bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of elevated insulin-like growth factor binding protein-1 (IGFBP-1) to predict outcomes in men with metastatic prostate cancer treated with androgen-deprivation therapy (ADT).
Authors: Sharma Jaya , Gray Kathryn P. , Nakabayashi Mari , Petrozziello Gillian , Evan Carolyn , Fichorova Raina , Kantoff Philip W. , Sweeney Christopher 
Published: February 2017

191 Background: IGF-1 has been shown to promote cancer growth by activation of PI3 kinase and downregulation of AMPK. IGFBP-1 shuttles IGF-1 across blood vessel membranes. Elevated IGFBP-1 blood levels may be indicative of tissue IGF-1 levels and has been associated with prostate cancer risk. We hypothesized that IGF-1 and IGFBP-1 blood levels might effect ADT efficacy. Methods: A retrospective analysis of IGF-1 and IGFBP-1 was undertaken in men commencing ADT for metastatic prostate cancer. Blood was drawn within one month of initiating ADT and stored. Proteins were measured using multiplex electrochemiluminescence assays. A cohort of 122 patients was compiled from a prospective trial (50 patients) and chart review (72 patients). A multivariate analysis (MVA) using a COX model was performed to identify associations between blood levels of the markers and time to the development of castration resistant prostate cancer (CRPC) and overall survival (OS). The covariates analyzed were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease. Results: At time of initiating ADT the cohort had a median age of 67 years, PSA of 27.4 and 82% had ECOG 0. 91% were Caucasian. 62% had extensive metastatic disease. Median OS was 42.2 months. The median (med) baseline levels for IGF-1 was 75.6 ng/ml and for IGFBP-1 was 1844 pg/ml. As detailed in the table, patients with IGFBP-1 levels above the median had significantly shorter time to development of CRPC and OS on MVA. There was no association between IGF-1 levels and time to CRPC development or OS. Conclusions: Elevated levels of IGFBP-1 are associated with shorter duration of ADT efficacy in men with metastatic prostate cancer. This correlative data supports the ongoing SWOG trial assessing whether IGF signaling blockade improves ADT efficacy, as has been seen in preclinical models. [Table: see text]
Preliminary results of a factorial phase II randomized trial of continuous (C) or intermittent (I) docetaxel (DOC) with or without estramustine (E) as first-line treatment for castration-resistant prostate cancer (CRPC) (HOPLITE trial).
Authors: Caffo Orazio , Lo Re Giovanni , Sava Teodoro , Buti Sebastiano , Sacco Cosimo , Basso Umberto , Zustovich Fable , Martini Thomas , Perin Alessandra , Veccia Antonello , Russo Lucianna , Facchini Gaetano , Barile Carmen , Gernone Angela , De Vivo Rocco , Pappagallo Giovanni L. , Galligioni Enzo 
Published: February 2017

220 Background: DOC given for 8 consecutive courses is considered a standard first line treatment for CRPC pts and I administration could reduce its impact on quality of life (QL). E is considered synergistic with DOC. Aim of this study was to evaluate in a 2 × 2 factorial design, if I DOC could improve QL compared to C DOC and whether E added to DOC could improve its activity. Methods: CRPC pts were randomized to: C DOC 70 mg/m2 i.v. q 3 wks for 8 courses, alone (arm A) or with E 280 mg/TID p.o. for 5 days starting on -1 day (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D. Results: From 11/06 to 10/10, 148 CRPC pts were enrolled and 124 pts are presently evaluable (24 too early). The median age was 69 (range 42–81) and the median baseline PSA was 55.6 (range 0.33–4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). QL outcomes of C and I groups, were not statistically different in terms of general QL items. 1-y PFS was also superimposable (10% and 13.5%, respectively) for DOC and DOC+E groups. The 2-y overall survival was also evaluated with no differences between I and C groups (42.5% and 53.7% respectively) and between DOC and DOC+E groups (42.8% and 53.5% respectively). Conclusions: These preliminary results seem to indicate that I treatment may not improve QL compared to C treatment. Moreover, the addition of E to DOC did not improve 1-y PFS of CRPC pts. Updated data with the complete sample analysis will be presented.
Pilot study of veliparib (ABT-888) with temozolomide (TMZ) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hussain Maha , Carducci Michael Anthony , Slovin Susan F. , Cetnar Jeremy Paul , Qian Jiang , McKeegan Evelyn Mary , Litvinovich Elizabeth , Chyla Brenda , Hetman Robert , Desai Bhardwaj , Giranda Vincent L. , Alumkal Joshi J. 
Published: February 2017

