bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of ITPR1/HIF-2α axis in protecting renal cancer cells against natural killer cells.
Authors: Messai Yosra , Noman Zaeem , Hasmim Meriem , Janji Bassam , Albiges Laurence , Escudier Bernard , Chouaib Salem
Published: February 2017

417

Background: Clear cell renal cell carcinomas frequently display inactivation of VHL gene leading to increased level of hypoxia inducible factors (HIFs). The specific role of VHL mutations and selective activation of HIF-2 alpha in modulating RCC susceptibility to cytotoxic immune response remains largely unknown. Methods: In this study, we used 786-0 RCC VHL-mutated cell line selectively induces HIF-2 alpha stabilization.Chromium release cytotoxicity assay was regularly used to evaluate tumor target cells sensitivity to NK-mediated lysis. Confocal microscopy was aso used to analyse immunologic synapse formation and for autophagy studies. Immunochemistry staining using RCC tissue microarrays was performed to evaluate HIF-2 alpha and ITPR1 expression in RCC patients. Results: We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared to the VHL-corrected cell line (WT7). This resistance was found to require HIF-2α stabilization. Based on global gene expression profiling and ChIP assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF-2α and targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Interestingly, using a large group (235) of RCC patients,we demonstrated the existence of a significant correlation between HIF-2α and ITPR1 expression Mechanistically, HIF-2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK mediated killing through the activation of autophagy in target cells by NK derived signal. Both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased Granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Conclusions: Our data provide insights into the link between HIF-2α, the ITPR1-related pathway and natural immunity and strongly suggest a role for the HIF-2α /ITPR1 axis in regulating RCC cell survival. Futur NK cell-based immunotherapy should integrate HIF-2/ITPR1 axis as intrinsic feature of resistance tumor cells to improve NK cell response in RCC patients.
Association of resistance to antiangiogenic therapy with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma.
Authors: Liu Xiande , Hoang Anh , Zhou Lijun , Kalra Sarathi , Yetil Alper , Sun Mianen , Ding Zhiyong , Tamboli Pheroze , Rao Priya , Karam Jose A. , Wood Christopher G. , Matin Surena F. , Zurita Amado J. , Bex Axel , Griffioen Arjan W. , Gao Jianjun , Sharma Padmanee , Tannir Nizar M. , Sircar Kanishka , Jonasch Eric
Published: February 2017

419

Background: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers which predict therapeutic resistance and guide combination therapy. Methods: Tissue microarrays with triplicate cores for each case were generated from 33 unaffected kidneys, 41 untreated primary RCC, and 42 bevacizumab and 39 sunitinib pretreated primary RCC from patients with metastatic RCC. Immunohistochemistry was used to visualize immune cell infiltration. Staining quantitation was performed using a Vectra multispectral system. Statistical analysis was performed using unpaired Student´s t-test. Results: We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. Here we found that anti-angiogenic therapy treated RCC primary tumors demonstrated increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient survival. Furthermore, anti-angiogenic therapy treated specimens showed higher infiltration of CD4+FOXP3+regulatory T cells (Tregs) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T lymphocyte infiltration and were negatively related to patient overall survival (OS) and/or progression free survival (PFS). Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Conclusions: This study indicates that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents.
Comparison of stereotactic body radiotherapy and conventional external beam radiotherapy in renal cell carcinoma.
Authors: Tinkle Christopher L. , Shiao Stephen Lawrence , Weinberg Vivian K. , Lin Amy M. , Gottschalk Alexander R.
Published: February 2017

434

Background: Renal cell carcinoma (RCC) is considered a radiation-resistant histology, often with poor response to conventionally fractionated external beam radiotherapy (EBRT). We compared outcomes for patients treated with EBRT versus stereotactic body radiotherapy (SBRT) for RCC. Methods: From 2004 and 2012, a total of 89 patients were treated with either EBRT or SBRT and retrospectively reviewed. Patients with locally recurrent RCC, bone or soft tissue RCC metastases, or primary RCC in a solitary kidney were included. 51 patients received EBRT, while 38 patients received SBRT. The median biologically effective dose (BED), assuming an α/β ratio of 10, was 32.6 Gy10 for the EBRT group and 48.0 Gy10 for the SBRT group. Local failure (LC) was defined pathologically or by imaging according to RECIST 1.1 and toxicity reported according to CTCAE v4.0 guidelines. Univariable and multivariable analyses using Cox’s regression model was performed to determine predictors of local control. Results: Median follow up from RT was 9.8 mo (range: <1-73 mo) with EBRT and 19.7 mo (range: <1-61 mo) with SBRT (p=0.26). EBRT patients were younger (p=0.02) and more were M1 (p=0.04), yet other baseline features did not differ significantly. Total RT dose, dose/fraction, and BED10 were significantly higher in the SBRT group (p≤0.002 for each), while number of fractions was significantly fewer (p<0.001). The 1-year LC estimate was 88% (95% CI, 72-96%) with SBRT and 50% (95% CI, 32-65%) with EBRT (p=0.001), with no significant difference in rate of distant recurrences (p=0.37). The 1-year progression free survival (PFS) and overall survival (OS) between the EBRT and SBRT groups were 17% (95% CI, 8-29%) vs. 39% (95% CI, 24-54%) (p=0.06) and 39% (95% CI, 25-52%) vs. 82% (95% CI, 65-91%) (p=0.002), respectively. The use of SBRT was the most important independent factor significantly predictive of local control on multivariable analysis (p=0.001, LLR test; HR=0.29, 95% CI, 0.13-0.61), while neither age nor metastasis at diagnosis was predictive. No drade 3-4 toxicity was observed in either RT group. Conclusions: The data support that SBRT improves local control over standard fractionation schemes. Higher dose per fraction, with a BED in the range of 48 Gy10, is a safe and effective local treatment modality for RCC.
Thermal ablation for the treatment of bone metastases (BM) in patients (pts) with metastatic renal cell carcinoma (mRCC): Experience from IGR.
Authors: Matias Margarida , Deschamps Frederic , Albiges Laurence , Loriot Yohann , Massard Christophe , Fizazi Karim , De Baere Thierry , Escudier Bernard J.
Published: February 2017

