bluuebunny/crossref_metadata_2025_split huggingface dataset:
Celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: Survival results from STAMPEDE (NCT00268476).
Authors: James Nicholas D. , Sydes Matthew Robert , Clarke Noel W. , Mason Malcolm David , Dearnaley David P. , Spears Melissa Ruth , Ritchie Alastair W S , Russell J. Martin , Parker Chris C. , Rentsch Cyrill A. , Wallace Jan , Barber Jim , Lydon Anna , Parmar Mahesh K B 
Published: February 2017

162 Background: STAMPEDE is a randomised controlled trial using a multi-arm multi-stage design. It recruits men (pts) with high-risk locally advanced or metastatic prostate cancer (PCa) starting long-term hormone therapy (HT) for the first time. The trial initially assessed adding one or two of three treatment approaches to standard-of-care (SOC). We report comparative survival data for the two original comparisons that stopped accrual early at pre-planned lack-of-activity analysis based on failure-free survival (FFS): celecoxib (Cox) and celecoxib + zoledronic acid (Cox+ZA). Methods: SOC was HT for at least 2yrs; RT was encouraged for men with M0 disease. Stratified randomisation allocated pts 2:1:1 to SOC (control), SOC+Cox or SOC+Cox+ZA. Celecoxib (400mg) was given twice daily until 1yr. Zoledronic acid (4mg) was given for six 3-weekly cycles then 4-weekly until 2yrs. The primary outcome measure was death from any cause. This pre-planned analysis is triggered by analysis of the “original comparisons” that continued accrual through all activity stages. Analyses use Cox proportional hazards model and flexible parametric models, all adjusted for stratification factors. Results: 1,245 men were contemporaneously randomised to these 3 arms (Oct2005-Apr2011). Groups were well balanced: median age 65yrs; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly-diagnosed; median PSA 66ng/ml. Median follow-up was 62m. Grade 3-5 adverse events were seen in 35% SOC, 32% SOC+Cox, 32% SOC+Cox+ZA. There were 295 control arm deaths (82% PCa); median survival 68m. The adjusted HR was 1.00 (95% CI 0.82-1.22; p=0.99; median OS 69m) for SOC+Cox vs SOC; and 0.86 (95%CI 0.70-1.06; p=0.16; median OS 74m) for SOC+Cox+ZA vs SOC. Pre-planned analyses in men with metastatic disease showed HR 0.78 (95%CI 0.62-0.99) for SOC+Cox+ZA vs SOC. Further data will be shown. Conclusions: These data show no survival advantage for the addition of celecoxib alone for men starting long-term HT for the 1st time. However, the addition of celecoxib combined with ZA demonstrated a survival advantage for men with metastatic disease, in a pre-planned analysis, and requires further investigation. Clinical trial information: NCT00268476.
Enhanced overexpression of hypoxia-related miRNA-210 in primary tumor of metastatic prostate cancer.
Authors: Eminaga Okyaz , Fries Jochen , Woetzel Fabian , Warnecke-Eberz Ute , Neiss Susanne , Heitmann Michaela , Herden Jan , Engelmann Udo , Heidenreich Axel 
Published: February 2017

166 Background: miR-210 is a known transcriptional target of the hypoxia-responsive HIF-1α signaling pathway. However, the association between the expression of miR-210 and the tumor progression in prostate cancer (PCa) remains unclear. Methods: We isolated miRNA by miRNeasy FFPE kit (Qiagen, Hilden, Germany) from paraffin-embedded tissues of 87 prostate specimens with adenocarcinoma of the prostate cancer in different tumor stages, with high-grade prostatic intraepithelial neoplasia (HGPIN) and normal tissues. Organ-confined PCa was defined as PCa with pT2 tumor stage, Gleason score ≤ 7a and PSA level < 10 ng/ml. PCa with pT3/4 or Gleason > 7a was defined as advanced PCa. PCa with pN1 were considered as metastatic diseases. Additionally, 3 cases with castration-resistant prostate cancer (CRPC) were considered. Quantitative miR-210 expression data were acquired and analyzed using a real-time TaqMan-based PCR with the ABI Prism 7900HT (Life Technologies, Darmstadt, Germany). ANOVA and post hoc analysis according to Turkey were performed using SPSS 22 (IBM, Armonk, USA). For silico analysis, Diana tools were applied to determine target genes of miR-210 and related functions and pathways. All the statistical tests were two-sided, and the level of statistical significance was set at P < 0.05. The small nuclear U6 RNA was used as an endogenous control. Results: ANOVA revealed significant differences in expression levels of miR-210 according to the tumor progression. Interestingly, organ-confined PCa showed the lowest expression level of miR-210 in our analysis. No sig. differences in miR-210 expression between normal tissues, HGPIN and organ-confined PCa and between advanced PCa, metastatic diseases and CRPC were observed. However, miR-210 expression was significantly higher in metastatic diseases and CRPC in comparison to organ-confined PCa. The silico analysis showed that genes regulated by miR-210 were associated with homologous recombination, non-homologous end-joining, the cell cycle regulation and synthesis of DNA. Conclusions: We observed an enhanced overexpression of hypoxia-related miRNA-210 in primary tumor of metastatic prostate cancer and CRPC in comparison to organ-confined PCa.
Comorbidity and the receipt of curative therapy for favorable-risk prostate cancer prior to and following the publication of PIVOT.
Authors: Mihalcik Stephen A. , Chen Ming-Hui , Braccioforte Michelle H. , Moran Brian Joseph , D'Amico Anthony V. 
Published: February 2017

