bluuebunny/crossref_metadata_2025 huggingface dataset:
Time from nephrectomy (Nx) as an independent prognostic factor in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies (TTs).
Authors: Procopio Giuseppe , Iacovelli Roberto , Verzoni Elena , Grassi Paolo , Testa Isabella , Garanzini Enrico , Nicolai Nicola , De Braud Filippo G.
Published: February 2017

517

Background: Nx has been established as a prognostic factor in mRCC and included in current prognostic classifications. Despite this, the prognostic value of time from Nx has not well established in patients (pts) treated with TTs. We aim to investigate if the time from Nx to diagnosis of metastatic disease is a prognostic factor in mRCC pts treated with TTs. Methods: Database of pts treated at Istituto Nazionale Tumori of Milan, was reviewed. Only pts who received an Nx were included in the final analysis. For each pt time from Nx to diagnosis of metastatic disease was collected and pts were divided in three groups based on time ≥ 1 year (A), < 1 year (B) or Nx performed at diagnosis of metastatic disease (C, cytoreductive). Age, sex, ECOG performance status and MSKCC prognostic group were also collected. Overall survival was calculated from the start of therapy to death or last follow-up. Median OSs were estimated with Kaplan-Meier method and compared with log-rank test; association of factors with survival was evaluated with Cox-analysis. Results: A total of 285 pts meet the inclusion criteria: median age was 60.8 y (IQR: 52.5 – 68), 73% were males; ECOG-PS was 0 in 61%, 1 in 34% and 2 in 5%. Prognosis based on MSKCC classification was good in 36%, intermediate in 49% and poor in 15%, and its prognostic value was confirmed (HR: 2.7; 95%CI, 2.1 – 3.4, p<0.001). Time from Nx was ≥ 1 year in 25%, < 1 year in 26% and concomitant to diagnosis of metastatic disease in 49% of cases. The median survival was 44.5 (95%CI, 35.6 – 53.5), 22.3 (95%CI, 16.1 – 28.5), 18.1 months (95%CI, 11.5 – 24.6) for the group A, B and C, respectively with a significant differenced for every comparison (A vs. B: p=0.041; A vs. C p<0.001 and B vs. C p=0.016). When time from Nx was compared to MSKCC in the multivariable analysis, this remain an independent prognostic factor (HR: 0.7; 95%CI, 0.6 – 0.9, p<0.001). Conclusions: In mRCC pts treated with Nx and targeted therapy, time from Nx is an independent prognostic factor. Pts with good prognosis based on MSKCC criteria who had Nx more than 1 year before the diagnosis of metastatic disease have better prognosis compared to a pts with the same MSKCC risk that receive Nx with cytoreductive intent.
Changing treatment paradigms in the era of targeted therapies.
Authors: Papavassilis Philipp Marius , Herrmann Edwin , Krabbe Laura-Maria , Hertle Lothar , Boegemann Martin , Moritz Rudolf , Thielen Barbara
Published: February 2017

518

Background: Our goal was to describe the change of treatment paradigms for metastatic renal cell carcinoma (mRCC) since targeted therapy became available in 2006. Methods: In this cohort population study we retrospectively investigated all mRCC patients who were treated with targeted therapy between 06/2006 and 06/2012 in the Department of Urology of the University of Münster. To distinguish nominal variables Fisher's exact test was used, in other respects Pearson's χ² test. For metrical variables the Mann-Whitney-U-Test was used. The log-rank test was chosen to derive differences between two or more groups with regard to survival. A p value <0,05 was considered statistically significant. Results: 50/158 (31.6%) patients with a median follow-up of 362 days were initially treated with immunotherapy. The most often used second line treatment after immunotherapy was sorafenib (29 patients, 58.0%). As first line treatment sunitinib was chosen most frequently (68 patients, 63.0%). There was no statistically significant difference in survival between the patients who were treated with immunotherapy and those who were not (572 vs. 554 days, p=0,745). 134 (84.4%) patients received cytoreductive nephrectomy before systemic treatment start. Comparing the survival curves there was a significant survival benefit in favor of nephrectomized patients (632 vs. 169 days, p<0,0001). Conclusions: After introduction of the new agents treatment paradigms have changed substantially. Immunotherapy is used only rarely. Cytoreductve nephrectomy should continue to be regarded as standard treatment.
Duration of targeted therapy in metastatic renal cell carcinoma patients with ECOG PS>2.
Authors: Tsimafeyeu Ilya , Petenko Natalia N. , Snegovoy Anton , Varlamov Sergey , Demidov Lev V.
Published: February 2017

520

Background: Targeted therapy has improved clinical outcomes in metastatic renal cell carcinoma (mRCC). However, patients with unfavorable performance status are often under-represented in clinical trials of mRCC. Methods: Patients with mRCC (clear or non-clear cell) and ECOG PS >2 were included in retrospective study.Primary objective of this study was to evaluate the overall duration of targeted therapy (ODT). ODT was defined as time from initiation of first-line therapy until the end of last-line therapy. Results: 79 patients with ECOG PS >2 (median age, 60 [48-70]; male, 73%; clear-cell RCC, 95%; MSKCC intermediate/poor risk, 97%/3%) were treated with sunitinib (77%), sorafenib (23%), everolimus (20%), bevacizumab + IFN (15%), pazopanib (4%), temsirolimus (2.5%) of which 55 (70%) received only first-line therapy, 24 (30%) received 2 lines, and 9 (11%) received 3 lines of therapy. The median ODT was 9.8 months (95% CI 6–13.6). The median time to progression of patients that received 1, 2 or 3 lines was 7.1, 5.9, and 6.3 months, respectively. One patient showed complete response and 2 patients had partial responses during first-line therapy, 2 patients had partial responses during second-line therapy, and 1 patient had partial response after 2 months of third-line therapy. Among the patients who discontinued treatment, disease progression was the most common reason for discontinuation. There was no unexpected serious toxicity. Conclusions: mRCC patients with unfavorable performance status could be treated with targeted therapy during 9.8 months.
Association of reduced GATA1 mRNA expression with clinicopathology and shortened recurrence-free survival in clear cell renal cell carcinoma.
Authors: Peters Inga , Dubrowinskaja Natalia , Kogosov Michael , Abbas Mahmoud , Hennenlotter Joerg , Kramer Mario W. , Scherer Ralph , Merseburger Axel S. , Kuczyk Markus A. , Serth Juergen
Published: February 2017

