bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of neuropsychiatric adverse events of enzalutamide and abiraterone acetate treatments reported in EudraVigilance in metastatic castration resistant prostate cancer patients.
Authors: Moreno Perez Maria Paola , Sanchez Iznaola Miguel , Garcia Angela , Muñoz del Toro Jacobo , Parra Rafael 
Published: February 2018

343 Background: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ), oral hormonal treatment of metastatic castration resistant prostate cancer (mCRPC), can have neuropsychiatric impact. Methods: The Proportional Reporting Ratio (PRR) was used to analyze evolution of suspected adverse drug reactions (ADRs) reported in real world, in EudraVigilance from March to August 2017. Results: From the total ADRs of AAP and ENZ reported in Eudra from March to August 2017, 1,162 were related to AAP and 5,101 were related to ENZ. ADRs of ENZ reported in Eudra in August were higher than those reported in March 2017, in all the neuropsychiatry ADRs analyzed. In the case of AAP, 44% of the neuropsychiatric suspected ADRs analyzed did not show new cases reported and 56% of the ADRs shown an increase, although it was not higher than 15 new cases reported. Conclusions: In August 2017, the updated ADRs of AAP and ENZ from Eudra were consistent with those observed in March 2017 (Iznaola et al.). It confirms an increasing trend of reporting neuropsychiatric ADRs of ENZ in mCRPC. Suspected ADRs of AAP reported remained steady.[Table: see text]
Blood-brain barrier penetration of [14C]darolutamide compared with [14C]enzalutamide in rats using whole body autoradiography.
Authors: Zurth Christian , Sandmann Steffen , Trummel Dagmar , Seidel Dietrich , Gieschen Hille 
Published: February 2018

345 Background: Darolutamide (ODM-201) (Daro) is an investigational oral and high-affinity androgen receptor antagonist. In preclinical studies, penetration of Daro through the blood–brain barrier (BBB) is negligible and in a retrospective safety analysis of the ARADES database for CNS-related adverse events (AEs), only 1 report of urinary incontinence was linked to Daro (Fizazi K, et al. 2015). Various clinical trials on enzalutamide (Enza) have reported CNS AEs (eg, seizure, falls, fatigue, pain). To understand the differences in CNS outcomes, we report an in vivo tissue distribution study with [14C]-labelled Enza and Daro in a head-to-head study in rats by means of quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Daro or [14C]Enza in the same formulation, administration volume, and radioactive dose. The animals were sacrificed at each drug’s specific tmax (time to reach the maximum concentration) in blood and brain and processed for QWBA. Results: At early time points [14C]Daro- and [14C]Enza-derived radioactivity was rapidly absorbed from the gastrointestinal tract and homogenously distributed throughout the body. By 8 h post dose, [14C]Daro was significantly eliminated from almost all organs/tissues, whereas [14C]Enza remained constant within the body. In contrast to [14C]Daro, high and persistent radioactivity was observed in brain for [14C]Enza. At tmax, the brain/blood-ratio of [14C]Enza was ~0.765, while [14C]Daro was about 10-fold lower at ~0.074. Conclusions: Results show that post dose, there was a 10-fold lower BBB penetration of [14C]Daro compared with [14C]Enza. At 8 h, [14C]Daro was rapidly eliminated and almost undetectable in all tissues, including brain, in contrast to [14C]Enza that remained constant. These data suggest that Daro might have a lower risk of inducing CNS-related AEs than Enza. Further clinical studies are ongoing.
Vimentin 3 and endothelin in prostate cancer.
Authors: Kohl Tobias , von Brandenstein Melanie , Stog Andreas , Schlosser Monika , Kuru Timur H. , Pfister David , Fries Jochen , Heidenreich Axel 
Published: February 2018

