bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of fPSA, [-2]proPSA and the Prostate Health Index for the early prediction of outcome in patients with metastatic castration resistant prostate cancer on therapy with abirateroneacetate.
Authors: Schlack Katrin , Krabbe Laura-Maria , Eminaga Okyaz , Semjonow Axel , Boegemann Martin 
Published: February 2017

241 Background: Abiraterone acetate (AA) prolongs overall survival (OS) in pre- and post-chemotherapy setting in patients with metastatic castration resistant prostate cancer (mCRPC). Biomarkers to predict response to therapy are limited. Prostate-specific antigen (PSA) and lactate dehydrogenase (LDH) are commonly used as response-indicators but are often misleading during early therapy. Assays for circulating tumor cells, which can be surrogate for poor survival, are not routinely available at most places. In this retrospective study we evaluated the role of the PSA-derivatives free PSA (fPSA), [-2]proPSA (p2PSA) and the prostate health index (PHI) in addition to PSA as indicators of response during early AA-therapy. Methods: Twenty-five men with mCRPC receiving AA between March 2012 and July 2015 at the University Hospital of Muenster were included and analyzed. The PSA response rate (RR) was monitored according to PCWG2-criteria. Dynamic PSA-, fPSA-, p2PSA- and PHI-changes at 8-12 weeks under therapy were analyzed as predictors of progression free survival (PFS) and OS using Kaplan-Meier-analysis (KMA) and uni- and multivariate cox-regression analysis (UVA and MVA). Results: Twenty men were chemotherapy naïve, 5 pretreated with docetaxel. The PSA RR was 44%. In patients with < or ≥ 12 months of PFS the relative change of median PSA and fPSA at 8-12 weeks compared to baseline differed significantly (p = 0.022 and 0.030). For men with ≤ or > 15 months of OS there was a trend for a difference in relative change of median fPSA (p = 0.058). In KMA declining fPSA at 8-12 weeks was associated with a median OS of 32 months compared to 21 months in men with rising fPSA. In UVA rising PSA and fPSA were non-significant predictors of poor OS (Hazard ratio (HR) = 1.3 and 2.5 (p = 0.717 and 0.159)). In MVA PSA and fPSA were independent predictors of poor survival (HR 6.7 and 12.8 (p = 0.050 and 0.012)). Conclusions: fPSA is easily available and cheap. When added to PSA information, change of fPSA at 8-12 weeks of AA therapy may be a promising therapy control marker to help physicians to make decisions weather to stop or to continue AA therapy in men with mCRPC.
The association of D4, 3-keto-abi (D4A) and response to abiraterone in castration-resistant prostate cancer (CRPC).
Authors: Emamekhoo Hamid , Alyamani Mohammad , Li Zhenfei , Elson Paul , Grivas Petros , Rini Brian I. , Petro Marianne , Stybor Sylvia , Salatino Anthony , Garcia Jorge A. , Sharifi Nima 
Published: February 2017

245 Background: Abiraterone (Abi), a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is a standard treatment for men with metastatic CRPC. Abi is converted to D4A by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A inhibits CYP17A1, 3βHSD, and steroid-5α-reductase (SRD5A) and has direct androgen receptor antagonist activity, which together make it a more potent agent than Abi in xenograft models. It is not known if conversion to D4A in patients (pts) correlates with response or resistance to Abi. Methods: Blood was collected (single time point on Abi) from CRPC pts who started Abi during 2011-2015. Abi and D4A were extracted from serum and analyzed by mass spectrometry. The purpose of this ongoing study is to assess the potential correlation between D4A and response to treatment. Results: 32 patients with CRPC had blood collected. 4 pts (12.5%) received ketoconazole and 6 (18.8%) chemotherapy prior to Abi. Median pre-Abi prostate-specific antigen (PSA) was 14.3 ng/ml (0.6-646.1). Median time from initiation of androgen deprivation therapy (ADT) to CRPC was 34.3 months (m) (6-129.6) and median time from CRPC to Abi initiation was 4.8 m (0-14.9). PSA decline > 50% (PSA50) on Abi was seen in 68% (12/31) and 73% (19/26) of pts at 3 and 6 m, respectively. Treatment with Abi was ongoing in 23/32 pts (74%), and discontinued in 8 pts (26%) due to disease progression (no follow up data on 1 pt) with median duration of Abi treatment 14.6 m (2.9-44.4 m) at last follow up. As the absolute concentration of detected levels of Abi and D4A varied significantly among pts, the percentage of the total extracted metabolites was used to assess correlation with response. Abi and D4A comprised 94.3% (73.8-97.4%) and 5.7% (2.6-26.2%), respectively, of total levels. Conclusions: Abi absorption and metabolism significantly vary among pts. Most of these pts had prolonged duration of response to Abi (74% ongoing treatment and median treatment duration 13.3 m in 8 pts that came off treatment). Longer follow up, accrual of pts with shorter duration of response, and sampling at multiple time points on Abi and at progression is ongoing to further evaluate the impact of D4A on treatment response.
Impact of symptomatic skeletal events on healthcare resource utilization, health-related quality of life and pain among patients with castration-resistant prostate cancer and bone metastases.
Authors: McKay Rana R. , Haider Batool , Duh Mei Sheng , Valdarrama Adriana , Nakabayashi Mari , Fiorillo Matthew , Ristovska Ljubica , Wen Lonnie Kent , Kantoff Philip W. 
Published: February 2017

