bluuebunny/crossref_metadata_2025 huggingface dataset:
Are we systemically under treating cisplatin-eligible patients with muscle invasive bladder cancer (MIBC) who are undergoing bladder preservation by chemoradiotherapy?
Authors: Sridhar Srikala S. , Bashir Shaheena , Chung Peter W. M. , Zlotta Alexandre , Fleshner Neil Eric , Bristow Robert G. , Kulkarni Girish S. , Teich Miriam , Alimohamed Nimira S. , Lo Gregory
Published: February 2017

417

Background: Neoadjuvant chemotherapy (NC) improves survival in MIBC pts regardless of local management-cystectomy or chemoradiation. NC use with chemoradiation has been limited as these pts are often elderly, frail and cisplatin-ineligible. But, as more fit, cisplatin-eligible pts opt for chemoradiation it is critical that we re-evaluate the feasibility and outcomes of giving NC followed by chemoradiation. Methods: We reviewed 25 MIBC pts with cT 2-4 N 0-1 M 0, undergoing chemoradiation between 2008-2014 at the Princess Margaret and Durham Regional Cancer Centers. All pts received NC with gemcitabine-cisplatin (2-4 cycles) then external beam radiation (median dose 60Gy) with concurrent cisplatin. Toxicities were recorded using CTCAE v 3.0. Response and outcomes were assessed by cystoscopy and imaging. Median follow-up was 29.7 mos and 6 pts had < 2 yrs of follow-up. Kaplan Meier analysis was used for survival. Results: Main reasons for a chemoradiation approach were pt preference 15/25 (60%) and comorbidities 10/25(40%). At diagnosis, median age was 69 (49-85), 76% were male, all were ECOG PS 0/1, median CrCl was 58.5 ml/min and 7/25 (28%) had hydronephrosis. CIS was seen in 10/25 (40%), LVI in 3/25 (12%) and node positivity in 2/25 (8%). All but 1 patient completed planned NC, where main Grade 3/4 toxicities as expected were neutropenia and infection. All planned radiotherapy and 83% of planned concurrent chemotherapy was given. Maximal TURBT was done in 76%. Cystoscopically post NC, 12/15 (80%) had a CR, 1/15 (7%) had CIS, and 2/15 (13%) had residual disease. Of the 12 pts with a CR, radiologically 4/12 had a CR, 2/12 had a PR and 6/12 had SD. Four pts required salvage cystectomy for local recurrence, 4 pts developed metastases and have died. Median OS was not reached, but the 2 yr OS rate was 73.8% (95% CI 50.3-87.4%). Conclusions: NC followed by chemoradiation, showed cystoscopic CR rates of 80% post NC and 2 yr OS rates of 73.8% suggesting this approach should be considered in cisplatin-eligible MIBC pts undergoing chemoradiation. Comparing outcomes between matched MIBC pts receiving NC and then chemoradiation or cystectomy also appears warranted.
Venous thromboembolism (VTE) risk in patients with localized urinary tract tumors (UTT).
Authors: Ramos Jorge , Wong Yu-Ning , Crabb Simon J. , Niegisch Guenter , Bellmunt Joaquim , Ladoire Sylvain , Hussain Syed A. , Baniel Jack , Golshayan Ali Reza , Powles Thomas , Rosenberg Jonathan E. , De Giorgi Ugo , Vaishampayan Ulka N. , Agarwal Neeraj , Pal Sumanta K. , Harshman Lauren Christine , Necchi Andrea , Recine Federica , Galsky Matt D. , Yu Evan Y. ,   RISC Investigators
Published: February 2017

422

Background: VTE is common in cancer patients, but there is limited data in patients with UTT. We previously demonstrated that non-urothelial histology, cardiovascular disease (CVD) or CVD risk factors or renal dysfunction increased VTE risk in metastatic UTT. In this study, we assessed the frequency and risk factors for VTE in localized disease. Methods: Data was collected via an electronic data capture platform from 29 centers. Patients diagnosed with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients without a date of diagnosis, last follow up, or VTE data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis, excluding VTEs diagnosed in the metastatic setting. Chi-squared analyses were used to assess differences in VTE rates for various patient, therapy, and tumor-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Results: 1131 patients were eligible for analysis. Perioperative chemotherapy was utilized in 46.9% (530/1131) of patients. 70.8% (801/1131) underwent definitive surgical intervention. There were 64 VTEs (cumulative incidence 5.7%). Treatment with chemotherapy (p = 0.609) or surgery (p = 0.886) did not increase VTE risk. In the univariate analysis, non-urothelial histology (p = 0.025), CVD or CVD risk factors (p = 0.004), renal dysfunction (p = 0.023), and radiation to the primary tumor (p = 0.048) were statistically significant factors. Multivariate analysis demonstrated that non-urothelial histology and CVD or CVD risk factors were associated with increased VTE risk (table). Conclusions: The VTE incidence of 5.7% in localized disease is lower than our previously reported rate in the metastatic setting (8.2%). Consistent with our findings in metastatic UTT, non-urothelial histology and CVD or CVD risk factors increase VTE risk in localized disease. Additional analyses to control for baseline demographics in patients treated with surgery and chemotherapy will be performed. [Table: see text]
Early toxicity in a randomized trial of high dose-rate (HDR) brachytherapy as monotherapy for low- and intermediate-risk prostate cancer.
Authors: Morton Gerard , Chung Hans T. , McGuffin Merrylee , Zhang Liying , Ravi Ananth , D'Alimonte Laura , Loblaw Andrew
Published: February 2017

