bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of abiraterone acetate (AA) and low-dose prednisone (P) in Japanese patients with newly diagnosed, metastatic, hormone-naïve prostate cancer (mHNPC): Subgroup analysis of LATITUDE trial.
Authors: Fukasawa Satoshi , Suzuki Hiroyoshi , Sato Fuminori , Hashine Katsuyoshi , Hasumi Hisashi , Matsumoto Hiroaki , Tsuchiya Tomohiro , Uemura Hirotsugu , Oya Mototsugu , Kanayama Hiroomi , Kawaguchi Kazushiro , Noguchi Hidehisa , Enjo Kentaro , Tran Namphuong , Todd Mary Beth , Fizazi Karim , Matsubara Nobuaki 
Published: February 2018

286 Background: Patients with high-risk mHNPC have a poor prognosis. In Japan, mHNPC accounts for approximately 10% of newly diagnosed prostate cancers. AAP was approved for the treatment of castration-resistant prostate cancer in Japan in July 2014. We now report the clinical benefit of AAP with ADT in Japanese patients with newly diagnosed, high-risk mHNPC. Methods: Interim analysis of the multinational, randomized, double-blind, placebo-controlled, phase 3 study, LATITUDE, was previously reported at ASCO2017. We evaluated the superiority of AA 1g + P 5 mg + ADT (AAP group) to ADT+PBOs of AA and P (P group) in mHNPC with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) for the subgroup of Japanese patients. Results: Of 1199 total patients in LATITUDE trial, 70 patients were Japanese (AAP group, n = 35; P group, n = 35). The hazard ratio (HR) for overall survival in the AAP group versus the P group was 0.635 (95% confidence interval [CI], 0.152 to 2.659) and HR for radiographic progression-free survival was 0.219 (95%CI, 0.086 to 0.560). The incidence of adverse events (AE) was 97% (34/35) in both groups. AEs that occurred in the AAP group at a frequency ≥10% compared with the P group included hypertension, hypokalemia, rib fracture, hematuria and hyperbilirubinemia. The incidence of Grade 3 and 4 AEs was 66% in the AAP group and 20% in the P group. As a whole, efficacy and safety of Japanese patients in LATITUDE were shown to be consistent with those of overall population. Conclusions: AAP has shown a favorable risk/benefit balance and may serve as a new treatment option to improve the prognosis of Japanese mHNPC patients with high-risk prognostic factors. Clinical trial information: NCT01715285.
Survival outcomes of pre-metastatic castration-resistant prostate cancer and the burden of developing metastasis: A systematic literature review.
Authors: Shore Neal D. , Rai Gershwinder , Fizazi Karim , Wilson Laura , Zhan Lin 
Published: February 2018

293 Background: Surgical or medical castration is an important component of prostate cancer treatment. However, resistance develops in almost all men and poor prognosis has been established once the disease metastasizes. A systematic literature review (SLR) was conducted to explore the treatment options and survival outcomes associated with non-metastatic castration-resistant prostate cancer (CRPC) and to understand the humanistic and economic impact of developing metastasis. Methods: The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and guidance from the National Institute of Health and Care Excellence, Centre for Reviews and Dissemination and Institute for Quality and Efficiency in Healthcare. The search designed to identify clinical and humanistic evidence from all countries and epidemiology, guidelines and economic evidence in Brazil, China, France, Germany, Japan, UK, and US. Results: Median overall survival for non-metastatic CRPC patients ranged from 44 to 74 months; median progression-free survival from 9 to 22 months; and median metastasis-free survival from 16 to 53 months. The most common form of metastasis was bone metastasis, which was associated with an increased risk of skeletal-related events (SREs). Quality-of-life was widely reported to decrease upon metastasis, driven by increased pain and SREs. Higher healthcare costs associated with metastatic CRPC were attributable to physician visits and treating bone-metastasis-related complications. Conclusions: Currently, there is a lack of approved therapies specifically for non-metastatic CRPC patients, who will invariably develop metastases with associated adverse clinical and economic implications. Delaying the onset of metastasis is an unmet clinical need for improved patient outcomes and couldl also lead to economic benefits for healthcare delivery systems.
Weekly cabazitaxel in elderly patients (EP) with metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel treatment: WeCabE, a phase II study.
Authors: Castagneto Bruno , Stevani Ilaria , Bortolus Roberto , Bearz Alessandra , Buosi Roberta , Chimienti Emanuela , Guglielmi Alessandra , Guglielmini Pamela , Santarossa Sandra , Fratino Lucia 
Published: February 2018