247 Background: Prostate cancer patients frequently develop bone metastases (BM), leading to symptomatic skeletal events (SSE). Given the real-world data on SSE are lacking, this study evaluated the impact of SSE on healthcare resource utilization (HRU), health-related quality of life (HRQoL), and pain in patients with castration-resistant prostate cancer (CRPC) and BM. Methods: Electronic medical records (EMR) and clinical database of a tertiary oncology center were used to identify CRPC patients with BM. SSE, including pathologic fracture, radiation to bone, spinal cord compression, and bone surgery, were extracted from medical charts. HRU, such as emergency room (ER), outpatient and inpatient visits, was determined from the EMR. A subset of patients who were alive and had clinic visits from 11/2014-7/2015 completed HRQoL (FACT-P) and pain (BPI-SF) surveys. The impact of SSE on HRU was evaluated using multivariate negative binomial regression. Survey scores were compared using Rank-Sum test and standardized effect sizes (ES); an ES ≥ 0.33 corresponds to meaningful differences between SSE and non-SSE groups. Lower FACT-P and BPI-SF scores suggest reduced HRQoL and less pain, respectively. Results: Of 832 patients, 207 developed ≥ 1 SSE (mean 1.5±0.8); 84% had radiation to bone. The median age at CRPC with BM diagnosis was 68 yrs. and follow-up after diagnosis was 2.1 yrs. Adjusting for baseline factors, the SSE group had significantly higher ER (incidence rate ratio (IRR) = 1.48; 95% confidence interval (CI) = 1.12, 1.95), outpatient (IRR = 1.17; 95% CI = 1.05, 1.30), and inpatient (IRR = 1.74; 95% CI = 1.34, 2.26) visits. Of 107 patients eligible for surveys, 103 responded. The mean FACT-P functional well-being score was 17.5 in SSE and 19.8 in non-SSE group (p = 0.16) with an ES of 0.36. Mean BPI-SF pain severity score was 2.5 in SSE and 1.6 in non-SSE group (p = 0.05) with an ES of 0.47, and that for worst pain was 3.6 and 2.3, respectively, (p = 0.03) with an ES of 0.5. Conclusions: The economic and quality of life burden of SSE amongst CRPC patients with BM is high, underscoring the need for preventive treatments for SSE in this population.
CK13 expression in prostate tumors of patients with bone metastases at diagnosis.
Authors: Liu Sandy 
Published: February 2017