521

Background: GATA1, a zinc-finger transcription factor and member of the GATA family proteins 1-6, is known to be involved in cell growth and apoptosis, especially in the erythroid lineage. Recent studies demonstrated that GATA1 interacts with p53 and its overexpression leads to an inhibition of the p53 gene function. Increased p53 expression levels have been shown to be associated with prognosis and tumor progression in renal cell carcinoma. Methods: Quantitative real-time reverse-transcribed polymerase chain reaction was applied to measure relative GATA1 mRNA expression levels in 135 kidney tissue samples, including 77 clear cell RCC (ccRCC) tissues and 58 paired adjacent normal renal tissue samples. Relative GATA1 expression levels were determined using the ΔΔCt method. Results: The mean GATA1 expression levels were significantly decreased in tumor tissues compared to adjacent normal tissues (p < 0.001, paired t-test). In univariate logistic regression analysis decreased GATA1 mRNA expression was associated with advanced tumor disease (p = 0.005), positive status of distant metastasis (p = 0.03) and lymph node metastasis (p = 0.011). Reduced GATA1 expression was associated with an increase risk of disease recurrence (p = 0.005, hazard ratio HR = 0.05). Status of distant metastasis remained also a significant independent parameter in the bivariate Cox regression model (p = 0.05, HR = 3.01). Conclusions: GATA1 mRNA expression is reduced in ccRCC and associates with a poor clinical outcome and worse clinicopathology, indicating a possible role of GATA1 in tumor development and aggressiveness of ccRCC. GATA1 could therefore serve as a new biomarker for tumor progression in ccRCC.
Neutrophil-lymphocyte ratio in small renal masses.
Authors: Bazzi Wassim , Dejbakhsh Sheila , Bernstein Melanie , Russo Paul
Published: February 2017

522

Background: Neutrophil-lymphocyte ratio has been shown to be a prognostic serum marker in some malignancies. We evaluated the association between preoperative neutrophil-lymphocyte ratio and baseline characteristics in patients with small renal masses. Methods: The charts of patients with renal masses ≤ 4 cm who underwent nephrectomy at Memorial Sloan-Kettering Cancer Center from January 2007 to July 2012 were reviewed retrospectively. Bivariable and multivariable analyses were used to examine the association between preoperative neutrophil-lymphocyte ratio (absolute neutrophil count/absolute lymphocyte count) and demographic and clinicopathologic variables. Results: Our cohort consisted of 1001 patients. Bivariable analysis showed significantly higher mean preoperative neutrophil-lymphocyte ratios in men (3.0 vs. 2.6 in women, p < 0.001) and Caucasians (2.9 vs. 1.9 in African-Americans, p < 0 .001), but no significant differences between patients with high (III−IV) or low (I−II) co-morbidity scores (2.9 vs. 2.8, p = 0.085) or between benign or malignant pathology (2.9 vs. 2.8, p = 0.972). Linear regression analysis showed a positive correlation between age and preoperative neutrophil-lymphocyte ratio (Pearson correlation coefficient (r) = 0.1268; p < 0.001), and a negative correlation between preoperative estimated glomerular filtration rate and preoperative neutrophil-lymphocyte ratio (r = -0.1246; p < 0.001). Multivariable analysis showed older age, male gender, and lower preoperative estimated glomerular filtration rate were associated with higher preoperative neutrophil-lymphocyte ratio. Conclusions: In patients with small renal masses, there is no evidence of an association between preoperative neutrophil-lymphocyte ratio and tumor pathology, but there is evidence it is affected by age, gender, and renal function.
A phase II study of S-1 in combination with sorafenib in metastatic renal cell carcinoma.
Authors: Sakai Hideki , Ohba Kojiro , Hashine Katsuyoshi , Tomita Yoshihiko , Shinohara Nobuo , Fujisawa Masato , Eto Masatoshi , Ozono Seiichiro , Tsukamoto Taiji , Akaza Hideyuki , Naito Seiji
Published: February 2017

