bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patients’ perspective of quality-of-life issues in a randomized study in open surgery of patients with renal cell carcinoma.
Authors: Kroger Dahlin Britt-Inger , Thurm Mascha , Winso Ola , Ljungberg Borje 
Published: March 2019

642 Background: This randomized study in patients treated with open surgery for renal cell carcinoma (RCC), aimed to evaluate if effective perioperative analgesia can be part of a multimodal approach to minimize morbidity and improve postoperative management [1]. To evaluate the patients’ perspectives, a survey was used before surgery and one month after surgery. Methods: Between 2012 and 2015, 135 patients with RCC, in all stages, were randomized to receive either spinal analgesia with added clonidine, or epidural analgesia in addition to general anesthesia: The patients were stratified according to surgical technique. Inclusion criteria: ASA score ≤ III, age > 18 years, and no chronic pain medication or cognitive disorders. The patient’s survey used was based on the EORTC QLQ-C30 formula. Wilcoxon Signed Rank test and Mann-Whitney-U tests were used for statistical evaluation. Results: Most patients (117 of 135, 86 %) responded to the survey postoperatively. Patients groups treated with partial nephrectomy or radical nephrectomy both had significantly reduced physical and social functioning while emotional functioning improved postoperatively. In both surgical groups the patients reported significant negative financial difficulties. Similar results was achieved for patients treated with either spinal or epidural anesthesia. The epidural group of patients experienced more negative social functioning but had an improved global health. When comparing the surgical procedures there was no significant difference in the quality of life parameters. However when comparing the analgesic groups, spinal anesthesia had significantly better physical and social functioning while the patients in the epidural group reported better global health. Conclusions: In this randomized controlled study on nephrectomy, patients treated with spinal analgesia with clonidine, had better physical and social functioning postoperatively than patients treated with epidural analgesia. Clinical trial information: NCT02030717.
Results of a phase II study to evaluate the safety and efficacy of RX-0201 in combination with everolimus in subjects with metastatic renal cell carcinoma (mRCC).
Authors: Agarwal Neeraj , Pal Sumanta K. , Lauer Richard C. , Chatta Gurkamal S. , Goel Sanjay , Singh Parminder , Sundararajan Srinath , Heaton Callie , Peterson Christine , Benaim Ely , Tagawa Scott T. 
Published: March 2019

646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, preventing AKT-1 expression and limiting the amount of downstream p-AKT. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. RX-0201, in combination with everolimus, to treat mRCC was evaluated in a Phase 1b/2 clinical study. Methods: This Phase 1b/2 study (2‐stage design, NCT02089334 ) evaluated the efficacy and safety of RX‐0201 in combination with everolimus in eligible subjects with mRCC. Eligible subjects must have had confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment. In Phase 1 subjects were enrolled at increasing doses of RX-0201 (delivered via continuous IV for 14 days) in combination with 10 mg/day everolimus in a modified 3+3 design. The target dose of RX-0201 identified in Phase 1, 250 mg/m2/day, was further evaluated in Phase 2. Primary objectives included the safety and efficacy at the recommended Phase 2 dose. The Phase 2 primary endpoint was progression free survival (PFS) benefit for at least 4.5 months. Results: Eleven subjects (7 males, 4 females) with mRCC were treated with RX-0201 (250 mg/m2/day) + everolimus (10 mg/ day) in Phase 2. The median age was 63 years, ECOG performance status at screening was 0 to 1, and 55% received ≥ 3 prior therapies. The median PFS in evaluable subjects was 4.9 months. Four subjects had stable disease after 6 months of treatment. The most frequent related adverse events ( > 15%) were G1/2 epistaxis, G3 fatigue, G1/2 nausea and G1 vomiting. Conclusions: In this mRCC population with extensive prior therapy, RX‐0201 in combination with everolimus was safe, well-tolerated, and showed promising efficacy. The results also support the therapeutic significance of the AKT-1/mTOR pathway in mRCC. Clinical trial information: NCT02089334.
Safety and efficacy of immune checkpoint inhibitors (CPI) in metastatic renal cell cancer (RCC) and urothelial cancer (UC) patients (pts) with pre-existing autoimmune disorders (AD).
Authors: Martinez Chanza Nieves , Xie Wanling , Kaymakcalan Marina D. , Nassar Amin , Abou Alaiwi Sarah , Nuzzo Pier Vitale , Flippot Ronan , Hamid Anis , El Bakouny Ziad , Wei Xiao X. , McGregor Bradley Alexander , Sonpavde Guru , Choueiri Toni K. , Harshman Lauren Christine 
Published: March 2019