257 CK13 Expression in Prostate Tumors of Patients with Bone Metastases at Diagnosis Sandy T. Liu, Radu Cadaneanu, Kevin Lai, Bao Zhang, Haibo Liu, Lihong Huo, Colette Galet, William Aronson, Matthew Rettig, Michael Lewis, Isla P. Garraway; University of California Los Angeles, Los Angeles, CA Background: Biomarkers of lethal prostate cancer (PCa) are needed for appropriate clinical management. Benign stem/progenitor (S/P) cells reside in the basal layer of prostatic ducts/acini and function as cells of origin for PCa. Aggressive tumor cells may co-opt properties of S/P cells, such as mechanisms of resistance to castration. Distinct prostate epithelial populations, including stem-like tubule-initiating cells (TIC), basal cells (BC), and luminal cells (LC) can be isolated from benign prostate tissue. In this study, gene expression analysis was performed on benign prostate to identify TIC markers that may persist in cancer. Methods: Microarray analysis was performed on Epcam+CD44-CD49fHi TIC, Epcam+CD44+CD49fHi BC, and Epcam+CD44-CD49fLoLC using Affymetrix Array. Data was analyzed using Partek Genomics and validated with RT-PCR. Immunohistochemistry (IHC) was performed on 1) prostate tissue microarray (TMA) from 332 prostatectomies 2) pretreatment tissue from stage M1 patients and 3) post-treatment prostate tissue. Results: Affymetrix identified increased cytokeratin 13 (CK13) expression in TIC relative to BC and LC. Rare CK13+ epithelia are seen in ducts/acini of benign prostate tissue. TMA IHC revealed CK13+ cancer cores in 9% of cases, and significantly correlated with recurrence (p = 0.031), progression to castration-resistance (p = 0.05), and metastases (p = 0.009). Biopsy tissue from hormone-naive patients with diffuse bone metastases displayed CK13+ tumors in primary and metastatic foci. Epithelial cells populating residual prostate glands following radiation and ADT also displayed CK13 expression. Conclusions: CK13+ tumors reflect a “stem-like” state, enabling survival in low-androgen conditions and interactions that support invasion/metastases. Further characterization of CK13+ PCa variants could lead to clinical trials investigating agents that may prevent/treat dissemination and progression.
Early abiraterone treatment after surgical castration in in vivo castration resistant prostate cancer (CRPC) tumors in nude mice.
Authors: Thelen Paul , Reupke Verena , Bremmer Felix , Jarry Hubertus 
Published: February 2017

263 Background: ADT is the initial therapy for advanced prostate cancer, and androgen biosynthesis inhibitors (abiraterone-acetate, AA) reveal clinical survival benefit for CRPC. On CRPC progression, therapy sequencing towards androgen receptor (AR) antagonism is applied and AA withdrawal / re-challenge strategies (+AA-AA+AA) succeeded in several case reports. Here we established a VCaP-tumor mouse model for a +AA-AA+AA-sequence and external testosterone-boosts (+AA[-AA+T]+AA). Methods: 20 tumor bearing mice (from 106 VCaP in Matrigel) received surgical ADT and then +AA-AA+AA, (AA intraperitoneal 70mg/kg, daily [Janssen-Cilag]), or +AA[-AA+T]+AA (+0.6 µl/kg Nebido [250mg testosterone-undecaonate/ml, Jenapharm]). Tumor growth was monitored with calipers. When tumors grew > 200 mm3, animals were castrated and treatment-sequences began when CRPC growth became evident (n = 15) or early one week after castration (n = 5). Expression analyses were performed with Experion, CSX-96 and ChemiDoc, chemicals, software (BioRad). Steroids were quantified by Dept. Clin. Chemistry. Results: 20 tumor-bearing mice received ADT. To interfere with ADT failure for 15 mice +AA-AA+AA (n = 7) or +AA[-AA+T]+AA (n = 8) commenced when tumors doubled within two weeks. Animals benefited a reduction of up to 210 mm3 receiving +AA-AA+AA, whereas a T-Boost in +AA[-AA+T]+AA revealed a loss of solid tumor mass as mean 42% (+/-21%) liquid effusion. No complete remission was observed, tumors > 1 cm3 were considered dead-of-disease (DOD). Another group (n = 5) was AA-treated one week after castration. There +AA-AA+AA and +AA[-AA+T]+AA resulted for one animal in DOD, however tumors of up to 990 mm3 underwent complete remissions (n = 4) and tumor-free untreated survival. AA-withdrawal is associated with progesterone decrease and DHEA increase. AR (+ AR-Vs) decreases to 95% expression immediately after -AA and to 39% (no AR-Vs) upon +T. Conclusions: Therapy sequences with AA-withdrawal/rechallenge may lead to tumor regression and complete tumor-free survival. Concomitant with tumor regression upon AA-withdrawal, AR overexpression is reduced, which may be boosted with testosterone supplementation.
Surrogacy analysis of prostate-specific antigen (PSA) decline for improved overall survival (OS) with enzalutamide (ENZ) in AFFIRM.
Authors: Armstrong Andrew J. , Saad Fred , Shore Neal D. , Fizazi Karim , Phung De , Dmuchowski Carl Frank , Hirmand Mohammad , Forer David , Scher Howard I. , De Bono Johann S. 
Published: February 2017

