bluuebunny/crossref_metadata_2025 huggingface dataset:
Gonadal function in male patients with metastatic renal cell cancer treated with sunitinib: Effects of testosterone replacement on quality of life.
Authors: Dalla Volta Alberto , Valcamonico Francesca , Cappelli Carlo , Delbarba Andrea , Ferrari Vittorio D. , Arcangeli Giuseppina , Rangoni Giovanni , Castellano Maurizio , Berruti Alfredo
Published: February 2017

525

Background: Sunitinib (S) is a standard first line treatment of metastatic renal cell carcinoma (mRCC). Asthenia and fatigue are the most prevalent toxicities but the relevant causes are not fully elucidated. Since endocrine glands are highly vascularized, the potent antiangiogenic effect of S can potentially impair their function. With the exception of hypothyroidism, the endocrine-related side-effects of S have not been extensively explored. Methods: We performed a cross-sectional study in which pituitary, thyroid, parathyroid, adrenal and gonadal functions were assessed in 25 mRCC patients who received 9 months of S therapy. Since a high prevalence of hypogonadism was observed, we subsequently enrolled 16 mRCC male patients in a prospective cohort study in which serum testosterone (T) serum free T, serum FSH and LH were evaluated at baseline and after 6 weeks (1 cycle) of S therapy. In patients eligible for testosterone replacement after andrologic evaluation, a FACT-G questionnaire for quality of life (QoL) assessment was prospectively administered at baseline and after 3 months. Results: In the cross sectional study 15/22 S treated male patients (68%) had serum T below the normal range and 13 of them (87%) presented with low/normal levels of LH. In the prospective study mean T levels (95% CI) were 5.04 ng/ml (3.4 - 6.7) at baseline and 4.1 ng/ml (3 - 5.3) after 6 weeks (p 0.05). The corresponding free T were 91.4 pg/ml (66 – 116.8) and 80.2 pg/ml (65 – 95.3) (p 0.24), respectively. Hypogonadism was observed in 5 (31%) patients at baseline and 10 (63%) patients after 6 weeks of S therapy. In the 5 patients becoming hypogonadic after S therapy, LH was 11.4 mU/ml (3.2 - 19.5) at baseline and 11.5 mUI/ml (0 – 23.5) after 6 weeks. Four patients were addressed to testosterone replacement. QoL significantly improved in 3 of them, with the strongest advantage in the physical comfort area. Conclusions: S therapy induces hypogonadism in a high proportion of male patients with mRCC. Low or inappropriately normal LH levels are consistent with a pituitary origin of the endocrine disorder. Testosterone replacement may improve the QoL and treatment tolerance.
Clinical utility of a custom next-generation sequencing panel in the diagnosis of needle biopsies from renal masses.
Authors: Gowrishankar Banumathy , Janakiraman Manickam , Padmanabhan Raghavendra , Thodima Venkata Jaganmohan , Spaliviero Massimiliano , Stratton Kelly Lynn , Soni Rekha , Durack Jeremy C. , Chaganti Raju S.K. , Solomon Stephen Barnett , Coleman Jonathan A. , Kamalakaran Sitharthan , Houldsworth Jane
Published: February 2017

528

Background: Image-guided core-needle biopsies are increasingly being utilized to assist in the management of patients with renal masses, where only limited material is available for analysis. In this study, the performance of a custom next-generation sequencing (NGS) panel was evaluated for diagnostic and prognostic utility in this setting. Methods: DNA was available for NGS from 41 of 48 core-needle biopsies from renal masses previously submitted to array-CGH (aCGH) in this IRB-approved study. The targeted NGS panel comprised genes mutated in renal cancer, prognostic SNPs, and a 3Mbp SNP backbone. After library preparation from as little as 25ng DNA, sequencing was performed (MiSeq, Illumina), variants identified using CLCbio, and genomic gain/loss estimated by CNVKit (Talevich E, et al, manuscript in preparation). A classification algorithm based on 15 copy number alterations (CNAs) was applied to aCGH and NGS CNA profiles (PMID: 25498568). Histology of the biopsy or resected specimen (if available) served as the gold standard. Results: By histology, the 41 profiled biopsies comprised: 13 clear cell RCC (ccRCC), 9 papillary RCC (pRCC), 2 chromophobe RCC (chrRCC), 12 benign neoplasms, 2 unclassified, 2 high grade/poorly differentiated RCC, and 1 non-diagnostic. Among ccRCC, aCGH correctly subtyped 8/13. No CNAs were detected in the remaining 5, but for which NGS detected CNAs in 3/5 and TET2 mutations in 1. Mutations in PBRM1 and BAP1 with reported prognostic significance in ccRCC were found in 3 and 1 specimens respectively. Apart from 1 without any detectable mutations or CNAs, aCGH and NGS correctly subtyped 8/9 pRCCs based on CNAs. Also, activating MET mutations were seen in 2 pRCC specimens. aCGH and NGS accurately diagnosed the 2 chrRCC and detected pRCC-related CNAs in 2/13 benign neoplasms. In the two unclassified specimens, both methods identified ccRCC-related CNAs. Notably, NGS identified CNAs and mutations in the biopsy non-diagnostic by histology. Conclusions: Overall, targeted NGS can robustly detect genomic alterations requiring only limited DNA, that together with histology, contributes important diagnostic and prognostic information in the management of renal mass patients.
Nephrectomy status, race, and overall survival in patients with metastatic renal cell carcinoma.
Authors: Robertson Dale Kesley , Zhang Chao , Liu Yuan , Gillespie Theresa Wicklin , Kucuk Omer , Carthon Bradley Curtis , Master Viraj A. , Issa Muta , Petros John , Harris Wayne B.
Published: February 2017