17 Background: On July 19, 2012, the Prostate Cancer Intervention versus Observation Trial (PIVOT) was published and reported that after a median follow up of 10 years, radical prostatectomy neither improved overall survival nor reduced prostate cancer (PC)-specific mortality in men with low-risk PC compared to watchful waiting. However, the trial’s applicability may be somewhat limited by the participants’ poorer-than-average overall health. This study aimed to evaluate the impact of the PIVOT by assessing practice patterns before and after its publication. Methods: Between October 1997 and May 2013, 6,818 men with low-risk (n = 5,081, 74.5%) or favorable intermediate-risk (N = 1,737, 25.5%) PC were treated with curative intent at the Chicago PC Foundation. We compared the proportions of these men with ≥2, 1, or 0 comorbid conditions, restricted to myocardial infarction, congestive heart failure, diabetes mellitus, and coronary artery disease. We assessed for a trend in these proportions by time tertile prior to the PIVOT’s publication and compared them one month following PIVOT to the final pre-publication time tertile. Results: Of 6,818 men treated with curative intent, 5,208 (76.5%), 1,307 (19.2%), and 293 (4.3%) had 0, 1, and ≥2 comorbidities, respectively. Prior to PIVOT, the proportion of men with the greatest comorbidity (≥2) increased by time tertile (3.5% vs. 4.2% vs. 5.4%; p = 0.002), while 1 month following publication, there was a decline in the proportion of men with the highest degree of comorbidity (5.4% vs. 2.9%; p = 0.05). In addition to the drop in men with greatest comorbidity, men treated following the publication of the PIVOT were also younger (median age 65.7 vs. 66.8 years; p = 0.04), more likely to be black or Hispanic (24.7% vs. 17.4%; p = 0.003), and more likely to have favorable intermediate than low-risk PC (36.1% vs. 28.4%; p = 0.007). Conclusions: Following the publication of the PIVOT, men with low or favorable intermediate-risk PC whose health was poorer than the national average were less likely to undergo curative treatment, whereas men at higher risk for harboring occult high grade PC despite favorable-risk indices were more likely to undergo curative treatment.
Aldo-keto-reductase 1C3 expression as an independent risk factor for occurrence of castration resistant prostate cancer in high risk prostate cancer treated with neoadjuvant therapy and prostatectomy.
Authors: Hashimoto Yasuhiro , Tanaka Toshikazu , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