529

Background: The potential of S-1, an oral fluoropyrimidine derivative anticancer agent, for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We therefore studied the efficacy and safety profile of S-1 in combination with sorafenib in Japanese patients with mRCC. The recommended dosage of this combination therapy was based on the results of an associated phase I study, presented at the 2012 Genitourinary Cancers Symposium (Abstract #447). Methods: In this phase II study, we enrolled patients with clear-cell or papillary carcinoma who had received no previous treatment or not more than 1 regimen of cytokine therapy. S-1 was administered orally at 80-120 mg/day according to body surface area for 28 consecutive days of a 42-day cycle in combination with sorafenib (800 mg/day) until disease progression. The primary endpoint was the objective response rate (ORR), reviewed by an independent review committee. Results: A total of 21 patients aged 41-78 years were enrolled and were fully assessable for efficacy and safety. Most patients (90.5%) had clear-cell carcinoma, and 8 (38.1%) had received prior cytokine treatment. The ORR was 52.4% (90% CI, 32.8-71.4). One (4.8%) of the 21 patients had a complete response to this combination therapy, 10 (47.6%) had partial responses, and 10 (47.6%) had stable disease. The median progression-free survival was 9.8 months (95% CI, 6.5-14.3). There were no deaths. This combination therapy was well tolerated, and most adverse events were grade 2 or lower. The most common grade ≥3 drug-related adverse events were hypophosphatemia (71.4%) and elevated lipase levels (33.3%). Conclusions: Combination therapy with S-1 plus sorafenib showed promising results regarding the primary endpoint of ORR and had an acceptable toxicity profile in patients with mRCC. Clinical trial information: JapicCTI-090973.
Activity of abiraterone acetate in metastatic patients with castration-resistant prostate cancer (mCRPC) previously treated with ketoconazole: A prospective phase II study from the prostate cancer clinical trials consortium.
Authors: Kim Won , Wilton John , Zhang Li , Lin Amy M. , Fong Lawrence , Friedlander Terence W. , Hsieh Andrew Caleb , Aggarwal Rahul Raj , Rodvelt Tammy J. , Morse Allison , Bozeman Jeffrey , Weinberg Vivian K. , Molina Arturo , Mohler James , Fetterly Gerald J. , Szmulewitz Russell Zelig , Small Eric Jay , Ryan Charles J.
Published: February 2017

53

Background: Abiraterone acetate (AA), like ketoconazole (keto), inhibits CYP17, the rate-limiting enzyme in androgen biosynthesis. Since patients (pts) with prior keto treatment were excluded from the pivotal phase III AA trials, the utility of AA after keto is not well understood. This prospective study evaluated the efficacy of AA in pts who had received prior keto. Methods: Pts with progressive castration-resistant prostate cancer (mCRPC), prior keto therapy 28 days or more, and normal baseline organ function (including ACTH stimulation) tests were treated with AA 1,000 mg PO daily and prednisone 5 mg PO BID. Pts with prior chemotherapy were excluded. Serum androgen levels, including dehydroepiandrosterone (DHEA), were measured by liquid chromatography/mass spectroscopy (LC/MS) at baseline and during treatment for exploratory analyses. Radiographic progression-free survival (rPFS) was defined as freedom from: death, radiographic progression, or unequivocal clinical progression. Results: Forty two pts were enrolled. Median age was 71. Median prostate-specific antigen (PSA) was 47.5ng/dL. Median duration of prior keto was 38 weeks (range 5 to 207). Treatment with AA resulted in 30% or greater decline in PSA at 12 weeks in 20 pts (48%, 95% CI, 32-63%), and 50% or greater decline in PSA at 12 weeks in 16 pts (38%, 95% CI 24-54%). Median time to PSA progression (TTPP) was 16 weeks (range 4 to 64). Median rPFS was 24 weeks (range 1 to 88). Baseline serum DHEA levels were measured in 40 pts. Nine pts had DHEA less than the limit of quantitation (LOQ, 0.250ng/mL), and 31 pts had DHEA greater than or equal to LOQ. One pt with DHEA less than LOQ (1 out of 9, 11%, 95% CI 0.6-49%) had PSA decline 30% or more at 12 weeks, compared to 17 pts (17 out of 31, 55%, 95% CI 36-72%) with DHEA greater than or equal to LOQ (p=0.028). Median time to pain progression (TTPP) was 8 weeks (range 4 to 32) for pts with DHEA less than LOQ, compared to 18 weeks (range 4 to 64) for pts with DHEA greater than or equal to LOQ (p=0.012). Median rPFS was 12 weeks (range 4 to 24) for pts with DHEA less than LOQ, compared to 36 weeks (range 1 to 88) for pts with DHEA greater tha or equal to LOQ (p = 0.0006). Six pts remain on AA. Conclusions: A significant proportion of pts with prior keto exposure demonstrate clinical response to AA. DHEA levels via LC/MS merits further study as a predictive biomarker in pts treated with androgen synthesis inhibitors. Clinical trial information: NCT01199146.
A phase Ib study exploring the combination of everolimus and dovitinib in VEGF-refractory clear cell renal cancer.
Authors: Fitzpatrick Amanda Marie , Greenwood Michelle , Foreshew Abigail , Nixon Jude , Sahdev Anju , Sarwar Naveed , Lim Louise , Jones Robert J. , Chowdhury Simon , Crabb Simon J. , Powles Thomas
Published: February 2017

531

Background: Everolimus (mTOR inhibitor) and dovitinib (VEGF and FGF-2 inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. In this study we establish the tolerability and an early activity signal of this combination. Methods: Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalated doses of daily oral everolimus (5-10 mg PO OD) and dovitinib (200-500mg 5/7 days PO) Dose-limiting toxicities (DLTs) were assessed determine the MTD. An expansion cohort (n=15) was treated to obtain additional efficacy and safety information. Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg PO OD and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (CTC grade 1-4) of patients respectively. Frequent biochemical abnormalities occurred such as hypertrygliceridaemia in 67%. Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% CI 2.2-11 months). Conclusions: Dovitinib and everolimus had modest activity, but did not meet all of the the planned efficacy endpoints. Fatigue was the dose limiting toxicity. Clinical trial information: NCT01714765.
Markers of sunitinib-resistance in clear cell renal cell carcinoma: A gene expression analysis.
Authors: Reig Òscar , Marín-Aguilera Mercedes , Lozano Juan José , Gonzalez Blanca , Mallofré Carme , Campayo Marc , Gascon Pedro , Mellado Begoña
Published: February 2017