529

Background: In most settings median overall survival (OS) is longer for non-Hispanic whites relative to non-Hispanic blacks with metastatic renal cell carcinoma (mRCC). However, absence of nephrectomy has been a predictor of shorter OS for both groups. The primary objectives of this study were to define the reasons why patients with mRCC do not undergo nephrectomy and to correlate absolute contraindications to surgery with race and OS. Methods: Retrospective chart reviews of patients treated with targeted therapy for mRCC were conducted at the Winship Cancer Institute of Emory University and the AVAMC after obtaining institutional authorizations. Reasons for not undergoing nephrectomy were categorized as absolute, relative or no contraindication to nephrectomy. Descriptive statistics were employed along with Kaplan-Meier survival analysis. Results: See Table. The median OS (months) by nephrectomy status was 15.9 (6.8 – 24.7) vs. 41.8 (25.6 – 49.4), p value 0.0003, for patients at Emory with no nephrectomy vs. nephrectomy, respectively. The corresponding AVAMC values were 15.5 (8.5 – 29.5) vs. 45.2 (30.3 – 100.9), p value 0.0002. Conclusions: The number of patients with absolute contraindications to nephrectomy varied widely by race and institution, yet absence of nephrectomy was the predominant predictor of shorter OS in both settings. [Table: see text]
Socioeconomic disparities in the receipt of radiation for node-positive prostate cancer.
Authors: Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Chen Yu-Wei , Nezolosky Michelle Daniel , Nguyen Paul L.
Published: February 2017

53

Background: Radiation therapy in the setting of node-positive prostate cancer has been controversial, although some recent data suggests a survival benefit to radiation in this setting. We evaluated socioeconomic disparities in the receipt of radiation for node-positive prostate cancer to identify groups that may be less likely to receive this potentially life-saving treatment. Methods: We identified 3,283 patients with N1M0 prostate cancer diagnosed 1982-2011 using the Surveillance, Epidemiology, and End Results database who were treated with radiation or no local therapy. We conducted multivariable logistic regression to determine socioeconomic predictors of not receiving radiation treatment. Results: Several patient and demographic factors were associated with a reduced likelihood of receiving radiation: African American (AA) vs non-AA race (31.7% vs. 37.7%, adjusted odds ratio [AOR] 0.74, p = 0.012); unmarried vs married status (31.9% vs 38.6%, AOR 0.72, p < 0.001); bottom third vs top third in income level (33.7% vs. 39.8%, AOR 0.72, p < 0.001); age over 65 versus < = 65 years (34.6% vs 39.8%, AOR 0.81, p = 0.005); diagnosis before 2000 versus starting in 2000 (31.6% vs 43.5%, AOR 0.56, p < 0.001). In a separate analysis, patients under the age of 65 who had Medicaid or no insurance were less likely than patients with other insurance to receive radiation (43.5% vs 55.9%, OR 0.61, p = 0.041), although on multivariable analysis, no significant association persisted (p = 0.512). Conclusions: African American race, unmarried status, lower income level, older age, and insurance status were all associated with significantly reduced odds of receiving radiation therapy for node-positive prostate cancer compared with no local therapy. Given the accumulating data suggesting that radiation therapy can improve survival in node-positive patients, it is increasingly important to understand the reasons for these treatment disparities so that they can be reduced.
Comparison of sunitinib (su) versus temsirolimus (tem) in patients (pts) with poor-risk metastatic renal cell carcinoma (prmRCC).
Authors: Keizman Daniel , Neiman Victoria , Sella Avishay , Rosenbaum Eli , Gottfried Maya , Sarid David , Gez Eliahu , Maimon Natalie , Carducci Michael Anthony , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Peer Avivit , Neumann Avivit , Kovel Svetlana , Mermershtain Wilmosh , Rouvinov Keren , Feldhamer Ilan , Berger Raanan , Hammerman Ariel
Published: February 2017

539

Background: Based on a single phase 3 study, the mTOR inhibitor tem was approved as 1st line therapy for prmRCC. However, in daily practice, prmRCC pts are often treated with the VEGFR and PDGFR inhibitor su. We aimed to compare the clinical effectiveness of su vs tem in prmRCC pts. Methods: We performed an international multicenter retrospective study of pts with prmRCC (HENG criteria), who were treated in 8 centers across 2 different countries. 31 pts were treated with 1st line tem. Each tem treated pt was individually matched with a 1st line su treated pt, by clinicopathologic factors. The effect of tx type (tem vs su) on clinical benefit, progression free survival (PFS) and overall survival (OS), was tested using a chi-square test and partial likelihood test from cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and tx type (tem vs su), and outcome were performed using the entire pt cohort (n=62). Results: The groups were matched by age (median 65), gender (male 68%), prior nephrectomy (58%), renal cell carcinoma histology (clear cell 81%), smoking status (active in 35%), use of angiotensin system inhibitors (42%), and pre-tx neutrophil to lymphocyte ratio >3 (58%). In tem vs su treated pts, clinical benefit (partial response + stable disease) was 61% (n=19) (partial response 6%, n=2) vs 71% (n=22) (partial response 29%, n=9) (p=0.62). Median PFS was 5 vs 8 mos (p=0.08), and median OS 9 vs 17 mos (p=0.03). In multivariate analyses of the entire pt cohort (n=62), su tx was independently associated with OS (HR 0.6, p=0.001). Conclusions: In prmRCC patient, the VEGFR inhibitor su may be associated with an improved outcome vs the mTOR inhibitor tem.
Prospective assessment of the adherent perinephric fat in partial nephrectomies: Predictors and impact on peri-operative outcomes.
Authors: Dariane Charles , Badoual Cecile , Tordjman Joan , Clement Karine , Le Guilchet Thomas , Hurel Sophie , Mejean Arnaud , Timsit Marc Olivier
Published: February 2017