172 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) is a key steroidogenic enzyme that is implicated in the development of castration-resistant prostate cancer (CRPC). In this study, we examined AKR1C3 expression in surgical specimens of high risk prostate cancer treated with neoadjuvant LHRH + EMP, and we investigate the correlation between the expression level of AKR1C3 and the occurrence of CRPC. Methods: High-risk Pca was defined by the D’Amico stratification system. A total of 103 patients with high-risk Pca were enrolled in this study. The LHRH + EMP therapy included the administration of the LHRH agonist and 280 mg/day of EMP for six months before the radical prostatectomy. BCR was defined as the prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after the prostatectomy. Castration-resistant prostate cancer (CRPC) is defined by PSA or radiographic progression in the castrate levels of testosterone ( < 50 ng/dL). Along with the routine pathological assessment, AKR1C3 expression was evaluated in tissue microarray analysis (TMA) in all patients. A multivariable Cox proportional hazards model was used to evaluate the association between CRPC and clinical data. Results: The average patient age was 67.2 (49 to 78), and the median initial PSA level was 18.8 ng/mL (4.2–95.6). At a median follow-up period of 79.5 months, BCR occurred in 41 patients (39.8%) and CRPC occurred in nine patients (8.7%). In TMA, overexpression of AKR1C3 was seemed in 14 patients (13.6%). 5-year CRPC free survival rate of AKR1C3(+) patients (64.2%) was significantly lower than that of AKR1C3(-) patients (97.6%). (Log-rank test: p < 0.001) On multivariable analysis, AKR1C3 expression is an independent risk factor for occurrence of CRPC in this study. (p = 0.044). Conclusions: Although the present study was small and preliminary, overexpression of AKR1C3 is an independent risk factor for occurrence of CRPC in the high risk prostate cancer treated with neoadjuvant LHRH + EMP and prostatectomy. Further study is warranted to elucidate its clinical significance.
Amiloride effects on abiraterone antiproliferative activity in prostate cancer cells in vitro and on clinical management of abiraterone induced mineralocorticoid excess syndrome.
Authors: Valcamonico Francesca , Bedussi Francesca , Galli Diego , Dalla Volta Alberto , Fragni Martina , Vezzoli Sara , Ferrari Vittorio D. , Lazzari Barbara , Ferrari Laura , De Ferrari Francesco , Memo Maurizio , Berruti Alfredo , Sigala Sandra 
Published: February 2017

175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptoms and signs was the primary end point. Results: Prednisone, spironolactone and eplerenone induced an increase in the LNCAP proliferation rate and antagonized the AA-induced reduction of the cell proliferation in a concentration-dependent manner, while PF-03882845 did not. Amiloride at high concentrations induced cell death. When combined with AA +/- prednisone, amiloride at low concentration did not interfere with AA anti-proliferative activity however an additive inhibitory effect was observed at higher concentrations. The association of amiloride with hydrochlorothiazide led to a complete disappearance of all clinical and biochemical signs of abiraterone induced MCES in the 5 treated patients. Conclusions: Amiloride and PF-03882845 do not negatively interfere with the AA inhibition of proliferative activity of prostate cancer cells in vitro. The association of amiloride plus hydrochlorothiazide is efficacious in the management AA induced MCES.
Screen failure rates in contemporary phase II/III therapeutic trials in genitourinary malignancies.
Authors: Wong Sarah E. , North Scott A. , Sweeney Christopher , Stockler Martin R. , Sridhar Srikala S. 
Published: February 2017

176 Background: Screen failures cost effort, time and resources estimated at about $2000 per patient (Bienkowski RS et al 2008). There is little published data about the frequency or causes of screen failures in genitourinary (GU) cancer clinical trials. Methods: We reviewed published articles and contacted study investigators on 42 key phase 2 and 3 trials in advanced GU cancer run from 1999 to 2015. We sought data on the numbers and causes of screen failures. Screen failures were defined as individuals who underwent screening but were not enrolled in the trial. Results: Among all 11 phase 3 trials in prostate cancer, the mean screen failure rate was 25% (17.9%-30.3%). In 4 recent trials evaluating novel androgen receptor pathway targeted agents, abiraterone and enzalutamide before or after chemotherapy for castration-resistant disease, the mean screen failure rate was 28% (range 22% to 30%). Only 2 of 3 prostate cancer chemotherapy trials completed after 2008 collected screen failure data with screen failure rates of 18 and 21%. The main reason for screen failures among all prostate cancer clinical trials was ineligibility. Among 14 phase 3 trials in kidney cancer, 5 reported rates and the mean screen failure rate was 24% (range 21%-27%). The main reasons again were ineligibility, with a very small percentage due to patient refusal. Among 17 phase 2 or 3 trials in bladder cancer, 6 reported rates and the mean screen failure rate was 13% (range 2.04% - 22.8%). The main reasons were primarily ineligibility and patient refusal to a lesser extent. Only (16/42) 38% of the trials published screen failure rates-73% of those in prostate cancer (all completed after 2008), 29% in kidney cancer, and 24% in bladder cancer. Conclusions: Contemporary trials in GU cancer that collected screen failure data had fairly consistent failure rates of 20-30% in prostate and kidney cancer. Many trials did not collect data on the numbers of and reasons for screen failures. Greater standardization of definitions, methods and reporting are needed to better understand and improve screen failure rates in GU cancer trials.
Imaging characteristics of patients with prostate cancer who discontinued active holistic surveillance on 3T multiparametric prostate MRI.
Authors: Katz Aaron , Liu Corinne , Fontes Andrew S , Kosinski Kaitlin E. 
Published: February 2017