437

Background: Local treatment of BM in mRCC pts comprises different approaches including thermal ablation techniques as well as radiofrequency ablation (RFA) and cryotherapy. We report our experience for the treatment of BM of mRCC pts using thermal ablation. Methods: The medical records of all pts with mRCC submitted to thermal ablation of BM from Feb 2008 to Oct 2013 were retrospectively analyzed. Intention of treatment was recorded in 3 categories: complete treatment of all BM in pts with oligometastatic disease or prevention of skeletal related events (SRE) risk and/or pain relief in pts with multimetastatic disease. The local control rate and prognostic factors for local failure (LF) were analyzed including patient characteristics, extension of disease, BM characteristics and type of treatment. Results: 22 pts with BM of mRCC were treated by thermal ablation techniques, with 32 procedures (3 pts had >=3 BM treated). Histology of primary tumor was clear cell in 20 and chromophobe carcinoma in 2 pts. At time of BM treatment, Heng prognostic score was good, intermediate and poor in 36, 59 and 5% of pts. Median age was 67 yrs (48-85). A majority of men were treated (16/22=73%). In 34%, pts had BM synchronous with the primary. BM presented cortical bone erosion in 69% and neurological structures in the vicinity in 50%. Intention of treatment was complete control of BM in 43% and prevention of risk of SRE and/or pain relief in 57% of pts. Cryotherapy was performed in 72% and RF in 28% of cases. Concomitant cimentoplasty and arterial embolization was performed in 70% and 30% respectively. Pain relief was achieved in 81% of pts. LF occurred in 19% of pts (n=6) (95% CI: 4-33%). The median follow-up was 13.4 months (95% CI: 11-21). Median OS was not reached. 86% of pts are still alive at 12 months. The unfavorable prognostic factors for LF were BM size >50 mm (p=0.035) and neurological structures in the vicinity (p=0.0083). Conclusions: Thermal ablation techniques are treatment options that should be considered in the curative and palliative treatment of BM in pts with mRCC. When indications are carefully discussed, these techniques have the potential to achieve good local control and acceptable survival.
Metformin use and outcome of sunitinib treatment in diabetic patients with metastatic renal cell carcinoma.
Authors: Keizman Daniel , Ish-Shalom Maya , Peer Avivit , Gottfried Maya , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Neiman Victoria , Rosenbaum Eli , Sarid David , Gez Eli , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Carducci Michael Anthony
Published: February 2017

440

Background: Sunitinib (Su) is a standard treatment (tx) for metastatic renal cell carcinoma (mRCC). Pre-clinical and clinical studies in several cancer types suggest that the antidiabetic agent metformin (Met) has antitumor activity. Met may negatively regulate mTOR activity. Its effect on the outcome of targeted therapies in mRCC is poorly defined. We analyzed the effect of Met use on the outcome sunitinib tx in diabetic patients (pts) with mRCC. Methods: We performed a retrospective study of an unselected cohort of diabetic pts with mRCC, who were treated with Su in 7 centers across 2 countries. Pts were divided into 2 groups: (1) Met users and (2) Met naive. The effect of Met use on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from Cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and Met use, and outcome were performed using the entire pt cohort. Results: Between 2004-2014, 108 diabetic pts with mRCC were treated with sunitinib. There were 52 Met users (group 1) and 56 nonusers (group 2). The groups were balanced regarding the following clinicopathologic factors: age, gender, HENG risk, past nephrectomy, mRCC histology, ≥2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su-induced hypertension (HTN), and Su dose reduction/tx interruption. Clinical benefit (partial response + stable disease) in group 1 vs. group 2 was 96% vs. 84%, while 4% vs. 16% had disease progression within the first 3 months of tx (p=0.054). Median PFS was 15 vs. 11.5 months (p=0.1). Median OS was 32 vs. 21 months (p=0.001). In multivariate analyses of the entire pt cohort (n=108), factors associated with PFS were active smoking (HR=2.7, p<0.0001) and pre-tx NLR >3 (HR 1.8, p=0.012). Factors associated with OS were Met use (HR 0.2, p<0.0001), HENG risk (HR 3.3, p=0.008), active smoking (HR=2.9, p<0.0001), liver metastases (HR 1.8, p=0.004), and pre-tx NLR >3 (HR 3.3, p<0.0001). Conclusions: Met use may improve the OS of diabetic pts with mRCC that are treated with Su.
An alternative titration schedule of axitinib in metastatic renal cell carcinoma.
Authors: Alva Venur Vyshak , Wood Laura S. , Elson Paul , Martin Allison , Beach Jennifer , Garcia Jorge A. , Rini Brian I.
Published: February 2017