300 Background: Docetaxel (Doc) and Cabazitaxel (Cab) every 3 weeks with daily prednisone are standard first and second line chemotherapies in mCRPC. In daily practice, many mCRPC pts are aged > 65 years and around 20% are aged > 75years. MATuRITY registry shows that taxanes therapy provides EP with increased chances of surviving even in case of frailty. EP unfit due to their comorbidities are at risk of AE related to the chemo-treatment, so an appropriate adjustment of the dosage and schedule should be take into account. According to SIOG guidelines, G-8 Screening Tool represents a key tool to identify a suitable subset of EP able to receive cab. Methods: WeCabE enrolled mCRPC EP ≥ 70 and < 85 years, G8 Score 8-14, PS 0-2. Cab was administered at a dose of 8mg /m2 (10mg/m2 if well tolerated) for 4 out 5 weeks Use of G-CSF was allowed. Median PFS, primary endpoint, was evaluated according to PCWG-2. Secondary endpoints were: PSA Response, ORR, OS, Safety, Geriatric assessment (Minimal Data Set according with Elderly Task Force EORTC) on outcomes. PSA response, safety, impact of the treatment on pain and G8 score pre and post cab were analysed. Results: At time of this analysis 14 EP enrolled in WeCabE were analysed. Median age was 78 years, 35.7% of pts were 80-85 years. Median number of cycles received, in pts who ended treatment was 4. Overall 55.6% of pts reached a PSA response while 33.3% achieved a stability. 42.8% of pts ended therapy without a worsening/rising of symptoms, 42.8% and 14.4% showed, respectively, mild and severe pain at end of cab. G8 best score improvement during treatment was 1.28 (median). The most common AE G 3-4 was fatigue (20%) while G1-2 toxicities were diarrhea (40%) and fatigue (60%). Only one pt experienced neutropenia and anemia G3-4. Conclusions: These preliminary results confirm the usefulness of G8 tool to identify elderly mCRPC pts suitable to receive chemotherapy. It suggests that weekly cabazitaxel, in elderly mCRPC, is effective including in very old pts ( > 80 ), with a manageable safety profile. Additional results will be presented at ASCO GU meeting. Trial partially supported by Sanofi Genzyme Clinical trial information: 2014-001647-20.
Treatment patterns for metastatic hormone-sensitive prostate cancer (mHSPC) progressing after up-front docetaxel in combination with androgen deprivation therapy (D-ADT).
Authors: Barata Pedro C. , Emamekhoo Hamid , Mendiratta Prateek , Gopalakrishnan Dharmesh , Koshkin Vadim S. , Tyler Allison Janine , Ornstein Moshe Chaim , Grivas Petros , Gilligan Timothy D. , Rini Brian I. , Kyriakopoulos Christos , Garcia Jorge A. 
Published: February 2018

305 Background: D-ADT increases overall survival (OS) in men with mHSPC. All patients (pts) however progress and develop castration-resistant prostate cancer (CRPC). Little is known about response to subsequent therapy and outcomes in this setting. Methods: Retrospective analysis of consecutive mHSPC pts treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison. We aimed to describe baseline, progression characteristics, treatment choices, sequence and outcome of subsequent therapy. Results: A total of 146 mHSPC pts were treated with D-ADT (6% 1-2 cycles; 94% ≥3 cycles). Final analysis included 136 pts, median age 65 (range 35-86), 65% GS≥8, 79% high-volume disease. Median number of D cycles was 6 (1-6). PSA declined to “0” at 12 and 24 months in 32% and 25% of pts, respectively. Median time to CRPC (biochemical, clinical or radiographic) was 19.6 months (95% CI, 16.6-22.6). 57 pts (42%) received ≥1 subsequent treatment after CRPC [46 hormonal therapy (HT) (21 abiraterone acetate, 19 enzalutamide, 6 ASN-001); 4 Sipuleucel-T; 4 radium-223, 5 chemotherapy (2 carboplatin-based, 2 cabazitaxel, 1 D); 3 temsirolimus/bevacizumab]. Treatment response was independent from time to CRPC (≥12 months, p = 0.264). Pts receiving HT as the first subsequent treatment had a median rPFS of 13.3 months (95% CI, 10.1-16.5) compared with 3.1 months (95% CI, 0-15.8) for non-HT (p = 0.332). Treatment choice was independent of GS (p = 0.513), visceral disease (p = 0.374) and time to CRPC (p = 0.500). Most CRPC pts treated with ≥2 lines of therapy received one HT (n = 21) followed by a different HT (43%), chemo (38%), radium-223 (14%) or olaparib (10%). 57% of pts were alive at 2 years. Longer OS correlated with time to CRPC (p = 0.010) and first subsequent treatment with HT (p = 0.009) but not with visceral disease (p = 0.258), GS (p = 0.599) or sequence of therapies received (HT/HT vs HT/non-HT, p = 0.836). Conclusions: Prior D-ADT did not preclude subsequent treatment response in CRPC pts, independent of time to CRPC. The choice of first-line treatment for CRPC may impact survival in favor of those who start HT.
Tracking of long-term B-cell memory responses using B-cell receptor (BCR) sequencing in prostate cancer (PC) patients (pts) treated with sipuleucel-T (sip-T).
Authors: Zhang Li , Kandadi Harini , Paciorek Alan , Chang Nancy N. , Sheikh Nadeem Anwar , Fong Lawrence 
Published: February 2018