18 Background: Early-stage patients with prostate cancer can decide to go on Active Holistic Surveillance (AHS) to avoid over-treatment of a disease that has a high probability of being indolent. These patients are also placed on a special diet with vitamin supplements. We evaluate the imaging characteristics of this particular set of patients with prostate cancer with early-stage disease who are on a special diet and vitamin supplements, discontinued AHS and received definitive treatment. Methods: 300 consecutive 3T Multiparametric Prostate MRI (MP-MRI) were identified from March 26, 2012, to June 29, 2015. 200 patients (age 44 to 84 years) were identified in the active surveillance program. 114 patients had an initial MP-MRI prior to starting AHS and had at least one follow up MP-MRI after beginning AHS. 14 (12%) patients (age 60 to 79 years) discontinued AHS due to changes on a follow up MRI suggesting clinically significant prostate cancer. The MRI imaging findings were evaluated and correlated with pathology results, if available. Results: Of 14 patients, 3 (21%) patients had an enlarging MRI lesion compared to a previous MRI, 2 (14 %) patients had a new MRI lesion(s) suspicious for cancer, and 9 (64%) patients had suspicion or confirmation of extracapsular extension. 7 (50%) patients had a biopsy after a follow up MP-MRI with 6 (43%) demonstrating tumor upgrading. Length of time on AHS ranged from 4 months to 110 months. Prostate-specific antigen (PSA) levels and PSA density prior to beginning AHS ranged from 4.8 to 12.0 and 0.04 to 0.39, respectively. All were treated with definitive treatment, majority with unilateral focal cryoablation. Conclusions: The small number of patients with worsening disease on follow-up MP-MRI supports the role of AHS in patients with early-stage prostate cancer. MP-MRI is a useful tool in following patients on AHS and can extract patients who potentially may have clinically significant cancer and who may benefit from definitive treatment.
Use of crowdsourced research to develop a prognostic model for first-line metastatic castrate resistant prostate cancer (mCRPC).
Authors: Zhou Fang Liz , Guinney Justin , Wang Tao , Bare J. Christopher , Norman Thea C , Bot Brian , Shen Liji , Winner Kimberly Kanigel , Friend Stephen Henry , Abdallah Kald , Stolovitzky Gustavo A. , Xie Yang , Costello James 
Published: February 2017

180 Background: Project Data Sphere, LLC (PDS) and Sage Bionetworks/DREAM have completed the “Prostate Cancer DREAM Challenge” (Challenge), a crowdsourced competition, using historical prostate cancer clinical trial data from PDS. The Challenge aimed to improve prognostic models for overall survival (OS) and to explore predictive models for treatment toxicity in mCRPC patients. Methods: Control arms of 4 randomized phase III trials (total 2,070 patients) were used as training and validation data sets for the Challenge: ASCENT2, MAINSAIL, VENICE and ENTHUSE33. All subjects were first line mCRPC patients receiving docetaxel treatment. Curated baseline clinical covariates (demographics, comorbidity, prior treatment, laboratory, lesion and vital signs) were modeled along with raw clinical data tables. The primary purpose of the Challenge was to develop a prognostic model for OS (SubChallenge 1). The models were scored using concordance index and integrated area under receiver operator curve (iAUC) from 6-30 months. The published mCRPC OS model of Halabi, et al., JCO, 2014, was used as the benchmark. Results: The Challenge attracted over 160 active participants who formed 50 teams that submitted final models for SubChallenge 1. Median iAUC was 0.76 (0.67-0.78) with a maximum score of 0.792. Over half (n = 35) of these models exceeded the published benchmark (0.743 iAUC). Teams explored new methodologies such as model-based imputation and machine learning techniques to develop the best performing models. Many leveraged raw clinical data sets to create their own covariates and expanded beyond existing prognostic models. Conclusions: The Challenge externally validated Halabi’s first line prognostic model. New prognostic models were proposed and validated with significant improvements over the benchmark. Further analyses are needed to examine the winning models for new prognostic factors and to validate them using additional trial data from PDS. The Challenge drove interest from cross-disciplinary teams of global experts to explore and enhance their technical abilities using real clinical data whilst serving as a vehicle to accelerate medical innovation.
Correlation between radiographic progression-free survival (rPFS) and overall survival (OS): Results from PREVAIL.
Authors: Morris Michael J. , Beer Tomasz M. , Loriot Yohann , Higano Celestia S. , Armstrong Andrew J. , Sternberg Cora N. , De Bono Johann S. , Tombal Bertrand F. , Parli Teresa , Bhattacharya Suman , Krivoshik Andrew P. , Phung De , Rathkopf Dana E. 
Published: February 2017