44

Background: Evidence supports the use of high dose-rate brachytherapy (HDR) as monotherapy for selected patients with low- and intermediate-risk prostate cancer when given in schedules of 4 or more fractions. There is limited data on the safety and efficacy of HDR given in fewer fractions. Our purpose is to report on acute toxicity (within 3 months) and early changes in health-related quality of life in a randomized trial comparing a single fraction and a 2-fraction protocol. Methods: A single center, randomized phase II clinical trial of HDR either as a single fraction of 19 Gy (1F), or as two fractions of 13.5 Gy (2F) given 1 week apart was undertaken between June 2013 and April 2015. Eligible patients had NCCN low- or intermediate-risk disease, a prostate volume < 60 cc, International Prostate Symptom Score (IPSS) of 18 or lower, no previous prostate surgery and no use of androgen deprivation therapy. Treatment was delivered using an out-patient ultrasound-based technique. Follow-up assessment was with CTCAE v4, IPSS and Expanded Prostate Composite Index (EPIC). Results: A total of 168 patients were randomized: 86 to 1F and 82 to 2F arms. Median age was 65 years, median prostate volume was 35 cc, and 91% had intermediate risk. Median follow-up was 12 months. Only 3 patients (1.8%) experienced acute grade 2 GI toxicity. The percentage of acute grade 2 GU toxicities is as follows: retention (48%), frequency (20%), urgency (4%). One patient experienced grade 3 hematuria. Ten patients (6%) had urinary retention but only 4 (2.5%) required use of a catheter for longer than 2 days. There was no difference in rate of grade 2 toxicity between treatment arms; the only factor associated with grade 2 urinary retention on univariate and multivariate analysis was prostate volume (p=0.0033). Mean EPIC urinary (p=0.0016) and sexual domain scores (p<0.0001) were lower at 6 months with no difference between treatment arms. Bowel and hormonal domain scores were unchanged. Conclusions: HDR 19 Gy x 1 or 13.5 Gy x 2 is very well tolerated acutely with no acute bowel toxicity. Mild to moderate acute urinary symptoms are common. No difference is found in acute toxicity or early health-related quality of life between treatments. Clinical trial information: NCT01890096.
Identification of novel immunomodulatory tumor biology through comprehensive characterization of a metastases-specific epigenome in patients with metachronous primary and metastatic urothelial carcinoma (UC) tumor pairs.
Authors: Hahn Noah M. , Cramer Harvey M , Badve Sunil S. , Cheng Liang , Gokmen-Polar Yesim , Miller David F , Buechlein Aaron , Rusch Douglas B , Fang Fang , Frankhouser David , Bundschu Ralf , Javkhlan-Ochir Ganbat , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Gardner Thomas A. , Yan Pearlly , Nephew Kenneth P , Marchionni Luigi
Published: February 2017

452

Background: The Cancer Genome Atlas project identified a distinct cluster of hypermethylated muscle-invasive UC tumors in one third of patients. It is unknown if this epigenetic biology persists or changes in UC metastases. The present study aimed to identify uniquely hypermethylated regions in UC metastases compared to their matched primary tumors. Methods: UC patients with paired formalin fixed paraffin embedded tissue samples ( > 75% tumor) from primary and metachronous metastatic tumors were identified. DNA methylation was analyzed on the Illumina HiSeq platform by double-enzyme reduced representation bisulfite sequencing (dRRBS). Results were analyzed by BS-seq within BSmooth open source software. Alignment and methylation estimation was done using Bismark open source software. CpG regions with coverage < 2 in more than 66% of samples were removed to reduce false positive results. Differentially methylated regions (DMRs) in metastases compared to primary tumors were determined by paired t-test. Gene set enrichment analysis (GSEA) of the top 5% DMRs was performed utilizing multiple gene set collections including c7IMMUNO. A false discovery rate of < 10% defined significant DMRs. Results: 15 UC primary/metachronous metastases pairs were analyzed. After filtering for low coverage, 1,781,762 loci remained for analysis. After merging loci within 2500 bp of each other, the top 5% DMRs resulted in 18,452 DMRs. GSEA including the c7IMMUNO gene set identified multiple previously undescribed hypermethylated genes modulating immune function through TGF-beta and Treg signaling including: TGFBR2, TGFBR3, SMAD1, SMAD3, SMAD4, BACH1, BACH2, and VDR all q < 0.05. Conclusions: We identified numerous genes with immunomodulatory functions significantly hypermethylated in UC metastases compared to their matched primary tumors. Our findings provide rationale to examine epigenetic approaches as a means to improve clinical outcomes of UC patients treated with immunotherapy. Our small sample size limits definitive conclusions and warrants validation in independent data sets.
Prognostic value of lymphovascular invasion in squamous cell carcinoma of the urinary bladder.
Authors: Vernez Simone Lucia , Spradling Kyle , Morgan Jacob B , Lotan Yair , Shokeir Ahmed , Abol-Enein Hassan , Mosbah Ahmed , Ghoneim Mohamed , Youseff Ramy F
Published: February 2017

454

Background: The prognostic value of lymphovascular invasion (LVI) has been well studied in urothelial carcinoma of the bladder (UCB) but not in squamous cell carcinoma (SCC). Herein, we evaluate the association of LVI with oncologic outcomes of SCC following radical cystectomy (RC). Methods: We retrospectively evaluated 1280 patients who underwent RC and pelvic lymph node dissection (LND) for invasive bladder cancer between 1997– 2003 at a single institution in Mansoura, Egypt. Only patients with pure SCC pathology were included. Prognostic significance of LVI was evaluated for patients with SCC. Results: Our cohort included 360 patients with SCC. Median patient age and follow-up were 55 years (20 – 87) and 44 months (0 – 108), respectively. LVI was present in 47 (13.1%) and lymph node metastasis (LN+) was present in 66 (18.3%). In Kaplan-Meier analyses, 5-year disease free survival rates for LVI-/LN- and LVI+/LN- patients were 80.2±3% and 38.9±12% (p < 0.001), respectively; 5-year cancer specific survival rates were 88.2±2% and 50.4±13% (p < 0.001), respectively. Moreover, cancer specific mortality was highest in LVI+/LN- patients (HR = 3.657; 95% CI: 1.614 – 8.284; p = 0.002). Multivariate Cox-regression analyses showed that LVI+ status was independently associated with disease recurrence (HR = 2.827; 95% CI: 1.451 – 5.509; p = 0.002 and cancer specific mortality in patients with SCC (HR = 3.657; 95% CI: 1.614 – 8.284; p = 0.002). Conclusions: Lymphovascular invasion is a strong independent predictor of oncological outcomes after RC for SCC of the urinary bladder. The incorporation of LVI status into classic prognostic models for SCC of the bladder may lead to improved identification of high-risk patients.
Your opinion counts: How do you treat atypical/suspicious cytology?
Authors: Longo Thomas Andrew , Gopalakrishna Ajay , Fantony Joseph J , Inman Brant Allen
Published: February 2017