444

Background: Titration of axitinib for metastatic renal cell carcinoma (mRCC) is currently based on tolerance with escalation from 10 mg/day to 14 mg/day and then to 20 mg/day. However, not all patients who can be titrated upward require a higher dose for response, nor do all patients tolerate the increased dose levels. An alternative titrating strategy was employed based on radiographic response, tolerance, and using intermediate dosing levels. Methods: In this retrospective analysis of mRCC, axitinib was initiated at 10 mg/day (5 mg BID). Response was assessed with CT scans at 6 weeks after each dosing change. Patients with response by MASS criteria and acceptable toxicity (<grade 2) were continued on the same dose. If the patient had no response and grade 2 toxicity the dose was reduced by 1 mg/day. Results: Twenty-eight patients were started on axitinib as per the above titration scheme between May 2013 and June 2014. Twenty four patients had clear cell, 3 had papillary and 1 had chromophobe mRCC, and all patients had received at least one prior systemic therapy. The final dose of axitinib ranged from 2 mg/day through 20 mg/day. Eleven patients did not change from the starting dose. Ten patients (36%) underwent dose escalation whereas 7 patients required dose reduction. Overall, for the 17 patients who had their dosage adjusted, the median time to final (current) dose was 9.9 weeks (range, 6.0-23.7), and the median time within a dose was 6.6 weeks (range, 1.1-10.0). Five of 10 patients who required dose escalation ended up on doses other than 14 mg/day or 20 mg/day (three at 12 mg/day and two at 16 mg/day). Among the dose-escalated patients, two patients had grade 1 diarrhea, one each had grade 3 diarrhea, grade 2 diarrhea, grade 1 nausea, grade 2 fatigue, grade 1 hypertension and grade 1 hand foot syndrome. The objective response rate was 17% with a median PFS of 7.4 months. Conclusions: Axitinib dose titration guided by radiographic response and toxicity is a feasible strategy with acceptable overall disease control and good tolerance. A prospective study is warranted.
Correlation between everolimus discontinuation or dose reduction induced by stomatitis or cutaneous toxicity and clinical outcome in patients with metastatic renal cell carcinoma.
Authors: Burgio Salvatore Luca , Santoni Matteo , Medri Matelda , Scarpi Emanuela , Burattini Luciano , Rossi Lorena , Savini Agnese , Berardi Rossana , Stanganelli Ignazio , Conteduca Vincenza , Cascinu Stefano , De Giorgi Ugo
Published: February 2017

448

Background: Patients (pts) presenting with persistent moderate to severe stomatitis or cutaneous toxicity during everolimus may need of treatment discontinuation or a dose reduction. We assessed the correlation between stomatitis or cutaneous toxicity associated with either everolimus discontinuation or dose reduction and clinical outcome pts with metastatic renal cell cancer (mRCC). Methods: We retrospectively reviewed the clinical data of pts with mRCC treated with everolimus in two Italian Centers. Clinical evidence of stomatitis or cutaneous toxicity toxicity inducing a treatment discontinuation or a dose reduction were considered stomatitis-cutaneous toxicity events (SCTE). SCTE were evaluated and corresponding clinical data were reviewed for response and clinical outcome. Response was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Results: Seventy-nine mRCC pts treated with everolimus (57 male, 22 female; median age 69 years, range 44–88) were evaluated. Fifty-two pts (66%) received everolimus as second-line therapy, while 27 (34%) as third-line. SCTE were observed in 20/79 pts (25%) at a median of 30.5 days on everolimus treatment (range 10–270 days). Tumor response was evaluable in 77 of 79 patients (19 of 20 SCTE pts and 58 of 59 non-SCTE). Partial response or stable disease was achieved in 15 of 19 pts with SCTE (79%) compared to 28 of 58 (48%) with no SCTE (p=0.03). After a median follow up of 19 months (range, 1 to 39), the median progression-free survival (PFS) was 5.5 months (95% CI 3.4-7.7) and the median overall survival (OS) was 17.2 months (95% CI 13.2-24.4). A significant difference was found in the median PFS equal to 7.5 months (95% CI 3.4-24.4) in SCTE pts vs. 3.7 months (95% CI 2.7-7.5) in non-SCTE, p = 0.047, and in the median OS equal to 30.6 months (95% CI 14.8-not reached) in SCTE pts vs. 14.0 months (95% CI 9.9-17.7) in non-SCTE, p=0.004. Conclusions: These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC pts treated with everolimus.
High-dose interleukin-2 (HD IL-2) for metastatic renal Cell carcinoma (mRCC): Contemporary utilization trends in the United States.
Authors: Allard Christopher B. , Gelpi-Hammerschmidt Francisco , Harshman Lauren Christine , Faiena Izak , Modi Parth K , Chung Benjamin I. , Singer Eric A. , Chang Steven L.
Published: February 2017

449

Background: Targeted therapies (TT) have revolutionized treatment of mRCC with broad based efficacy and tolerability but ultimately all patients progress. While HD IL-2, the prior standard of care treatment, is associated with significant toxicities, it remains the only agent proven to elicit durable complete responses albeit rarely. This study evaluated trends in HD IL-2 use for patients with mRCC during the TT era. Methods: Our study cohort was comprised of a weighted sample of 2,351 patients with mRCC undergoing HDIL-2 treatment from 2004-2012, from the Premier Hospital Database (Premier Inc., Charlotte, NC), a nationally representative hospital discharge database. We employed descriptive statistics and fitted multivariable regression models, accounting for clustering and weighting, to identify predictors of treatment toxicity and tolerability. Results: We found a progressive decrease in the use of HD IL-2 from 2004 to 2008 with a general upward trend thereafter. HD IL-2 was increasingly concentrated at academic centers representing the site of treatment for 24% of patients in 2004 versus 90% of patients in 2012. Most patients were men (75.3%), Caucasian (70.7%) and aged <60 (59.6%) with lung metastases (60.9%) and otherwise healthy (64.72%, Charlson comorbidity index=0). Our adjusted analysis showed that severe hypotension was associated with patients <50 years (odds ratio [OR]: 1.35, p=0.045), while the likelihood of receiving ≥2 cycles of HDIL-2 was associated with good health (CCI=0, OR: 1.72, p=0.004) and having >1 metastatic site (OR: 4.32, p<0.001). Conclusions: Over the past decade, the use of HD IL-2 initially diminished coinciding with the widespread availability of TT but has remerged potentially due to renewed enthusiasm for immunotherapies showing promising efficacy with novel immune checkpoint inhibitors in mRCC. HD IL-2 has increasingly been limited to academic centers and our analysis suggests a strong selection bias for younger, healthier patients who can better tolerate the toxicities and those with a greater burden of metastatic disease. Future studies are warranted to determine the optimal role of HDIL-2 in the contemporary treatment of mRCC.
A first catch, non-DRE urine exosome gene signature to predict Gleason 7 prostate cancer on an initial prostate needle biopsy.
Authors: Donovan Michael J. , Noerholm Mikkel , Bentink Stefan , Belzer Susan , Skog Johan , Brown Gordon Andrew , Cochran James S. , O'Neill Vince
Published: February 2017

