bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supression of tumor progression and metastasis in renal cell carcinoma by miR-192, miR-194, and miR-215.
Authors: Khella Heba W. Z. , Bakhet Marize , Allo Ghassan , Jewett Michael A. S. , Girgis Andrew , Bjarnason Georg A. , Yousef George M. 
Published: February 2017

385 Background: miRNAs play a crucial rule in tumor progression and metastasis. We previously identified miR-192, miR-194 and miR-215 to be down-regulated in metastatic compared to primary clear cell renal cell carcinoma (ccRCC). In this work, we examine the role of miR-192, miR-194, and miR-215 in RCC progression and aggressiveness. Methods: We examined the role of these three miRNAs on tumor cell migration and invasion abilities using RCC cell line models. We performed target prediction analysis and experimentally validated the targets using independent approaches. In addition, we examined the clinical utility of miR-215 as a potential prognostic marker in RCC by measuring miR-215 expression using qRT-PCR in 61 formalin-fixed paraffin-embedded tissues from primary ccRCC and correlated the expression levels with clinical outcome. Results: Restoration of miR-192, miR-194, and miR-215 expression decreased cell migration and invasion in RCC cell lines. Target prediction analysis identified three potential targets of these miRNAs; MDM2, TYMS, and SIP1/ZEB2. We validated the miRNA-target interaction experimentally using three approaches. First by measuring the effect of miRNA overexpression on mRNA and protein levels of the predicted target, then by measuring the effect of miRNA overexpression on a luciferase signal of a vector containing the 3’UTR of the predicted target, and finally, by validating these interactions in vivoby examining the presence of an inverse correlation between miRNA changes and the expression levels of their targets on clinical specimens. In 61 patients with resected ccRCC tumors, we found that low miR-215 expression in the primary was associated with a significantly reduced recurrence-free survival. (26.4 vs. 49.2 months, respectively, p = 0.0320). Conclusions: Our analysis showed that miR-192, miR-194, and miR-215 are involved in RCC metastasis and that miR-215 predicts for recurrence in patients with resected RCC. Our findings pave the way to the clinical use of miRNAs as prognostic markers and potential therapeutic targets.
The role of FGF signaling in VEGF-pathway targeted therapy resistance: Data from patients and model systems.
Authors: Ho Thai Huu , Warneke Carla L. , Hoang Anh , Tamboli Pheroze , Wang Fen , Jonasch Eric 
Published: February 2017

386 Background: Angiogenesis plays a role in tumor growth and is partly mediated by factors in both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) pathways. Brivanib inhibits both VEGF receptor 2 and FGF receptors (FGFR)-1/2. Methods: Nephrectomy material from 40 patients with metastatic renal cell carcinoma (RCC) receiving sorafenib ± interferon was assessed by immunohistochemical (IHC) staining. The Ariol imaging platform was used to stratify the specimens based on intensity of staining for FGF biomarkers: FGFR-1 and fibroblast growth factor receptor substrate 2 (pFRS2). The relationship between fibroblast growth factor pathway marker levels and progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox proportional hazards regression methods. To assess the efficacy of dual targeting of VEGF and FGF receptor signaling by brivanib, we treated a xenograft RCC mouse model with sunitinib, brivanib, or sunitinib followed by brivanib. Results: Our analysis indicated that more intense FGFR-1 staining was associated with shorter PFS (p = 0.0452), and that pFRS2 staining were not significantly associated with PFS (p = 0.2610). FGF pathway activation was associated with decreased PFS in patients with metastatic RCC treated with sorafenib. Xenograft mice were treated with 20 mg/kg sunitinib and after an initial stabilization phase, resistance developed by day 20. A switch to 30 mg/kg brivanib prolonged the stabilization phase after progression on sunitinib (p = 0.0033). Conclusions: The PFS of patients treated with sorafenib is associated with FGF pathway activation. In a xenograft RCC mouse model, brivanib overcame the tumor escape after initial treatment with sunitinib. Switching from sunitinib to brivanib at the time of tumor escape prolonged the stabilization phase and overcame a sunitinib-induced resistance phenotype. The results suggest that FGF pathway activation mediates both innate and acquired tumor resistance to VEGF receptor inhibition. The efficacy of dual inhibition of FGF and VEGF in the subset of patients with increased FGF activation prior to treatment requires further study.
Changing trends in pelvic lymphadenectomy in radical prostatectomy with the advent of robotic surgery.
Authors: Sohn William , Paciorek Alan , Carroll Peter , Penson David F. , Dash Atreya 
Published: February 2017