463

Background: Urine cytology has often been reported as a highly specific but poorly sensitive test. Cytology is reported as positive, negative, atypical, or suspicious. Atypical/suspicious cytologies account for roughly a quarter of the results and present a clinical dilemma. Physicians’ risk aversion means they are typically treated as positive and result in clinical action. We test the effects of this assumption on sensitivity and specificity. Methods: After IRB approval, we queried clinical and pathology databases to identify all subjects at Duke University Medical Center who had undergone both a urine cytology and a cystoscopy from 1/2003 to 1/2012. Diagnostic test performance metrics were calculated using logistic models: (a) a generalized estimating equation (GEE) and (b) a generalized linear mixed model (GLMM). These take into account clustered/correlated test results that occur due to repeated testing within subjects. Results: A total of 990 unique subjects were identified that provided 4,733 pairs of cytology and cystoscopy for analysis. Our cohort was 61% male, 75% Caucasian, and had 54% current or former smokers. Of cytologies, 1898 (40%) were negative, 423 (9%) positive, and 2408 (51%) suspicious or atypical. When suspicious/atypical cytology results using the GLMM model were classified as positive, the specificity was 62% [95%CI: 58-66%] and the sensitivity was 41% [95% CI: 38-44%]. When these results were re-classified as negative, this had the effect of a large increase in specificity 100% [95%CI: 100-100%] with a consequent decrease in sensitivity 0% [95%CI: 0-2%]. Conclusions: In our study, the performance of urine cytology depended heavily on how the equivocal (atypical/suspicious) results were classified and dealt with. Our sensitivity was maximized when equivocal cytologies were considered positive, but at significant detriment of the specificity. Contrarily, our specificity improved greatly when the equivocal results were considered negative, but at the expense of a poor sensitivity. Furthermore, the diagnosis of an atypical/suspicious cytology was higher at our medical center than reported in the literature, and therefore significantly overestimated the performance of the urine cytology test.
Advanced tissue-based image analysis techniques integrated with biomarker-morphometric multiplex immunofluorescence to provide prostate cancer risk stratification models post-surgery.
Authors: Donovan Michael , Khan Faisal M , Scott Richard , Zeineh Jack , Koll Giovanni , Gladoun Nataliya , Charytonowicz Elizabeth , Fernandez Gerardo
Published: February 2017

47

Background: We have previously validated the importance of utilizing the intact tissue section and quantitative biomarker strategies for developing prognostic prostate cancer outcome models. We sought to further expand upon these constructs by applying next-gen advanced image analysis tools using multiplex immunofluorescence (IF) integrated with clinical variables on an independent cohort. Methods: Utilizing a 686 patient radical prostatectomy tissue microarray population with median 8 years follow-up from Roswell Park Cancer Institute, NY, we selected an initial subset of 98 patients to construct a training model; applying multiplex immunofluorescence with CK-18 (epithelial cells), CK 5/6 (basal cells), androgen receptor (AR), Ki67, AMACR and DAPI (nuclear marker). Images were captured with an Nikon i90 microscope equipped with a CRI multiplex camera, a Bayesian probabilistic approach was used to derive features that reflect tumor grade and co-locate - quantify IF biomarker expression within various glandular sub-types. Multivariate models were constructed to predict disease progression (i.e., clinical failure (CF) = PSA rise post-adjuvant therapy, or metastasis, or death) with c-index (CI) to estimate performance. Results: A 98 patient with the following clinical features: mean PSA 6.6 ng/mL, prostatectomy Gleason score, PGS 6, 34%; >/=PGS 7, 55%; LN+ 2%, +SM 19%; + ECE 49% ; + SVI 3%. CFevent rate 13%. Two models (i.e., +/- LN status) employing 47 features with 7 clinical variables (e.g., PSA and Gleason) had comparable outcomes, CI 0.84. The number one feature selected in both models was an imaging feature reflecting prostate cancer gland architecture and differentiation. Combined AR levels with gland phenotype and CK-18 composition characterized a relevant phenotype dependent upon feature inclusion in the model generated. Conclusions: We have established the importance of utilizing the intact tissue section when developing accurate prognostic prostate cancer models. Additional studies with expanded training and test patient cohorts are underway to confirm and validate these initial findings.
Subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Escudier Bernard J. , Motzer Robert J. , Powles Thomas , Tannir Nizar M. , Davis Ian D. , Donskov Frede , Grünwald Viktor , Heng Daniel Yick Chin , Hutson Thomas , Melichar Bohuslav , Nosov Dimitry , Rini Brian I. , Salman Pamela , Sternberg Cora N. , Szczylik Cezary , Wolter Pascal , Arroyo Alan M , Mangeshkar Milan , Agarwal Neeraj , Choueiri Toni K.
Published: February 2017