543

Background: The surgical complexity of partial nephrectomy (PN) can be partly anticipated using renal morphometric scores that do not consider patient related issues such as obesity or perirenal fat. Our primary objective was to prospectively assess the predictive factors for adherent perinephric fat (APF) and its impact on the onset of complications. The secondary objective was to correlate the surgical appraising with the histological reality of APF. Methods: Fifty consecutive patients undergoing robotic or open PN were prospectively included from November 2014 to March 2015. The previously published Mayo adhesive probability score (MAP score) was calculated and compared to the per-operative surgical assessment of APF using a 0 to 3 scale (APF being defined by a score ≥ 2). Fat was analyzed histologically for fibrosis (HES staining and picrosirius red) and inflammatory infiltrate of macrophages (immunohistochemistry using anti-CD68 antibody). Results: APF was present in 18 patients (36%), with no impact on surgical approach (31.3% vs 38.9 robotic way, without surgical conversion). APF was associated with longer operating time (169 min vs. 146 min, p = 0.036) and increased blood loss (469 mL vs 179 mL, p = 0.014). Duration of clamping, rate of positive margins, blood transfusion and the Clavien-Dindo score were not different (Table 1). In multivariate analysis, only male gender (p = 0.044), age (p = 0.014) and MAP score (p = 0.00057) were significant predictors of APF. Histologically, APF was characterized by a marked fibrosis but no macrophage infiltrate. Conclusions: APF can be accurately predicted using radio-clinical data as the MAP score, combined with age and gender. APF is associated with increased operative time and blood loss without impacting the rate of complications. Histological analysis of APF demonstrates significant fibrosis without inflammatory infiltrate. [Table: see text]
First-line sunitinib versus pazopanib in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Ruiz Morales Jose Manuel , Wells J Connor , Donskov Frede , Bjarnason Georg A. , Lee Jae-Lyun , Knox Jennifer J. , Beuselinck Benoit , Vaishampayan Ulka N. , Brugarolas James , Broom Reuben James , Bamias Aristotelis , Yuasa Takeshi , Srinivas Sandhya , Ernst D. Scott , Pezaro Carmel Jo , Wood Lori , Kollmannsberger Christian K. , Rini Brian I. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2017

544

Background: Sunitinib (SU) and Pazopanib (PZ) have been compared head-to-head in the first-line phase III COMPARZ study in metastatic renal cell carcinoma (mRCC). We compared SU versus PZ, to confirm outcomes and subsequent second-line therapy efficacy in a population-based setting. Methods: We used the IMDC to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS2 and PFS2 were also evaluated. Results: We obtained data from 3,606 patients with mRCC treated with either first line SU (n=3226) or PZ (n=380) with an overall median follow-up of 43.5 months (m) (CI95% 41.4 – 46.4). IMDC risk group distribution for favorable prognosis was 440 (17.3%) for SU vs 72 (25%) for PZ, intermediate prognosis 1414 (55.6%) for SU vs 153 (53%) for PZ, poor prognosis 689 (27.1%) for SU vs 62 (22%) for PZ, p= 0.0027. We found no difference between SU vs. PZ for OS (20.1 [CI95% 18.76-21.42] vs. 23.68 m [CI95% 19.54 - 28.81] p=0.19), PFS (7.22 [CI95% 6.76 - 7.78] vs. 6.83 m [CI95% 5.58 - 8.27] p=0.49). The RR was similar in both groups (Table 1). Adjusted HR for OS and PFS were 0.952 (CI95% 0.788 – 1.150 p=0.61) and 1.052 (CI95% 0.908 – 1.220 p = 0.49), respectively. We also found no difference in any second-line treatment between either post-SU vs. post-PZ groups for OS2 (12.88 [CI95% 11.89 – 14.19] vs. 12.91 m [CI95% 10.3 – 19.1] p=0.47) and PFS2 (3.67 [CI95% 3.38 – 3.87] vs. 4.53 m [CI95% 3.08 – 5.35] p=0.4). There was no statistical difference in OS2 and PFS2 if everolimus was used after SU or PZ (p = 0.33 and p = 0.41, respectively) or if axitinib was used after SU or PZ (p = 0.73 and p = 0.72, respectively). Conclusions: We confirmed in real world practice, that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. [Table: see text]
Assessing the frequency of somatic mutations in high-risk clear cell renal cell carcinoma to provide new perspectives.
Authors: Manley Brandon , Tennenbaum Daniel , Casuscelli Jozefina , Hsieh James
Published: February 2017

548

Background: Previous large collaborative studies have been conducted to characterize the genetic mutations found in Clear Cell Renal Cell Carcinoma (ccRCC). However, these studies have covered all stages of disease. We examine the genetic frequency of mutations in recurrently mutated genes found in ccRCC among patients with advanced localized ccRCC, defined as T3 disease and no known metastasis at presentation. Methods: Reviewing data from The Cancer Genome Atlas (TCGA), The International Cancer Genome Consortium (ICGC), The Cancer Genomics Project Tokyo, Japan and our prospectively collected intuitional database we identified 76 patients with ccRCC and T3 disease. We calculated the frequency of several previously reported recurrently mutated genes including VHL, PBRM1, SETD2, BAP1, KDM5C, TERT (including promoter), TP53, MTOR, and PTEN. .We also reviewed and reported corresponding clinical information for this cohort. Results: Table provides the frequency of somatic mutations as well as demographic information of our cohort. Mutual exclusivity was found between mutations of BAP1 and TERT in all patients studied. Additionally, KDM5Cmutations were found in 20% of our patients. Conclusions: These results describe the frequency of several recurrently mutated genes present in high-risk ccRCC. The mutual exclusivity between BAP1 and TERT, both having been associated with aggressive disease, suggests a possible interesting relationship between the two. Focusing our investigation on a more precise cohort of patients’ staged disease allows for new perspectives on the genetics present. Further investigation into how these mutation burdens differ from lower-risk disease deserves further investigation. [Table: see text]
Phosphodiesterase type 5 inhibitors (PDE5i) and prostate cancer recurrence.
Authors: Loeb Stacy , Folkvaljon Yasin , Robinson David , Schlomm Thorsten , Garmo Hans , Stattin Pär
Published: February 2017

