bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-course hormonal therapy and the risk of death from prostate cancer in men with intermediate-risk prostate cancer undergoing high-dose radiation therapy.
Authors: Keane Florence K. , Chen Ming-Hui , Zhang Danjie , Moran Brian Joseph , Braccioforte Michelle H. , D'Amico Anthony Victor 
Published: February 2017

27 Background: We assessed the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable and favorable intermediate-risk prostate cancer (PC) who received dose-escalated radiotherapy (RT) with or without short-course androgen deprivation therapy (ADT). Methods: The cohort consisted of 2,668 men with intermediate-risk PC (71.3% favorable, 28.7% unfavorable) who were treated with dose-escalated RT with or without ADT (median 4 mos.) from 1997 - 2013. Fine and Gray's competing risks regression was used to assess whether ADT decreased PCSM-risk in an adjusted multivariable model (Table). An interaction term was included to assess for potential differences in the impact of ADT on PCSM risk in men with favorable versus unfavorable intermediate-risk PC. Results: After a median follow-up of 7.84 years, there were 393 deaths (14.73%), of which 33 were from PC (8.40%). There was significant reduction in PCSM-risk in men with unfavorable intermediate-risk PC who received ADT (AHR 0.39, 95% CI 0.16 to 0.92, P=0.033), but no significant difference in PCSM-risk in men with favorable intermediate-risk PC who received ADT (AHR 0.68, 95% CI 0.19 to 2.49, P=0.561). Conclusions: While ADT reduced PCSM-risk in men with unfavorable intermediate-risk PC, there was no significant improvement in men with favorable intermediate-risk PC, suggesting that for these patients ADT in addition to dose-escalated RT may not be required to minimize PCSM-risk. [Table: see text]
Dual targeting of the androgen receptor and hypoxia-inducible factor-1α pathways to synergistically inhibit castrate-resistant prostate cancer.
Authors: Figg William Douglas , Fernandez Elena V. , Reece Kelie M , Ley Ariel M , Troutman Sarah M , Sissung Tristan M. , Price Douglas K. , Chau Cindy H. 
Published: February 2017

270 Background: Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). While enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and HIF-1α are key regulators of these processes, dual targeting of both signaling axis represents an attractive therapeutic approach. Methods: Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. Cells were stimulated with dihydrotestosterone (DHT) or the hypoxia mimetic cobalt chloride. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. Results: In prostate cancer cells, gene expressions of AR targets (KLK3, FKBP5, TMPRSS2) were repressed by HIF-signaling; conversely, HIF-1α target expressions (VEGF, ENO1, LDHA) were induced by DHT-mediated AR signaling. Treatment of CRPC cells with enzalutamide and chetomin or HIF-1α siRNA attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced VEGF protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells. Additionally, HIF-1α siRNA synergistically increased enzalutamide-induced apoptosis. Conclusions: Combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene specific HIF-dependent expression, prostate cancer cell growth, and apoptosis.
Characteristics of African Americans (AAs) treated with sipuleucel-T (sip-T): Comparison of clinical trial and real-world experience.
Authors: Tutrone Ronald F. , Ahaghotu Chiledum , Armstrong Andrew J. , Higano Celestia S. , Cooperberg Matthew R. , Belkoff Laurence H. , Olsson Carl A. , Goel Sanjay , Tyler Robert Claude , LIll Jennifer Susan , Gray Todd E. , McCoy Candice , Sartor A. Oliver 
Published: February 2017