653 Background: The pivotal clinical trials of CPI generally excluded pts with AD given concern for serious exacerbations. There is limited data on the safety and efficacy of CPI in this population. Methods: We conducted a retrospective single center analysis of RCC and UC pts treated with CPI. Pts were grouped by presence or absence of AD. We catalogued the incidence of new irAEs (CTCAEv4), AD exacerbations, objective response rate (ORR, RECIST 1.1), and overall survival (OS, Kaplan Meier). Competing risk models estimated cumulative incidences of irAEs and CPI discontinuation using 6 months (mos) as a benchmark. Results: 271 RCC and 220 UC pts were identified. Median followup was 21 mos for RCC and 13 mos for UC. 25 (9%) RCC and 27 (12%) UC had pre-existing AD; most commonly dermatologic and rheumatologic. A minority (3% RCC/4% UC) had clinically active AD requiring concurrent immunomodulators. AD exacerbations occurred in 8 (32%) RCC and 12 (44%) UC; median time to exacerbation was 86 (25-270) and 27 (8-300) days, respectively. Cumulative incidence of new irAEs at 6 mos was numerically higher in RCC AD pts (50% vs 37%). CPI discontinuation and clinical outcomes were similar among AD and non-AD pts (Table). Conclusions: CPI are active in advanced RCC and UC pts with pre-existing AD. Exacerbations and new irAEs should be expected, but AD pts can experience similar outcomes and rates of drug discontinuation. Larger scale investigations are warranted. [Table: see text]
Relation between clinicopathological findings and PD-1 or PD-L1 status in non-clear cell renal cell carcinoma by a multicenter study.
Authors: Matsumoto Hiroaki , Nagao Kazuhiro , Samoto Masahiro , Mori Junichi , Shimizu Kosuke , Inoue Ryo , Yamamoto Yoshiaki , Yano Seiji , Hirata Hiroshi , Shimabukuro Tomoyuki , Matsuyama Hideyasu 
Published: March 2019

654 Background: We investigated correlation of their pathological findings and their prognostic factors in non-clear cell renal cell carcinoma (ncRCC) diagnosed by both regional pathology (RP) and central pathology (CP) in multicenter study. Methods: In January 2005 to December 2014, 140 cases of ncRCC diagnosed by radical or partial nephrectomy were assessed. We assessed their pathological diagnosis by one central pathologist using the 2016 WHO classification tumor of the kidney. We assessed the correlation between clinical parameters or pathological findings and their prognosis. Then, we performed immunohistochemical analysis using PD-1 related antibody in ncRCC. Results: Median follow up was 32.7 months (1-134). Median age was 66 years, 99 males and 41 females. Pathological stage was pT1a: 58, pT1b: 30, pT2a: 17, pT2b: 6, pT3a: 21, pT3b: 2, pT4: 3 cases, respectively. In RP, histology was papillary (PAP): 60 (42.9%), chromophobe (CHR): 49 (35.0%), containing with sarcomatoid components (SAR): 14 (10.0%) and other histology: 17 (12.1%) cases, respectively. The tumors evaluable by CP were 127 cases, PAP: 52 (40.9%), CHR: 31 (24.4%), SAR: 20 (15.7%) and other histology: 24 cases (18.8%), respectively. The overall concordance rate was 59.5% between RP and CP. In multivariate analysis, SAR was extremely poor prognosis in ncRCC. The high neutrophil lymphocyte ratio (NLR) and at high CRP value were also poor prognostic factors. So, we stratified three risk groups using three factors, namely NLR, CRP and SAR. In overall survival, there were significant prognostic differences within three groups (p = 0.0014). In immunohistochemistry, PD-1 or PD-L1 expression correlated with poor overall, cancer specific and recurrence free survival in ncRCC. In multivariate analysis, PD-L1 expression was most significant prognostic factor for ncRCC. Conclusions: These results suggest that Risk stratification by three risk factors is useful prognostic model and the expression of PD-1 and PD-L1 may be a useful prognostic factor in ncRCC.
Clinical activity of ipilimumab plus nivolumab (Ipi/Nivo) in patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC).
Authors: Gupta Ruby , Ornstein Moshe Chaim , Gul Anita , Allman Kimberly D , Ball Jessica , Wood Laura S. , Garcia Jorge A. , VonMerveldt Dendra , Hammers Hans J. , Rini Brian I. 
Published: March 2019