349 Background: An upregulation of vimentin 3, a truncated version of the full length vimentin, with an unknown function, was previously described by our group, in a direct dependency of increased ET-1 levels. We analyzed now vimentin 3 in further genitourinary cancers. Here, we describe our findings how vimentin 3 is part of the signaling pathways from Endothelin-1 (ET-1) and the Endothelin-A-Receptor (ETAR) and how it correlates with aggressive tumor behavior in a PCa cell culture and in human tissue and serum samples from PCa patients. Methods: DU145 cells were cultured. We stimulated with ET-1 with and without artificial downregulation of the ETAR, the ETBR or both receptors. A scratch assay was performed to demonstrate the influence of ET-1. Proteins were then extracted and WB for vimentin full length and vimentin 3 was performed. Additionally we analyzed ET-1 and vimentin 3 in serum from prostate cancer patients using ELISA and we did IF and IHC staining for vimentin 3 in human prostate cancer tissue. Results: Treatment with ET-1 and downregulation of the ETBR lead to a significant increased migration of DU145 cells after 3 and 6 h. The corresponding WB showed increased vimentin 3. ELISA showed increased levels of ET-1 in samples of prostate cancer patients compared to patients with no cancer history. ELISA could also demonstrate elevated levels of vimentin 3 in serum of patients with local disease and significantly elevated values in metastatic prostate cancer patients compared to patients with no cancer history. Conclusions: The data presented shows that ET-1 stimulation leads to overexpression of vimentin 3 in prostate cancer cell cultures and a concomitant aggressive biological behavior. Here we previously described the direct interaction of Vimentin 3 in prostate cancer and the activation mechanism via ET-1 and the ETAR. IHC, IF show an upregulation of the truncated variant Vimentin3 in tissue samples. In an Vimentin 3 ELISA we could show that this truncated variant is increased and therefore represents a potential biomarker. Highest values of vimentin 3 were measured using ELISA in serum of patients with recurrent and metastatic disease also suggesting that vimentin 3 correlates with aggressive tumor behavior.
Effect of a tumor staging template on consistency and clarity of prostate cancer staging.
Authors: Nasseri Ryan , Levy Susan S , Cohen Edward , Dato Paul , Prime Hillary , Dijeh Uchey , Filicko James , Ball Catherine E , Gaylis Franklin 
Published: February 2018

35 Background: Risk stratification (RS) is central in assessment and treatment of Prostate cancer (PCa). Accurate clinical staging (cT-Stage) based on AJCC criteria is a key component of RS and certain quality measures (PQRS #102). We assessed the potential of a tumor staging template (TST) embedded into an electronic medical record (EMR) to improve consistency and clarity of clinical tumor staging based on digital rectal examination (DRE) near the time of prostate needle biopsy (PNB). Methods: Retrospective analysis before TST implementation followed by prospective analysis after implementation of the TST was performed at Genesis Health Care Partners. Study period was January 1, 2017 through August 23, 2017. TST was implemented into the EMR and physicians were trained in its use on April 1, 2017. CT-Stage was independently categorized based on physicians’ notations. Descriptions of DRE included; confident-explicit (CE) (cT-Stage documented), confident-implicit (CI) (cT-Stage not documented, DRE amply detailed to interpret cT-Stage), and unconfident- inability to discern T-stage (UI). Classification categories prior to and after TST implementation were compared and analyzed using a chi-square test. Two cohorts were evaluated; men at risk for PCa undergoing PNB, and men with diagnosed PCa. Results: 573 PNBs were analyzed: 234/573 before TST (40.2%) and 339/573 after TST (59.8%). 305/573 (53.2%) PNBs were positive for PCa: 118 before TST and 187 after TST. In men at risk of PCa, CE staging increased from 15.8% to 57.8% (p < 0.001) after TST use. Overall staging (CE+CI) increased from 73.5% to 89.1% (p < 0.001), while UI staging decreased from 26.5% to 10.9% (p < 0.001) after TST use. In men with positive PNBs, CE staging increased from 28.8% to 62.6% (p < 0.001) after TST use. Overall staging (CE+CI) increased from 75.4% to 88.8% (p = 0.004), while UI staging decreased from 24.6% to 11.2% (p = 0.003) after TST use. Conclusions: In an era of precision-oriented medicine, accurate clinical tumor assessment, description, and staging is of great importance in RS and treatment recommendation. Our study demonstrates the ability of a standardized EMR-embedded, AJCC based template to improve the consistency and clarity of clinical staging of PCa.
Enhancer of zeste-homolog 2 (EZH2) expression and clinical outcomes in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Giridhar Karthik , Costello Brian Addis , Sosa Carlos , Huang Haojie , Kohli Manish 
Published: February 2018