55

Background: Phosphodiesterase type 5 inhibitors are commonly used for management of erectile dysfunction after prostate cancer (CaP) treatment. Single-institution studies have reported conflicting data on PDE5i use and recurrence after radical prostatectomy (RP). We re-evaluated the association between PDE5i use after RP and RT with biochemical recurrence in a nationwide, population-based registry. Methods: We performed a nested case-control study using data from the National Prostate Cancer Register of Sweden (including >98% prostate cancer cases nationwide), linked to the national Prescribed Drug Register. Among men with localized CaP who underwent primary RT or RP from 2006-2007 with 5 years of follow-up, we identified those with biochemical recurrence (n=293 cases). For each case, we identified 20 controls who were recurrence-free at the event date of the index case, using incidence density sampling stratified by age and treatment (n=5,767 controls). Multivariable conditional logistic regression was used to examine the relationship between overall PDE5i use and cumulative pill number with biochemical recurrence. Results: Among men treated by RT, PDE5i were not associated with BCR (OR 0.97, 95% CI 0.48-1.94), adjusting for marital status, education, income, PSA, clinical stage, Gleason score, and proportion of positive biopsies. As shown in the table, PDE5i were not associated with biochemical recurrence after RP adjusting for clinical features (OR 0.79, 95% CI 0.60-1.05), or with additional adjustment for surgical pathology (OR 0.83, 95% CI 0.62-1.10). Men whose cumulative number of PDE5i pills was above the median had a slightly lower risk of biochemical recurrence in the clinical model, and no difference in risk of biochemical recurrence after adjustment for RP features. Conclusions: Our results from a population-based setting suggest against an increased risk of biochemical recurrence among men using PDE5i after CaP treatment. [Table: see text]
Prognostic utility of a multi-gene signature (the cell cycle proliferation score) in patients with renal cell carcinoma (RCC) after radical nephrectomy.
Authors: Morgan Todd Matthew , Mehra Rohit , Wolf J. Stuart , Gangnang Fosso Placede , Orr Brian , Wu Shulin , Sangale Zaina , Stone Steven , Wu Chin-Lee , Feldman Adam S.
Published: February 2017

555

Background: There are currently no RCC biomarkers being routinely used in the clinic, and prognostic nomograms rely almost entirely on tumor size, stage and age. There is a critical need for improved prognostic discrimination given the increasing awareness that some patients may be managed with active surveillance, while others with higher risk disease might benefit from adjuvant therapy following surgery. We hypothesized that a previously developed multi-gene proliferation signature would predict long-term oncologic outcomes in surgically resected RCC. Methods: The cell cycle proliferation (CCP) score was derived after radical nephrectomy in 305 patients who were treated at a single center from 2000 to 2007 for clear cell, papillary or chromophobe RCC with localized disease (N0M0). Sixty-four percent of the cohort had stage I disease. Outcomes were either disease recurrence (local or metastatic), or disease specific mortality (DSM). Association with outcomes was evaluated by CoxPH survival analysis and likelihood ratio tests. Hazard ratios (HR) are given for one-unit increase in CCP score (equivalent to a doubling of gene expression). Results: Patient data were censored at 5-years of follow-up, by which time 32 patients (10%) recurred and 16 (5%) died of disease. The median CCP score was 0.095 (IQR -0.50 to 0.60). In univariable analysis, CCP score was a significant prognostic variable for both recurrence (p < 10-4) and DSM (p < 10-5). After adjusting for clinical variables including tumor size, stage, and grade, the CCP score HR for recurrence was 1.74 (95% CI (1.14, 2.65)), and for DSM was 2.59 (95% CI (1.43, 4.67)). There was no interaction between CCP and any clinical variable. A prognostic model combining clinical and molecular information will be presented along with external validation in a second cohort (N~400). Conclusions: The CCP score appears to be a significant and independent predictor of key long-term oncologic outcomes in patients who have undergone nephrectomy for RCC, providing prognostic information beyond what is available from clinical parameters. Once validated, the CCP score may have utility in the clinical management of patients with RCC.
External validation of a prediction model of survival after cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC).
Authors: Bex Axel , van Werkhoven Erik D. , Noe Allard , Karam Jose A. , Matin Surena F. , Margulis Vitaly , Stewart Grant , Staehler Michael D. , Wood Christopher G.
Published: February 2017