659 Background: Ipi/Nivo is a standard of care for pts with metastatic clear cell RCC. The clinical activity of Ipi/Nivo in patients with metastatic nccRCC remains poorly defined. Methods: Metastatic nccRCC pts who were treated with Ipi/Nivo at Cleveland Clinic or UT Southwestern were retrospectively reviewed. Ipi/Nivo was administered as per CHECKMATE 214. Computed tomography imaging was obtained at baseline and every12 weeks to assess disease response per RECIST 1.1 criteria. Baseline pt characteristics, outcome to therapy and adverse effects as per CTCAE v5.0 were collected. Results: Thirteen pts with metastatic nccRCC histology who were treated with Ipi/Nivo were identified. The median age was 60 years (range, 32-81). Non clear cell histologies included adenocarcinoma of renal origin not otherwise specified (2), unclassified (3), papillary (3), chromophobe (3), translocation (1) and medullary histology (1). Nine pts had ECOG PS 0; four pts had ECOG PS 1. Eleven patients were male and two female. IMDC risk group at time of initiation of Ipi/Nivo was favorable (2 pt), intermediate (10 pts) and poor (1 pt). Nine pts received Ipi/ Nivo as first line treatment, three pts received Ipi/Nivo after prior TKI and one pt received Ipi/ Nivo as third line treatment after prior chemotherapy and nivolumab monotherapy. In total, eight pts have thus far undergone restaging scans with three pts demonstrating partial response (PR), one pt demonstrating stable disease (SD) and four pts demonstrating progressive disease (PD). Two pts experienced grade 2 diarrhea, one after 4 cycles and another after 3 cycles of Ipi/Nivo and required prednisone. One pt demonstrated grade 3 hepatotoxicity after 2 cycles of Ipi/Nivo and required prednisone and Mycophenolate Mofetil while another pt demonstrated grade 1 hepatotoxicity after 3 cycles of Ipi/ Nivo requiring prednisone. One pt experienced grade 2 pancreatitis requiring steroids after one dose of Ipi/Nivo. One pt experienced grade 2 fatigue after 1 cycle of Ipi/Nivo requiring prednisone. Conclusions: Ipi/Nivo is feasible and safe in patients with metastatic nccRCC with preliminary evidence of anti-tumor activity. Updated clinical data will be presented.
Preliminary results of phase I clinical trial of high doses of seleno-L-methionine (SLM) in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.
Authors: Garje Rohan , Brown James A. , Nepple Kenneth Gerard , Dahmoush Laila , Bellizzi Andrew , Bonner Jaime , Mott Sarah L , Zamba Gideon , Laux Douglas Earl , Milhem Mohammed M. , Rustum Youcef M. , Zakharia Yousef 
Published: March 2019

660 Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.
Mechanisms underlying the association between sarcopenia and poor oncologic outcomes in clear cell renal cell carcinoma.
Authors: Sanchez Alejandro , Kuo Fengshen , Petruzella Stacey , Akin Oguz , Paris Michael , Russo Paul , Chan Timothy An-thy , Mourtzakis Marina , Hakimi A. Ari , Furberg Helena 
Published: March 2019

662 Background: Sarcopenia (low skeletal muscle mass) is associated with poor outcomes in patients with ccRCC. The mechanisms underlying this association are unclear. To understand this association, we examined gene expression differences by sarcopenic status in patients with ccRCC. Methods: The cohort consisted of 62 ccRCC patients treated by nephrectomy and previously transcriptomically-profiled in the Cancer Genome Atlas. Computed tomography scans without contrast performed within two months of surgery were reviewed to determine skeletal muscle cross-sectional area. Sarcopenia (yes/no) was defined according to gender-specific international consensus definitions. Baseline differences in clinicopathologic characteristics were assessed using the Chi-squared test for categorical and t-test for continuous variables. Differential expression analyses were performed using the R package “DESeq2.” Gene set enrichment analyses (GSEA) and single-set GSEA were used to evaluate differences in MSigDB Hallmark gene sets and estimate immune cell infiltration, respectively. P-values were corrected for multiple testing (p-adjust). Results: The cohort was predominantly male (82%), white (97%) and had localized disease (58%). Median age was 58.9 years (SD: 12.1). Sarcopenic (47%) patients were older (p < 0.001), obese (p < 0.001), and presented with higher AJCC stage (p = 0.006). In primary tumor specimens, sarcopenic patients demonstrated increased expression of angiogenic, inflammatory (e.g., IL-6, TNF-alpha), and epithelial mesenchymal transition programs (p-adjust < 0.05). Furthermore, sarcopenic patients had higher macrophage (p = 0.003) and Th17 immune cell infiltration (p = 0.003). Conclusions: Our findings suggest that ccRCC patients who are sarcopenic harbor gene expression programs associated with more aggressive biology. Increased macrophage infiltration and decreased Th17 immune cell infiltration have been previously associated with worse prognosis in ccRCC. It is not clear whether sarcopenia is a cause or consequence of tumor aggressiveness. Validation of these results in a larger cohort of patients and orthogonal validation are ongoing.
Assessment of intratumor heterogeneity using imaging texture features in clear cell renal cell carcinoma.
Authors: Udayakumar Durga , Dwivedi Durgesh , Zhang Ze , Xi Yin , Wang Tao , Madhuranthakam Ananth J , Kapur Payal , Fulkerson Michael , Diaz de Leon Alberto , Lewis Matthew , Cadeddu Jeffrey A , Margulis Vitaly , Brugarolas James , Bagrodia Aditya , Pedrosa Ivan 
Published: March 2019

