bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between body composition and hormone sensitivity for androgen deprivation therapy in metastatic prostate cancer patients.
Authors: Kashiwagi Eiji , Shiota Masaki , Imada Kenjiro , Monji Keisuke , Takeuchi Ario , Inokuchi Junichi , Tatsugami Katsunori , Eto Masatoshi 
Published: May 2019

e16500 Background: Obesity has been reported to have an influence on prostate cancer incidence and its aggressive phenotype but this remains controversial. Body mass index (BMI) is useful marker of obesity but it does not represent body fat percentage precisely. The relationship between body composition and the efficacy of androgen deprivation therapy (ADT) has not well been studied. Here, we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. Methods: This study enrolled hormone-sensitive metastatic prostate cancer patients who were treated with primary ADT from April 2006 to August 2009 in Kyushu University Hospital, and who underwent a CT scan prior to primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm2), and BMI. Results: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival (PFS) and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio [HR]: 0.448; 95% CI = 0.206–0.922; P= 0.028). Conclusions: This study demonstrated that higher psoas muscle ratio predicts longer OS among non-localized prostate cancer patients treated with primary ADT. [Table: see text]
Radium 223 (Ra-223) experience in twenty-four castration resistant prostate cancer (CRPC) patients treated at West Virginia University (WVU) 2014-2018.
Authors: Ahmad Zeeshan , Arays Ruta , Veselicky Kenneth , Kolodney Joanna Amy , Hogan Thomas F. 
Published: May 2019

e16502 Background: Ra-223 was FDA approved for CRPC with symptomatic bone metastases without visceral metastatic disease. Methods: De-identified IRB exempted records were abstracted for demographic, clinical, and laboratory data from CRPC men treated with Ra-223 at WVU 2014-2018. Results: 24 men had in total 95 Ra-223 infusions; 20 men (83%) were referred from outside institutions. Average ages (yrs; ranges) were 63 (48-87) at initial PC diagnosis; 68 (49-89) at first WVU-visit; and 69 (54-89) at first Ra-223 infusion. At diagnosis, 4 men (17%) had prostatectomy; 12 (50%) were M1/stage 4; PSAs ranged from 7-9,600 ng/mL. In 24 men, there were 73 courses of different androgen deprivation therapies (ADT); all had one, 22 (92%) two, 17 (71%) three, & 10 (42%) four or more; 68 (93%) of the 73 ADT trials preceded Ra-223. In 24 men, 19 (79%) had docetaxel or cabazitaxel chemoRx; 10 of 19 (53%) had 2nd line and 2 of 19 (11%) had 3rd - 4th line; chemoRx preceded Ra-223 in 18 of the 19 men (95%). In 24 men, 19 (79%) received 33 courses of radiation; in 9 of 33 (27%) the prostate was targeted; another 24 (73%) were palliative; 18 of 19 men (95%) had radiation before Ra-223. In 24 men, 24 had a 1st Ra-223 infusion, 21 (88%) a 2nd, 16 (67%) a 3rd, 12 (50%) a 4th, 12 (50%) a 5th, and 10 (42%) a 6th infusion; 14 men (58%) did not complete 6 infusions, most stopping for clinical decline or death. In 24 men, median overall survival (OS) from first Ra-223 infusion to last visit or death was 4.9 months (0-33); OS from last Ra-223 infusion was 1.2 months (0-28); 13 men (54%) remain alive & 3 (13%) continue Ra-223. Conclusions: Our CRPC patients’ best OS of 4.9 months with Ra-223 does not match the 14.9 months first reported (NEJM 2013; 369:213-223). Fourteen of our 24 men (58%) did not complete 6 planned Ra-223 infusions because of clinical decline or death. This may represent a “real world referral bias” of heavily pre-treated patients as documented above. Selecting more appropriate patients for Ra-223 is currently under review (https://www.esmo.org/Oncology-News/EMA-PRAC-Recommends-Restricting-Use-of-Prostate-Cancer-Medicine-Radium-223-Dichloride)
A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa): Tolerability and geriatric asssessment (GA) results.
Authors: Zittel Jason , Fung Chunkit , Babu Dilip Sankar , Guancial Elizabeth A. , Sahasrabudhe Deepak M. , Bylow Kathryn A. , Burfeind John D. , Musto Kaylinn , Wang Bokai , Patil Amita , Messing Edward M. , Mohile Supriya Gupta , Kilari Deepak 
Published: May 2019