499

Background: Cabozantinib (C) inhibits tyrosine kinases including VEGFRs, MET, and AXL. The METEOR phase 3 trial (NCT01865747) met its primary endpoint of significant improvement in PFS with C versus everolimus (E) in pts with advanced clear cell RCC and prior exposure to VEGFR TKIs (7.4 mo median PFS [C] vs 3.8 mo [E], HR = 0.58, 95% CI, 0.45 to 0.75; p < 0.001). The improvement in PFS was accompanied by a significant improvement in ORR and a trend for improved OS at an interim analysis. Safety profiles of C and E in this trial were similar to prior experience with each drug in this pt population. This analysis further evaluates PFS and ORR across pt subgroups. Methods: Pts had advanced RCC with clear cell component, measurable disease per RECIST 1.1, KPS ≥ 70%, and were stratified by MSKCC prognostic criteria and number of prior VEGFR TKIs. Pts must have progressed during treatment or within 6 months of the last dose of their most recent VEGFR TKI. 658 pts were randomized 1:1 to receive C (60 mg QD) or E (10 mg QD). The primary endpoint was PFS among the first 375 pts randomized. ORR was a secondary endpoint. Results: In the PFS group, 187 pts were randomized to C and 188 to E. 73% pts had 1 and 27% pts ≥ 2 prior VEGFR TKIs; 43% pts had favorable, 41% intermediate, and 15% poor risk by MSKCC criteria. Across multiple subgroups defined by baseline characteristics, PFS HRs favored C over E. PFS HRs were similar for subgroups defined by prior number of TKIs (HR = 0.56 [1 prior] and 0.67 [ ≥ 2 prior]), and showed higher activity of C over E in pts with fewer MSKCC risk factors (HR = 0.54 [0 factors], 0.56 [1 factor], 0.84 [ ≥ 2 factors]) or with metastases in various organs (HR = 0.47 [lung mets], 0.53 [liver mets], 0.50 [bone mets]). Detailed analysis of the clinical activity of C and E (PFS and ORR) across pt subgroups will be presented, including treatment duration with first VEGFR TKI ( < or ≥ 6mo), receipt of prior anti-PD1/PDL1 agents, time to progression after most recent TKI ( < or ≥ 3mo), and frequency/location of metastases. Conclusions: The METEOR trial met its primary endpoint of improved PFS, and subgroup analyses of the endpoints PFS and ORR generally favored C over E in patients with advanced RCC. Clinical trial information: NCT01865747.
Immunomodulation by HDAC inhibition: Results from a phase II study with entinostat and high-dose Interleukin 2 in renal cell carcinoma patients (CTEP#7870).
Authors: Pili Roberto , Quinn David I. , Hammers Hans J. , Monk Paul , George Saby , Dorff Tanya B. , Olencki Thomas , Shen Li , Hutson Alan , Piekarz Richard , Carducci Michael Anthony
Published: February 2017

500

Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that the class I HDAC inhibitor entinostat has synergistic antitumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of Tregs. Thus, we have conducted a Phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic clear cell renal cell carcinoma. Methods: The primary objectives were to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria were clear cell histology and being fit to receive high dose IL-2. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed dose of IL-2 (600,000 units/kg every 8 hrs). To test our hypothesis, the fixed sample size at the Phase II dose level was 36 with a type I/II error of 10%. If 11 or more of the pts have a response, the hypothesis that the response rate is ≤ 20% is rejected. Results: Dose levels 1 and 2 were completed without DLTs and 5 mg entinostat was the Phase II recommended dose. No severe adverse events were observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were lymphopenia (50%), neutropenia (9%), and hypophosphatemia (6%). To date, we have enrolled 39 pts at dose level 2, and 35 have completed one cycle (84 days). Four pts were not evaluable. Twelve pts have achieved objective response (39%; 9 PR, 3 CR) with a median time to response of 81 days (55-96). The median PFS has not been reached with a median follow-up of 437 days (30-1428). Preliminary results show decreased Tregs and monocytic MDSCs following treatment and suggest an association of increased CD14+/CD86+ and CD14+HLADR+cells with objective response. Conclusions: The results from this phase I/II suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells (R21CA137649; U01CA70095). Clinical trial information: NCT01038778.
FGFR2 expression to predict survival outcome in patients with metastatic papillary renal cell carcinoma.
Authors: Tsimafeyeu Ilya , Naumova Alexandra , Stepanova Evgenia , Khasanova Alfia , Varlamov Ilya , Wynn Nigel , Snegovoy Anton , Demidov Lev V.
Published: February 2017

506

Background: In our previous study we showed that fibroblast growth factor receptor 2 (FGFR2) mutations are rare across papillary types of renal cell carcinoma (pRCC). The aim of the present study is to test FGFR2 expression for association with survival outcome in the largest patient cohort to date. Methods: Formalin-fixed, paraffin-embedded specimens of removed primary tumors from 214 untreated metastatic pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody (Santa Cruz Biotechnology). Expression was quantified by consensus of two independent observers using a four-value intensity score (0, 1+, 2+, and 3+) and the percentage (0-100%) of the extent of reactivity. Expression was scored according to the percentage of positive cells present among all tumor cells in the section. The cytoplasmic and nuclear expression score was obtained by multiplying the intensity and reactivity extension values (range, 0-300). FGFR2 expression was tested for associations with progression-free survival (PFS), overall survival (OS) and best objective response. Results: Expression of FGFR2 was observed in 23% (49/214) of primary pRCC, mostly in cytoplasm of tumor cells. 2 of 214 (1%) patients had nuclear FGFR2 expression. Intensity was 3+ in all cases. Expression of FGFR2 was significant lower in the normal tissue of kidney (1%, P=0.001). FGFR2 expression was strongly associated with a number of metastatic sites (2 and more metastatic sites vs. 0-1), type 2 of pRCC, lower nucleolar grade (P<0.001). FGFR2-positive patients had significantly shorter OS and PFS in first-line therapy (P<0.05; Table). On multivariate analysis, FGFR2 expression, MSKCC risk group, and type of pRCC were found to be independent predictors of survival. Conclusions: In this study, we described immunohistochemical expression of FGFR2 in a large series of pRCC specimens. FGFR2 expression was found to be prognostic factor for survival in patients with metastatic pRCC. Clinical trial information: rosoncoweb2011. [Table: see text]
Analysis of mutational status in recurrently mutated genes in clear cell renal cell carcinoma and overall survival in patients with metastatic disease at time of nephrectomy.
Authors: Manley Brandon , Casuscelli Jozefina , Tennenbaum Daniel , Hakimi A. Ari , Hsieh James
Published: February 2017