45

Background: There is a critical need to reduce initial prostate biopsies (PB) in the PSA ‘gray zone’ of 2-10 ng/mL. Non-invasive screening tools that add predictive value for identifying high-grade, Gleason score (GS) ≥7 should impact on the current diagnostic paradigm. We have developed standardized processes to isolate exosomal-RNA from first-catch urine specimens and sought to identify a gene signature that reliably differentiates GS7+ from GS6 and benign disease. Methods: First-catch non-DRE urine specimens were collected at six sites in standard collection vessels without preservative, stored at 2-8C (up to two weeks) and shipped on ice to a central laboratory (Exosome Diagnostics, St. Paul, MN). Upon receipt, samples were filtered (0.8um), and exosome isolation and RNA extraction performed. RT-qPCR RNA copy numbers of ERG and PCA3, normalized to SPDEF, were measured to generate a three-gene signature, defined to yield a score S between 0 and 30, where S>10 predicts GS7+ vs. GS6 and benign lesions with optimal NPV, Sensitivity and Specificity. Results: Urine samples from 170 men (PSA 2-10 ng/mL, first biopsy,40 mL; median age 62 years, median PSA 5.1 ng/mL, 70% negative DRE, 77%, no family history, 82% Caucasian) of 453 total, with comparable demographics, were evaluated. With 46% and 21% prevalence of positive biopsy for any cancer or GS7+ disease, respectively, a dichotomous gene signature demonstrated good clinical performance in predicting biopsy result. For GS7+, the NPV and PPV were 98.6% and 34.7%, respectively. A continuous score alone had an AUC of 0.76 for discriminating GS7+ from GS6 and benign disease and the results were significantly better than the prostate cancer prevention trial risk calculator (PCPTRC), AUC 0.60. Conclusions: A novel, non-invasive urine exosome gene signature demonstrated independent, negative predictive value for the diagnosis of GS7+ from first biopsy patients with ‘gray zone’ serum PSA. Its use in the biopsy decision process could result in fewer prostate biopsies once validated on an expanded prospective cohort.
Association between primary tumor protein expression and response to sunitinib in patients with metastatic renal cell carcinoma.
Authors: Ornstein Moshe Chaim , Knezevic Vlado , Rini Brian I. , Vaishampayan Ulka N.
Published: February 2017

450

Background: Sunitinib is FDA-approved and widely used as frontline treatment for metastatic renal cell carcinoma (mRCC), but there is a large degree of variability in patient (pt) response to therapy. The association of baseline primary tumor expression of multiple proteins and objective response to sunitinib was investigated. Methods: Primary tumor samples from clear cell mRCC pts treated with sunitinib as frontline therapy at two academic institutions were retrieved. Layered immunohistochemical (LIHC) assay which allow the detection of multiple biomarkers in a single tissue section was used to evaluate the expression of 8 proteins (VEGFR1, VEGFR2, p-mTOR, p-4E-BP1 S65, VEGF A, 4E-BP1, PDGFRb, CAIX) on tumor cells. Pts were characterized as Responders (Complete Responders (CR), Partial Responders (PR) and Stable diseases (SD)) or Non-Responders (NR) based on investigator-assessment. The 8 proteins were tested separately and the area under the receiver operator characteristic (ROC) curve (AUC) analysis was used to compare the predictive power of each biomarker and their combinations. Results: 38 pts were eligible for evaluation; 29 responders and 9 non-responders. Of the 8 biomarkers tested individually, only PDGFRb and CAIX were statistically significant in providing a predictive value for response to sunitinib. Of the different possible biomarker combinations, the combination of increased levels of CAIX expression and decreased 4E-BP1 expression provided the highest ROC AUC (0.9) for predicting response. When stable disease cases were removed from the responders group, in addition to CAIX and 4E-BP1, increased levels of PDGFRb expression predicted response (AUC was 0.889). Conclusions: Baseline primary tumor expression of CAIX and 4E-BP1 is associated with an objective response to sunitinib in pts with mRCC.
Identification of actionable targets in chromophobe renal cell carcinoma detected by multiplatform molecular analysis.
Authors: Abbosh Philip , Geynisman Daniel M. , Doll Nancy , Hauben ADAM , Reddy Sandeep K. , Millis Sherri Z. , Uzzo Robert G.
Published: February 2017