533

Background: Sunitinib is a standard first line treatment of metastatic renal cell carcinoma (ccRCC). Approximately 20% of patients experience primary resistance to therapy and no predictive biomarkers are available. The aim of our study is to discover novel biomarkers to predict response to sunitinib and to generate hypothesis about mechanisms of intrinsic resistance. Methods: Gene expression analysis was performed in formalin-fixed paraffin embedded (FFPE) samples from 44 patients with metastatic ccRCC treated with sunitinib in our institution. Affymetrix Human Gene 2.0 ST array was performed in primary tumors from 6 extremely sensitive (progression free survival (PFS) > 24 months) and 8 refractory (progression disease as best response) ccRCC. Technical validation with qPCR (Fluidigm Dynamic 96.96 Array) was performed in the whole cohort. The ΔΔCt method was used to quantify the relative amount of mRNA. Clinical and pathological data were correlated with gene expression. Results: 330 genes were differentially expressed between refractory and sensitive patients (p≤0.05). Network analysis showed 16 significant networks represented. Gene expression of 96 selected markers was tested in 47 primary tumors and 24 metastases. We found IL8, VEGF and NOTCH pathways upregulated on refractory patients. Survival analysis showed that the overexpression of IL8 correlated with a worse PFS (HR: 2.42, 95%CI1.27 – 4.63, p=0.0075) and overall survival (OS) (HR: 3.42, 95%CI 1.50 – 7.79, p=0.0034). Overexpression of VEGFBcorrelated with a prolonged PFS (HR 0.52, 95% CI 0.28 – 0.98, p=0.0415). Conclusions: Our results confirm the predictive value of IL8 expression in a cohort of ccRCC patients treated with sunitinib and suggests novel biomarkers of response to sunitinib. These data will be further validated in an independent cohort of patients.
Results of a phase II trial of docetaxel (DOC), bevacizumab (BEV), and androgen deprivation therapy (ADT) for biochemical relapse (BCR) after definitive local therapy for prostate cancer (PC).
Authors: McKay Rana R. , Gray Kathryn P. , Hayes Julia H. , Bubley Glenn J. , Rosenberg Jonathan E. , Kantoff Philip W. , Taplin Mary-Ellen
Published: February 2017

54

Background: Despite primary treatment for localized PC, 20-30% of men experience a BCR, detected by a rise in prostate-specific antigen (PSA). Though 30% of these patients develop metastatic disease, the optimal treatment of men with BCR has yet to be determined. In this trial, we evaluate the efficacy of DOC, BEV, and ADT for men with BCR after local therapy for PC. Methods: 41 men with a BCR and PSA doubling time of ≤10 months (mos) were enrolled. Patients received 4 cycles of DOC (75 mg/m2) every 3 weeks, 8 cycles of BEV (15 mg/kg) every 3 weeks, 18 mos of a luteinizing-hormone releasing hormone (LHRH) agonist, and 15 mos of bicalutamide (50 mg daily) beginning after completion of DOC. The primary endpoint was the proportion of patients free from PSA-progression 1 year after completion of ADT. Secondary endpoints included PSA response, testosterone recovery, and toxicity. Results: Median follow-up was 27.6 mos. Median age at diagnosis was 58 years. Median PSA at diagnosis was 6.7 ng/mL, with the majority of patients (59%) having Gleason 7 disease. Most patients underwent radical prostatectomy +/- radiation therapy (n=36). At baseline, 33 men (81%) had a normal testosterone (> 240 ng/dL). The table describes the PSA responses for the entire cohort. 10 men (28%) had a normal testosterone 6 mos after completing ADT. 17 men (47%) had a normal testosterone 12 mos after completing ADT, of whom 5 (29%) had a PSA <0.2 ng/mL at that time. There were 15% grade 1, 34% grade 2, 39% grade 3, and 12% grade 4 adverse events (AEs). The most frequent grade 3-4 AEs included neutropenia (24%), febrile neutropenia (11%), and hypertension (9%). Conclusions: DOC, BEV, and ADT for BCR resulted in complete responses in 16 men (44%) 1 year after completion of therapy. Longer follow-up is needed to determine the efficacy of this regimen. Clinical trial information: NCT00658697. [Table: see text]
Assessment of time from cytoreductive nephrectomy (CN) to initiation of targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Vuong Winston , Chang Mark , Ruel Nora , Hsu Joann , Carmichael Courtney , Figlin Robert A. , Pal Sumanta Kumar
Published: February 2017

540

Background: For patients (pts) with de novo mRCC, the initiation of TT typically occurs at a window of 4-6 weeks following CN. Although this practice is thought to mitigate impaired wound healing, bleeding and other complications (cx) in the perioperative period potentially related to antiangiogenic TT, there is limited data to support this practice. Methods: An institutional database including over 670 pts with RCC was interrogated. Pts with de novo mRCC who had received CN and subsequent TT were identified. When available, demographic data, Charlson comorbidity index (CCI), body mass-index (BMI) and surgical data (estimated blood loss [EBL], intraoperative cx, etc.) were recorded. ICD-9 codes recorded up to 90 days following CN were evaluated; newly applied diagnoses with possible relationship to surgery were considered to be potential postoperative cx. For continuous variables, the Spearman correlation test was used to determine associations with time to TT. For categorical variables, Kaplan-Meier analyses were conducted to determine if time to TT varied across subgroups. Results: Of 270 pts with mRCC, 79 pts received cytoreductive nephrectomy. Of these, 36 pts received TT as an initial treatment strategy (others received IL-2, IFN or chemotherapy), and 30 pts had a documented date of TT initiation. Two pts were removed given receipt of preoperative TT, resulting in a total of 28 pts in the current analysis. Median time to TT was 46 days (range, 28-93). Median overall survival for the overall cohort was 17.2 months. No association was found between age, BMI, CCI, number of sites of metastasis and time to TT. Time to TT did not vary by race (Caucasian v other) or class of TT (VEGF-directed therapy v mTOR inhibitor). Furthermore, EBL and the frequency of intraoperative cx did not vary by time to TT. The most frequently encountered postoperative cx included pleural effusion, pain, fatigue and nausea. Conclusions: With the caveat of our small sample size, the lack of an association between operative cx and time to TT suggests that an abbreviated timeframe between CN and TT may be entertained. These findings warrant exploration in larger series and/or prospective validation.
Effect of irradiation of renal cell carcinoma (RCC) cell lines on RCC tumor-associated antigen (TAA) specific CD8+ T-cell stimulation.
Authors: Janda Gregory , Habiby Kermany Mohammad , Romano Michelle , Heit Lilia , Singh Anurag , Warren Graham Walter , Schwaab Thomas
Published: February 2017