272 Background: AA men are underrepresented in randomized clinical trials (RCTs) for prostate cancer, despite an almost 2-fold greater incidence in AA vs Caucasian populations. Sip-T is an autologous cellular immunotherapy approved by the FDA and EMA for the treatment of certain patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. AA enrollment in three sip-T phase 3 RCTs was 5.8% (n=43). While no definitive conclusions were drawn, median overall survival (OS) suggested AAs benefit from sip-T. PROCEED, an ongoing phase 4 registry, expanded efforts to increase AA enrollment to better characterize this population and the safety, product parameters (PP), and OS of AAs treated with sip-T. Methods: PROCEED enrolled 1973 pts treated with commercial sip-T within 6 months of registration. Efforts, such as selecting racially diverse sites and highlighting AA enrollment in PROCEED communications and investigator meetings, were used to boost AA enrollment. Baseline Gleason score, Eastern Cooperative Oncology Group performance status (ECOG), prostate-specific antigen (PSA), and alkaline phosphatase (ALP) were compared between RCTs and PROCEED. Safety and survival analyses are ongoing. Results: PROCEED AA enrollment was 11.7% vs 7.1% US RCT nonwhite enrollment rate and approaches the US AA population of 13.7%. Baseline AA pt characteristics were: lower median PSA and ALP levels in PROCEED vs RCTs, higher ECOG >0 in PROCEED vs RCTs, and higher Gleason score ≥8 in PROCEED vs RCTs (Table). Conclusions: Efforts to boost AA enrollment in PROCEED to a proportion comparable to the US AA population succeeded. The lower baseline PSA of AAs in PROCEED is similar to the PSA observed in the entire PROCEED population. Safety, PP, and OS will be reported with longer follow-up. Clinical trial information: NCT01306890. [Table: see text]
Pretreatment neutrophil/lymphocyte ratio (NLR) prior to steroids as a prognostic factor in metastatic castrate refractory prostate cancer (mCRPC) patients treated with taxanes.
Authors: Chan David , McLachlan Jennifer Mary , Crumbaker Megan , Marx Gavin M. 
Published: February 2017

273 Background: The neutrophil/lymphocyte ratio (NLR) has been demonstrated to be a prognostic factor in multiple malignancies. Prior analyses have demonstrated conflicting results in correlation between NLR and overall survival (OS) in mCRPC. Prednisone and dexamethasone, commonly used in chemotherapy regimens for prostate cancer, have been demonstrated to affect neutrophils and hence NLR. We investigated the correlation between pre-dexamethasone NLR and OS in patients with mCRPC. Methods: We performed a retrospective single-center study of patients with mCRPC who received taxane-based chemotherapy (docetaxel or cabazitaxel) between 9/2005 and 12/2012. Patients were included if blood test results were available between 3 and 28 days prior to commencement of chemotherapy. Baseline demographics and NLR were correlated with OS using a Cox proportional hazards model. Results: 42 patients were included, 9 of whom were still alive, with median age 70 and median follow-up 23.1 months. Median OS was 24.1 months. 36 were commenced on docetaxel-based chemotherapy and 6 on cabazitaxel-based chemotherapy. Considering NLR as a categorical variable, OS was significantly better in patients with NLR<5 (n=28) compared to those with NLR>5 (n=14), with median OS 32mo vs 15.4mo and HR 2.155 (95% CI 1.072-4.332, p=0.0007 by log-rank test). In multivariate analyses, NLR (p=0.008) and age (p=0.048) were independent predictors of overall survival. In sensitivity analyses, when including NLRs within 48 hours of chemotherapy initiation, the correlation between NLR and OS was only marginally significant (p=0.048). Conclusions: HighNLR is an adverse prognostic marker for decreased overall survival in mCRPC patients undergoing taxane-based chemotherapy. Previous conflicting results regarding its value may be related to the effect of steroids on NLR.
Biweekly cabazitaxel as post-docetaxel treatment for metastatic castration resistant prostate cancer (mCRPC): Findings from an early safety analysis of the Prosty II trial.
Authors: Kellokumpu-Lehtinen Pirkko-Liisa Irmeli , Marttila Timo , Hervonen Petteri , Kataja Vesa V , Utriainen Tapio , Luukkaa Marjaana , Taalikka Mikko , Kautio Anna-Liisa 
Published: February 2017