224 Background: Castration-resistant PC tumors exhibit increased PARP activity (critical enzymes for DNA damage repair). Veliparib is a novel, oral, potent inhibitor of PARP-1 and PARP-2. Preclinically, resistance to oral TMZ treatment in the PC3-Luc prostate cancer mouse model was reversed when mice were treated with veliparib. Based on the synergistic interaction, we evaluated the efficacy and safety of veliparib + TMZ in mCRPC pts. Methods: Eligible pts had mCRPC, PSA>2 ng/mL, progressed on at least one docetaxel based therapy and adequate organ function. Pts received veliparib 40 mg BID Days (D) 1-7 and TMZ D1-5 in 28D cycle (C) until disease progression (PD) or unacceptable toxicities. Tumor response was assessed every 8 weeks. Primary objective: Efficacy based on rate of PSA decline of 30% or greater. Secondary objectives: safety, RECIST objective response rate, progression-free survival (PFS), overall survival (OS) and biomarker analyses. A sample size of 25 pts provided 76% power to differentiate between PSA response rates of 5 and 20% at 1-sided type I error rate of 0.1. Results: 26 pts were enrolled; median age 67 years [55, 81]; median baseline PSA 107 ng/ml (6.9, 4584.4); 7/26 (27%) had 2 prior therapies. Median Cs of veliparib + TMZ received were 2 (range 1–9). Most frequent treatment related adverse events (AE) were fatigue (50%), nausea (38%) and constipation (23%). Grade 3/4 AEs in >10% of pts was thrombocytopenia (15%). All pts are off therapy. 25 pts were PSA response evaluable; 2 pts had a confirmed PSA response; 1 pt had a 37% decrease in PSA while the other pt had a 96% decrease in PSA and a 40% reduction in tumor size. 4/25 pts had stable disease for a minimum of 4 months (m). Median PFS was 2.1 m [95% CI: 1.8, 3.9]; 11/26 pts have died with median OS of 9.1 m [95% CI: 5.5, 11.7]. There was a negative correlation between change from baseline in circulating tumor cells and PFS. Conclusions: Veliparib + TMZ were well tolerated with evidence of some activity. Due to lack of activity of TMZ in CRPC,veliparib-induced potentiation of TMZ may not be clinically significant. Other combinations will be explored with higher doses of veliparib. Biomarker data will be presented.
Predicting clinical outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.
Authors: Cha Eugene K. , Shariat Shahrokh F. , Kormaksson Matthias , Novara Giacomo , Rink Michael , Lotan Yair , Scherr Douglas , Raman Jay D. , Kassouf Wassim , Zigeuner Richard , Bensalah Karim , Weizer Alon Z. , Bolenz Christian , Roscigno Marco , Koppie Theresa M. , Fristche Hans-Martin , Ficarra Vincenzo , Langner Cord , Wood Christopher G. , Margulis Vitaly ,   Upper Tract Urothelial Carcinoma Collaborative Group
Published: February 2017

267 Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. Methods: Our study included 2,244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant CIS. The cohort was split for development (12 centers, n=1273) and external validation (11 centers, n=971). Results: At a median follow-up of 45 months, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p-for-trend <0.001), lymph node metastasis (HR:1.98, p=0.002), lymphovascular invasion (HR:1.66, p<0.001), sessile tumor architecture (HR:1.76, p<0.001), and concomitant CIS (HR:1.33, p=0.035) were associated with disease recurrence. Similarly, T classification (p-for-trend <0.001), lymph node metastasis (HR:2.23, p=0.001), lymphovascular invasion (HR:1.81, p<0.001), and sessile tumor architecture (HR:1.72, p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be utilized for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.
Association between variants on 8q24 and prostate cancer: A review and meta-analysis.
Authors: Troutman Sarah M. , Sissung Tristan M. , Cropp Cheryl D. , Venzon David J. , Spencer Shawn D. , Price Douglas K. , Figg William Douglas 
Published: February 2017