451

Background: Chromophobe renal cell carcinoma (chRCC) is a rare kidney cancer subtype that infrequently metastasizes or recurs after definitive local therapy. Limited biomarker data exists to prognosticate outcome or predict response to therapy. We explored the utility of multiplatform tumor profiling, which uses immunohistochemistry (IHC) and targeted next generation sequencing (tNGS) to identify druggable targets, with the intent of developing targeted therapy protocols in patients with (chRCC). Because of the non-aggressive nature of small chRCCs, we excluded T1a tumors. Methods: Cases were identified from 65,000+ tumors submitted for commercial testing at Caris Life Sciences. All tissues were internally reviewed by a dedicated genitourinary pathologist to confirm diagnosis. Markers were analyzed on tumor tissue removed during partial or radical nephrectomy. IHC was performed on 19 proteins. FISH was performed on EGFR, HER2, and TOP2A. tNGS was performed on 47 genes. Results: Twelve patients with chRCC were profiled. Five patients had metastatic disease. Median age was 54 years old; 50% of patients were male. One patient had a T1b tumor, two patients had T2 tumors, 8 patients had T3 tumors, and one had a T4 tumor. Thymidylate synthase (TS), ribonucleotide reductase M1 (RRM1), and O-6-methylguanine-DNA methyltransferase (MGMT) expression was absent in 12/12, 11/12 and 11/12 tumors, respectively. PTEN expression was absent in 7/12 of tumors. cKIT and PDGFR was expressed in 6/9 and 0/4 tumors, respectively. Lastly, point mutations in APC and TP53 were detected in 1/7 and 3/7 tumors, respectively. No mutations were identified in the other 45 genes tested and no changes in copy number were identified. Conclusions: Biomarker analysis showed that advanced chRCC might be amenable to chemotherapy with 5-fluorouracil, gemcitabine, or temozolamide because of absent TS, RRM1, and MGMT expression, respectively. Such rationale has been used successfully in targeted treatment of other cancers. In addition, sunitinib or imatinib but not sorafenib might be preferred tyrosine kinase inhibitors, as cKIT but not PDGFR was detected.
Robustness of the 16-gene signature for prediction of recurrence-free interval in localized clear cell renal cell carcinoma.
Authors: Escudier Bernard J. , Koscielny Serge , Maddala Tara , Svedman Christer , Verkarre Virginie , Radulescu Camelia , Neuzillet Yann , Timsit Marc Olivier , Hemmerlé Isabelle , Tsiatis Athanasios C. , Bonham Michael , Knezevic Dejan , Martini Jean-Francois , Williams James Andrew , Lebret Thierry , Goddard Audrey D. , Mejean Arnaud
Published: February 2017

455

Background: The Renal Cancer assay is a clinically validated RT-PCR assay developed to estimate the risk of recurrence in stage I-III clear cell renal cell carcinoma (ccRCC) patients (pts) treated with nephrectomy. The assay measures expression of 16 genes that are combined to calculate the Recurrence Score result (RS). The RS is associated with recurrence, renal cancer-specific survival and overall survival (all p<0.001) (Escudier, ASCO 2014). The performance of the RS in clinically relevant subgroups, compared to the Leibovich score, and its within-patient variability was examined. Methods: The algorithm, endpoints, methods, and analysis plan were pre-specified prior to merging clinical and molecular data. RT-PCR of RNA from fixed paraffin-embedded ccRCC tissue was performed without knowledge of clinical data. Recurrence-free internval (RFI) was analyzed using Cox regression stratified by stage with data censored at 5 years, and Kaplan-Meier methods. Multivariable models incorporating the Leibovich score were used to assess the additional contribution of the RS to prediction of recurrence. Within- and between-tumor block reproducibility was assessed in an independent study using two separate tumor blocks from 8 pts, where each block was analyzed at 3 depths. Results: RS was generated in 626/645 pts (97%): 398 stage I, 54 stage II, 174 stage III. Median follow up was 5.5 yrs. The RS was significantly associated with risk of recurrence after adjustment for the Leibovich score (HR=4.20, p<0.001). Additionally, the performance of RS was similar across age groups (<60, 60-70 or ≥70), gender, nephrectomy type, tumor size (≤4, 4-7 or >7cm), grade, and presence/absence of invasion (all interaction p>0.29). Within-patient variability in the score (std. dev. of 1.73 and 4.74 RS units for within- and between-tumor block, respectively) was lower than patient-to-patient variability (std. dev. of 15.6 in validation study). Conclusions: The 16-gene signature remains strongly associated with risk of recurrence after adjustment for the Leibovich score and performs consistently across clinically relevant subgroups. Examination of within-patient and between-patient variability indicates that the score is robust to tumor heterogeneity.
Correlation of endothelial angiopoietin-2 expression with tumor angiogenesis and response to sunitinib in metastatic renal cell carcinoma.
Authors: Rautiola Juhana , Lampinen Anita , Ristimäki Ari , Mirtti Tuomas , Joensuu Heikki , Bono Petri , Saharinen Pipsa
Published: February 2017

461

Background: The endothelial growth factor angiopoietin-2 (Ang2) is a target for novel anti-angiogenic therapies, but its potential as a biomarker remains unknown. Methods: We evaluated Ang2, CD31 and Ki67 expression in tumors of 136 patients with metastatic RCC (mRCC) treated with first-line sunitinib from tumor samples. Results: Ang2 was exclusively expressed in the endothelial cells of tumor blood vessels. Using a cutoff of ≥50 Ang2+ vessels/microscopic field, 38% of the samples had high Ang2 expression. High Ang2 expression correlated with high CD31+ vessel density (p=0.002). 91% of patients with high Ang2 expression had partial response (PR) or stable disease (SD) as best response to sunitinib compared to 76% of those with low Ang2 expression (p=0.033). High CD31+ vessel density correlated with high clinical benefit rate (p=0.015), and with low levels of Ki-67+ tumor cells (p=0.018). Combined high expression of both Ang2 and CD31 predicted a better clinical benefit rate with 100% of the patients with high Ang2 and CD31 expression (n=25) achieving PR/SD compared to 77% among the rest of the patients (n=101; p=0.007). Only one (8%, n=12) patient with papillary RCC had high Ang2 expression, whereas 49 (41%, n = 120) patients with clear cell RCC had high Ang2 expression (p=0.03). Conclusions: In this first study to investigate Ang2 expression and outcome in mRCC patients treated with an angiogenesis inhibitor, high Ang2 expression in the tumor vasculature was predictive for sunitinib efficacy.
Exploring the effect of medication features in renal cell carcinoma: A patient preference study.
Authors: Srinivas Sandy , Mansfield Carol , Sandin Rickard , Hauber A. Brett , Hariharan Subramanian , Matczak Ewa , Pugh Amy , Chen Connie
Published: February 2017