276 Background: Docetaxel (D) administered at 2-week intervals was better tolerated than the standard 3-week D in mCRPC. In addition, the overall survival was better with the 2-weekly D dosing in our Prosty I trial (Kellokumpu-Lehtinen et al. Lancet Oncol 2013;14:117-124). The aim of the Prosty II trial was to evaluate the safety of 2-weekly cabazitaxel (C) as post-docetaxel treatment for m CRPC. The safety of the first 40 patient (pts) is reported below. Methods: 40 pts were allocated to receive C 16 mg/m² i.v. d1 and d14 q4 wks. At baseline, WHO performance status was 0 in 33% of pts and 1 in 67% of pts and the median serum PSA level was 342 µg/L (range 3.7-2425)). The primary endpoint was safety. Study identifier: NCT01558219. Results: A total number of 144 cycles of C were administered. No prophylactic G-CSF was used. The most common Grade 3/4 adverse events (AE, expressed as % pts experienced Grade3 or Grade 4 AE) were neutropenia 12.5/2.5%, pain 12.5/0%, fatique 5/2.5%, anemia 5.0/0%, neutropenic infections 2.5/0%, leucopenia 2.5/0%, mucositis 2.5/0%, increase of alkaline phosphatase 5/0% and limb edema 2.5/0. In addition one Grade 4 pulmonary embolism and one intracerebral hemorrhage occurred. In one pt, cancer related bone fracture occurred during the second C cycle (Grade 4 AE). Altogether up to cycle 6 no AE was reported in 1 pt (2.5%), Grade 1 AE in 3 pts (7.5%), Grade 2 in 17 pts (42.5%), Grade 3 in 13 pts (32.5%) and Grade 4 in 5 pts (12.5%). Conclusions: Biweekly cabazitaxel seems to be well tolerated treatment for heavily pretreated advanced mCRPC patients.
Opioid use among prostate cancer patients with bone metastases.
Authors: Yaldo Avin , Wen Lonnie Kent , Ogbonnaya Augustina , Valderrama Adriana , Kish Jonathan K , Eaddy Michael , Kreilick Charles , Seal Brian S. 
Published: February 2017

278 Background: Bone metastases (mets) occur in ≥90% of men with castrate-resistant prostate cancer (PC), causing significant pain and resource use. Opioids are frequently used in managing pain throughout the course of care, but few studies have quantified the incremental use of opioids after the onset of bone mets. This study describes treatment patterns and incremental use of opioids among PC patients diagnosed with bone mets. Methods: Prostate cancer patients (ICD9=185.xx or 233.4) newly diagnosed with bone mets (ICD9=198.5) from 2006-2012 were identified from MarketScan databases. Patients were required to be ≥40 years, continuously eligible for medical and pharmacy benefits ≥12 months pre and ≥6 months postdiagnosis, and without evidence of other primary cancers during the study period. Patients were initially categorized as non-users of opioids (<10 days use), short-term users (≥10 but <60 days use), or long-term users (≥60 days use), and further by presence of skeletal-related events (SREs). Type of opioid therapy, proportion of time on opioids, morphine equivalent dose, and NSAID use were evaluated pre and postdiagnosis. Results: There were 4,476 patients identified for inclusion; 438 (9.8%) had an SRE. Mean age was 72 and 1.6% had chronic pain at baseline. The proportion of opioid users increased from 25.2% at baseline to 32.9% after diagnosis (P<0.0001). Among opioid users, the proportion of long-term users increased from 29.9% to 45.5% (P<0.0001). Use of monotherapy short-acting opioids decreased (pre 79.0% vs post 71.9%; P<0.0001), with a corresponding increase in mixed-action opioids (pre 13.3% vs post 23.4%; P<0.0001). Mean morphine equivalent dose (pre 7.1mg vs post 9.9mg; P<0.0001) and proportion of time on opioid therapy also increased substantially (pre 28.3% vs post 54.7%; P<0.0001). NSAID use decreased after bone met onset (pre 21.9% vs post 15.5%; P<0.0001). Opioid use and radiation therapy were more evident in patients with SREs (opioids 21.9%, opioids + radiation 32.6%, radiation 29.5%), and mean morphine equivalent dose was 10.8mg. Conclusions: Long-term opioid use and dose significantly increased after bone met onset in PC. Novel strategies that mitigate bone pain and minimize opioid use should be evaluated in this population.
Testing a prognostic model in patients with metastatic castrate resistant prostate cancer (MCRPC) treated prechemotherapy with abiraterone.
Authors: Pan Shermaine , Prasad Kellati , Hall Emma , Swindell Ric , Charnley Natalie 
Published: February 2017