309 Background: Sip-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sip-T’s induction of B-cell responses to PAP and other antigens correlates with improved survival (Sheikh 2013, GuhaThakurta 2015). Cancer vaccine-induced changes to BCR repertoire are unknown. To assess changes in BCR repertoire upon booster treatment, we compared patients retreated with sip-T (P10-1) to treatment-naïve patients (STRIDE). Methods: STRIDE pts (N = 52) received sip-T with concurrent or sequential enzalutamide for mCRPC (Petrylak 2015). P10-1 pts (N = 8) previously treated with sip-T for androgen-dependent PC were retreated with a booster course for mCRPC, after a median of 8.9 years (Beer 2017). Blood samples were collected at baseline (wk 0) and during (wk 2, 4)/post-sip-T (wk 6, 26, 52). Deep sequencing was performed using the ImmunoSEQ assay (Adaptive Biotechnologies). BCR diversity was assessed by clonality, and BCR dynamics by fold-change analysis (Zhang 2017). Results: BCR repertoire had significantly higher clonality in P10-1 vs STRIDE (wk 0: p = 0.003, wk 2: p < 0.001, wk 4: p < 0.001), suggestive of a more focused BCR repertoire. P10-1 also showed increased clonality from wk 0 to 4 (p = 0.063), whereas STRIDE showed a significant increase in clonality from wk 0 to 6 (p = 0.039), suggesting that BCR repertoire focused earlier in P10-1. Starting at wk 2, more clones remained in the repertoire in P10-1, indicating that sip-T stimulated immunologic memory early, after 1st retreatment (p < 0.05). There was less change over time (clonal shuffling) within the 100 most abundant baseline clones in P10-1 (p = 0.080), suggesting more relevant clones preexisted at baseline and enriched over time. After the first two sip-T infusions, more clones contracted in P10-1 (p = 0.027, p = 0.014), whereas more new clones were generated in STRIDE (p = 0.083, p = 0.003). Conclusions: Sip-T induces long-lasting changes in the BCR repertoire. Sip-T retreatment leads to quicker focusing of BCR repertoire than initial treatment. These results are consistent with sip-T inducing durable immunologic memory.
Comprehensive analysis of AR alterations in cell free DNA from prostate cancer patients.
Authors: Ledet Elisa , Lilly Michael B. , Sonpavde Guru , Agarwal Neeraj , Nagy Rebecca J , Sartor A. Oliver 
Published: February 2018