463

Background: Limited information exists about patient preference (PP) for renal cell carcinoma (RCC) medication profiles, especially related to uncertainty in outcomes, potential correlation between toxicity and efficacy, and dosing schedules. Methods: RCC patients in the United States and Canada completed an online survey with questions that examined PP for medication profiles by varying efficacy (progression free survival [PFS]), tolerability (fatigue, hand-foot syndrome, hypertension, diarrhea) and dosing schedules (with or without 2 week break). A discrete-choice experiment (DCE) survey tested the impact of information on correlation between PFS and toxicity on medication choice, with half of the sample randomly assigned to receive the information. Separate exploratory questions assessed patient tradeoff between higher toxicity during treatment vs. the chance of longer PFS (2+ years) and type of dosing schedules, respectively. Results: The interim survey results included 343 RCC patients (172 metastatic (mRCC), 96 currently on treatment). In the exploratory questions, 50% of mRCC patients and 51% of patients receiving treatment selected the option with higher toxicity and a 5% higher chance of longer PFS. Patients who received information on a potential correlation between tolerability and PFS were more likely to say they would tolerate worse toxicity for a 5% higher chance of longer PFS than those who did not receive the information (49% vs. 31%). A majority of RCC patients preferred a treatment with a 2-week break in the dosing schedule compared to continuous treatment (59% vs. 25%). When told side effects were worse during the treatment period for the medication with the break vs. the continuous treatment (moderate vs. mild), 42% of RCC patient, 50% of mRCC patients, and 55% patients on treatment still preferred a break. Additional DCE analysis is underway and will provide more results on patient preferences for medication profiles, including the importance of information received. Conclusions: Patients have heterogeneous preferences over medicine features and outcomes. Physicians need to provide patients with comprehensive information about medication features and efficacy to provide a personalized and optimal approach to treatment.
Quantitative comparison of mRNA level of corticotropin- releasing factor peptide family in normal kidney and corresponding clear cell renal cell carcinoma specimens.
Authors: Tezval Hossein , Merseburger Axel S. , Kuczyk Markus A. , von Klot Christoph , Serth Juergen
Published: February 2017

466

Background: Urocortin (Ucn), a 40 amino acid peptide, belongs to the corticotropin releasing factor (CRF) family and exerts its actions mainly in the periphery through activation of two CRF receptors (CRFRs), CRFR1 and CRFR2 and a binding protein (CRFBP/CRHBP). Both receptors are G-protein coupled and binding of Ucn leads to activation of cAMP-dependent protein kinases via elevation of cAMP levels. Ucn and Urocortin III (UcnIII) are involved in conditions such as regulation of local inflammation, angiogenesis, and inhibition of proliferation. Suppression of neovascularization and inhibition of tumor cell cycling by Urocortins is modulated through CRFRs. Activation of CRFRs by e.g. Ucn inhibits angiogenesis via reduction of vascular endothelial growth factor (VEGF) and suppresses the cell proliferation. Here we characterized the whole CRF family on mRNA levels quantitatively comparing the normal and clear cell carcinoma of the kidney (ccRCC). Methods: In this study we measured the mRNA level of Ucn, UcnIII, CRFR1, CRFR2 and CRHBP in 78 RCC samples and paired histologically normal appearing tissues using quantitative PCR. Statistical analyses were carried out using univariate logistic regression analysis. Results: We found tumour specific down regulation of mRNA expression of UcnIII, CRFR1, CRFR2 and CRHBP in samples of RCCs with clear cell histology compared to paired normal tissues (P<0.01 for all targets). Only Ucn did not show any expression difference between two groups (p=0.17). Conclusions: For the first time we showed the expression profile of the whole CRF peptide family in ccRCC compared to normal kidney on mRNA level. Our data underlines the malfunction of this actually strong protective and anticancer system in renal malignancy and shows the involvement of CRF system in carcinogenesis in kidney. More studies are necessary to find out the detailed roles of the CRF system in renal carcinoma.
Propensity score matched analysis of metastasis-free survival for patients with high-risk prostate cancer treated with definitive radiation therapy or radical prostatectomy.
Authors: Meeks Marshall , Markovina Stephanie Subasic , Vetter Joel , Paradis Alethea , Michalski Jeff M. , Sandhu Gurdarshan Singh
Published: February 2017