350 Background: In prostate cancer, overexpression of EZH2 is associated with disease recurrence, androgen independent growth, cell invasion, and metastases. We evaluated the prognostic significance of EZH2 gene expression in metastatic biopsies from men with CRPC. Methods: EZH2 (RNA) expression was evaluated in two serial metastatic site biopsies in patients (pts) prior to treatment with abiraterone acetate and prednisone (pre-AA/P) and after 12 weeks of treatment (post-AA/P). All pts were enrolled and prospectively followed for clinical outcomes. The primary endpoint was overall survival (OS), defined as the time from CRPC to death or last follow-up. Cox proportional hazard regression analysis was performed on EZH2 expression using normalized fragments per kilobase million (FPKM) > 1 for association with OS and time to treatment failure (TTF). Results: Of 92 enrolled pts, 59 pts had (pre-AA/P) gene expression using RNA-seq, 45 had paired pre and post-AA/P RNA-seq available for analysis. In pre-AA/P samples, the median EZH2 expression was 4.82 FPKMs (range 1.05-38.8). Elevated expression of EZH2 was associated with shorter OS [hazard ratio (HR) 2.58, p = 0.016]. Radiographic progression at 12 weeks was more frequent in high EZH2 tumors compared to low EZH2 tumors (48% vs 20%, p = 0.03, Fisher’s exact test) No statistically significant associations were identified between EZH2 expression and TTF. In paired post-AA/P biopsies, EZH2 expression increased in 13/45 tumors and decreased in 32/45 tumors. The median log2 fold change in EZH2 expression was -1.38 (range -6.7 to 3.1). In post-AA/P biopsies, no associations were identified between an increase in EZH2 expression and OS or TTF. Conclusions: EZH2 expression represents a potential novel prognostic biomarker in mCRPC and warrants further exploration. Clinical trial information: 01953640.
Independent assessment of TP53 and PTEN as predictors of response to enzalutamide (ENZ) or abiraterone acetate (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew W , Rathi Nityam , Gill David Michael , VanAlstine Sidney , Poole Austin , Agarwal Neeraj , Maughan Benjamin Louis 
Published: February 2018

351 Background: Alterations in androgen receptor signaling are well-established mechanisms of resistance to medical castration. Pre-clinical studies suggest that alterations to key tumor suppressor genes, such as TP53 or PTEN, may also be associated with development of androgen independence as an alternate mechanism of castration-resistance. Previous studies have shown that TP53 inactivation and PTEN loss are predictive of response to novel androgen axis inhibitors. Here, we independently assess whether TP53 and PTEN genomic alterations are predictive of response to ENZ and AA in men with mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Next-generation sequencing (NGS) was performed on predominantly primary tumor tissue for 343 somatic and germline genetic alterations using FoundationOne. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Patients with mCRPC who were treated with any line AA or enzalutamide were included. We performed a univariate analysis to assess the predictive value of TP53 and PTEN. Only patients treated with single-agent therapy were included. Results: Of 141 men with prostate cancer and NGS available, 56 were included. Most patients were treated with abiraterone (n = 50), and only 6 with enzalutamide. 28.6% had PTEN loss and 35.7% had a TP53 mutation. OS and PFS did not differ significantly according to PTEN or TP53 status. Median OS was 40.9 months and not reached for men with and without TP53 mutation (HR 1.85, p = 0.31). Median PFS was 7.5 months and 9.5 months for men with and without TP53 mutation (HR 1.18, p = 0.60). Median PFS was 7.2 months and 9.5 months for men with and without PTEN loss (HR 1.15, p = 0.66). Median OS for PTEN was not mature enough to analyze. Conclusions: In our independent cohort, neither TP53 mutation nor PTEN loss is predictive of response to androgen-directed therapy in men with mCRPC patients. However, this is a relatively small retrospective sample with few events. These results should be considered exploratory only.
A meta-analysis on individual data of bone-targeting radio-isotopes in men with bone metastases from castration-resistant prostate cancer.
Authors: Aarab Terrisse Safae , Parker Chris C. , Eleni Karamouza , Sartor A. Oliver , James Nicholas , Pirrie Sarah , Collette Laurence , Tombal Bertrand F. , Chahoud Jad , Smeland Sigbjørn , Erisktein Bjørn , Pignon Jean-Pierre , Fizazi Karim , Le Teuff Gwénaël 
Published: February 2018