182 Background: In PREVAIL, enzalutamide (ENZA) significantly improved OS (hazard ratio [HR] 0.71; P < 0.0001) and rPFS (HR 0.19; P < 0.0001) compared with placebo in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Using data from the final analysis at 439 rPFS events we showed a strong correlation between investigator and central review. Here we report sensitivity analyses (SAs) from the final analysis of investigator-assessed rPFS and the association between investigator-assessed rPFS and OS. Methods: The coprimary endpoint of rPFS was defined as time from randomization to the earliest objective evidence of centrally assessed radiographic progression, defined by PCWG2 guidelines for bone disease and RECIST v1.1 for soft-tissue disease, or death within 168 days of treatment discontinuation. Bone progression was captured using a validated bone scan data capture assay. Four SAs were performed on investigator-assessed rPFS to evaluate the impact of: (1) progression in bone, (2) clinical progression, (3) a required confirmatory scan for soft-tissue disease progression, and (4) all deaths, regardless of length of time after study drug discontinuation. Associations of investigator-assessed rPFS and OS were calculated using Pearson’s correlation coefficient, Spearman’s rho, and Spearman’s rho estimated through the Clayton copula. Results: Treatment effects remained significant with each SA, with HRs of (1) 0.21 (95% confidence interval [CI] 0.18, 0.27), (2) 0.21 (95% CI 0.17, 0.26), (3) 0.23 (95% CI 0.19, 0.30), and (4) 0.23 (95% CI 0.19, 0.30) (P < 0.0001 for each). Results of rPFS and OS associations are presented in the table below. Conclusions: SAs of rPFS in PREVAIL demonstrated a robust and consistent treatment benefit with ENZA. We observed a modest association between rPFS and OS. However, some unaccounted factors, such as post-protocol treatment, could have reduced the strength of the association of rPFS and OS in the placebo arm. Clinical trial information: NCT01212991. [Table: see text]
MLL translocation in two castration-resistant prostate cancer (CRPC) patients.
Authors: Chowdry Rajasree Pia , Ledet Elisa M. , Phelan Mary C. , Sartor A. Oliver 
Published: February 2017

186 Background: The mixed-lineage leukemia (MLL) protein is a histone methyltransferase that regulates multiple genetic elements. Chromosomal rearrangements of the MLL gene result in expression of MLL-fusion proteins that occur in a subset of acute leukemias and are associated with poor prognosis. The MLL protein complex has been shown to interact with the androgen receptor via the MLL-menin subunit and, in model systems, MLL-menin inhibition blocks CRPC growth. We describe 2 cases of metastatic CRPC with a translocation in the MLL gene. Methods: In our institution, fluorescence in situ hybridization (FISH) testing of bone marrow specimens is routinely performed using the MLL Breakapart probe from Cytocell, Ltd (Cambridge, UK). The probe consisted of an 87 kb segment labeled in red that covered a region telomeric to the MLL locus and a 168 kb segment labeled in green centromeric to MLL. The FISH assay was performed according to manufacturer’s instructions. Results: MLL translocation was found coincidentally in 2 patients. The first was a 50 year old male with CRPC who had progressed on abiraterone and multiple chemotherapy regimens. A bone marrow biopsy was done to evaluate pancytopenia and pathology revealed metastatic prostate cancer marrow infiltration, without any evidence of leukemia or myelodysplasia. FISH studies revealed a rearrangement of the MLL locus using the MLL Breakapart probe. The second patient was a 77 year old male with metastatic CRPC who had also progressed through multiple hormonal and chemotherapy regimens. Bone marrow biopsy was done to evaluate thrombocytopenia and pathology revealed metastatic prostate cancer occupying nearly 100% of the marrow. Cytogenetics revealed complex karyotype and FISH was positive for MLL gene rearrangement by the same assay. There was no evidence of leukemia or myelodysplasia in either case. Conclusions: Translocation of the MLL gene is well documented in leukemia but has not been described in CRPC. Additional studies are warranted regarding the frequency and importance of this potential therapeutic target.