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Background: National Comprehensive Cancer Network (NCCN) category 1 recommendation for localized high risk prostate cancer (HR-PCa) is definitive radiation therapy (RT) and androgen deprivation therapy (ADT). Radical prostatectomy (RP) is also an accepted treatment for patients with localized HR-PCa. Here we report a propensity score-matched analysis of institutional outcomes for patients with HR-PCa treated with RP or RT. Methods: Medical recor ds of patients with localized NCCN HR-PCa treated at our institution from 2002-2011 were reviewed. RT consisted of 73.8-77.4 Gray to the prostate and seminal vesicles; regional lymph nodes were treated for pre-treatment probability of involvement ≥15%. A combination of nearest neighbor propensity score matching on age, Adult Comorbidity Evaluation-27 score [a validated comorbidity index], prostate specific antigen (PSA), biopsy Gleason, and clinical T-stage (cT) and exact matching on PSA, biopsy Gleason, and cT was performed. Multivariate cox-proportional hazards regression was used to compare metastasis-free survival (MFS) and overall survival (OS) (calculated from date of diagnosis). Results: 246 patients were identified (160 RP and 86 RT). Propensity score matching resulted in 62 matched pairs. For the RP group, minimally invasive surgery (70.9%) and lymph node dissection (100%) were common. ADT was administered to 37.1% and 80.6% of patients receiving RP and RT, respectively. Median follow-up was longer for the RT group (51.4 vs 41 months, p = 0.004). Five-year rates of metastasis for RT and RP were 8.9% and 33% (p = 0.003), and for death were 25.9% and 17.6%, respectively (p = 0.31). MFS was significantly better for patients treated with definitive RT compared to RP, while OS was not different (Table). Conclusions: In our cohort with HR-PCa, treatment with RT resulted in a MFS advantage over RP. This was not accompanied by an improvement in OS.The difference in MFS may possibly be related to the importance of early adjuvant ADT. [Table: see text]
Association of baseline IL-8 and ferritin with clinical outcome with everolimus and BNC105P in the DisrupTOR-1 trial.
Authors: Pal Sumanta Kumar , Azad Arun , Bhatia Sumeet , Drabkin Harry A. , Costello Brian Addis , Sarantopoulos John , Kanesvaran Ravindran , Lauer Richard C. , Sweeney Christopher , Hahn Noah M. , Sonpavde Guru , Richey Stephen Lane , Breen Timothy , Kremmidiotis Gabriel , Leske Annabell F. , Doolin Elizabeth E. , Bibby David C. , Simpson Jeremy Andrew , Iglesias Jose Luis , Hutson Thomas E.
Published: February 2017

475

Background: The vascular disrupting agent (VDA) BNC105P shows synergy with everolimus in preclinical models. The DisrupTOR-1 trial included a phase I component exploring this combination and a randomized phase II component comparing everolimus with BNC105P (Arm A) to everolimus monotherapy (Arm B) (Pal et al. ESMO 2014). Methods: Pts with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized in the phase II study component. In Arm A, patients received a 7 day lead-in dose of everolimus followed by dosing with BNC105P. Patients in Arm A had optional blood collections prior to administration of BNC105P and 3 hours after receiving BNC105P. A fluorescence-based assay was used to characterize a broad panel of analytes at each time point. Biomarkers were assessed in both a static and dynamic fashion. For the former, biomarkers were stratified by median value, and progression-free survival (PFS) was compared in resulting subgroups using the Kaplan-Meier method. For the latter, change in biomarker level before and after BNC105P infusion was stratified by median difference, and PFS was compared in resulting subgroups using the Kaplan-Meier method. Results: 139 pts were randomized with 69 and 67 evaluable pts in Arms A and B, respectively. Dynamic biomarkers were assessed in a total of 44 patients who received everolimus with BNC105P. Increases in matrix metalloproteinase-9 (MMP-9) and stem cell factor (SCF) were associated with improved PFS (p=0.0421 and p=0.0291, respectively). Decreases in sex hormone binding globulin (SHBG) and serum amyloid protein (SAP) were associated with improved PFS (p=0.0184 and p=0.0063). With respect to static biomarkers, elevated baseline ferritin and lower baseline IL-8 were associated with improved PFS (p=0.0291 and p=0.0149, respectively). Conclusions: Several static and dynamic biomarkers in the DisrupTOR-1 trial were associated with PFS. A prospective biomarker-driven study examining everolimus with BNC105P selected by baseline IL-8 and ferritin is in development. Clinical trial information: NCT01034631.
Systemic PD-1/PD-L1 inhibition combined with local vascular-targeted photodynamic therapy (VTP): Effects on primary tumor and prevention of lung metastasis in a preclinical RCC model.
Authors: O'Shaughnessy Matthew , Murray Katie S , LaRosa Stephen , Monette Sebastien , Kim Kwanghee , Scherz Avigdor , Coleman Jonathan A.
Published: February 2017

477

Background: Immune checkpoint inhibitors targeting the PD-1 pathway have shown activity against advanced renal cell carcinoma in phase 2 clinical trials. The response to PD-1 inhibition is not consistent however and may depend on host factors (ie. PD-L1 expression). Strategies that modulate immune regulation in the tumor microenvironment can impact responses to PD-1 pathway inhibitors. We have previously shown that VTP treatment of primary tumors using the novel photosensitizer WST-11 induces a defined local inflammatory response. We sought to evaluate whether response to PD-1/PD-L1 inhibition could be enhanced with VTP treatment of primary tumors. Methods: Balb/c mice bearing orthotopically implanted Renca kidney tumors were treated with IgG alone, anti-PD-1/anti-PD-L1 monoclonal antibodies (mAbs), VTP alone, or VTP + mAbs. VTP treatment of the primary tumor was performed 10 days (d10) after tumor implantation. Primary tumor response, enumeration of lung metastases and histologic analysis was performed on d21. Results: Treatment of the primary tumor with VTP and systemic PD-1/PD-L1 inhibition (n=15) resulted in regression of primary tumors whereas PD-1/PD-L1 inhibition alone (n=21) or VTP treatment alone (n=16) did not (no gross tumor vs. median tumor size 96mm2 vs 36 mm2 vs 81 mm2for combination vs mAbs alone vs VTP alone vs control, p<0.0001). Significant treatment effect was also observed in the combined treatment group by histologic analysis. Furthermore, growth of lung metastases was prevented with the combined treatment regimen compared to either treatment alone (median number lung mets=3 vs 56 vs 53 vs 23 for combination, mAb alone, VTP alone and control, respectively, p=0.0252). Conclusions: Only the combination of systemic PD-1/PD-L1 inhibition and local VTP provided primary tumor control and prevention of distant metastasis. Modulation of the inflammatory response in the tumor microenvironment with local therapy such as VTP may enhance the effects of systemic PD-1/PD-L1 blockade to provide better local and metastatic tumor control that can be investigated in prospective clinical trials.
Correlation of apparent diffusion coefficients (ADCs) on diffusion-weighted (DW) magnetic resonance (MR) imaging with lesion size and prostate cancer risk.
Authors: Salami Simpa Samuel , Yaskiv Oksana , Turkbey Baris , Villani Robert , Ben-Levi Eran , Rastinehad Ardeshir
Published: February 2017