28 Background: Racial disparities in the incidence prostate cancer exist but remain unexplained. Recent studies implicate single nucleotide polymorphisms (SNPs) within the 8q24 region as a risk factor for prostate cancer (PCa) and the frequency of variant alleles at these SNPs appear to differ by race. To determine the association between 8q24 polymorphisms and PCa among men of different races, we performed meta-analyses, stratified by race. Methods: Twenty-nine studies of seven SNPs and one microsatellite marker located within the 8q24 region were included in the meta-analyses. Allelic odds ratio (OR) values and confidence intervals were calculated using the Mantel-Haenszel test. This test assumes homogeneity so we first used the Breslow-Day test to determine whether or not the assumption of homogeneity was valid in each population. Results: PCa risk was associated with the following SNPs in all included races: rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737(-8). PCa risk in Caucasians was conferred by rs6983267 (OR = 1.22 (1.17-1.27)), rs1447295 (OR = 1.43 (1.45-1.49)), rs6983561 (OR = 1.45 (1.30-1.61), rs7837688 (OR = 1.55 (1.39-1.73)), rs16902979 (OR = 1.39 (1.29-1.49)), and DG8S737(-8) (OR = 1.32 (1.12-1.56)). In African American men, a significant association was found for rs1447295 (OR = 1.1 (1.02-1.18)), rs6983561 (OR = 1.43 (1.29-1.59)), rs16901979 (OR = 1.39 (1.29-1.49)), and DG8S737(-8) (OR =1.34 (1.19-1.50)). Alleles associated with PCa risk in Asians were rs6983267 (OR = 1.15 (1.04-1.26)), rs1447295 (OR = 1.39 (1.25-1.54)), rs6983561 (OR = 1.68 (1.51-1.88)), and rs16901979 (OR = 1.65 (1.48-1.85)). The risk allele at rs1447295 was also associated with PCa risk among Hispanic men. Conclusions: 8q24 contains SNPs that are associated with PCa risk, but the strength of this association depended on race. Racial disparities in the incidence of PCa may in part be accounted for by 8q24 variants.
Phase II study of gemcitabine, cisplatin, and sunitinib (S) in patients with advanced urothelial carcinoma (UC).
Authors: Galsky Matt D. , Hellerstedt Beth A. , O'Rourke Mark Allen , Vogelzang Nicholas J. , Kocs Darren M. , McKenney Scott A. , Melnyk Anton M. , Hutson Thomas E. , Rauch Mary Ann , Wang Yunfei , Asmar Lina , Sonpavde Guru 
Published: February 2017

282 Background: Sunitinib (S) has single-agent activity in patients with advanced urothelial carcinoma (UC). Preclinical studies in UC demonstrate at least additive antitumor activity combining S with gemcitabine (G) or cisplatin (C). Methods: Patients with chemonaïve metastatic UC were enrolled in a multicenter phase II trial with overall response rate (ORR) as the primary endpoint. The initial dosing regimen, based on a phase I trial (Reck, 2010), was G 1000 mg/m2 IV (Days 1 & 8), C 70 mg/m2 IV (Day 1), and S 37.5 mg PO daily (Days 1-14)/each 21-day cycle (up to 6 cycles), followed by S 37.5 mg daily until progression. Results: From December 2008 to August 2009, 15 eligible patients enrolled. Seven of 15 patients discontinued treatment early (median: 3 cycles) due to toxicity, most often due to recurrent neutropenia and thrombocytopenia. Intrapatient dose reductions were required for G (12/15), C (8/15), and S (10/15). Eight of 15 patients experienced serious adverse events. Based on the toxicity profile, enrollment was held and the dosing regimen was revised to G 800 mg/m2 IV (Days 1 and 8), C 60 mg/m2 IV (Day 1), S 37.5 mg PO daily (Days 1-14). From December 2009 to April 2011, 18 additional patients were enrolled. Despite the reduced starting doses, intrapatient dose reductions were required for G (13/18), C (9/18), and S (15/18). The most frequent Grade 3-4 toxicities for both groups were neutropenia (70%), thrombocytopenia (58%), and anemia (30%). Antitumor activity is shown in the Table. Median PFS was 7.9 and median OS was 13.8 months. Conclusions: Combination G+C+S is poorly tolerated and results in activity comparable to historical results with G+C alone. Supported in part by a grant from Pfizer Inc. [Table: see text]
A phase I trial of intravesical antisense oligonucleotide targeting heat shock protein 27 (OGX-427) for the treatment of non-muscle-invasive bladder cancer.
Authors: So Alan I. , Black Peter C. , Chi Kim N. , Hurtado-Col Antonio , Gleave Martin E. 
Published: February 2017