e16518 Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In this phase II study, we evaluated Enz and Dut/Fin in lieu of ADT for at-risk older patients with HNSPCa. Methods: Eligible patients were ≥65 years (y); at high risk of AEs from ADT by GA or treating physicians; metastatic (M1) or non-metastatic (M0) HNSPCa with a PSA doubling time ≤ 9 months and testosterone > 50ng/dl. They received Enz 160 mg/day and Dut 0.5 mg/day or Fin 5 mg/day until disease progression. GA was performed at baseline and week (wk) 61 and/or at the time of progression. GA included validated tests: Instrumental Activities of Daily Living (IADL), fall history, Short Physical Performance Battery (SPPB), Geriatric Depression Scale (GDS), and Montreal Cognitive Assessment (MOCA). The prevalence of impairment for each assessment was calculated; change in prevalence from baseline to wk 61 was analyzed using paired sample t-test. Results: 43 patients were enrolled in the study. Median age at enrollment was 78 y (range 66-94) and 93% were ECOG 0-1; 37% (n = 16) had M0 and 63% (n = 27) had M1 HNSPCa, with the majority (67%) having Gleason 6 or 7 disease. At baseline, 18.6% met the cutoff for impairment for IADLs, 53.7% for SPPB, 7.9% for GDS and 64.3% for MOCA; 9.8% had a recent fall. Median baseline PSA was 11.38 ng/ml (range: 2-145). At the time of analysis, 29 men (67.4%) remain on study treatment. 95.3%, 74.4% and 46.5% of patients reported at least one Grade 1, 2 or 3 AE respectively. No patient had a Grade 4 AE and one Grade 5 AE was reported but was an unrelated event. The most common Grade 3 AEs were hypertension (27.8%), GI (19.4%), and cardiac (8.3%); all Grade 3 GI AEs reported were deemed unrelated to the study drugs. Only impairment in ≥ 1 IADL showed a statistically significant increase in prevalence at wk 61 of treatment (40.6%) compared to baseline (18.6%, p = 0.036). Conclusions: For older men with HNSPCa, Enz with Dut/Fin demonstrated efficacy with reasonable toxicity profile, and no significant impact on the majority of GA domains. Clinical trial information: NCT02213107.
Does a food intervention makes abiraterone treatment affordable?
Authors: Van Erp Nielka P. , Benoist Guillemette Emma , Gerritsen Winald R. , Mehra Niven , Burger David , Hamberg Paul , van Oort Inge , Lubberman Floor 
Published: May 2019

e16523 Background: Abiraterone is registered for metastatic prostate cancer. It is used in a fixed oral dose of 1000mg OD in a fasted state in combination with 10mg prednisone daily. Although large differences in the effect of food on abiraterone exposure are reported (ranging from 1-10 fold increase in area under the concentration time curve (AUC)) it is generally accepted that abiraterone is much better absorbed in the presence of food. By administering abiraterone with food a reduced dose can be given while maintaining equivalent abiraterone exposure. Moreover aadministering abiraterone with food is more patient friendly and it could significantly reduce the treatment costs of abiraterone.The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast compared to the standard intake of 1000mg OD in fasted state. Methods: In this phase I cross-over multi-center study abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic prostate cancer who were treated with 1000 mg abiraterone in a fasted state, followed by 500 mg taken with a continental breakfast. After both periods of 14 days, abiraterone plasma exposure was measured. Bioequivalence was assumed when the GMR (fed/fasted) of the AUC0-24h and Cmax and their 90% confidence interval (CI) were within the range of 0.8 and 1.7. Results: 14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. GMR (fed/fasted) AUC0-24h was 0.88 (90% CI 0.73-1.07), GMR Cmax was 1.03 (CI 0.79-1.34) and the GMR of Ctrough was 0.81 (90% CI 0.60-1.10). Conclusions: Ingesting 500mg abiraterone with a continental breakfast was not considered bio-equivalence when compared to 1000mg taken fasted. The criteria for bio-equivalence could not be met due to the large variability in pharmacokinetics of abiraterone within and between patients. Due to this large variability in abiraterone exposure, we believe that dose optimization by food intake is not a feasible strategy for abiraterone. The intake of abiraterone with food could not be advised based on the results presented in our study. Clinical trial information: NCT02883166. [Table: see text]
The National Radium-223 Dichloride Audit group: Data from patients in UK oncology centers with metastatic castration-resistant prostate cancer treated with radium-223 dichloride.
Authors: Randhawa Manreet , Jones Robert J , Stratton Irene ,   National Radium-223 Dichloride Audit Group
Published: May 2019