542

Background: Radiation increases the immunogenicity of many cancers. We have previously shown increased immunogenicity of RCC with cell line irradiation. Herein, we describe the effect of irradiation of RCC cell lines on the expression of TAAs as well as several molecules involved in CD8+ T Cell (CTL) mediated tumor cytotoxicty and the in vitro effect of tumor irradiation on NY-ESO-1 specific CTL clones. Methods: Six RCC cell lines (ACHN, 786-0, 769-P, Caki-1, A-498, A-704) were cultured and exposed to 0, 12 or 16 Gy of ionizing radiation. Cells were isolated at 2, 24 and 48 hours after irradiation. Expression of cell surface molecules (CD95, CD54, Calreticulin, NYESO-1, CA-9, 5T4, MUC-1 and HSP-70) was assessed using multi-color flow cytometry. Results are reported as mean relative increase from control (dose 0 Gy, time 2 hours post irradiation). In a second experiment, NY-ESO-1 specific CTL clones were cultured in the presence of A-498 cells that were subjected to radiation under the above noted conditions and assessed using an ELISPOT assay. Negative control consisted of only CD8+ T Cells. Results: The ELISPOT experiment demonstrated stimulation of NY-ESO-1-specific CTL by irradiated A-498 cells. Negative control showed no stimulation, with only 4 spots. An increase in spots was observed from 79 and 82 spots at 2 hours post-irradiation to 166 and 205 spots at 48 hours post-irradiation for 0 Gy and 16 Gy, respectively. Conclusions: Sublethal irradiation of human RCC cell lines increases their immunogenicity, provoking TAA-specific T cell stimulation. [Table: see text]
Distribution and geographic accessibility of prostate cancer clinical trials in the United States.
Authors: Galsky Matt D. , Latif Asma , Stensland Kristian D. , Moshier Erin L. , McBride Russell , Hendricks Ryan , Sonpavde Guru , Godbold James H. , Hall Simon J , Oh William K. , Wisnivesky Juan P.
Published: February 2017

59

Background: An extremely small proportion of patients with cancer in the United States (US) enroll in clinical trials. While several barriers to trial accrual have been described, the geographic distribution and accessibility of clinical trial sites has not been comprehensively explored. Methods: ClinicalTrials.gov was queried to identify all active US clinical trials exploring first-line therapies for metastatic prostate cancer (PCa) on 9/16/2012. We evaluated the geographic distribution of trial sites and determined the relationship between the number of sites and the number of patients with advanced PCa per county and evaluated heterogeneity using Lorenz curves. We also estimated the minimum driving distance required to access a clinical trial site from each ZIP code in the continguous US; a distance >30 miles was defined as high travel burden consistent with prior studies. Results: We identified 958 sites associated with 42 PCa clinical trials (Table). The geographic distribution of clinical trial sites was very inhomogeneous with several states having only 1-2 trial sites. Among 3185 US counties, 2,669 (83.8%) had no clinical trials available for first-line treatment of metastatic PCa. Counties with larger populations of patients with advanced PCa had significantly higher numbers of clinical trial sites. For every 100 additional patients with advanced PCa per county, the number of available trial sites increased by 21.0% (95% CI: 16.5-25.7%). However, Lorenz curves indicated a high degree of inequality in trial accessibility (Gini index 0.71). Approximately 31% of the US population resided >30 miles from a PCa trial site. Conclusions: Clinical trials sites are poorly accessible, geographically, to a large subset of US PCa patients, a finding that likely contributes to dismal accrual. Innovative solutions are required to address geographic barriers to access. [Table: see text]
The effect of low-dose GTx-758 on free testerone levels in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Getzenberg Robert H. , Smith Jordan , Hancock Michael L. , Tutrone Ronald , Flaig Thomas W. , Dalton James T. , Steiner Mitchell S. , Westenfelder Karl R , Szucs Miklos
Published: February 2017