520

Background: Using the genetic profile of a tumor, clinicians may be able to give insight in to the aggressiveness or indolence of a patient’s disease. The choice to initiate or hold systemic therapy for those with metastatic disease may be aided by knowing which mutations put a patient at an accelerated risk of death from their disease. Identifying genomic markers in clear cell renal cell carcinoma (ccRCC) for patients with metastatic disease at time of nephrectomy may assist in the decision to initiate early systemic therapy even in those with stable clinical disease. Methods: Using available data from The Cancer Genome Atlas (TCGA), The International Cancer Genome Consortium (ICGC), The Cancer Genomics Project Tokyo, Japan and our intuitional database we identified 157 patients who had metastatic disease at time of nephrectomy. We performed statistical analysis to compare the presence of mutations in five recurrently mutated genes (VHL, PBRM1, SETD2, BAP1 and KDM5C) in ccRCC and overall survival. For each gene, Kaplan-Meier estimates for patients with and without mutations were generated and compared using the Log-rank test and Cox proportional hazards regression. Results: Out of the five recurrently mutated genes analyzed, we found that only mutations in BAP1 showed a statistically significant decrease in overall survival for patients who had metastatic disease at time of nephrectomy. Patients without a mutation in BAP1 had an estimated median overall survival of 32.2 months, whereas patients with a mutation in BAP1 had an estimated median overall survival of 15.4 months, HR 1.717 (CI 1.038 –2.839), p-value=0.0326. Conclusions: Patients with mutations in BAP1 show a statistically significant decrease in overall survival compared to those without mutations in these patients with terminal disease. Given these findings early initiation of systemic therapy may be considered even in those with small or stable residual disease.
The anticancer effects of supinoxin (RX-5902) in renal cell cancer.
Authors: Lee Young , Mazhari Reza , Kim Deog Joong
Published: February 2017

524

Background: DEAD box RNA helicase DDX5/p68 may play several important roles in cancer. In particular, phosphorylated p68 has been shown to be associated with cell transformation, epithelial mesenchymal transition (EMT), and cell migration, deeming it a promising target for novel anti-cancer therapeutics. We have previously shown that Supinoxin (RX-5902) interacts with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway. Methods: In this study, we first demonstrated anti-proliferative effects in ten renal cancer cell lines with a high level of sensitivity to Supinoxin (IC50 of 39 nM); TK-10 was the only resistant cell line in this study. We also sought to examine the tumor growth inhibition (TGI), tumor growth delay (TGD), and survival benefits of Supinoxin in the human renal cell carcinoma tumor (Caki-1) xenograft mouse model, using two different dosing schemas: weekly dosing at 20-160 mg/kg for 4 weeks, or 50-70 mg/kg daily (5 days on/2 days off) for 3 weeks. Results: Weekly dosing of Supinoxin at 160 mg/kg resulted in a 75% TGD (P < 0.001). Daily administration of Supinoxin resulted in dose-dependent TGI (80 and 96%; Day 21) and TGD (68 and 104%, P < 0.001), and extended the overall survival of the animals at both doses (P < 0.0001). At the dose of 70 mg/kg daily, 6/10 animals demonstrated partial tumor regressions and 1/10 a complete tumor regressions. Supinoxin did not result in a reduction in body weight gain, treatment related deaths, or clinical observations in either of the dosing schemas. Sunitinib (60 mg/kg; daily for 21 days) resulted in TGD for both in vivo studies validating the Caki-1 model herein. Conclusions: These data support the potential therapeutic activity of Supinoxin in renal cell cancers. A Phase I study of Supinoxin on relapse/refractory solid tumors is ongoing (NCT02003092).
Phase II trial of high-dose interleukin-2 (IL-2) and stereotactic radiation therapy (SABR) for metastatic clear cell renal cell carcinoma (ccRCC): Interim analysis.
Authors: Hannan Raquibul , Ishihara Dan , Louder Kristi , Ahn Chul , Margulis Vitaly , Arriaga Yull Edwin , Courtney Kevin Dale , Timmerman Robert D. , Brugarolas James
Published: February 2017

532

Background: We report a planned interim analysis of a single-arm, open-label, phase II trial of HD IL-2 and SABR in multiple ccRCC metastatic sites. Methods: Metastatic ccRCC patients eligible for IL-2 were enrolled and received SABR of 1 or 3 fractions (fx) to up to 6 sites. IL-2 (Proleukin) was administered within 84 hours from the last SABR fx at 600,000 IU/kg every 8h for up to 14 doses in a monitored setting followed by another week after a week break. Eligible (responding) patients received a second course in > 12 weeks. The primary endpoint is the response rate (RR) as evaluated by iRECIST. The study is powered to detect a 60% improvement compared to the historically reported 23% RR for IL-2. Results: 16 patients were enrolled between August 2013 and July 2015; two were withdrawn from the study due to cardiac events prior to receiving IL-2 infusions. The median follow up was 9 months. A median of 2 (1-3) sites were treated with SABR with a median dose of 24.5 Gy (21-27 Gy) for single fx and 30Gy for 3 fx (25-33 Gy). All patients received the first week of IL-2 with a median of 10.5/14 doses; 64% received the second week (9/14) with a median of 7/14 doses. Two patients refused a second week of IL-2 and one was unable to receive it due to thyrotoxicosis. PICC line DVT delayed the second week of IL-2 in two patients. 29% of patients (4/14) received a second course of IL-2. The rate of grade 3 toxicity was 64% with no > grade 3 toxicity. The overall toxicities were expected of IL-2 treatment, transient and resolved after treatment discontinuation. In two cases, grade 1 toxicity was attributed to SABR. At this interim, ten patients underwent at least two follow up scans and were evaluable for outcome analysis. The RR was 40%, with one patient presenting complete response and 3 patients showing partial response. The median duration of overall response was 5 months, with a median stable disease duration of 6 months. Local control rate for SABR-treated lesions was 95%. Conclusions: The addition of SABR to IL-2 increased the RR in mRCC patients of about 2-folds compared to IL-2 alone, despite the reduced number of patients receiving the second week of IL-2. No significant increase in toxicity was observed. Clinical trial information: NCT01896271.
The impact of active smoking on survival outcome in metastatic renal cell carcinoma patients treated with targeted therapy.
Authors: Li Haoran , Kroeger Nils , de Velasco Guillermo , Donskov Frede , Sim Hao-Wen , Wells Connor , Stukalin Igor , Agarwal Neeraj , Parekh Hiral D. , Rini Brian I. , Knox Jennifer J. , Pantuck Allan J. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2017