352 Background: Among bone-targeted radio-isotopes (RI), Radium-223 (an α-emitter) is the only one with clearly demonstrated overall survival (OS) benefit in men with castration-resistant prostate cancer (CRPC). The aim of this meta-analysis is to estimate the OS impact of RI in men with CRPC. Methods: An individual patient data meta-analysis was carried out from randomized trials with inclusion period 1993-2013. Eligible trials included more than 50 patients, mandated bone metastases from CRPC and randomly evaluated RI. Endpoints were OS (primary), symptomatic skeletal events (SSE) and toxicity. A fixed-effect model was used. The log-rank test stratified by trial was used to estimate individual and overall hazard ratios (HR). Subset analyses were performed by the type of radiation (α vs. β emission) and by trial comparison: RI + Chemotherapy (CT) vs. CT, RI+ External beam radiotherapy (EBRT) vs. EBRT, RI vs. EBRT. Results: From 9 identified trials, data from 6 trials comprising 2081 patients (min: 64, max: 921) were collected with 2 trials representing 80% of data. The data from 3 trials (n = 341) were not available. The overall effect on OS favoured RI with HR = 0.86 [0.77-0.95] but high heterogeneity between trials (p < 0.001, I2= 79.6%). The overall effect of α- emitters on OS (HR = 0.70 [0.58; 0.83], 2 trials, n = 985) significantly differed from that of β-emitters (HR = 0.96 [0.84; 1.10], n = 4 trials, n = 1096) (interaction p = 0.0041). The overall effect on SSE favoured RI with HR = 0.81 [0.69-0.93] (4 trials, n = 1806) with marked between trial heterogeneity (p = 0.08, I² = 55.3%) and a significant difference (p = 0.02) by the type of RI (α-emitters: HR = 0.65 [0.52-0.82]-2 trials, β-emitters: HR = 0.93 [0.77-1.13]-2 trials). Conclusions: In men with metastatic CRPC a significant improvement of OS and SSE was obtained with bone targeted α-emitter radio isotopes, but not with β-emitter. However, some between trial heterogeneity of effects on OS need further investigations.
Progression free survival in patients with castrate resistant metastatic prostate cancer: Does sequence matter?
Authors: Kase Adam McLain , Cook Cheryl , Tan Winston 
Published: February 2018

356 Background: Approval of multiple therapeutic agents for castrate resistant prostate cancer (CPRPC) has improved survival and also quality of life. However, how to optimize sequencing is still an ongoing challenge for most clinicians. Methods: A retrospective chart review of patients treated with FDA approved regimens for castrate resistant prostate cancer from 2002 to 2017 at Mayo Clinical Florida was completed. Data on progression free survival of the various treatment sequences including abiraterone, docetaxel, and enzalutamide were reviewed. Results: One hundred patients were included in the study. Those on clinical trial were excluded. All patients were on LHRH agonist /antagonist and were continued while on the subsequent treatments. The first line therapy progression free survival (PFS) was 245 days with abiraterone acetate (AA), 307 days with enzalutamide (E) and docetaxel 285 days, respectively. The second line therapy PFS was 201 days with AA and 166 days with E. When AA was given after E PFS was 97 days and when E was given after AA the PFS was 68 days. E given after docetaxel resulted in a PFS of 390 days for one patient. Conclusions: In this chart review, enzalutamide had the longest PFS when used as the first line therapy and the PFS was improved when used as a second line after docetaxel. This retrospective review suggests therapy sequencing may be optimized to increase progressive free survival in patients with metastatic castrate resistant prostate cancer.
Inherited germline mutations in men with prostate cancer.
Authors: Reid Robert , DiGiovanni Marcie , Bernhisel Ryan , Brown Krystal , Saam Jennifer , Lancaster Johnathon 
Published: February 2018