39 Background: It is important to determine whether changes in technology have impacted surgical practice. With the adoption of robotic surgery, it is our hypothesis that rates of pelvic lymphadenectomy (LND) have decreased, even when controlling for cancer risk and comorbidities. To assess whether adoption of surgical technology versus practice patterns in the extent of surgery over time changed, we propose to compare the rates of pelvic LND at the time of radical prostatectomy during the time period when robotic surgery was adopted. Methods: Data was extracted from CaPSURE, a multi-institutional, longitudinal observational database of men with prostate cancer. A total of 3,938 men diagnosed with localized prostate cancer between 2000 and 2011 were included in the analysis if they underwent surgical extirpation. The inclusion of LND was calculated for both groups. Other information included site type, age at diagnosis, comorbidities, and CAPRA risk assessment score. Results: A total of 3,616 open retropubic prostatectomies and 322 robotic prostatectomies were included for analysis. Among the open prostatectomies, 78.9% underwent pelvic LND. During the same time period, among robotic prostatectomies, 45.3% underwent pelvic LND. There was a statistically significant correlation between method of radical prostatectomy and the performance of LND (p < 0.001). There were no statistically significant differences between the two groups in CAPRA score, age, or comorbidities (p= 0.06, 0.29, and 0.60; respectively). The adjusted odds ratio of LND for the open group compared to the robotic group is 5.90 (95% CI [4.48,7.78]) while adjusting for clinical stage, grade, and PSA. Conclusions: Controlling for other factors, the difference in rates of LND between the open and robotic groups were statistically significant. These data suggest changes in surgical practice may have been altered by the adoption of a new technique to perform surgery (rather than new scientific data supporting omission of LND).
Real-world treatment patterns in third-line patients with metastatic renal cell carcinoma (mRCC): The changing landscape in the United States.
Authors: Pal Sumanta Kumar , Malangone Elisabetta , Bhurke Sharvari , Gorritz Magdaliz , Stern Lee , Coombs John , Turnbull James D. , Wang Xufang , Liu Zhimei 
Published: February 2017

390 Background: Several targeted therapies (TTs) have become available in mRCC in recent years for first- and second-line use, including sorafenib (So), sunitinib (Su), bevacizumab (Be), temsirolimus (Te), everolimus (Ev), pazopanib (Pa), and most recently, axitinib (Ax). This study aimed to examine the current treatment patterns in mRCC patients who fail second-line therapy. Methods: Data were obtained from a large national U.S. claims database for patients with an RCC diagnosis and at least 3 lines of TT between January 1, 2004, and June 30, 2011. Patients were age 18 or older at diagnosis with at least 3 months of follow-up prior to initiation of third-line therapy. Patient characteristics and treatment patterns were examined for the final population. Results: A total of 812 mRCC patients initiated third-line therapy with So, Su, Be, Te, Ev, or Pa. The sample was majority male (70%) with a mean age of 60 years (SD=10.7). A large proportion of patients were from the South (42%), and the majority of the sample (72%) had commercial insurance. The most common sites of metastases at any time were lung (71%) and bone (52%). The most common first-line agent was Su (52%) and the most common second-line single agents were Te (25%) and Ev (17%). The most frequently used single-agents in third-line were Te (21%) and Ev (19%). Third-line treatment choice differed by year; Te (51%) was most common in 2007 while Ev and Pa were most common between 2009 and 2011. Additionally, the most frequently prescribed sequences of single agents were VEGF→mTOR→VEGF (25%), VEGF→mTOR→mTOR (25%), and VEGF→VEGF→mTOR (22%). Conclusions: The results demonstrate a rapidly changing therapeutic scenario for mRCC in the United States. The number of targeted therapies prescribed in third-line increased from 1 in 2006 to 4 in 2007 and 6 in 2011. This evolution of third-line therapies is possibly due to physicians adapting their practice with the advent of novel mRCC treatment options. These results are in line with the NCCN guidelines, with VEGF and mTOR being the most commonly prescribed first- and second-line single agents, respectively.
Treatment outcome with mTOR inhibitors for 65 cases of non-clear cell renal cell carcinoma: Association of long-term responses and oncogenomic events.
Authors: Voss Martin Henner , Bastos Diogo Assed , Karlo Christoph , Patil Sujata , Ajeti Albulena , Hakimi A. Ari , Feldman Darren Richard , Molina Ana M. , Berger Michael F. , Hsieh James , Motzer Robert John 
Published: February 2017