552

Background: Smoking increases the risk of developing renal cell carcinoma (RCC). The prognosis of active smokers compared with non-smokers with metastatic RCC (mRCC) has not been well characterized. Methods: Smoking data from 1,842 patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium (IMDC) from 8 Cancer Centers. Patients were categorized as current, former and non-smokers at the time of starting targeted therapy, and analyzed for differences in IMDC risk criteria, response rate (RR), progression- free-, (PFS) and overall survival (OS). Results: Overall, 292 (15.9%), 755 (41.0%), and 795 (43.1%) were current, former, and non-smokers. There were no differences in sarcomatoid features, number of metastatic sites or non-clear cell histology in either former or current smokers when compared with non-smokers. Likewise, former smokers had statistically similar IMDC risk groups compared to non-smokers. However, current smokers were more likely to have hypercalcemia (p=0.004), neutrophilia (p=0.038), thrombophilia (p=0.002), and more patients had higher numbers of IMDC risk features (p=0.014) when compared with non-smokers. The RR at first-line targeted therapy of former (p=0.89) and current smokers (p=0.13) were similar to non-smokers. No differences in PFS were noted: 7.7 vs. 7.6 vs. 6.2 months (mo) in non-, former (p=0.92), and current smokers (p=0.66). Interestingly, while former- and non-smokers had comparable OS times (23.7 vs. 23.1 mo; p=0.71), current smokers had significantly shorter OS (15.8 mo; p=0.001) than non-smokers. Current but not former smoking status was an independent poor prognosis factor (HR=1.28; p=0.006) when adjusted for the IMDC risk criteria. Moreover, each pack year increased the risk of death 1% (HR=1.01; p=0.039). Conclusions: Active smoking is associated with more advanced IMDC risk criteria and diminished OS in mRCC patients treated with targeted therapy agents. On the other hand, patients who quit smoking returned to a similar risk of death compared to patients who never smoked. Smoking cessation should be a counselling priority among mRCC patients receiving targeted agents.
Impact of dose reduction on survival in patients starting sunitinib (SU) or pazopanib (PA) as first-line for metastatic renal cell carcinoma (mRCC).
Authors: Iacovelli Roberto , Derosa Lisa , Massari Francesco , Verri Elena , Galli Luca , Ciccarese Chiara , Cossu Rocca Maria , Cianci Claudia , Bimbatti Davide , Aurilio Gaetano , Antonuzzo Andrea , Fantinel Emanuela , Cullura Daniela , Ricci Sergio , Modena Alessandra , Falcone Alfredo , Tortora Giampaolo , Nole Franco
Published: February 2017

553

Background: SU and PA are both VEGFR TKI approved for treatment of mRCC. Previous studies reported that the reduced dose (RD) is not recommended for the beginning of therapy (Motzer et al. 2012) and suggested a direct correlation between dose and effectiveness of therapy (Houk et al. 2010). We aim to investigate if patients (pts) that decreased the dose during treatment have different outcomes compared to those who continue a standard dose (SD). Methods: All pts affected by mRCC who started SU or PA at SD have been included. Pts were divided into two groups: RD and SD, based on whether they reduced the therapy or not. The main reasons for dose change have been collected and the RD group was defined into 2 levels (1st level: SU37.5mg/d, 4/2 or PA 600mg/d; 2nd level: SU25mg/d, 4/2 or PA 400mg/d). Pts were stratified by IMDC prognostic criteria and differences in pts’ characteristics between RD and SD groups were evaluated as well as median PFS and OS. Results: A total of 280 pts have been included. Median age was 62y and 68% was male; 54% had good prognosis, 40% intermediate and 6% poor. First-line was SU in 84% and PA in 16% of cases. A total of 123 (44%) pts decreased the dose to first- (89%) or second-level (11%). The main reasons were hand-foot syndrome (17.9%), diarrhea (15.4%) asthenia (14.6%), mucositis (13.0%) and thrombocytopenia (11.4%). Significant differences between RD and SD groups were the female sex (40% vs. 25%; p = 0.01) and the rate of primary refractory disease (11% vs. 31%: p < 0.001). Median PFS and OS were 12.4 and 34.9 mos, respectively. In RD group, the median time before dose reduction was 3.5 mos. Excluding the primary refractory pts, median PFS was 18.6 and 15.0 mos (p = 0.06) and median OS was 68.0 and 40.7 mos (p = 0.14) in RD and SD group, respectively. In RD group, no differences between 1st- and 2nd-level of dose were observed both in PFS (11.0 vs. 13.1 mos; p = 0.82) and OS (42.8 vs. 36.0 mos; p = 0.78) after reduction. Conclusions: Dose reduction is a frequent event in pts who started a first-line therapy with SU or PA. This study reports that DR does not affect the survival of pts who initially started SU and PA at standard dose.
Comparative effectiveness of pazopanib and sunitinib as first-line therapy for patients with advanced/metastatic renal cell carcinoma in a U.S. community oncology setting.
Authors: Hirsch Bradford Richard , Jiao Xiaolong , Wilson Thomas , Hackshaw Michelle Denise , Jonasch Eric , Ghate Sameer , Perez Jose Ricardo , Vogelzang Nicholas J.
Published: February 2017