663 Background: Intratumoral heterogeneity (ITH) relates to aggressiveness in clear cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of kidney cancer. Percutaneous biopsies have high diagnostic accuracy. However, ITH lowers their reliability in larger, heterogeneous tumors. Haralick texture features extracted from a gray level co-occurrence matrix (GLCM) is a robust method to assess intrinsic tumor imaging characteristics. Some of these features, including entropy as a measure of ITH, have recently been used in differentiating malignant from benign tumors in various organs. We aim to understand how tumor entropy extracted from magnetic resonance (MR) imaging correlate with tumor grade (aggressiveness) and gene expression heterogeneity in ccRCC. Methods: This IRB-approved, prospective study included T2-weighted (T2W) and arterial spin labeled (ASL) MR images of 62 patients with ccRCC. The GLCM was constructed for regions-of interest (ROI) within the tumor and 13 Haralick texture features were estimated. Correlations between texture features and tumor grade were evaluated by logistic regression and quantified by the area under the receiving operating characteristic (ROC) curve (AUC). RNA sequencing of 182 tumor samples in 49 resected tumors was performed. Entropy was correlated with standard deviation (SD) of normalized gene expression levels in multiple samples from the same tumor. Spearman correlation (rho) was computed for each gene. False discovery rate q values < 0.05 were considered statistically significant. Results: Entropy was higher in high-grade than low-grade tumors (11.28 ± 0.52 vs. 10.95 ± 0.65) on T2W (q = 0.028) and ASL (10.45 ± 1.15 vs. 9.65 ± 1.29) (q = 0.013). Entropy had an AUC of 0.70 (T2) for high-grade prediction and was weakly correlated with tumor size (R2 = 0.2). Higher T2 and ASL entropy correlated with higher SD of gene expression. Gene ontology analysis of top correlated genes revealed strong enrichment of genes in metabolic processes. Conclusions: Higher MRI entropy predicts high tumor grade and correlates with increased heterogeneity in gene expression of metabolic processes.
Genomic and clinical determinants of recurrence in localized clear cell renal cell carcinoma (ccRCC).
Authors: Bakouny Ziad , Abou Alaiwi Sarah , Nassar Amin , Flippot Ronan , Nuzzo Pier Vitale , Bossé Dominick , Wei Xiao X. , McGregor Bradley Alexander , Harshman Lauren Christine , Signoretti Sabina , Kwiatkowski David J. , Choueiri Toni K. 
Published: March 2019

664 Background: Multiple clinical risk scores and gene expression models have predicted recurrence in localized ccRCC. However, few studies explored genomic alterations (GA) predicting recurrence. Methods: We assessed genomic and clinical correlates of disease-free survival (DFS) in surgically treated localized ccRCC using a targeted next generation sequencing (NGS) platform (Oncopanel/PROFILE) and publicly available NGS and clinical data from TCGA. Univariable and stepwise multivariable Cox regression models (stratified by database) were performed. Results: 478 patients (123 patients from our institution and 355 patients from TCGA) were included. 150 (31.4%) patients experienced a DFS event (recurrence or death) and 94 (19.7%) died at 3.1 years (yrs) of median follow-up. Median DFS was 6.3 (5.4-7.2) yrs and the 5-yr overall survival rate was 70.8% (64.9-76.7). On multivariable analysis, 4 clinical factors and mutations in 3 genes were significantly associated with recurrence (Table). Conclusions: Our study suggests that PTEN, BAP1 and KDM5C GA may improve on clinical factors for prediction of localized ccRCC recurrence. Further work is needed to determine if these GA could improve existing validated risk models. [Table: see text]
The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB).
Authors: Hakimi A. Ari , Ged Yasser , Flynn Jessica , Hoen Douglas R , Di Natale Renzo G , Blum Kyle A , Makarov Vladimir , Kuo Fengshen , Carlo Maria Isabel , Lee Chung-Han , Voss Martin Henner , Ostrovnaya Irina , Chan Timothy An-thy , Motzer Robert J. 
Published: March 2019

666 Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]