283 Background: There is a need for prognostic models in metastatic prostate cancer to determine optimal treatment pathways on development of castrate resistance. Abiraterone is an androgen biosynthesis inhibitor. Efficacy was proven in patients with MCRPC prechemotherapy in the COU-AA-302 trial with PSA PFS 11.1 months (Raj et al New Eng J med 2013). We have previously investigated prognostic factors in MCRPC (Charnley et al J Clin Oncol 2014). We reported a prognostic model which predicts that if alk phos rise ≥100 in the preceding 3 months and/or Hb<11 there is no response. The model was correct in 78.9% of responders and 55% of non responders (overall 66.7%). We test the model in an independent group of 81 patients prechemotherapy, some from a different treating centre. Methods: 81 patients with metastatic CRPC received abiraterone 1g daily prechemotherapy. Response to abiraterone was defined as a 50% reduction in PSA. Alk phos rise ≥100 in the previous 3 months and Hb<11 were related to PSA response. Results: 19 patients had both alk phos rise ≥100 in the preceding 3 months, and Hb<11. None of these patients had a PSA response. For the 31 patients with no risk factors 66% of cases responded. The predictive model was correct in 66% of true responders, and 85.3% of non responders, 74.1% overall. Conclusions: In this group of 81 patients with castrate resistant metastatic prostate cancer a previously defined model, which incorporates alk phos rise ≥100 in the preceding 3 months and/or Hb<11 is 74.1 % accurate in an independent group of patients. No patients with both alk phos rise>100 in the preceding 3 months, and Hb<11, responded to abiraterone. The model has potential in guiding treatment pathways on development of castrate resistance in prostate cancer, but needs to be tested in a greater number of patients.
Characterization of differences between prostate cancer (PCa) patients presenting as de novo versus primary progressive metastatic disease.
Authors: Finianos Antoine Nafez , Gupta Kanika , Meshikhes Mariam , Shimony Maya , He Chao , Guebre-Xabiher Hiwot , Simmens Sam , Aragon-Ching Jeanny B. 
Published: February 2017

285 Background: In 2014 alone, 29,480 men are projected to die of PCa (Cancer Statistics, 2014).Approximately 4% are metastatic on presentation (de novo, dn) while a subset of men progress on to metastatic disease during the course of their disease (primary progressive, pp). We sought to characterize and compare differences in disease characteristics and outcomes between those who present as dn vs pp metastatic disease in our institution. Methods: A retrospective chart review of dn vs pp metastatic patients for the past 2 years was undertaken. Characteristics such as demographics, Gleason score, duration of hormone sensitivity, and treatment, were obtained. T-test and Fisher’s exact test were used to test differences in patient and disease characteristics between dn and pp metastatic patients. Results: Preliminary results on 10 de novo and 13 primary progressive patients are presented herein. Statistically significant differences were noted for median age at diagnosis: de novo 66.5 years of age (range=48-71) vs primary progressive 58 years of age (range 42-77), p=.05; Median duration of hormone sensitivity: de novo 149.5 days (range=91-440) vs primary progressive 444.5 days (range 91-3041), p = 0.0002; Median Gleason Score: de novo 9 (range 6-10) vs primary progressive 8 (range 6-9), p = .002. Although there was a tendency towards higher mean and median of PSA levels for the de novo (225.16 and 50 ng/ml, respectively) vs primary progressive (16.97 and 28.2 ng/ml, respectively), the difference was not statistically significant (p=.15). There was also non-significant trends for the de novo group to be more likely to have a lymph node metastasis (70%, p=.40) and Caucasian (62%, p=.16) compared to the primary progressive group (46% lymph node metastasis, 23% Caucasian). Conclusions: While the reported samples are small, our data reveals a potential difference in disease aggressiveness in those presenting with de novo metastatic cancer with higher-risk disease and shorter time to castration resistance. Further data collection is underway and a prospective trial assessing the difference molecularly between both groups is planned to confirm these findings.
Health-related quality of life in patients with advanced prostate cancer undergoing treatment with TRIPTOrelin Pamoate SIX month formulation: Results of the non-interventional TRIPTOSIX study.
Authors: Eisenhardt Andreas , Schneider Tim , Scheithe Karl , Colling Christiane , Heidenreich Axel 
Published: February 2017