60

Background: Luteinizing hormone-releasing hormone (LHRH) agents used for androgen deprivation therapy (ADT) were designed to lower total testosterone (T) levels to those achieved by orchiectomy for palliative care of advanced prostate cancer. This castration equivalent level was based upon the lower limits of quantitation (50ng/dL) of outdated assays. Contemporary assays reveal that actual total T levels in men after orchiectomy are significantly lower (<20ng/dL), with 30 to 40% of men on LHRH agonists not achieving that level. There is growing literature showing that lower T levels correlate with improved outcomes. Additionally, the biologically active form of T is unbound, free T. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that increases sex hormone binding globulin (SHBG), lowers free T levels, and ameliorates estrogen deficiency side effects associated with ADT. Methods: In a phase II open label study (G200712), 38 men with metastatic castration resistant prostate cancer (mCRPC) were continued on their current form of ADT along with a low dose of GTx-758, 125 mg, for at least 90 days. Exclusion criteria included men at increased risk for venous thrombolic events (VTE). Results: The initial 14 patients in this trial completed 90 days on study and are evaluable for select trial endpoints. All treated men had a greater than or equal to a 150% increase in SHBG levels. Eleven of the 14 men began the study with suboptimal castration (free T >0.7 pg/ml) and 91% (10 out of 11) of these men became optimally castrated by day 90. Four out of 14 patients had a more than 45% decrease in prostate-specific antigen. Stable or improved hot flashes and bone turnover markers were observed in 71% and 73% of treated men, respectively. While some patients experienced adverse events, none were vascular related and there were no serious adverse events or VTEs. Conclusions: The majority of patients on an LHRH agonist enrolled in this phase II study had suboptimal levels of free T that were further lowered by GTx-758 administration. GTx-758 treatment resulted in stabilization and/or improvement in reported hot flashes and bone turnover, two major side effects of ADT. While the phase II clinical trial is ongoing, and full results are forthcoming, these preliminary findings show that 125 mg of GTx-758 has clinical effectiveness and is well tolerated. Exploration of 250 mg a day is planned. Clinical trial information: NCT01615120.
Surgeon volume and disparities in post-operative complications among black men.
Authors: Konijeti Ramdev , Ruhotina Nedim , Reese Stephen , Chung Benjamin I. , Kibel Adam S. , Chang Steven L.
Published: February 2017

66

Background: Racial and ethnic disparities related to prostate cancer treatment are well-described. Lower rates of postoperative complications are noted in men who undergo radical prostatectomy (RP) at high-volume centers or by high-volume surgeons. We assessed whether access to high-volume providers might account for ethnic disparities in postoperative complications from RP. Methods: Using a nationally representative dataset of hospital discharge information, the Perspective Database (Premier Inc, Charlotte, NC), we examined all men who underwent RP (ICD9 60.5) between 2003 and 2010. Data were stratified based on patient characteristics (age, race, marital status, insurance status, Charlson Comorbidity Index), hospital characteristics (number of beds, teaching vs. nonteaching, urban vs. rural, and geographic region), surgical approach (robotic vs. nonrobotic), surgeon volume (low [less than 5], intermediate [5 to 24], and high [more than 24]), and complications (based on Clavien classifications I-V), if any. A logistic regression model accounting for clustering & survey weights was constructed to assess the association of surgeon volume & ethnicity on postoperative major complications (i.e., Clavien III-V). Results: In a multivariate model incorporating clinicodemographic and hospital information, black men continued to demonstrate a higher odds for major complication (OR 1.3 [1.02-1.7]). However, when further incorporating surgeon volume to the multivariate model, there was no longer any difference in the odds for a major complication for black men (OR 1.2 [0.97-1.6]). Patients who underwent RP by intermediate-volume surgeons and high-volume surgeons had a lower incidence of postoperative major complications compared to those treated by a low-volume surgeon (OR 0.6 [0.5-0.7] & 0.4 [0.3-0.5], respectively). Compared to white men, the odds of undergoing RP by a high-volume surgeon are lower for black men (OR 0.6 [0.5-0.8]). Conclusions: Our data demonstrate that access to high-volume surgeons may explain the increased odds for postoperative major complications among black men undergoing RP. Further research related to barriers to health care access & further efforts at removing said barriers for black men is warranted.
Gleason score upgrade among 10,282 men who underwent surgery as initial treatment in 2010: A population-based study.
Authors: Zhang Hong , Messing Edward M. , Ahmed Hamza , Chen Yuhchyau
Published: February 2017

72

Background: Active surveillance is now accepted initial management for men who have localized prostate cancer with low risk of disease progression. Many criteria have been used for patient identification, including Gleason score (GS) obtained from prostate biopsy. Because of concerns of sampling error, some have recommended repeated biopsy before committing to active surveillance. However, there is limited information about the risk of missing high grade disease using the current standard biopsy approach. This study seeks to compare GS difference from biopsy and surgery to provide an estimated rate of GS upgrade. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was used to identify men with American Joint Committee on Cancer stage T1-2cN0M0 prostate cancer diagnosed between January 2010 and December 2010. Patients who underwent prostatectomy were selected for further analysis. Based on prostate-specific antigen (PSA) levels and GS, cases were divided into low (PSA <=10 and GS <=6) and intermediate (10<PSA<=20 or GS=7) risk groups. The rates of GS upgrade were reported for each group. Chi-square tests were used to assess differences in categorical variables (e.g. age and race) between groups of GS upgrade and no change/downgrade. Results: A total of 10,282 men were evaluated, with 9.2% (n=942) having low-risk disease, and 90.8% (n=9340) having intermediate-risk disease. Among men with low-risk prostate cancer, 22.3% (n=210) had GS upgrade and 0.8% (n=8) had GS 8 disease. Among men with intermediate risk disease, 26.2% (n=2446) had GS upgrade and 2.3% (n=214) had GS 8 disease. There was no statistically significant difference in either age or race distribution among men who had GS upgrade versus no change or downgrade at the time of surgery. Conclusions: A substantial number of low- and intermediate-risk prostate cancer patients had GS upgrade at the time of surgery, but few had upgraded to GS 8 high risk disease. These observations suggest that repeat biopsy prior to active surveillance may not be necessary.
Biologic consequences of androgen receptor (AR) activity in MDV3100-resistant LNCaP cells and dependence on AR full length.
Authors: Yamamoto Yoshiaki , Loriot Yohann , Beraldi Eliana , Zhou Tianyuan , Kim Youngsoo , Monia Brett P. , MacLeod A. Robert , Fazli Ladan , Zoubeidi Amina , Gleave Martin Edwin
Published: February 2017