556

Background: In 2013 a model to predict cancer-specific survival (CSS) after CN was published (Eur Urol 63:947-52, 2013), consisting of a preoperative nomogram to predict 6-month (mo) probability of death (PoD) based on serum albumin and serum lactate dehydrogenase and a postoperative nomogram (12-mo PoD) to which were added pathologic primary tumour stage, nodal stage and intraoperative blood transfusion. We externally validated the model with a contemporary European dataset of patients treated in the VEGF-targeted therapy era. Methods: After having received the original calibration indices, data from 205 mRCC patients who underwent CN between 2006 and 2013 at 3 European centres in Amsterdam, Edinburgh and Munich were used for external validation. Next to the variables for the nomogram, age, MSKCC, IMDC, number and metastatic sites and subtype were collected. Both nomograms were used to obtain predictions for the subjects. Based on the quantiles of the distribution of predictions subjects were grouped into 4 categories and Kaplan-Meier estimates calculated as were calibration plots of observed versus predicted PoD. Since all subjects had follow-up for > 1.25 years CSS at 6 and 12 mo as a dichotomous outcome and the ROC curves were plotted. Results: With a median follow-up of 29 mo and a median OS of 15 (95% CI 12-22) mo for the entire cohort, 32 and 82 patients died from RCC at 6 and 12 mo after CN respectively. For the pre- and postoperative nomogram the respective ROC curve had an AUC of 0.667 and 0.712. In the preoperative calibration plot the observed PoD at 6 mo was higher than the predicted, resulting in a lower discrimination when compared to the original validation (0.76 and 0.74 for pre- and postoperative nomograms respectively). Conclusions: In external validation the pre- and postoperative nomograms perform well in patients with primary mRCC. Their discrimination is in the reported range of MSKCC and IMDC risk scores, which were not developed to address the decision of CN (concordance index 0.657 and 0.71, Lancet Oncol 14:141-8, 2013). Although discrimination of the preoperative nomogram was lower in external validation, it retains ability to predict early death after CN.
Outcomes of second targeted therapy in metastatic renal carcinoma: A retrospective chart review in the EU.
Authors: Heng Daniel Yick Chin , Park Jinhee , Signorovitch James E. , Yang Hongbo , Song Jinlin , Patel Dony , Lin Chinjune , Powles Thomas
Published: February 2017

558

Background: This study describes the real-world outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus (EVE), sorafenib (SOR), and axitinib (AXI) as 2nd targeted therapy in the UK, Germany, and France. Methods: A retrospective chart review was conducted among oncologists and urologists in the UK, Germany and France. Charts were reviewed for adult mRCC patients satisfying the following eligibility criteria: 1) experienced disease progression on 1st targeted therapy with sunitinib or pazopanib; 2) initiated 2nd targeted therapy with EVE, AXI, or SOR between 10/2012 and 6/2013. Kaplan-Meier analysis was used to estimate overall survival (OS) after initiation of 2nd targeted therapy among all patients and stratified by type of 2nd targeted therapy. Results: A total of 281 charts were reviewed, with 99, 91, and 91 mRCC patients receiving EVE, AXI, and SOR as 2nd targeted therapy, respectively. Mean age was 60.6 years old at initial mRCC diagnosis and 65.5% were male. The majority of patients used sunitinib (79.4%), with the rest using pazopanib (20.6%) as 1st targeted therapy. Median duration of 1st targeted therapy was 9.7 months. At the initiation of 2nd targeted therapy, 91.8% of patients had an ECOG score ≤ 2. The most common sites of metastases were lung (71.2%), bone (53.0%), and lymph nodes (47.0%). Median OS from the initiation of 2nd targeted therapy among all patients was 21.8 months (95% CI: 16.5-26.2). The median OS was 23.0, 23.5, and 18.7 for EVE, AXI, and SOR respectively. The majority of patients (87.5%) initiated 2nd targeted therapy on the recommended dose. Patients receiving AXI had a higher rate of dose increase (13.2%), compared to EVE (1.0%) and SOR (0.0%), while patients on EVE had a higher rate of dose decrease (12.1%), compared to AXI (5.5%) and SOR (8.8%). Conclusions: In this retrospective chart review study of several EU countries, the observed median OS was numerically comparable for EVE and AXI, but rates of dose adjustment differed by treatments. Retrospective chart reviews may be subject to selection bias and errors in data entry, and further analysis is underway to address confounding effects of unobserved patient characteristics.
A novel preoperative inflammatory marker prognostic score in patients with clear cell renal cell carcinoma.
Authors: Sekar Rishi Robert , Patil Dattatraya , Pearl Jeff , Baum Yoram , Kucuk Omer , Harris Wayne B. , Carthon Bradley Curtis , Alemozaffar Mehrdad , Filson Christopher Paul , Ogan Kenneth , Master Viraj A.
Published: February 2017

566

Background: Several inflammatory markers have been singularly studied as potential biomarkers in clear cell renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate. We hypothesize that a combination of preoperative C-Reactive Protein (CRP), albumin, Erythrocyte Sedimentation Rate (ESR), corrected calcium, and AST/ALT ratio into a RCC Inflammatory Score (RISC) could serve as a rigorous prognostic indicator in patients with clear cell RCC. Methods: Patients that underwent nephrectomy for localized clear cell RCC were queried from our nephrectomy database. The optimal threshold for individual biomarkers was determined using grid search methodology, receiver operating characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. The final score, RISC, was the sum of all points accrued from each biomarker (Table). ROC and chi-square analysis was performed to compare the prognostic ability of RISC to SSIGN and UISS. Impact on overall survival was analyzed with multivariate logistic regression analysis. Results: 280 patients were included in the study. Area under the curve (AUC) for RISC, SSIGN and UISS was 0.77, 0.78, and 0.81, respectively. Chi-square analysis of AUCs revealed no statistically significant difference between RISC, SSIGN, and UISS (p= 0.975 and p =0.299, respectively). On multivariate analysis, after adjusting for confounding variables, each unit increase in RISC was associated with a 31% increase in mortality (HR=1.31, 95%CI 1.13-1.50, p<0.001). Conclusions: RISC is an independent and significant predictor of overall survival in clear cell RCC with accuracy at least as good as other established prognostic tools. Notably, RISC is composed of standardized laboratory markers easily and cost-effectively obtained preoperatively, allowing crucial prognostic information to be integrated into medical decision making prior to surgery. [Table: see text]
Axitinib treatment among patients with mRCC in a U.S. community oncology setting: A retrospective study of 135 patients.
Authors: Hutson Thomas , Jiao Xiaolong , Wilson Thomas , Cisar Laura A. , MacLean Elizabeth A.
Published: February 2017