287 Background: Preserving quality of life (QoL) is an important therapeutic aim in advanced prostate cancer (PCa). The effects of treatment on QoL were studied in a non-interventional study performed from 2010 until 2012 evaluating 1 year of treatment with a LHRH agonist, triptorelin pamoate 6-month depot (TP 6M). Methods: Data of 564 patients with advanced PCa treates in 129 German urology outpatient clinics were analysed. Data on QoL were collected by EORTC questionnaires (QLQ-C30 and -PR25) at baseline, 6 months and 12 months. The QLQ-C30 assesses functional QoL, global health and symptoms of disease, the QLQ-PR25 covers PCa specific symptoms and sexual activity. A clinically relevant improvement, i.e. increase of ≥10 points in the QLQ-C30 global health status/QoL scale, defined treatment responders. Response at month 6 compared to baseline was the primary study endpoint. Results: GlobalHealth Related (HR) QoL was similar over the 1 year follow-up period with a mean (± SD) score of 60.9 (±21.8) at baseline and 61.7 (±22.2) at 12 months. Within the first 6 months, 24.0% of patients were identified as responders (i.e. a clinically relevant improvement in this parameter of ≥10 points). The responder rate was maintained at 12 months of treatment (25.5%). This trend in QoL was also seen in the QLQ-C30 subscales, which were generally similar over the study period. QLQ-PR25 scores were also found to be similar over 1 year, although some deterioration was reported by sexually active patients, as expected. Subgroup analyses on response rates identified age, risk group, pretreatment for PCa and baseline QoL scores as predictors of change in QoL. Conclusions: Treatment with TP 6M over 12 months is associated with few changes in HRQoL and might lead in some patients to clinically meaningful improvements of HRQoL.
Comparison of genetic alterations from the bladder cancer genome atlas (TCGA) and a prospective set of high-grade urothelial carcinoma tumors using a CLIA laboratory next generation sequencing assay.
Authors: Iyer Gopa , Bagrodia Aditya , Cha Eugene K. , Boyd Mariel Elena , Zehir Ahmet , Cheng Donavan T , Hyman David Michael , Bambury Richard Martin , Arcila Maria E. , Ladanyi Marc , Viale Agnes , Al-Ahmadie Hikmat , Berger Michael F. , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B. 
Published: February 2017

298 Background: The type and frequency of recurrent, targetable alterations in muscle-invasive, treatment-naïve urothelial cancer (UC) have been well-catalogued through the bladder TCGA. We sought to validate these findings within a prospective cohort of patients (pts) with progressive UC treated at our institution. This cohort typifies the UC patient population managed by medical oncologists. Methods: Pts with a diagnosis of UC were enrolled onto an IRB-approved protocol between 1/14/14 and 7/29/14, which allowed for sequencing of all exons in 341 oncogenes and tumor suppressor genes using an exon capture next generation sequencing assay (NGS) platform (MSK-IMPACT) in a CLIA lab from tumor and matched germline DNA. Somatic point mutations, truncations, copy number alterations, and insertions/deletions were detected. Results: 49 UC pts were sequenced, 5 (10%) having upper tract disease. 33 (67%) tumors were pure UC histology with the remainder containing divergent differentiation. 17 samples (24%) were metastatic in origin, and 40 samples were analyzed from pts who had received prior chemotherapy. The most common alteration identified was point mutations within the TERT promoter (71%), a region not sequenced by TCGA. Additional alteration frequencies were similar between both sets. FGFR3 mutations overlapped with both PIK3CA and TSC1 alterations and co-alterations were observed between FGFR3 and CDKN2A as well as PIK3CA and CCND1. Conclusions: TERT promoter mutations were found at high frequency in the MSK-IMPACT tumor cohort. The frequency and type of alterations identified in the bladder TCGA are similar to the MSK-IMPACT cohort, suggesting that TCGA data can be used to guide clinical trials in the metastatic, pre-treated population. Overlap of alterations within and across core signaling pathways underscores the need for functional validation of alterations and for rational combinations of targeted therapies to effectively treat advanced UC. [Table: see text]