bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive molecular and genomic characterization of pancreatic tropism in metastatic renal cell carcinoma.
Authors: Singla Nirmish , Choi Jacob , Onabolu Oreoluwa , Woolford Layton , Stevens Christina , Tcheuyap Vanina , McKenzie Tiffani , Xie Zhiqun , Wang Tao , McKay Renee , Christie Alana , Kapur Payal , Rini Brian I. , Brugarolas James 
Published: March 2019

633 Background: Patients with metastatic renal cell carcinoma (mRCC) involving the pancreas have been shown to exhibit a relatively indolent course, yet the biologic explanation is unclear. We sought to characterize the genomic landscape of patients with mRCC harboring pancreatic metastases to identify molecular drivers of pancreatic tropism. Methods: mRCC patients harboring pancreatic metastases from UTSW and Cleveland Clinic were identified. Clinicopathologic data and oncologic outcomes were analyzed. Samples were obtained from primary tumors, metastatic sites (including pancreatic or other distant metastases), and matched normal tissue. Whole exome (WES) and RNA sequencing of tumors was conducted. Patient-derived xenograft (PDX) models were generated from a subset of patients, and the engrafted tumors were analyzed. Results: 31 mRCC patients with pancreatic metastases were included with 54 tumor samples derived from the primary tumor or thrombus (24), pancreatic metastasis (21), or other metastatic sites (9). Median follow-up was 101 months. Clinicopathologic characteristics were similar between the two institutional cohorts, and all but one patient were favorable or intermediate IMDC risk. All patients had clear cell histology. 8 patients (26%) were metastatic at diagnosis, and median time to metastasis in the remaining patients was 74 months (IQR 32-120). Overall (OS) and cancer-specific (CSS) survival did not vary by IMDC risk group. Morphologically, tumors largely displayed low-grade acinar patterns. WES with matched normal tissue and RNAseq were completed with adequate quality for 48 and 30 samples, respectively. 14 PDX lines were generated, of which 5 (36%) engrafted stably (≥2 passages). WES from 2 tumorgraft specimens revealed preservation of specific mutations in the corresponding human samples. Conclusions: mRCC patients with pancreatic metastases exhibit remarkably favorable survival outcomes. The relatively indolent biology of these tumors is reflected histologically and genomically and can be recapitulated in PDX models. Understanding tumor heterogeneity may help refine prognostic models for mRCC and hold implications for improved personalization of therapy.
Adiponectin-AdipoR1 axis in renal cell carcinoma plays a pivotal role in tumor progression and drug resistance.
Authors: Sun Guangxi 
Published: March 2019

634 Background: It is well established that renal cell carcinoma (RCC) is an obesity-associated cancer. Adiponectin, a major adipocyte-secreted adipokine, plays anti-tumor properties in many malignancies, but exerted paradoxical actions on RCC. Herein, we investigated the effects of adiponectin on RCC progression and resistance to sunitinib, and to exploit this molecular mechanism. Methods: Tissues were collected from 126 patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitor (TKI) therapy. Tumor Adiponectine receptor 1 (AdipoR1) and Adiponectine receptor 2 (AdipoR2) were detected by immunohistochemistry. Assays with RCC cell lines were used to examine the signal transduction pathways of adiponectin in RCC. Results: AdipoR2 was generally lower expressed than AdipoR1 in mRCC tumor (15.6% vs 89.1%, p < 0.001). AdipoR1 expression, but not AdipoR2, was a significant independent predictor of favorable responding to TKI and good survival outcomes. In cultured RCC cells adiponectin inhibited migration and invasion of RCC cells and sensitized cells to killing by sunitinib. Mechanistic investigations of ligand–receptor interactions revealed that AdipoR1 could hinder migration and invasion of RCC cells by blocking GSK3β and β-Catenin pathway and increase cells sensitivity to sunitinib through inhibiting AKT and NF-κB pathway. However, AdipoR2 was not associated with the tumor-limiting properties of adiponectin. Conclusions: These results show that AdipoR1 is a potential prognostic marker for favorable outcomes of mRCC patients. Adiponectin-AdipoR1 axis could be a plausible target to impede tumor progression and sensitize tumors to TKI therapy.
Does increasing time to surgery affect survival in stage I renal cell carcinoma? Analysis of the national cancer database.
Authors: Cotta Brittney , Ryan Stephen , Eldefrawy Ahmed , Sarkar Reith , Bradshaw Aaron , Meagher Margaret Frances , Hamilton Zachary , Murphy James Don , Derweesh Ithaar 
Published: March 2019