567

Background: The COMPARZ trial demonstrated that pazopanib was non-inferior to sunitinib regarding their efficacy as first line of therapy (LOT) for advanced/metastatic RCC (aRCC). However, no studies have compared the effectiveness of pazopanib to sunitinib outside the clinical trial setting. The purpose of this study was to compare the clinical outcomes of the two therapies in a US community oncology setting. Methods: A retrospective study was conducted using US Oncology’s (USON) iKnowMed electronic health record (EHR) database, supplemented with chart review. Patient eligibility criteria included: ≥ 18 years of age at first diagnosis of aRCC, treated with pazopanib or sunitinib as the 1st LOT between 11/1/2009 – 8/31/2012 in the USON with ≥ 2 office visits. A propensity score (PS) matching was performed to match patients receiving pazopanib to sunitinib. Clinical outcomes including progression free survival (PFS), overall survival (OS) and adverse events (AEs) were compared. Results: A total of 177 patients on pazopanib and 739 patients on sunitinib were identified from the EHR database. After PS matching, 153 pts were included in pazopanib and sunitinib cohort respectively. The mean age, gender distribution, and the Heng disease risk groups were similar between the two cohorts (p>0.05). No significant difference in PFS was observed with pazopanib (median: 9.3 [95%CI, 7.0 to 11.8] months) compared to sunitinib (median: 8.3 [95%CI, 6.4 to 10.9] months, p = 0.43). Similarly, no significant difference was observed in OS for pazopanib (median: 22.3 [95% CI, 16.2 to 31.7] months) compared to sunitinib (median: 26.3 [95% CI, 16.4 to 38.2, p = 0.76] months). AEs (any grade) including diarrhea, hypertension, nausea, vomiting, fatigue were significantly lower in sunitinib (p<0.05) while anorexia was lower in pazopanib (p<0.05). Conclusions: Consistent with the results of COMPARZ, no significant difference was observed in PFS and OS among aRCC patients treated with pazopanib or sunitinib as the 1st LOT in the real world. AEs seemed to be less common with sunitinib, and this may be partially attributed to the limitation of retrospective data.
Randomized phase I/II trial of two schedules of bortezomib and bevacizumab (BBmibmab) in metastatic renal cell cancer: USC trial 4K-05-1.
Authors: Quinn David I. , Wei Denice , Massopust Kristy , Ketchens Charlean , Hu James , Goldkorn Amir , Aparicio Ana , Sadeghi Sarmad , Pinski Jacek K. , Averia Monica , Groshen Susan G. , Dorff Tanya B.
Published: February 2017

574

Background: VEGF agents are a mainstay of therapy in advanced RCC. Bev has activity in RCC but was licensed with interferon-α, which can produce side effects and reduced QoL. Based on non-overlapping side effect profiles, we studied bortezomib (Bmib), a proteasome inhibitor, with the VEGF ligand monoclonal antibody, bevacizumab (Bmab). Primary objective was to examine safety/toxicity of 2 dose schedules of Bmib with Bmab with secondary aims of efficacy (benchmarked to NCI data) and correlatives. Methods: From 2005 and 2014, 62 RCC patients with clear cell or papillary predominant histology treated with 0-4 prior therapies were screened: 10 screen failed, 4 were ineligible (2 treated, 2 not) leaving 48 eligible patients, of whom 46 were evaluable for safety and efficacy endpoints with 20 in each of the phase II dose schedules. Regimens were randomly allocated, stratified by MSKCC group. Results: Best tolerated doses of Bmib with Bmab 10mg/kg IV q3wks on each regimen were A: 1.3 mg/m2 on D 1, 4, 8 and 11 q3wks & B: 1.8 mg/m2on days 1 and 8 q3wks. MSKCC strata: low, intermediate, high risk in 43, 42%; 48, 49%; 9, 9% for schedules A and B, respectively; other baseline factors were not significantly different between A & B. Overall: nephrectomy 90%; ECOG 0 73%; male 71%; median age 57 years; Caucasian 48%, Hispanic 33%, Black 8%, Asian 10%;. Median cycles both arms: 5. Best RECIST 1.0 response PR: 13%, 13%; SD 52%, 48%; PD 26%, 35%; Reason off therapy: PD 58, 67%; toxicity 25, 17% in arms A, B. Median OS: 33.4, 14.7 months (p=0.69), TTP 11.2, 9.4 months, PFS 7.3, 6.6 months (p=0.61) in arms A, B. Grade 3+ tox: A 14/24 vs. B 13/24, p=1.0. Arm A had numerically more skin toxicities and grade 2/3 hematological tox (Plats and WBCs) compared to arm B but this was not statistically significant. Conclusions: Randomized comparisons of novel agents are feasible in renal cell cancer using risk factor algorithms. This VEGFrTKI contemporaneous series of Bmab based therapy with 2 schedules of Bmib suggests potential better outcomes for schedule A with more frequent dosing of Bmib – further sensitivity analysis is ongoing to determine whether this is explained by histology or therapeutic sequencing or likely to suggest proteasome as a target in RCC. Clinical trial information: NCT00184015.
Histological architectures of clear cell carcinoma and their correlation to clinicopathologic features.
Authors: Kimura Go , Takeda Hayato , Akatsuka Jun , Endo Yuki , Kondo Yukihiro
Published: February 2017