569

Background: We have previously reported differences in a variety of outcome measures between clinical trial and real world use of several therapies for advanced renal cell carcinoma (RCC) (Vogelzang NJ, et al. Clin Genitourin Cancer, 2015, Hutson TE et al. Lancet Oncol, 2013, Motzer RJ, et al. NEJM, 2013). In an attempt to better understand the real-world use of axitinib in patients (pts) with metastatic RCC (mRCC) after one prior systemic therapy, a retrospective study was conducted using the US Oncology’s (USON) iKnowMed electronic health records database and medical record review data. Methods: Eligibility criteria were: pts with mRCC ≥ 18 years of age at first diagnosis, treated with VEGFR-TKIs or immunotherapy including IL-2 and IFN as first line of therapy (LOT), received second or third line axitinib between 1/1/2012 and 10/31/2014, with ≥ 2 visits within the USON. LOT was defined based on treatment sequence. Dosing analysis included duration of therapy, dose change, and reasons for discontinuation. Results: 135 pts met eligibility criteria. The most common prior therapies were sunitinib (48.5%) and pazopanib (48.5%) for pts with axitinib as 2nd LOT (n=68), and everolimus (55.2%), temsirolimus (19.4%), and pazopanib (14.9%) for pts with axitinib as 3rdLOT (n=67). 80.7% (109) of pts started axitinib at 5mg BID, and 68.9% remained at this dose. 17.8% had a dose increase mainly due to physician’s choice and 13.3% a dose decrease mainly due to toxicity. The median duration of therapy was 4.57 months (mean 6.32, SD 5.91, range 0.03-35.49). Axitinib was discontinued in 91 (67.4%) pts, and the most common reasons for discontinuation were disease progression (39.3%) and toxicity (17.0%). Conclusions: In the community oncology setting, axitinib was commonly used in the 2nd and 3rd line setting for pts with mRCC. The usage pattern appears to be consistent with published NCCN guideline recommendations. Surprisingly and in contrast to our experience with other agents for RCC, dose changes were less common and duration of therapy was consistent with the pivotal clinical trial results. These findings suggest ease of use among community oncologists and patient tolerance are key features of axitinib.
Patient disability and treatment variation among older adults with kidney cancer.
Authors: Tan Hung-Jui , Chamie Karim , Litwin Mark S. , Hu Jim
Published: February 2017

573

Background: Beyond age and comorbidity, functional status shapes the long-term survival potential of patients with cancer. Accordingly, we explored the relationship between preexisting disability and surgery among older adults with kidney cancer. Methods: Using SEER-Medicare data from 2000–2009, we sampled 28,326 patients ≥66 years old diagnosed with primary kidney cancer. Disability was quantified using function-related indicators (FRI)—claims indicative of patient dysfunction (e.g., mobility-assist devices, falls). We used competing risk regression to assess the relationship between FRI score and non-cancer-related mortality and generalized estimating equations to estimate the probability of surgery according to FRI score, adjusting for patient and tumor stage. Results: We identified 13,619 (48.1%) adults with ≥1 FRI. Disability was associated with older age, greater comorbidity, female gender, unmarried status, lower socioeconomic status, and higher cancer stage (p<0.001). Patients with a FRI score of 1 (SHR 1.10, 95% CI 1.04–1.16) and ≥2 (SHR 1.52, 95% CI 1.44–1.60) had higher likelihoods of non-cancer-related death compared with those with a FRI score of 0. Predicted 10-year incidence of non-cancer-related death was 35, 38, and 48% while the incidence of kidney cancer-related death was 26, 28, and 29% for patients with FRI score of 0, 1, and ≥2, respectively. Patients with FRI of ≥2 received surgical treatment less often than those without disability (OR 0.61, 95% 0.56–0.66), though treatment probabilities remained high for patients with loco-regional disease and low for adults with metastatic cancer (Table). Conclusions: Among older adults with kidney cancer, functional status stands as a significant predictor of long-term survival. Although preexisting disability modulates treatment use to some degree, receipt of cancer-directed surgery appears largely determined by cancer stage. Patient functionality should be considered more heavily when deciding treatment for kidney cancer. [Table: see text]
Phase II study of axitinib for downstaging cT2a to cT1 renal tumors for allowing partial nephrectomy (AXIPAN).
Authors: Patard Jean-Jacques , Bernard Jean-Christophe , Bensalah Karim , Baumert Herve , Lang Herve , Jacqmin Didier , Duclos Brigitte , Ravaud Alain , Laguerre Brigitte , Albiges Laurence , Arnoux Armelle , Escudier Bernard
Published: February 2017