635 Background: Optimal timing for surgical treatment of localized renal cell carcinoma (RCC) remains undefined. We sought to determine the survival impact of time to definitive surgical treatment for Stage 1 RCC and elucidate factors associated with a delay in surgical care utilizing the National Cancer Database (NCDB). Methods: The NCDB was queried for Stage 1 RCC cases (cT1N0M0) from 2004-2013 treated with partial or radical nephrectomy. Quartiles were formed from the range of time to surgery of the entire cohort in days: early defined as the first two quartiles and delayed as the fourth. Descriptive analyses were conducted between early and delayed groups. Overall survival (OS) between early and delayed groups was calculated with Kaplan-Meier analysis. Multivariable analysis was performed to determine factors associated with delay in surgical care. Results: 38,859 patients were analyzed. Median time to treatment was 40 days (IQR 22-68). Early (≤40 days, n = 23,712) and delayed ( > 68 days, n = 15,147) groups had a median follow-up of 44.8 and 41 months, respectively (p < 0.001). Delayed surgery was more frequent with African-Americans (14.8% vs. 9.1%, p < 0.001), patients with government or no insurance (53.7% vs. 45.1%, p < 0.001), males (60.7% vs. 58.3%, p = 0.001), and Charlson Comorbidity Index (CCI) ≥2 (9.7% vs. 6.7%, p < 0.001). Kaplan-Meier analysis demonstrated survival benefit to the earlier treatment group, with 5 year OS of 85.5% and 80.9% (p < 0.001; Figure). On multivariable analysis, increasing age (OR = 1.001, p = 0.015), African-American race (OR = 1.5, p < 0.001), increasing distance from treatment center (OR = 1.005, p = 0.001), residence in areas with low high school graduation rates (OR = 1.42, p < 0.001), residence in an area of > 1 million population (OR = 1.6, p < 0.001), and CCI ≥2 (OR = 1.4, p < 0.001) were independently associated with increasing time to surgery. Conclusions: Surgery of T1 RCC carried out beyond 9 weeks after diagnosis is associated with reduced overall survival compared to patients treated within 6 weeks. Time to definitive surgical treatment should be a quality of care metric, with special attention given to populations most at risk for delays in care.
Prevalence, disease-free (DFS) and overall (OS) survival of contemporary high-risk renal cell carcinoma (RCC) patients eligible for adjuvant checkpoint inhibitor trials: A RECUR database analysis.
Authors: Dabestani Saeed , Beisland Christian , Stewart Grant , Capitanio Umberto , Jarvinen Petrus , Nisen Harry , Bensalah Karim , Guðmundsson Eirikur , Lam Thomas B , Marconi Lorenzo , Fernandèz-Pello Sergio , Monagas Serenella , Powles Thomas , Meijer Richard Paul , Volpe Alessandro , Staehler Michael D. , Ljungberg Borje , Bex Axel 
Published: March 2019