314 Background: Somatic alterations identified in cfDNA may be associated with prognosis. Select AR alterations are associated with abiraterone/enzalutamide resistance in PCa. The goal was to characterize AR amplifications (amps) and somatic point mutations (muts) detected in cfDNA from PCa patients and to relate those changes to non-AR alterations detected in the cfDNA landscape. Methods: cfDNA data was obtained from a heterogeneous group of unique PCa pts who underwent Guardant360 testing (Guardant Health, Redwood City, CA). This assay includes next generation sequencing for full exonic coverage of 73 genes and amplifications in 18 genes. The AR amps/muts detected in cfDNA testing were reported. Results: Over 6,800 genomic alterations including AR amps/muts were identified in 892 PCa patients. Pts were a median age of 70 (range = 41-93) at testing. 49% (n = 436) had AR amp only, 32% (n = 283) had nonsynonymous (NS)-muts only, 18% (n = 165) had both amp and NS-muts; < 1% (n = 8) had synonymous AR muts only. AR amps had a mean absolute copy number of 3.3 (range = 1.2-165.2). Many patients had multiple AR muts; a total of 112 unique muts were identified in the AR gene, some of which are poorly characterized. The most prevalent AR muts were L702H (n = 220), T878A (n = 129), H875Y (n = 102), W742C (n = 75), W742L (n = 34), F877L (n = 19), and T878S (n = 14). The AR muts with the highest mutant allele fraction were H875Y, T878A, and L702H. Aside from AR, among these selected pts, amps/muts were identified in 74 other genes including TP53 50% (n = 449), MYC 34% (n = 301), BRAF 32% (n = 287), PIK3CA 29% (n = 259), MET 25% (n = 224), CDK6 26% (n = 229), EGFR 24% (n = 219), FGFR1 21% (n = 189), and APC 12% (n = 112). DNA repair gene alterations were detected in combination with AR alterations, BRCA2 8% (n = 69), BRCA1 5% (n = 42), and ATM 3% (n = 28). Conclusions: To our knowledge, this is the largest dataset ever reporting AR alterations in cfDNA. Both amps and muts, were frequently found in cfDNA from PCa pts. The common AR muts were L702H, T878A, H875Y and W742C/L, which are linked to resistance to abiraterone, enzalutamide or bicalutamide. Determining the association with other somatic cfDNA alterations and clinical outcomes may be critical for conceiving optimal treatment strategies.
A phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone: DRREEM trial.
Authors: Kosaka Takeo , Shinojima Toshiaki , Kikuchi Kayoko , Hagiwara Sachiko , Kojima Shin-ichiro , Hongo Hiroshi , Ueda Koji , Miyake Shinji , Oya Mototsugu 
Published: February 2018

329 Background: We previously reported a novel cell reprogramming approach, termed drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting the cancer stemness-related gene network, and identified ribavirin as a candidate drug for overcoming docetaxel-resistant castration-resistant prostate cancer (CRPC). We conducted this phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone. (DRREEM trial) Methods: In this clinical study, patients received intravenous docetaxel at 60-75 mg/m2is intravenously administered on Cycle1-Day1 in combination with the investigational drug (ribavirin). Docetaxel is administered at 3-week intervals (1 cycle) (total: 3 cycles). During administration, the dose may be reduced based on the subject’s condition if necessary. The primary endpoint was safety. Accessory evaluation items included prostate-specific antigen (PSA) response, objective response rate, health-related quality of lifel. Exploratory items included changes in CTC count, cfDNA, and exosome. Patients with progressive CRPC based on PSA and/or radiographic criteria, performance status (PS) 0–1, and normal renal and hepatic function were eligible. Results: Six patients were enrolled in this study; average age was 71.7±4.2. Average serum PSA concentration was 100.1±128.0 ng/ml (range: 3.0-336.8). The median cycle of docetaxel received before the study was 6 cycles. Safety: Grade 3/4 adverse events requiring dose modification were not observed. Two patients showed PSA reduction. Three patients showed stable disease. Changes in the blood concentrations of ribavirin, docetaxel, and prednisolone were within normal range. Conclusions: This combination of ribavirin with docetaxel was well tolerated with a promising response rate that justifies further investigations in docetaxel-resistant CRPC. This clinical study provides a useful drug re-positioning model in the area of translational medicine. Clinical trial information: UMIN000021107.
Frequency of liver test increases on abiraterone acetate in men with castrate-resistant prostate cancer (CRPC): Natural history, management, and outcome.
Authors: Colomba Emeline , Marret Grégoire , Baciarello Giulia , Massard Christophe , Loriot Yohann , Albiges Laurence , Carton Edith , Alexandre Jerome , Huillard Olivier , Culine Stephane , Fizazi Karim 
Published: February 2018