575

Background: Laparoscopic Radical nephrectomy (RN) is the current standard of care for large organ confined renal tumors while partial nephrectomy (PN) is recommended for tumor sizes up to 7 cm. PN preserves long term renal function with possible effect on overall survival. Axitinib, a potent VEGFR TKI can reduce the size of primary tumor in metastatic setting. Our primary objective was to test the ability of axitinib to reduce the size of large tumors for shifting from a RN to a PN indication. Methods: Patients with localized (cT2N0M0) RCCs were enrolled in a prospective phase II trial assessing the effect of neoadjuvant axitinib prior to surgery (PN or RN). Main inclusion criteria were: age ≥ 18, histologically proven clear cell RCC, MDRD creatinine clearance ≥ 60 ml/min, cT2a N0NxM0 tumors ( Ø> 7cm; ≤ 10 cm). Medical treatment consisted in axitinib 5 mg up to 10 mg tw/d during 2 to 6 months prior surgery according to radiological response. Results: A total of 18 patients including 11 men (61%) and 7 women (39%) with a median age of 60 yrs were enrolled. Median baseline tumor size, R.E.N.A.L. score, serum creatinine and MDRD estimated GFR were: 7.5 cm, 11, 0.8 mg/dl and 96.5 ml/min respectively. Duration of treatment was 2, 4 and 6 months in 12 (66%), 3 (17%) and 3 cases (17%), respectively. After neoadjuvant treatment median tumor size and RENAL score decreased to 5.9 cm and 10. 93 % of patients presented a decrease in maximum tumor diameter, with median size reduction of 21.7%. Out of the 17 patients who were operated, 16 (94%) underwent a PN (9 robotic and 7 open), including 84% of the cases which were performed for tumors ≤ 7cm. At 1 month from surgery, median serum creatinine and MDRD estimated GFR were 0.88 mg/dl and 88 ml/min, respectively. Medical and surgical complications rate was 11% including 1 embolization for severe bleeding and 1 Clavien V complication at 1 month after surgery due to massive myocardial infarction. Conclusions: Neoadjuvant axitinib in cT2renal tumors allowed cT1 downstaging and nephron sparing surgery in more than 80% of the cases. However, PN procedures remained high complexity cases requiring adequate surgeon expertise and information of the patients for possible morbidity of these procedures. Clinical trial information: RECF2256.
Cost-effectiveness analysis of initial management strategies for low-risk prostate cancer.
Authors: Thong Alan E. , Lee Justin K. , Carlsson Sigrid V. , Ehdaie Behfar
Published: February 2017

58

Background: A proportion of men with low-risk prostate cancer managed expectantly with active surveillance (AS) go on to definitive treatment in part due to initial understaging during transrectal ultrasound (TRUS) guided biopsy. Newer diagnostic tools including genomic tumor profiling, magnetic resonance (MR) imaging, and MR-ultrasound fusion biopsy have been advocated as effective strategies to risk-stratify men prior to entry into AS. We developed a decision analytic model to determine the cost-effectiveness of various initial management options for low-risk prostate cancer. Methods: A decision tree was constructed with repeat TRUS guided biopsy, MR imaging, genomic tumor profiling, and radical prostatectomy as initial management options with downstream Markov nodes to model annual recurring risks of continued AS, definitive treatment, and death from other causes. Value was optimized from the societal perspective over a lifetime horizon. We evaluated model heterogeneity and assumptions on the probability of understaging and test performance characteristics using Monte Carlo microsimulation and probabilistic sensitivity analysis. Results: At a willingness-to-pay (WTP) threshold of $100,000 per quality adjusted life year (QALY), immediate radical prostatectomy and genomic tumor profiling were dominated strategies with higher costs and lower effectiveness. MR imaging with MR-ultrasound fusion biopsy when targetable lesions are identified was the optimal strategy across 93% of simulations with an incremental cost-effectiveness ratio of $1,096 per QALY. Eliminating uncertainty in our model would lead to cost savings and increased effectiveness. This expected value of perfect information was $516 per patient. Conclusions: With multiple initial management options for low-risk prostate cancer, clinical decision-making can be challenging. Cost-effectiveness analysis demonstrates that image-guided biopsy techniques deliver optimal value from both a patient and societal perspective. However, given the prevalence of low-risk prostate cancer, there is value to be obtained from additional research to optimize management strategies.
STAT-3 and Β-catenin expression in metastatic clear cell renal cell carcinoma (mRCC).
Authors: Fares Aline Fusco , Cunha Isabela , Araujo Daniel Vilarim , Boente Leonardo de Azevedo , Garcia Daniel , Rinck Jose A. , Formiga Maria Nirvana Cruz
Published: February 2017

583

Background: In mRCC, there are no prospectively validated biomarkers to guide the treatment and therapy decision is based on prognostic scores and histology. STAT-3 and Wnt/b-cateninare cell proliferation pathways and have already been related to prognostic in renal cell carcinoma. Objective: to evaluate the role of STAT-3 and b-catenin expression as prognostic biomarkers in clear cell mRCC. Methods: 684 medical records of renal cell carcinoma patients treated at AC Camargo Cancer Center from 2007 to 2015 were reviewed. 86 out of 684 patients fulfilled the study criteria: metastatic clear cell carcinoma, no sarcomatoid features, previous systemic therapy, previous nephrectomy and available tumor specimens from metastatic site. Pathological samples were arranged in a TMA. The number of positive stainings cells for each antibody in each core was categorized as low positive or negative versus highly positive expression. Results: We had available tissue blocks from 47 tumors. 32/45 patients (71,1%) had highly positive membrane b-catenin and none of the patients was positive for nuclear b-catenin. 27 /45 (60%) were categorized as low positive or negative STAT-3. There was no statistically significant association between STAT-3 and b-catenin expression with clinical prognostic criteria (MSKCC and Heng criteria). In the multivariate analysis, KPS < 80% (p = 0.02; HR: 2.7), time from nephrectomy to metastasis < 1 year (p = 0.04; HR: 2.1), no hypothyroidism (p = 0.05; HR: 2.4) and MSKCC criteria (p = 0.02; HR: 2.5) were confirmed as negative prognostic factors. Associative analysis showed that none of the patients with negative membrane b-catenin had response to systemic therapy (p=0.02). OS was 35.5 months (IC 22.2-48.8) and PFS was 12.5 months (IC 10.0-14.0). Conclusions: in our cohort, STAT-3 and B-catenin expression are not associated with the prognostic criteria (MSKCC and Heng). The loss of B-catenin expression is associated to a worse response rate to antiangiogenic therapy in metastatic clear cell renal cancer. [Table: see text]
External validation of preoperative AST/ALT (De-Ritis) ratio as a prognostic indicator in localized and metastatic renal cell carcinoma.
Authors: Patil Dattatraya H , Sekar Rishi Robert , Pearl Jeff , Baum Yoram , Alemozaffar Mehrdad , Filson Christopher Paul , Ogan Kenneth , Master Viraj A.
Published: February 2017