636 Background: Designing adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk RCC despite use of validated risk scores. Methods: RECUR is a European multicenter database capturing patient and tumour characteristics, recurrence patterns and survival of all patients treated with (partial) nephrectomy for non-metastatic RCC from 2006 to 2011 at each participating center. We evaluated prevalence, DFS and OS of RCC according to eligibility criteria of adjuvant trials IMMotion 010 (NCT03024996, IM), Checkmate 914 (NCT03138512, CM), Keynote-564 (NCT03142334, KN) and RAMPART (NCT03288532, RP), which all predominantly recruited high-risk clear cell RCC patients. Results: Of 2669 relevant patients in RECUR, 424(15.9%), 681(25.5%), 579(21.7%) and 1221(45.7%) met eligibility criteria for IM, CM, KN and RP respectively (p < 0.001). Median DFS and OS estimates (Kaplan-Meier) in RECUR corresponding to each trial placebo arm were 37.5 (95%CI 30.4–44.6) and 89.6 (95%CI 76.1–103.0) months for IM, 89.4 (95%CI 66.1–112.7) and 96.2 (95%CI 79.8–112.6) months for CM, 62.6 (95% CI39.6–85.6) and 86.6 (95%CI 74.3–98.9) months for KN and finally at 144 months (DFS not reached) and 123.8 (95% CI 110.1 – 137.4) months for RP. Additionally, at pairwise analysis of evaluated trials, DFS estimates were significantly different between all trials (p < 0.001) except between CM and KN (p = 0.125), while OS estimates did not differ significantly between all trials except between RP and the other three trials (p = 0.002). Conclusions: Percentages of eligible high-risk RCC patients in RECUR were low to moderate and, together with estimated placebo arm DFS and OS, varied due to differences in trial eligibility criteria. These differences may impact on the results and interpretation of the trials.
Direct impact of clinical research in metastatic renal cell carcinoma (mRCC): A cost-effectiveness analysis of patient care outcomes and cost savings in a real-life scenario of a large public university hospital in Spain.
Authors: Garcia-Garro Silvia , Gajate Pablo , Gómez-de-Salazar Esther , Alonso Gordoa Teresa , Rodriguez-Sagrado Miguel Angel , Molina CerrilloMD Javier , Manzano Luis , Bermejo Teresa , Carrato Alfredo , Grande Enrique 
Published: March 2019

637 Background: Public health sustainability is a major concern worldwide. Clinical research is considered to leverage patient care outcome but also can lead costs savings and, subsequently, to maintain public health system. Thus, we analyzed the direct impact of clinical research in terms of improvement in clinical outcomes and costs related to research in patients with mRCC in real-life setting. Methods: We retrospectively collected data related to overall survival (OS) and direct health care costs from all mRCC patients who were treated with oral anti-tumour medication and followed at the Medical Oncology Department of Ramón y Cajal University Hospital in Madrid, between January 2010 and February 2017. A statistical analysis comparing the outcomes of patients included in clinical trials versus those not included was conducted. Results: In the study period, 65 patients were newly diagnosed with mRCC and received treatment. Those patients included in clinical trials showed higher median OS (91 vs. 29 months. HR 0.389; 95% CI: 0.150: 1.000; p=0.04). Median direct cost per mRCC patient in ‘real-life’ was €67,376. Median cost for a patient enrolled in at least one clinical trial was €53,673 vs. €63,834 for those who were never recruited for a trial. Participation in clinical trials contributed to a decrease in total health expenditure by 9.02% (€362,367), mainly due to reduction in the cost of medications and diagnostic tests (91.46% vs. 8.54%, respectively). Furthermore, clinical trial participants have required less number of hospitalizations (0.08 vs. 1.75) and emergency visits (0.39 vs. 3.2) per patient. Conclusions: Under the public health system perspective, participation in clinical trials is related to an improvement in overall survival as well as direct and indirect cost savings in mRCC patients.
The association of NOX4 mediated nuclear colocalization and overall survival in renal cell carcinoma.
Authors: Kaushik Dharam , Wang Hanzhang , Ashcraft Keith A. , Nazarullah Alia , Liss Michael A. , Pruthi Deepak , Mansour Ahmed , Tye Cooper B. , Chowdhury Wasim , Bacich Dean , O’Keefe Denise , Rodriguez Ronald 
Published: March 2019

