2005-2011) with mRCC were categorized into: 1.) CN followed by targeted therapy or 2). initial targeted therapy. Additional exclusions were age < 66, due to chance of uncaptured non-Medicare care, competing non-renal stage IV cancer and non-clear cell histology. Targeted therapy was identified from Medicare Part D files (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib, temsirolmus, everolimus) and duration of use. Clinical data, including co-morbidities, were obtained from Medicare inpatient and outpatient files, and cancer data from Medicare-linked SEER files. Unadjusted and multivariable Cox proportional hazards regression determined association between survival in the two groups. Propensity matching with bootstrapping was performed to control for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases screened, 491 met the inclusion criteria. Median survival in the initial CN group (N = 194) was 20 months (IQR 12-32) compared to 14 months (IQR 6-27) in the initial targeted therapy group (N = 297, p < 0.01). On multivariable analysis upfront CN was associated with improved survival (HR 0.57 95% CI 0.44, 0.74). On propensity matched analysis the survival advantage (average treatment effect on the treated, ATT) for upfront CN was 7.4 months (95% CI 3.86, 11.21). Conclusions: This study population closely resembles the treatment groups in ongoing randomized trials on the surgical management of mRCC in the targeted therapy era and demonstrates a survival advantage for upfront CN.