576

Background: The aim of this study is to clarify the relationship between histological architectures (HA) and clinicopathological features (CF) in clear cell carcinoma (CCC). Methods: Between 1984 and 2014 nephrectomy or partial nephrectomy were performed in 723 renal cell carcinoma cases in our hospital. Among them 603 cases (83.4%) were CCC. We reviewed the pathological reports and found 556 CCC cases had description of HA. The relationship between HA and CF were investigated. Results: HA were as follows: small acinar (SA)/acinar (A) in 453 cases (81.5%), large acinar (LA)/solid (S) in 113 (20.3%), papillary (P) in 54 (9.7%), Cystic (C) in 121 (21.8%) and tubular in 53 (9.5%). By the Spearman rank correlation, significant correlation was observed between HA and tumor grades: SA/A (rho -0.408, p < 0.0001), LA/S (0.567, p < 0.0001), P (0.257, p < 0.0001), C (-0.241, p < 0.0001). Acinar sizes were correlated with tumor grade (0.541, p < 0.0001), tumor size (0.435, p < 0.0001) and local stage (0.414, p < 0.0001). LA/S or P showed low microvessel density evaluated by CD31 immunostaining, which resulted in weaker attenuation in corticomedullary phase of enhancement CT. On the contrary SA had high microvessel density and high attenuation after enhancement. Conclusions: HA is well-correlated with tumor grade, tumor size and local stage, and could be predicted by dynamic CT pattern preoperatively.
The loss of BAP1 protein expression in the first recurrence site of metastasis to predict prognosis.
Authors: Miura Yuji , Inoshita Naoko , Ozaki Yukinori , Tanabe Yuko , Suyama Koichi , Ikeda Masaomi , Okaneya Toshikazu , Takano Toshimi
Published: February 2017

599

Background: It is well known that the loss of BAP1 protein expression in primary site of clear cell type renal cell carcinoma (ccRCC) is prognostic marker. However, the existence of intratumoral heterogeneity in primary site of ccRCC makes it difficult to assess accurate prognosis. The aim of this study is to investigate the heterogeneity of BAP1 expression in metastatic sites and to evaluate the possibility as a prognostic marker. Methods: We collected samples of both primary and matched metastatic sites of the first recurrence in 41 metastatic ccRCC patients. Immunohistochemistry (IHC) for BAP1 and PBRM1 protein expression were performed on at least two tissue microarray (TMA) sections from primary site and at least one TMA sections from metastatic sites. We retrospectively analyzed the association of the IHC with clinical outcomes. Results: 41 primary and metastatic sites were available for this analysis. The most of metastatic sites were lung (68.3%) and lymph node (12.2%). BAP1 protein expression-positive, -negative and -heterogeneity in primary/metastatic sites were 29/29 (70.7/70.7%), 8/11 (19.5/26.8%) and 4/1 (9.8/2.4%), respectively. PBRM1 protein expression-positive, -negative and -heterogeneity in primary/metastatic site were 22/27 (53.7/65.9%), 9/11 (21.9/26.8%) and 10/3 (24.4/7.3%), respectively. The concordance between primary and metastatic site for BAP1 and PBRM1 protein expression was 82.9 and 63.4%, respectively. Median overall survival (OS) from the first recurrence of metastasis in patients with BAP1-positive and -negative in metastatic sites was 97 and 51 months, respectively (p = 0.0275). Median OS from the first recurrence of metastasis in patients with PBRM1-positive and -negative in metastatic sites was 82 and 58 months, respectively (p = 0.44). Conclusions: There is more intratumoral heterogeneity for BAP1 and PBRM1 in primary site than metastatic sites of ccRCC. The loss of BAP1 protein expression by IHC in metastatic sites predicts poor clinical outcome.
The immune landscape of renal cell carcinoma and its association with intratumoral clonality.
Authors: Winer Andrew G. , Senbabaoglu Yasin , Gejman Ron , Ostrovnaya Irina , Kaffenberger Samuel D. , Voss Martin Henner , Coleman Jonathan A. , Russo Paul , Hsieh James , Sander Chris , Hakimi A. Ari
Published: February 2017

605

Background: Clear cell renal cell carcinoma (ccRCC) is among the most highly infiltrated tumors despite a relatively low mutation burden. Despite success in treating subsets of these patients with immunotherapy, the high immune-infiltration of ccRCC remains a conundrum that has not been sufficiently addressed. Methods: We utilized an original RNAseq-based aggregate immune score (Senbabaoglu Y, bioRxiv, 2015) to compare immune infiltration levels across 20 tumor types profiled in The Cancer Genome Atlas (TCGA) and validated our results with an independent cohort of ccRCC patients (Sato Y, Nat Genet, 2013). We also evaluated the immunogenic effect of intratumoral heterogeneity (ITH) through an analysis of clonal architecture in ccRCC tumors from both of the aforementioned data sets using the SciClone (Miller C, PLoS Comput Biol, 2014) algorithm. Results: We identified ccRCC as an immunogenic outlier that is unique from other highly infiltrated tumors in its exceptional overexpression of antigen presentation machinery compared to normal tissue. In a focused decomposition of immune cell levels within the 415 ccRCC tumors from TCGA, three unique clusters of tumors emerged primarily separated by varying degrees of T cell infiltration; termed (1) T-cell-enriched, (2) heterogeneous, and (3) non-infiltrated groups. These clusters were validated in an independent ccRCC cohort of 101 patients. A comparison of the degree of clonality with immune infiltration levels revealed that tumors with less ITH (i.e. fewer subclones) had significantly higher immune infiltration in both the TCGA and the validation cohort . Conclusions: Our findings provide novel insight into the immune landscape of ccRCC tumors and explore a potential mechanism for the immunogenicity of these tumors. Such information can potentially be used to aid in predicting therapeutic response to immunomodulatory agents.