639 Background: NOX4 protein are involved in cell differentiation, migration and apoptosis. We recently demonstrated that NOX4 in renal cell carcinoma (RCC) is an energetic sensor and couples energy metabolism to drug-resistance. In this study we demonstrate that enhanced nuclear localization of NOX4 is correlated with poor survival. Methods: We identified 350 RCC patients with (n = 85) and without (n = 265) venous tumor thrombus (VTT) who underwent radical nephrectomy with or without thrombectomy at our institution between 2013-2016. Fifty patients with RCC and VTT were matched 1:1 to patients with RCC and no VTT. Tissue Microarray (TMA) consisting of primary renal tumor, adjacent renal tumor and VTT were created. These matched TMA (n = 174) were stained with NOX4 antibodies; scanned using the Aperio scanning system and analyzed with the ImageScope software. The RCC nucleus was evaluated for roundness, elongation and size. NOX4 nuclear staining was categorized based on intensity as either strong positive, moderate, weak or no localization. Differential protein expression between the primary tumor, adjacent normal parenchyma and VTT was assessed using the Chi-squared test or t-test. Progression-free survival (PFS) and overall-survival (OS), stratified by NOX4 staining intensity, was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox regression model was used to investigate effect of NOX4 staining on survival in multivariate analyses. Results: NOX4 nuclear colocalization was higher in patients who had progression and death from RCC. On univariate analysis, the intensity of NOX4 protein expression in the nucleus was significantly associated with PFS (HR 1.67, 95%CI (1.08-2.57; p = 0.02) and OS (HR 2.31, 95%CI (1.26-4.24; p = 0.007). On multivariate analyses the association between NOX4 protein expression and OS remains statistical significance (HR 2.09, 95%CI (1.05-4.18, p = 0.037). Conclusions: We provide evidence that in high grade/high stage cancer, NOX4 is colocalized within the nucleus of RCC. The prognostic role of NOX4 was determined at the protein level. We provide rationale for further investigation of NOX4, which may serve as a checkpoint in RCC.
Cost implications of multi-parametric magnetic resonance imaging in prostate cancer active surveillance.
Authors: Yu Michelle , Maganty Avinash , Macleod Liam C , Yabes Jonathan G , Fam Mina M , Bandari Jathin , Furlan Alessandro , Turner Robert , Filson Christopher Paul , Davies Benjamin John , Jacobs Bruce Lee 
Published: March 2019

65 Background: Multi-parametric resonance imaging (mpMRI) has emerged to improve disease risk-stratification and decrease number of repeat biopsies in men on prostate cancer active surveillance (AS). However, the impact of mpMRI on cost of AS has not been established. We thus characterize the impact mpMRI on cost of AS in the Medicare population. Methods: Using SEER-Medicare files we identified men ≥66 years old with localized grade group I-II prostate cancer diagnosed 2008-2013. With an established algorithm, we classified men into active surveillance with and without mpMRI. We then determined cost of surveillance in each group using inflation-adjusted Medicare payments for surveillance-related procedures and their sequalae (i.e. PSA tests, prostate biopsies, post-biopsy complications and mpMRIs). Multivariable median regression compared cost and procedural-intensity for men who received mpMRI and those who did not. Results: We identified 9,081 men on AS with median follow up 45 months (IQR 29-64 months). 7,856 (87%) men did not receive mpMRI and 1,225 (13%) did. On multivariable median regression, receipt of mpMRI was associated with an additional $449 (95%CI $391-$507) in Medicare payments per year. Younger age, treatment in the west or northeast, greater population density and treatment later in the study period were associated with increased cost of AS. Conclusions: Among Medicare beneficiaries on AS, mpMRI is associated with additional annual cost to Medicare. MpMRI may be a marker of more stringent AS, which is likely more costly than watchful waiting. Future studies are needed to determine optimal use of mpMRI during AS to maximize value.
Sunitinib for metastatic renal cell carcinoma: A systematic review and meta-analysis of real world and clinical trials data.
Authors: Moran Michael , Nickens Dana J. , Adcock Katherine , Desscan Arial , Bennetts Meg , Charnley Natalie , Fife Kate 
Published: March 2019