391 Background: Temsirolimus and everolimus are standard agents in the management of advanced renal cell carcinoma, but the registration trials primarily enrolled patients with clear cell histology. We assessed outcome in patients with non-clear cell RCC (ncRCC) treated with mTOR inhibitors at our center. Methods: Clinical features and histologic subtypes were characterized for ncRCC patients treated with single-agent temsirolimus or everolimus. Outcome was analyzed using the Kaplan-Meier method to determine progression free survival (PFS) and overall survival (OS). Genomic analysis of outliers with either durable or poor response was done by next-generation sequence analysis of tumor tissue and germline DNA. Results: 65 patients received temsirolimus (n = 46) or everolimus (n = 19). Histologic subtypes included papillary (n = 16), chromophobe (n = 9), collecting duct (n = 6), translocation-associated (n = 3), and unclassified (n = 31) RCC. Median follow-up for survivors is 29 mos. Median treatment duration for 52 patients, who continue therapy or stopped due to progression or death, is 2 mos. 8 patients (12.3%) were treated for ≥ 1 year (max. 37 mos), including papillary (n = 3), chromophobe (n = 2) and unclassified (n = 3) RCC. Tumor analysis identified genomic determinants of long term response in 2 unclassified RCC (complete functional loss of TSC1 and TSC2, respectively). No such changes were seen in 2 patients with chromophobe RCC and rapid progression on therapy. Conclusions: A subset of ncRCC patients derives benefit from mTOR inhibitors, but most have poor outcome. Durable responses can be linked to oncogenomic alterations within the mTOR pathway, and future goals should include the identification and characterization of such predictive tissue biomarkers. [Table: see text]
Updated phase I results of a phase I/II trial of BNC105P with everolimus in patients with metastatic renal cell carcinoma (mRCC).
Authors: Hutson Thomas E. , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Galsky Matt D. , Bylow Kathryn A. , Cowey Charles Lance , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Sonpavde Guru , Logan Theodore , Hahn Noah M. , Sweeney Christopher , Sarantopoulos John ,   Hoosier Oncology Group
Published: February 2017

397 Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during cycle 1. Results: Updated results from the completed phase I component confirm the BNC105P/everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia, and oral mucositis were also observed. 8 of the 12 phase I subjects achieved disease stabilization (7 of these subjects had a minimum time on therapy of 18 weeks, 6 cycles). Across all subjects a median of 6 cycles (range: 1-21) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in a randomized phase II study. Clinical trial information: NCT01034631.
Could a biomarkers-based patients' selection help to plan a clinical trial with targeted agents (TA) for metastatic renal cell carcinoma (mRCC)? Interaction and power analysis of randomized trials (RCTs).
Authors: Massari Francesco , Maines Francesca , Pilotto Sara , Bonomi Maria , Giannarelli Diana , Brunelli Matteo , Martignoni Guido , Tortora Giampaolo , Bria Emilio 
Published: February 2017