286 Background: The treatment options to prevent recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC) are limited. Heat Shock Protein 27 (Hsp27) is a cytoprotective protein that has been shown to be important in a variety of malignancies, including bladder cancer (BCa), where it has been linked to therapeutic resistance and disease progression. OGX-427 is a 2nd generation (2’-MOE) antisense oligonucleotide that potently inhibits Hsp27 expression in vitro and in vivo. Methods: We initiated a phase I clinical study to assess the safety, pharmacokinetic (pk), pharmacodynamic (pd) and biologic effects of intravesical treatments of OGX-427 using a presurgical dose-escalating design for patients with BCa. Eligible patients include patients with Ta, T1 or carcinoma-in-situ and candidates for transurethral resection of the bladder tumor (TURBT), or patients with muscle invasive BCa (>cT2) and candidates for radical cystectomy (RC). Patients are treated with intravesical OGX-427 on days 1,3,5, and 8 and then undergo surgery on day 9-12. Dose is escalated after tolerability and safety assessment for each cohort at 20uM, 50 uM, 100uM, 250uM, 500uM, and 750uM. Results: To date, we have enrolled 13 patients in the trial and have completed the 250uM cohort. 12 patients had NMIBC and one had cT2 disease and underwent a cystectomy. No significant drug-related adverse events have been reported; no dose limiting toxicity was observed and only one patient developed gross hematuria (grade 1) within 24 hours of administration of drug that spontaneously resolved. Pathological staging of surgical specimens revealed that five patients (38%) had complete responses (p0). The remaining NMIBC patients had pTa tumors that ranged from G1-G2; the sole patient undergoing cystectomy had pT2aG3 bladder cancer. Accrual of the two remaining cohorts will be complete shortly and the pd and pk analysis will be performed once all specimens are available. Conclusions: OGX-427 is well tolerated intravesically with minimal toxicity. Our results indicate early evidence of activity of OGX-427 against bladder cancer that requires confirmation in phase II/III studies.
Extended lymphadenectomy and adjuvant chemotherapy in muscle-invasive bladder cancer treated by radical cystectomy.
Authors: Bostrom Peter J. , Mirtti Tuomas , Nurmi Martti , Laato Matti , Van Rhijn Bas W.G. , Fleshner Neil Eric , Finelli Antonio , Jewett Michael A. S. , Moore Malcolm J. , Sridhar Srikala S. , Tannock Ian , Zlotta Alexandre 
Published: February 2017

287 Background: Level 1 evidence is weak for adjuvant chemotherapy (AC) after cystectomy, but surveys indicate physicians refer patients for AC more frequently than for neoadjuvant chemotherapy (NC). The exact benefit of an extended pelvic lymph node dissection (ePLND) remains debated. We addressed the issue of AC and ePLND analyzing two academic centers RC databases with opposite approaches, one using ePLND and AC, the other performing a limited lymph node dissection and no AC. Methods: Two ethics approved RC databases including consecutive BC patients undergoing RC at the University Health Network, Canada and the University of Turku, Finland were studied. Excluding non-urothelial cases and patients receiving NC, 563 patients were available for analysis. Clinicopathological variables, rate and extent of PLND and rate of adjuvant cisplatin-based chemotherapy were analyzed using the χ2-test. Kaplan-Meier method and multivariate Cox regression analysis were used to analyze survival. Results: In Toronto, patients had more extensive PLNDs (>10 nodes removed, 58% vs. 8%, p<0.001), higher rate of nodal metastases (26% vs. 7%, p<0.001), and received more often AC (21% vs. 1%, p<0.001). Positive margin rates were similar (4% in both centers). No BC specific survival difference was demonstrated in ≤ pT2a or in pT4a tumors. There was a trend for improved survival in pT2b tumors (10y BC specific survival 65% vs. 42%, p=0.23) and a significant difference favouring the Toronto cohort in pT3a and pT3b tumors (55% vs. 31%, p=0.025; 43% vs. 28% p=0.06, respectively). In multivariate analysis, N-stage (HR 2.5, 95% CI 1.5-4.1; p<0001) and ePLND (HR 0.53, 95% CI 0.31-0.93, p=0.026) significantly affected disease specific survival. The benefit of AC did not reach significance (HR 0.61, 95% CI 0.36-1.05, p=0.072). An interaction model combining ePLND and AC was significantly related to improved outcome (HR 0.49, 95% CI 0.26-0.92, p=0.026). Conclusions: Despite not being randomized, using 2 study cohorts that received completely opposite managements in terms of ePLND and AC, our results support that ePLND and AC may offer a survival advantage in T2b and especially in T3 BC treated with RC.
Influence of vascular comorbities and race on erectile dysfunction after prostate cancer radiotherapy.
Authors: Wang Yuefeng , Liu Tian , Rossi Peter J. , Cooper Sherrie , Jani Ashesh B. 
Published: February 2017