650 Background: Randomized controlled trials (RCTs) are the basis of approval for medical interventions, but may not fully reflect populations seen in clinical practice. Sunitinib is a widely used 1st-line treatment for patients (pts) with metastatic renal cell carcinoma (mRCC). This is the first large-scale meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and real-world data (RWD). Methods: PubMed, Ovid, MEDLINE and EMBASE were searched from 2000-2017 for RCTs and RWD studies of sunitinib as 1st-line treatment in pts with mRCC. Eligible studies contained a cohort of ≥50 adult pts per study arm. The meta-analysis combined RWD and RCT study arms, adjusting for data type (RCT or RWD). Recorded outcomes were: median progression-free survival (mPFS), median overall survival (mOS) and objective response rate (ORR). A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimate. Results: Of the studies that met eligibility criteria, mPFS, mOS and ORR were reported by 18, 19 and 15 studies, respectively. Combined RWD and RCT analyses are presented in the Table. Reported mPFS (RWD, 7.5–11.0; RCTs, 5.6–15.1 months) and ORR data (RWD, 14.0–34.6%; RCTs, 18.8–46.9%) were consistent with the overall estimates. Reported mOS showed greater variation in RWD (6.8–33.2 months) compared with RCTs (21.8–31.5 months). Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS or ORR. Interpretation of these results is limited by differences in trial design and cohort characteristics. Conclusions: This novel, large-scale meta-analysis validates sunitinib as an effective 1st-line treatment for pts with mRCC in both RCTs and everyday clinical practice. [Table: see text]
Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.
Authors: Singla Nirmish , Woolford Layton , Stevens Christina , Tcheuyap Vanina , Onabolu Oreoluwa , Xie Zhiqun , McKay Renee , Wang Tao , Christie Alana , Gahan Jeffrey , Bagrodia Aditya , Raj Ganesh , Sagalowsky Arthur I. , Lotan Yair , Cadeddu Jeffrey A , Margulis Vitaly , Kapur Payal , Brugarolas James 
Published: March 2019

651 Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. Whole exome sequencing was performed on 230 PDX lines. On MVA, sarcomatoid (OR 5.71, p < 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p < 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis. Efforts are underway to elucidate genomic drivers of engraftment.
Safety and efficacy of restarting immune checkpoint inhibitors (CPI) after immune-related adverse events (irAEs) in metastatic renal cell carcinoma (mRCC).
Authors: Abou Alaiwi Sarah , Martini Dylan J , Xie Wanling , Nassar Amin , Bakouny Ziad , Steinharter John A. , Nuzzo Pier Vitale , Flippot Ronan , Chanza Nieves M. , Wei Xiao X. , McGregor Bradley Alexander , Bilen Mehmet Asim , Choueiri Toni K. , Harshman Lauren Christine 
Published: March 2019

652 Background: CPI can induce a range of irAEs with various degrees of severity. Clinical experience with retreatment following clinically significant irAEs is growing. Methods: We retrospectively reviewed mRCC patients treated with CPI-based regimens who had >1 week therapy delay for irAEs at Dana Farber and Emory to characterize the safety and outcomes of retreatment. Toxicity was graded by CTCAEv5. Patients were divided into retreatment (R) and discontinuation (D) cohorts. Patient characteristics were compared by Fisher’s exact test or Wilcoxon’s rank sum test. ORR, OS and PFS were assessed descriptively. Results: Of 339 treated with CPI, 53 (16%) had irAEs warranting treatment interruption: 24 (45%) in R and 29 (55%) in D. Median (med) time to drug interruption was 2.0 (<0.1-74) months (mos) in D and 3.2 (<0.1-21) mos in R (p=0.89). Prior to irAE onset, 8 (28%) of cohort D and 5 (21%) of cohort R experienced partial responses (PR). While type of irAEs were balanced across D and R, initial irAEs were less severe in R vs D (all p<0.05) with fewer grade (gr) 3-4 events (29% vs 66%), less hospitalizations (25% vs 69%), and lower steroid requirements (>40 mg: 29% vs 79%). The most common irAEs in R were transaminitis, pancreatitis and dermatitis with 7 gr 3/4 events (pancreatitis, colitis, adrenal insufficiency and dermatitis). Median drug break before retreatment was 1.2 (0.3-4.8) mo. Subsequent irAEs occurred in 42% (n=10) after restarting (8 new, 2 recurrent) with 2 discontinuations; 6/10 were gr 3 with no gr 4/5 events. Median interval to irAE recurrence after retreatment was 2.1 (0.5-3.3) mos. Retreatment resulted in 4 (17%) PRs in patients whose disease had not responded prior to irAE (med time to PR from R = 2 mos). Conclusions: Despite a significant rate of irAE recurrence, most patients with prior clinically significant irAEs can be safely retreated. Retreatment can induce responses in an appreciable proportion of patients with no response prior to irAE. Larger studies are warranted to confirm these findings. [Table: see text]