357 Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: Men with PC who underwent testing with a multi-gene hereditary cancer panel (Myriad Genetic Laboratories) from September 2013–September 2017 were included. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 1004 men with a personal history of PC were identified: 606 (60.4%) with only PC and 398 (39.6%) with PC and ≥1 additional malignancy. The most common additional malignancies were breast (136) and colorectal cancer (134). The median age of diagnosis in men with only PC was 59, which is younger than tested men who had an additional malignancy (63) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 78.0% of men, including 68 (6.8%) who met based only on a personal/family history of PC and 330 (32.9%) who met in part due to a personal/family history of PC. PVs were identified in 12.9% of all men: 11.2% of men with PC only and 15.4% of men with PC and a second malignancy (Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and about a third had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]
Real world outcomes of upfront docetaxel for hormone naïve metastatic prostate cancer in an ethnically diverse inner-city population.
Authors: Pathak Surabhi , Thekkekara Romy Jose , Ahmed Ahmed T , Yadav Udit , Mullane Michael Russell , Batra Kumar Kunnal , Lad Thomas E. , Psutka Sarah P 
Published: February 2018

359 Background: Upfront docetaxel (UD) in castration-sensitive metastatic prostate cancer (CSPC) has improved failure-free and overall survival in the CHAARTED, GETUG-AFU 15 and STAMPEDE trials, resulting in a paradigm shift in practice patterns. However, the impact of docetaxel-based chemotherapy regimens in minorities and in real-world practice remains to be described. The objective of this study is to evaluate tolerability and response to UD in an inner-city ethnically diverse CSPC cohort. Methods: We retrospectively reviewed clinical data for CSPC patients at Cook County Hospital. Patients treated with UD and androgen deprivation (UD, n = 49, 2013-17) were compared to those receiving androgen deprivation alone (ADT, n = 42, 2010-17) using descriptive statistics and Cox Proportional Hazards analysis. Results: Median age was 59 and 60 years in UD and ADT, respectively. African Americans, Hispanics and Caucasians formed 69%, 18%, and 10% in UD and 64%, 9.5% and 26% in ADT. Median PSA at diagnosis was: UD 536 [72-1110] ng/ml, ADT 229 [54-999] ng/ml (p = 0.3). Gleason score > 7 was present in 89.8% [UD] and 92.8% [ADT]. UD and ADT had similar frequency of bone (91% vs. 95%, p = 0.5), visceral (12.2% vs. 11.9%, p = 0.9) and retroperitoneal nodal metastases (55% vs. 45.2%, p = 0.3). UD was initiated a median of 8 weeks from diagnosis. 94% in UD received > 3 cycles of chemotherapy. CTCAE grade > 3 events included anemia (6%); neutropenia (6%); infection (4%); diarrhea (4%); peripheral neuropathy (6%), and fatigue (2%). Median PSA nadir was 3.2 [0.5-40.1] vs. 3.45 [0.1-36.4] ng/ml and time to nadir was 20 [13-27] vs. 41 [19-69] weeks in UD vs. ADT. Biochemical progression was observed in 34.7% [UD] vs. 40.5% [ADT]. Median time to castration-resistance was UD: 39 [31-67] vs. ADT: 65 [34-76] weeks [HR: 0.9; 95% CI 0.4-1.8; p = 0.7]. There were 12 deaths [UD: 4; ADT: 8] during a median follow-up of 46 [23-86, UD] and 111 [68-157, ADT] weeks. Conclusions: In a diverse underserved population with CSPC, UD was well tolerated but was not associated with improvement in time to castration compared to ADT. These results warrant validation and underscore the importance of ensuring accrual of minorities in clinical trials.