74

Background: While recent reports link androgen receptor (AR) variants (AR-Vs) to castration resistant prostate cancer (CRPC), the biological significance of AR-Vs in AR-regulated cell survival and proliferation, independent of AR full length (AR-FL), remains controversial. To define the functional role of AR-FL and AR-Vs in MDV3100-resistant (MDV-R), we designed antisense oligonucleotide (ASO) targeting exon 1 and exon 8 in AR to knockdown AR-FL alone or in combination with AR-Vs and examined these effects in MDV-R LNCaP-derived cells in vitro and in vivo. Methods: We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR-FL and AR-V7 compared to CRPC LNCaP xenografts. Cell growth rates, protein and gene expression were analyzed using crystal violet assay, western blotting and real-time PCR, respectively. Exon 1 and 8 AR-ASO were evaluated in MDV-R49F CRPC LNCaP xenografts. Results: AR-V7 was transiently transfected in MDV-R49F cells and differential knockdown of AR-V7 and/or AR-FL by exon 1 versus exon 8 AR-ASO was used to evaluate relative biologic contributions of AR-FL versus AR-V7 in MDV-R LNCaP AR-V7 overexpressing cells. Exon 1 and 8 AR-ASO treatment in these cells similarly decreased prostate-specific antigen (PSA) expression and induced apoptosis as measured by caspase-3 and PARP cleavage and cell growth inhibition. To further define the functional role of AR-Vs in MDV-R LNCaP cells, we used a CE3 siRNA that specifically silenced AR-V7, but not AR-FL in MDV-R LNCaP cells. AR-V7 knockdown did not decrease PSA levels, did not induce apoptosis, and did not inhibit cell growth. In MDV-R LNCaP cells, exon 1 and 8 ASO similarly suppressed cell growth and AR-regulated gene expression in vitro and in vivo. Conclusions: These results indicate that the AR remains an important driver of MDV3100 resistance and, the biologic consequences mainly driven by AR-FL in MDV-R LNCaP models.
Sequential monitoring and characterization of circulating tumor cells (CTCs) using the epic sciences platform in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with recently approved therapeutics.
Authors: Ferraldeschi Roberta , Krupa Rachel , Louw Jessica , Tucker Eric , Bales Natalee , Marrinucci Dena , Flohr Penelope , Figueiredo Ines , Lorente David , Dittamore Ryan , De Bono Johann Sebastian , Attard Gerhardt
Published: February 2017

78

Background: The enumeration and molecular characterization of circulating tumor cells (CTCs) may allow sequential evaluation of drug-induced changes and mechanisms of drug resistance that cannot be practically performed by tissue biopsies. Methods: We utilized the Epic Sciences platform to identify and characterize traditional CTCs (CK-CD45+) and other CTC subpopulations (CK-CD45- CTCs and small CTCs) in sequential samples obtained from metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving abiraterone acetate (AA), enzalutamide (E), or cabazitaxel (C). Peripheral blood was collected pre-treatment, during treatment (at 1 to 4 weeks, to evaluate pharmacodynamics effects) and at progression. Nucleated cells were plated onto glass slides and subjected to immunofluorescence staining for CK, CD45, and AR, and CTC identification by fluorescent scanners. CTCs from a subset of patients were tested for PTEN loss and ERG rearrangements by FISH. CTCs from a second blood sample collected at the same time were captured and enumerated using CellSearch (Veridex). Fresh CRPC biopsies were available for 9 pts. Results: Initial results are available from 24 mCRPC pts (16 pts treated with AA; four with E; four with C; 17 out of 24 previously treated with docetaxel). Pre-treatment, the median CK+CD45- CTC count was 3.5 (range 0 to 98) cells/mL blood. Eleven pts had more than or equal to 5 CK+CD45- CTCs/mL pre-treatment and 5 out of 11 pts had an Epic CTC conversion to less than 5 CK+CD45- CTCs/mL with treatment. 8 out of 11 pts had a decline in CK+CD45- CTC count greater than 30%. Changes in AR expression and AR subcellular localization were observed during treatment as well as changes in count of CTC subpopulations. CellSearch count was available for 22 out of 24 pts. Twelve out of 22 had more than or equal to five CTCs/7.5mls captured using CellSearch, including 7 out of 12 with more than or equal to five CTCs/ml using Epic platform. Conclusions: Enumeration and molecular characterization of CTCs on the Epic Sciences platform during treatment is feasible and demonstrates drug-induced changes associated with changes in CTC count, AR expression and AR subcellular localization. These assays warrant further studies to validate their role as clinically useful biomarkers in mCRPC.
Identifying men at greatest risk of weight gain from androgen deprivation therapy.
Authors: Seible Daniel Martin , Gu Xiangmei , Hyatt Andrew , Beard Clair , Efstathiou Jason Alexander , Miyamoto David Tomoaki , Mitin Timur , Martin Neil E. , Beckman Joshua , Basaria Shehzad , Nguyen Paul Linh
Published: February 2017