e16524 Background: Clinicians in 17 UK oncology centres comprise the National Radium-223 Dichloride Audit (NRDA) group which is evaluating treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride (Xofigo). Methods: Patients commencing treatment from 1st September 2017 were included. Clinical and laboratory parameters were collected throughout treatment. Analyses used frequency tables and univariate analysis. Results: As of February 2019, data from 400 patients has been collected. We report the outcomes on the first 150 patients who are evaluable. At first treatment, median age was 72 years (25th to 75th centile: 67-78), 54% of patients had an ECOG performance status (PS) of 1, 32.6% of patients had a WHO pain score of 1, 60% of patients had an ALP level of < 220U/L and 26% of patients received docetaxel for mCRPC. The mean number of cycles completed was 5. Sixty patients (40%) did not complete 6 cycles and 42/60 (70%) discontinued due to disease progression. Changes in variables between treatment 1 and 6 are shown in Table. Adverse events reported were fatigue (76%), diarrhoea (38%), nausea/vomiting (35%), constipation (32%), anaemia (28%), thrombocytopaenia (12%) and neutropaenia (5%). There was no overall change in ECOG PS. In those who completed quality of life (QOL) questionnaires at treatment 1 and 6 (58%), there was no difference. Conclusions: The ongoing NRDA Group records data from mCRPC patients treated across the UK in routine care. To our knowledge, it is the first prospective analysis of such patients and the largest in assessing treatment patterns and outcomes including QOL data as well as standard laboratory parameters. Disclosures: The NRDA Group has been funded by a research grant from Bayer.[Table: see text]
Impact of hormone-therapy used in CRPC patients: Evaluation of abiraterone acetate/prednisone or enzalutamide on activity and cognitive functions in aged castrated mice.
Authors: Castel Hélène , Al Sagheer Tareq , Dubois Martine , Campart Cynthia , Desrues Laurence , Lange Marie , Gandolfo Pierrick , Joly Florence 
Published: May 2019

e16526 Background: Prostate cancer (PC) is a major public health problem and represents the most frequent cancer in elderly male patients. Although most patients initially respond to androgen deprivation therapy (ADT) through inhibition of gonadal testosterone biosynthesis, the majority of these patients will progress to metastatic castration-resistant PC (mCRPC). Novel oral agents targeting androgen signaling axis, abiraterone acetate (AA)+prednisone (P) and enzalutamide (ENZ) are available and used in mCRPC patients in addition to ADT, but their impact on cognition is not well understood. Recently, the AQUARiUS study (Thiery-Vuillemin et al., ESMO Open, 2018) showed that after treatment, median Quality of life score improved with AAP. Additionally, results from a phase 2 trial showed that a worsening of depression symptoms were more often detected in ENZ- than in AAP-treated patients (Khalaf et al., Eur Urol, 2018). Methods: Here we developed a preclinical animal model to clarify the potential impact of AAP or ENZ on emotional reactivity and cognitive functions including spontaneous activity, anxiety-like and depression-like behaviors or spatial memory and learning. Results: In aged castrated mice receiving per os vehicle or AAP or ENZ, we showed that, in contrast to AAP, exposure to ENZ reduced spontaneous activity and increased depressive-like behaviors. AAP-treated mice displayed diminished self-grooming suggesting lower arousal in a novel environment. None of the treatments provoked anxiety-like behavior, learning and memory deficits. However, the swimming strategies (Morris-water maze) in AAP and ENZ groups were slightly altered. Analysis of plasma from treated mice revealed a detectable level of corticosterone only in AAP group. Conclusions: These data establish the impact of ENZ on emotional reactivity and of both ENZ and AAP on subtle cognitive functions in castrated aged male subjects. It paves the road for future effective research that could lead to better management of quality of life in mCRPC.
Computer modelling in prostate anticancer therapy (COMPACT).
Authors: Prentice Mark , Man Kenneth , Jani Yogini , Payne Heather Ann , Wong Ian 
Published: May 2019