332 Background: Abiraterone acetate (abiraterone) in combination with prednisone is a standard of care for patients with metastatic CRPC. Abiraterone is seldom associated with liver toxicity and systematic monitoring of ALT and AST is required. Clinical management and outcome of these patients have not been described. Methods: We retrospectively identified 22 men with mCRPC with liver tests disorder occurring during abiraterone therapy from December 2009 to September 2017 from three oncology centers in France. Results: Thirty nine liver disorder events occurred in 22 patients during abiraterone therapy. The median age was 62 (50-80) years. Only one patient had liver metastasis. No patient had a history of chronic alcoholism. Accountability of the liver tests increase to abiraterone was doubtful in two patients who were receiving antibiotics when the event occurred. The incidence of AST increase (19 events) and that of ALT (20 events) were similar. Liver toxicity was of grade 1, 2, and 3 (CTCAEv4) in 5 (22.7%), 5 (22.7%), and 9 (40.9%) patients for ALT, and in 9 (40.9%), 6 (27.3%), and 5 (22.7%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 15.8 (4-95) weeks. The median time from highest ALT/AST increase to normalization was 7.7 (2-15) weeks. Normalization of liver test was observed in 19 (86.4%) patients, and 3 patients died of cancer progression before their liver tests had normalized. In 12 patients (54.4%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose. Abiraterone was discontinued in 6 patients (27.7%) due to liver test increase. It was reintroduced after a break in four patients and then discontinued in two for a subsequent liver disorder event. No patient reported symptoms clearly related to liver test increase. Conclusions: Liver tests increase is a quite rare event that typically occurs within the first 4 months on abiraterone, though it can also happen up to 20 months later. It is typically asymptomatic and most patients experience normalization of tests, either spontaneously or after dose reduction/discontinuation.
Novel nomograms for castration-resistant prostate cancer and survival outcome in patients with de novo bone-metastatic prostate cancer.
Authors: Zhao Jinge , Sun Guangxi , Liao Banghua , Zhang Xingming , Shen Pengfei , Chen Junru , Liu Jiandong , Zeng Hao 
Published: February 2018

336 Background: Treatments for de novo metastatic prostate cancer (mPCa) are evolving. However predictive models for this subset of the population are still lacking. The aim of this study is to develop nomograms to predict the incidence of castration resistant PCa (CRPC) and overall survival (OS) for de novo mPCa patients. Methods: Data from 449 de novo mPCa patients were retrospectively analyzed. Patients were randomly divided into either the training or the validation cohort. Predictive factors were selected by Cox-proportional model and further used for building predictive models. The outcomes were incidence of CRPC and OS. Results: Predictive parameters included: Gleason Score (GS), intraductal carcinoma of the prostate (IDC-P), ECOG status, alkaline phosphatase (ALP), hemoglobin (HGB) and prostate specific antigen (PSA). IDC-P and GS were the strongest prognosticators for both the incidence of CRPC and OS. Nomograms for predicting CRPC and OS had an internal validated C-index of 0.762 and 0.723, respectively. Based on the beta-coefficients of the final model, risk classification systems were constructed. For those with favorable-, intermediate- and poor-prognosis, the median time to CRPC was 62.6, 28.0 and 13.0 months (P<0.001), and the median OS was not reached, 55.0 and 33.0 months, respectively (P<0.001). Conclusions: We developed two novel nomograms to predict the incidence of CRPC and OS for de novo mPCa patients. These tools may assist physicians’ decision-making and design of clinical trials.
Angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.
Authors: Ghinea Nicolae 
Published: February 2018

341 Background: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination encountered in malignancies associated with highly enervated organs. However, the effect of cancer cells on the blood vessels nourishing the nerves (i.e., vasa nervorum) remains unknown. Methods: We used immunohistochemistry involving three specific antibodies that recognize different endothelial markers (CD34, VEGF-R2 and FSHR), and standard histochemical methods (HES, PAS, TRICHROM) to detect changes in the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients diagnosed with locally advanced prostate cancer (LAPC). Genes known to be implicated in the process of angiogenesis and vascular remodeling have been also explored. NanoString nCounter Analysis covering 86 target genes was used for comparison of gene expression levels between LAPC (6 frozen samples) and normal prostate (NP; 2 frozen samples). Results: The percentage of the area occupied by CD34-positive vasa nervorum endothelial cells associated to nerves with PNI was significantly higher than that in nerves without PNI (6.93 ± 1.08 versus 1.76 ± 0.32; p = 0.003), suggesting a process of angiogenesis. In 18/85 (21%) of patients diagnosed with LAPC the vasa nervorum arterioles had a thick (25 ± 5 µm) tunica media consisting of collagen fibers. More than 75% of CD34-positive vasa nervorum of nerves with or without PNI expressed FSHR. In contrast, none of vasa nervorum expressed detectable VEGF-R2. A panel of 19 genes was found to be significantly (p < 0.05), differentially expressed between LAPC and NP. Six of them (ANGPT1, ITGB3, PGGFB, VEGFC, FSHR, and SDC1) have previously been associated with tumor progression, angiogenesis, and metastasis. Other three genes (SELE, SELP, and ESAM) are known to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. Conclusions: Perineural invasion of cancer cells caused angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.