29 Background: Vascular comorbidities (VC’s) [hypertension (HTN), diabetes (DM) and/or hyperlipidemia (HL)] are known factors related to erectile dysfunction (ED) prior to radiotherapy (XRT). We have undertaken this study to understand the influence of VC’s on post-XRT ED incidence, and to further characterize ED incidence by racial groups. Methods: We reviewed the charts of 732 prostate cancer patients [267 white (W) and 465 African American (AA)] who received XRT [external beam radiotherapy (EBRT) and/or brachytherapy (BT)] with or without use of hormone therapy between 1999 and 2010. The number of pre-XRT VC’s (0, 1, 2, or 3) was determined by medical history and medication list. ED (defined by use of erectile aids or by documentation of moderate or high sexual dysfunction on patient history) was determined pre-XRT as well as 1, 6, and 12 months post-XRT and compared by follow-up interval since XRT, by number of VC’s, and by race in each case using the two sample proportion test. Results: ED incidence progressively increased with time from 22% pre-XRT to 52% 12 months post-XRT (p<0.001). Additionally, ED incidence increased with increasing of number of VC’s – 12-month incidences between patients with 0 vs 2 (p=0.024), 0 vs 3 (p<0.001), 1 vs 3 (p<0.001), and 2 vs 3 (p=0.004) VC’s were statistically significant (0 vs 1 and 1 vs 2 were non-significant). Pre-XRT ED incidence was 20% vs 23% (for W vs AA patients, p=0.156) due to higher incidence of VC’s in the AA group. At 12 month follow-up, ED incidences for W vs AA patients were 38% vs 45%, 46% vs 49%, 52% vs 57%, and 71% vs 75% with 0, 1, 2 and 3 co-morbidities, respectively (all p-values non-significant). Conclusions: Our analysis represents the first effort exploring post-XRT ED as determined by the number VC’s and by race. Our results suggest that number of VC’s have a significant effect on development of post-XRT ED. Pre- and post-XRT ED appear to be independent of race when number of VC’s are considered. Our results can be used to guide physicians in counseling patients on the incidence of ED by number of VC’s and as preliminary data for prospective efforts aimed at reducing post-XRT ED.
Survival differences in metastatic bladder cancer by geography.
Authors: Mandal Rakesh , Shah Binay Kumar 
Published: February 2017

314 Background: It is unknown if there is any geographical variation in survival among patients with bladder cancer. This study was conducted to evaluate the survival rates in the northern (latitude ≥40o) and southern regions (latitude < 40o) in the United States for the period of 2000-2008. Methods: We used Z-test in the Surveillance, Epidemiology, and End Results (SEER*Stat) program to analyze 1-year and 5-year relative survival rates of bladder cancer patients included in SEER database. Several cohorts categorized by race, gender, and age groups (<60 and ≥60 years) were examined to compare the survival rates in the northern and southern regions of the U.S. Based on the counties’ centroid, northern (latitude ≥40o) and southern (latitude < 40o) regions were determined. Results: The dataset comprised 6,501 and 664 patients with AJCC stage-IV bladder cancer among Caucasian and African Americans respectively. Among Caucasian men (<60 years), 1-year survival rates in the northern and southern regions were 66.2± 2.5% (n=372) and 57.5± 1.9% (n= 738) respectively. Similarly, 5-year year survival rates in the northern and southern regions were 27.5± 2.6% (n=372) and 20.1± 1.7% (n= 738) respectively. Thus the survival for this group was lower in the South compared to the North and was statistically significantly (1-year: Z-value = -2.723, p= 0.006; 5-year: Z-value = -2.909, p= 0.003). There was no significant difference in the survival rates among any other cohorts examined. Conclusions: Caucasian men (<60 year) with stage IV bladder cancer had lower 1- or 5-year relative survival rates in the South compared to the North. The survival difference in young Caucasian men with bladder cancer by geography may be due to differences in tumor biology resulting from the differential exposure to environmental carcinogens.