e16528 Background: Prostate cancer is the most common solid malignancy in men and despite improving radical therapies a proportion of patients will develop castrate resistant metastatic disease (mCRPC). Therapeutic options in mCRPC include abiraterone acetate and prednisolone (AA+P), enzalutamide (E) and docetaxel (D) with limited evidence to guide clinical choice between agents. COMPACT aims to collate data from multiple data sets within one hospital to assess clinical or biochemical factors that may guide therapeutic strategy. Methods: Data was collated on all patients recorded as receiving therapy with AA+P, E or D in the metastatic castrate resistant setting from the chemotherapy prescribing and dispensing systems and the pathology system at University College Hospital, London. Individual clinical notes were reviewed to determine the reason for stopping therapies. Data was collated in one dataset and analysed to present baseline demographic data. The log-rank test was used to analyse differences in the retention rate among AA+P, E and D. Results: 598 individual treatments were identified in 441 patients. 172 patients received AA+P, 119 E and 307 D with a mean age at treatment initiation of 74.1, 76.8 and 69.5 years respectively. Of the 144 patients receiving two or more treatment lines, 62% (n = 89) received D prior to either AA+P or E. E was first line therapy in 18% (n = 26) and AA+P in 20% (n = 29). 5 (3.5%) patients transferred directly from AA+P to E and 12 (8%) from E to AA+P. Kaplan Meir estimates for time to retention show no statistically significant differences when directly comparing AA+P, E and D on univariate analysis with chi squared test (AA+P vs E = 0.3609, p = 0.558 D vs E = 0.365, p = 0.5457, D vs AA+P = 0.0136 p = 0.9072). Conclusions: The COMPACT study has confirmed that it is feasible for single institutions to retrospectively review real world data from different sources, combining it into a workable database. Patient numbers were sufficient to statistically analyse the data for specific clinical factors that may correlate to a prolonged biochemical response to AA+P, E or D therapy. The failure to detect a statistically significant difference between therapies on univariate analysis may confirm that all three are acceptable treatments in mCRPC.
Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.
Authors: Butler Lisa , Irani Swati , Centenera Margaret , Ryan Natalie , Pegg Neil , Brooks Anthony Nigel 
Published: May 2019

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.
Family history in primary hormone therapy for prostate cancer from a community-based multi-institutional Japan-wide database.
Authors: Shiota Masaki , Onozawa Mizuki , Hinotsu Shiro , Eto Masatoshi , Naito Seiji , Akaza Hideyuki 
Published: May 2019

e16549 Background: Although a positive family history is known to increase the risk of morbidity of prostate cancer, little is known about the prognoses with hormone therapy of individuals with familial prostate cancer. Thus, in this study we aimed to determine the associations between hormone therapy and outcomes of a cohort of men with familial prostate cancer from a large community-based multi-institutional Japan-wide registry. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 15,873 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival, and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 247 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a significant favorable prognostic factor for progression-free survival among patients treated by castration, as was overall survival among patients with PSA level at diagnosis less than 100 ng/mL and those with low or intermediate J-CAPRA risk. Conclusions: Our findings indicate that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, with hormone therapy the prognoses of individuals with familial prostate cancer are comparable to those of individuals with sporadic prostate cancer.
Correlation between innate cytokine levels and progression in men with biochemically recurrent prostate cancer treated with intermittent hormonal therapy.
Authors: Hawley Jessica , Pan Samuel , Figg William Douglas , Lopez Bujanda Zoila , Strope Jonathan , Fojo Antonio Tito , Dallos Matthew , Aggen David Henry , Lim Emerson A. , Stein Mark N. , Hu Jianhua , Drake Charles G. 
Published: May 2019

e16554 Background: Suppressive cytokines have the potential to drive prostate cancer progression with consequent decreased survival. Assessing longitudinal cytokine changes may shed light on mechanisms of disease progression, resistance to therapy, and suggest new therapeutic targets. Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time of PSA progression (TTPP) were identified from a previously conducted phase III trial (NCT00020085). Serum samples were archived at baseline, three months after administration of ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay (MesoScale Discovery). Wilcoxon signed rank sum test was used to compare paired observations between time points. Kaplan-Meier analysis was used to calculate progression function (TTPP) dichotomized by above or below the median value of cytokines with Bonferroni adjustment. Pearson’s rank correlation coefficient was used to compare continuous variables. Results: Median TTPP was 399 days (range, 114 - 1641). Median PSA at baseline and progression were 8.5 ng/ml, (range, 1.0 - 76.6) and 5.3 ng/mL (range, 1.2 - 19.4), respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. TNF-α (P = 0.002), IL-23 (P = 0.002), and IP-10 (P = 0.001) significantly increased from baseline to post ADT. Patients with a detectable PSA after ADT had moderately elevated levels of IL-6 (P = 0.049) and IL-8 (P = 0.013) at PSA progression as compared to those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = 0.042). TNF-α was strongly correlated with IL-23 (r = 0.72, P < 0.001) and IL-8 (r = 0.59, P < 0.001) from baseline to after ADT and to PSA progression. NLR correlated strongly with IL-27 (r = 0.57, P < 0.001) and MIP-3α (r = 0.56, P < 0.001). Conclusions: Cytokines associated with the innate immune response were associated with an unfavorable clinical outcome in early prostate cancer. These data suggest cytokine blockade combined with ADT may warrant future investigation.