589

Background: Recently, the De-Ritis ratio, defined as the ratio of preoperative aspartate aminotransferase (AST) to alanine aminotransferase (ALT), was shown to be an independent predictor of overall and recurrence-free survival in a European cohort with localized renal cell carcinoma (RCC). In this study, we perform an external validation of the De-Ritis ratio as a prognostic indicator in a distinct cohort of patients with localized and metastatic RCC. Methods: Patients that underwent nephrectomy for localized and metastatic RCC between 2001 and 2014 with available laboratory values within one week of surgery were queried from the Emory Nephrectomy Database. De-Ritis ratio of 1.2 was used to divide subjects into high and low subgroups. Using clinical follow-up data, prognostic value of the De-Ritis ratio was analyzed using the Kaplan-Meier method and Cox proportional regression models. Results: In a cohort of 451 patients, an elevated De-Ritis ratio (AST/ALT ≥ 1.2) was associated with significantly decreased overall survival (log-rank, p=0.0023) and recurrence-free survival (Log-rank, p=0.0395). On multivariate analysis, De-Ritis ratio was shown to be an independent and significant predictor of overall survival (HR=0.52, p=0.002) and recurrence-free survival (HR=0.47, p=0.014) as seen in Table. Conclusions: Elevated De-Ritis ratio (AST/ALT ≥ 1.2) is an independent and significant predictor of overall and recurrence-free survival and is capable of differentiating high-risk disease in patients with localized and metastatic RCC. These findings are consistent with a previous study investigating the prognostic value of the De-Ritis ratio in a European cohort, and further validates its prognostic ability in a geographically distinct cohort including patients who presented with metastatic disease [Table: see text]
The role of ZNF395 in renal cell carcinoma proliferation, migration, and invasion.
Authors: Zhao Chen , Wood Christopher G. , Karam Jose A. , Maity Tapati , Wang Lei
Published: February 2017

592

Background: Zinc finger protein 395 (ZNF395) is frequently altered in several tumor types. However, the role of ZNF395 remains poorly studied in patients with clear cell renal cell carcinoma (RCC). In this study, we investigated the in vitro and in vivo role of ZNF395 in ccRCC. Methods: cBioPortal For Cancer Genomics was used to correlate the expression of ZNF395 with RCC patient clinical, pathological and molecular profiles. ZNF395 protein and mRNA levels were studied in several RCC cell lines in vitro. Subsequently, ZNF395 knockdown was performed in 786-O and UMRC3 RCC cells and overexpression was done in Caki-1 and 769-P RCC cells. We then evaluated ZNF395 modulation in these cell lines by in vitro MTT, migration and invasion assays. Finally, we studied the effect of ZNF395 knockout and overexpression in vivo using SCID xenograft models. Results: Patients with higher expression of ZNF395 experienced longer disease-free survival and overall survival. Using in vitro models, we confirmed that knockdown of ZNF395 decreased ZNF395 expression, and increased proliferation, migration and invasiveness of 786-O and UMRC3, while overexpression of ZNF395 increased ZNF395 expression, and reduced proliferation, migration and invasiveness of Caki-1 and 769-P. Using in vivo mouse models, knockdown of ZNF395 expression in 786-O promoted tumor growth while its overexpression in Caki-1 resulted in tumor growth inhibition. We are currently performing experiments to understand the process by which ZNF395 regulates ccRCC pathogenesis. Conclusions: Our data support the role of ZNF395 as an important tumor suppressor gene in the pathogenesis of RCC.
Sorafenib versus sunitinib as first-line treatment in metastatic renal cell carcinoma: Largest multicenter retrospective analysis.
Authors: Sheng Xinan , Zhang Hailiang , Li Xuesong , Chi Zhihong , He Zhisong , Ye Dingwei , Guo Jun
Published: February 2017

594

Background: For the mRCC patients, selecting the first-line regimen for a particular patient has become a hard decision for clinicians. However, there was few clinical studies directly comparing the efficacy of first-line treatment with sorafenib and sunitinib. Methods: Reviewing medical records at the Peking University Cancer Hospital, Fudan University Cancer Hospital and Peking University First Hopital from May 2005 to March 2015 revealed 483 patients receiving sorafenib (400 mg orally BID continuously in a 4-week cycle) and 362 patients receiving sunitinib (50 mg orally daily in a 6-week cycle; 4/2 schedule) as the first-line targeted therapy. Results: Median follow-up was 23.0 months (95% CI: 2.5-25.4 months).There was significant differences in progression-free survival (PFS) between the sorafenib and sunitinib groups (11.1 months [95% CI: 8.00-13.00] vs 10.0 months [95% CI: 9.00-14.00], respectively; P = 0.028) .No significant differences was seen in overall survival (24.0 months [95% CI: 20.00-29.00] vs 24.0 months [95% CI: 18.00-31.00], respectively; P = 0.298). A subgroup analysis based on Karnofsky performance status (KPS), pathological type, Memorial Sloan Kettering Cancer Center score, metastases, and tumor load was also conducted. Clinical benefit rate was higher in sorafenib-treated patients (94.67%) than sunitinib-treated patients (84.33%). Multivariate analysis revealed that sorafenib had superior efficacy in patients with a KPS of < 90 and significantly better PFS (hazard ratio: 0.460 [95% CI: 0.222-0.954]). Conclusions: To our knowledge, this is largest mutli-center retrospective study determined the efficacy of sorafenib versus sunitinib as first-line therapy for mRCC patients. Our study results support administration of sorafenib as an effective first-line treatment agent in Chinese patients with mRCC.