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Background: A negative correlation between ADC values and Gleason risk of prostate cancer (CaP) has been reported by the NIH. We correlate ADC values on DW MR imaging with lesion size and risk stratification of CaP. Methods: Men with abnormal DRE or PSA underwent a 3T MP-MRI (T2, DWI, and DCE) with an endorectal coil. ADC maps were calculated using b values of 0, 500, 1,000 and 1,500; additional b 2000 images were obtained separately. Three radiologists (EB, RV, AR) reviewed and graded all lesions using the 5-point Likert scale and PI-RADS score. A total of 268 men with suspicious lesion (s) on MRI were prospectively enrolled. The UroNav system (Invivo, Florida) was used to perform MR/TRUS fusion-guided prostate biopsies, obtaining one biopsy core in axial and sagittal planes from each lesion. Our institution’s pathologist reviewed all biopsies. Lowest ADC values of suspicious lesions were correlated against lesion size and Gleason risk stratification. Results: The median age and PSA were 65.0 years and 7.4 ng/mL respectively. An average of 1.5 (378/256) suspicious lesions per patient was identified on the MP-MRI. Median volume of MRI target lesions was 0.36 cm3. The cancer detection rate of fusion biopsy on lesion level analysis was 45.2 % (171/378). The mean ± SD ADC values (x 10-6 mm2/sec) for lesions negative and positive for CaP were 1022 ± 260 and 724 ± 223 respectively (p <0.0001). The mean ± SD ADC values (x 10-6 mm2/sec) for lesion size < 0.2 cm3, 0.2 – 0.5 cm3, 0.5 – 1.0 cm3, and > 1 cm3 were 771 ± 246, 677 ± 206, 629 ± 119, and 500 ± 86respectively. Higher risk CaP was associated with lower ADC values with AUC of 0.77 (p=0.0001). The mean ± SD ADC values (x 10-6 mm2/sec) for low (≤6), intermediate (7), and high (8-10) Gleason grade CaP were 845 ± 285, 687± 195, and 628 ± 145 respectively. Conclusions: The ADC value of suspicious lesions on MRI has an inverse correlation with lesion size and prostate cancer risk. It may be a useful in predicting CaP and its clinical significance. Further studies are needed to determine its value in stratifying patients for prostate biopsy, active surveillance and/or treatment.
Genetic polymorphisms of PDGFR/VEGFR2/VEGFR3/RET and their relevance to thrombocytopenia in mRCC patients treated with sunitinib.
Authors: Sheng Xi Nan , Kong Yan , Chi Zhihong , Cui Chuan Liang , Si Lu , Mao Li Li , Lian Bin , Li Si Ming , Tang Bixia , Wang Xuan , Yan Xieqiao , Dai Jie , Guo Jun
Published: February 2017

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Background: Since Asian are more susceptible to hematologic toxicity caused by sunitinib. The adverse effect difference differs from that of Caucasian may be related to genetic polymorphism. This study is to explore the characteristics of gene phenotypes and potential relationship between genetic polymorphisms and thrombocytopenia in Chinese patients with metastatic clear-cell renal cell carcinoma (mcc-RCC) treated with Sunitinib. Methods: Ninety-three mcc-RCC patients treated with sunitinib were enrolled in this study. Genotype analyses were done before treatment and thrombocytopenia was recorded on the first three cycles of treatment. Genetic polymorphisms of PDGFR (rs35597368, rs1800810, rs1800813, rs1800812) AVEGFR2 (rs2071559, rs1531289, rs7692791, rs1870377) AVEGFR 3 (rs307826) ARET (rs1799939) were analyzed for a possible association with thrombocytopenia (grade 3/4) incidences. Results: Gene types of total of 10 single nucleotide polymorphisms in 4 candidate genes were according with Hardy-Weinberg law. Grade 3/4 thrombocytopenia incidence is 29%. Test results demonstrated that the incidence of grade 3/4 thrombocytopenia was increased when CG genotype in PDGFR 1171C/G (rs1800810) (p=0.048) or when GA genotype in PDGFR 735G/A (rs1800813) (p=0.050) or when AA genotype in VEGFR2 1718T/A (rs1870377) (p=0.001) were present. Conclusions: The mutation in locus of rs1800810, rs1800813 and rs1870377 may intensify the inhibition of PDGFR or VEGFR2 by sunitinib, causing the increase thrombocytopenia incidence. It is help to look for the biomarker about side effect for the patients with metastatic clear-cell renal cell carcinoma treated with sunitinib.