80

Background: Androgen deprivation therapy (ADT) is a mainstay of prostate cancer therapy. Weight gain is among the adverse metabolic changes associated with ADT, and may contribute to cardiovascular comorbidity. A better understanding of the risk factors for weight gain on ADT is important for optimal management of ADT-associated morbidity. Methods: A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT. The primary endpoint was weight change at one year from ADT initiation, with the secondary aim to stratify risk of weight gain by baseline patient characteristics. Statistical analyses were performed using two-tailed t-tests and linear regression. Results: Men in our cohort exhibited a significant increase in weight (p=0.0005) in the one year following ADT initiation. Three risk factors for weight gain on ADT were identified: younger than age 65 (5.98 pounds gained, p=0.001 vs. 1.63 pounds, p= 0.09 for age 65+), body mass index (BMI) less than 30 (4.36 pounds gained, p=0.00002 vs. 0.22 pounds, p=0.87 for BMI 30+), and non-diabetic status (3.43 pounds gained, p=0.0003 vs. 0.57 pounds, p=0.74 for diabetics). An aggregate risk scoring system was contrived to allow for weight change prediction by total number of risk factors present: scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of -2.42 (p=0.43), +0.9 (p=0.56), +2.9 (p=0.01) and +8.3 pounds (p= 0.0001) respectively. Weight gain increased significantly with increasing risk score (p-trend= 0.0005), decreasing baseline age (p-trend= 0.004) and decreasing baseline BMI (p-trend= 0.01). Conclusions: Younger than age 65, BMI less than 30, and non-diabetic status were each significantly associated with weight gain one year after starting ADT. Increasing weight gain was strongly associated with increasing number of baseline risk factors. Although metabolic consequences were previously considered most significant for patients with preexisting comorbidity, these data suggest younger, slimmer, and non-diabetic patients may be at higher risk for gaining weight on ADT. As these three categories of men generally have higher endogenous testosterone (T) levels prior to ADT compared to older, obese, and diabetic men, the magnitude of T decline following ADT might explain these findings.
1.5-year post-treatment follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase 3 ALSYMPCA study.
Authors: Nilsson Sten , Vogelzang Nicholas J. , Sartor A. Oliver , Bottomley David , Coleman Robert E. , Skjorestad Irene , Wahba Mona , Parker Chris
Published: February 2017

9

Background: Ra-223 is a first-in-class alpha-emitting pharmaceutical recently Food and Drug Administration approved for treatment (tx) of patients (pts) with CRPC and symptomatic bone metastases (mets). In ALSYMPCA, Ra-223 significantly improved overall survival by 3.6 months versus placebo (pbo) (HR = 0.70; 95% CI, 0.58-0.83; P < 0.001) and was well tolerated. Reported here are long-term safety data ~1.5 years after the last pt’s final injection (inj) from the entire ALSYMPCA safety population. Methods: Eligible pts had progressive CRPC with ≥ 2 symptomatic bone mets and no known visceral mets, were receiving best standard of care, and had received docetaxel or were unfit for or declined docetaxel. Pts were randomized 2:1 to 6 inj of Ra-223 (50 kBq/kg IV; q 4 wk) or matching pbo. Only adverse events (AEs) considered tx related by the investigator were reported during follow-up. Long-term safety data were assessed by specific diseases, including acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or primary cancer in other organs. Results: ALSYMPCA safety population included 901 pts (Ra-223, n = 600; pbo, n = 301). Overall, 25 (4%) Ra-223 and 8 (3%) pbo pts had ≥ 1 tx-related AE (Table). During follow-up, primary cancer in other organs was reported in 5 pts (Ra-223, n = 2; pbo, n = 3). Conclusions: Ra-223 is an effective and well-tolerated tx for CRPC with symptomatic bone mets. No major safety issues were identified within ~1.5 years after tx in the ALSYMPCA safety population. Clinical trial information: NCT00699751. [Table: see text]
Clinical outcomes of patients (pts) age 80 or older treated with docetaxel (DOC) as first-line chemotherapy for castration-resistant prostate cancer (CRPC): Results of an Italian multicenter retrospective study (DELPHI study).
Authors: Veccia Antonello , Burgio Salvatore Luca , di Lorenzo Giuseppe , Ortega Cinzia , Scognamiglio Florinda , Aieta Michele , Zustovich Fable , Mattioli Rodolfo , Mansueto Giovanni , Facchini Gaetano , Procopio Giuseppe , D'Angelo Alessandro , Spizzo Gilbert , Donini Maddalena , Bortolus Roberto , Vicario Giovanni , Zucali Paolo A. , Basso Umberto , Lo Re Giovanni , Caffo Orazio ,   DELPHY Study Group
Published: February 2017

92

Background: Docetaxel (DOC) represents the treatment of choice in the first line treatment for patients (pts) with castration-resistant prostate cancer (CRPC). However, when CRPC is diagnosed in pts age 80 or older, the fear of high toxicity degree usually limits chemotherapy use due to both pts frailty and several comorbidities occurrence. The present retrospective study is aimed to assess the clinical outcomes in this very elderly CRPC population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all pts age 80 and older CRPC pts from participating institutions, treated with DOC in clinical practice, recording the pre- and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we collected a consecutive series of 115 pts from 28 Italian hospitals. The median age was 82 (range 80 to 90). The median baseline prostate-specific antigen (PSA) was 92 ng/ml (range 3 to 2,981); 83% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 39%, 9%, and 8% of the pts, respectively. Median Cumulative Illness Rating Scale score was 3 (range 0 to 11), median Activity Daily Living index score was 0 (range 0 to 5), median Instrumental Activities of Daily Living score was 0 (range 0 to 5). The DOC was administered on 3 week or weekly schedule basis (43%/57%). A PSA reduction greater than 50% was observed in 55% of the pts; an objective response was observed in 15% of the 60 pts who underwent a radiological re-evaluation at the treatment end. Grade 3-4 toxicities were: anemia (2%), neutropenia (10%) , thrombocytopenia (2%), fatigue (10%), diarrhea (4%), nausea (2%), renal (2%), and febrile neutropenia (2%). The median progression-free survival (PFS) and overall survival (OS )were 7 months and 20 months, while the 1 year PFS and OS rates were 21.2% and 71.5%, respectively. Conclusions: This data suggests that selected very older (age 80 and older) CRPC pts may received DOC with a good toxicity profile. In this pts population the treatment, both on 3 week or weekly schedule, is able to produce survival outcomes comparable to pivotal trials (18 months).