399 Background: To predict the clinical benefit of TA in mRCC, several studies have analyzed some angiogenesis-related biomarkers including soluble VEGF and VEGF-Receptors, VEGF polymorphisms, IL-8 polymorphisms, and VHL mutations. We performed a power analysis to assess how much a biomarker-based approach can affect the sample size of a trial in mRCC. Methods: Hazard ratios (HR) for survival with 95% confidence intervals (CI) for overall survival were extracted and cumulated according to a random-effect model from RCTs. A sensitivity analysis according to ‘biomarker-selection’ approach and to ‘unselected’ fashion was accomplished in order to test for interaction. Testing for heterogeneity was performed as well. Results: A correlation between a featured biomarker and treatment effect was reported in three RCTs (1987 patients). The attrition rate for the survival analysis according to the molecular analysis was 45% (range 20 to 60%). In spite of the extremely different bio-markers’ profiles, demonstrated by the significant observed heterogeneity (p = 0.002), we found an Hazard Ratio (HR) for overall survival of 0.60 (95% CI 0.40-0.89; p = 0.013) and a significant interaction according to strategy (‘biomarker-selected’ vs.‘unselected’) (p = 0.025), supporting a differential effect of these drugs when administered according to a predictive phenotype. In the ‘unselected’ sample, considering the intention to treat analysis (all randomized patients) the HR was 0.90 (95% 0.80-1.00; p = 0.06). From a clinical trial design perspective, if targeting these expected survival differences, with a power 80%, and a alpha-error 0.05, the required events are described in the table. Conclusions: With the aim to avoid the attrition of the heterogeneity of biomarkers’ selection and drugs, we speculate that the sample size of a planned clinical trial design in mRCC according to a biomolecular classifier may help to shorten the gap between clinical research and practice. [Table: see text]
Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02/AUO AP 09/95): Ten years follow-up.
Authors: Wiegel Thomas , Bottke Dirk , Bartkowiak Detlef , Bronner Claudia , Steiner Ursula , Siegmann Alessandra , Golz Reinhard , Störkel Stephan , Willich Normann , Semjonow Axel , Stöckle Michael , Rübe Christian , Althaus Peter , Rebmann Udo , Kälble Tilman , Feldmann Horst J , Wirth Manfred , Hinke Axel , Hinkelbein Wolfgang , Miller Kurt 
Published: February 2017

4 Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. The EORTC-phase-III- study suggested a 20% better biochemical control (bNED) after 10 years for RT but no survival advantage. In contrast, the SWOG trial stated not only a gain in bNED but also an improved metastasis free and overall survival after 12 years follow-up. Now, 10-years results from the ARO 96-02 study are available, which are based on the most precisely defined cohort among the three trials. Methods: 385 men with prostate cancer were randomized to either 60 Gy RT (arm A; n=193) or WS (arm B; n=192) before achieving an undetectable PSA. Pts. were stratified for Gleason-score, margin status, neoadjuvant hormonal treatment and stage (pT3a+b vs. c). When the undetectable PSA-level after RP was not achieved, progressive disease was stated and the pts. left arm A/B. Data analysis was by intent-to-treat (ITT). PSA-progression for pts. with undetectable post-RP PSA was defined as two consecutive increasing PSA. The primary endpoint was bNED. The study was powered to demonstrate a 15% increase in bNED for RT. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was 111.3 months for arm A and 113.3 months for arm B . bNED at 10 years increased to 56% for arm A (RT) compared with 35% for arm B (WS) (hazard ratio= 0.51; p = 0.00002. Out of 307 ITT pts., 15 died from prostate cancer, 23 for other and 5 for unknown reasons. There was no significant profit from ART regarding the endpoints metastasis-free survival (p=0.56) or overall survival (p=0.59). Worst late side effects to the rectum were two grade 2 cases after ART. Grade ≥2 bladder toxicity occurred in 4 out of 148 ITT pts. No grade 4 events were reported. Conclusions: With only one grade 3 case of late toxicity, ART was safe in pT3 prostate cancer. At 10 years median follow up, it reduced the risk of bNED by 49%. The study was not powered to detect differences in OS. Clinical trial information: ARO 96-02/AUO AP 09/95.
RAD001 and zoledronic acid in patients with renal cell carcinoma with bone metastases (RAZOR): A randomized phase II trial.
Authors: Broom Reuben James , Hinder Vicky , Sharples Katrina , Proctor Janie , Duffey Steven , Pollard Stephanie , Fong Peter C.C. , Forgeson Garry , O'Donnell Anne , Harris Dean Laurence , Deva Sanjeev , Jameson Michael B. , North Richard T. , Grey Andrew , Findlay Michael P. N. 
Published: February 2017

402 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety. Results: Heng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); p<0.0001); CTX on R+Z relative to R was 77% (95% CI (68%, 83%); p<0.0001). For FACT-BP there was no evidence of a difference (p = 0.5) but addition of Z was favourable for BPI Severity -1.1 (-2.2, 0.23; p = 0.05) and BPI Interference -1.3 (-2.5, 0.03; p = 0.06). Median PFS was 7.5 mo (95% CI 3.4, 14.7) on R+Z and 4.6 mo (95% CI 3.2, 6.3) on R (p = 0.03). Median time to 1st SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03). Conclusions: Addition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease. Clinical trial information: ACTRN12609000980235.