266 Background: ENZ significantly increased OS for men with metastatic castration-resistant prostate cancer (mCRPC) vs. placebo and significantly decreased PSA levels. However, the prognostic significance and role of PSA falls as a surrogate for OS are not established. Methods: Men in the AFFIRM trial were grouped by maximal unconfirmed PSA decline during the 1st 90 days of treatment in a post-hoc analysis. Each PSA decline criterion was assessed for surrogacy for OS by the proportion of treatment effect (PTE)-explained and Prentice criteria. We also assessed the association of PSA decline with OS, progression-free survival (PFS), and pain response. Results: ENZ improved OS (hazard ratio 0.63, p < 0.001) and was associated with higher rates of PSA declines when compared to placebo (odds ratio > 19.0, p < 0.001). Greater declines in PSA were associated with longer OS, PSA PFS, radiographic PFS, and higher pain response when compared with no PSA decline or PSA increase (table). All decline measures from baseline were highly prognostic for OS and several ( > 0%, ≥ 30%, ≥ 50% declines) explained a proportion of the treatment effect (PTE 1.07–1.29, 95% CI lower bounds > 0.63), in which treatment was no longer significant after adjustment for the decline measures (p > 0.20). Full surrogacy was not demonstrated. Conclusions: In AFFIRM, > 0, ≥30%, and ≥50% PSA declines within 90 days of treatment fulfilled Prentice surrogacy criteria 1–3. Prentice 4, equivalency of survival adjusting for PSA decline outcomes, could not be demonstrated. PSA declines are associated with longer PFS and improved pain response. External prospective validation is needed. Clinical trial information: NCT00974311. [Table: see text]
Body mass index at mCRPC, weight change, and survival in advanced prostate cancer.
Authors: Chow Lydia D. , Ledet Elisa M. , Steinberger Allie E. , Guccione Jeffrey R. , Sartor A. Oliver 
Published: February 2017

270 Background: Body mass index (BMI) at diagnosis is associated with increased risk of fatal prostate cancer, but the link between BMI at mCRPC and cancer progression is less clear. Cachexia, often defined as involuntary weight loss > 5% over 6 months, is common in advanced cancers. The goal of this study was to examine the link between BMI at mCRPC and weight change as it relates to cancer progression, the outcomes of survival, and treatment use in a single-institution setting. Methods: 58 mCRPC patients treated at Tulane Hospital were identified, 41 of whom had an overweight BMI at mCRPC (BMI > 25) and 17 with normal BMI at mCRPC (BMI < 25). All patients had a confirmed prostate cancer death. Survival, treatment history, and percent weight change were compared according to BMI status. Rate of percent weight change was defined as the change in weight per day, from date of mCRPC diagnosis to the last treatment stop date or death date (“mCRPC days”). Linear regression, overall survival (OS), and nonparametric analyses were performed. Results: There was no significant difference between the normal and overweight BMI groups in overall survival, from date of diagnosis to death (median = 1835 days vs. 2710 days respectively). Additionally, the difference in survival from mCRPC to death was not statistically significant (median = 630 days vs. 799 days, p = 0.115). Use of Taxotere was not significantly different (47% vs. 68% respectively); however, overweight patients (n = 28) more likely received Abiraterone than normal BMI patients (n = 2) (p-value = 0.0001). The rate of percent weight change was significantly different for normal and overweight patients (mean = –0.050%/day vs. –0.019%/day, p = 0.003). Linear regression analysis showed that mCRPC days had a significant effect on percent weight change (p = 0.0109), and this effect was not significantly different between BMI groups (p = 0.6991). Conclusions: Survival after mCRPC was not significantly different between BMI groups. We observed a significant effect of mCRPC days on percent weight change, with a similar effect for both BMI groups. This outcome is expected, as more time would allow for greater weight changes to occur. Larger studies are needed to fully evaluate these observations.
Comparison of survival of African-American (AA) patients (pts) in docetaxel (D)-based combination therapies in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima , Madan Ravi Amrit , Ning Yang-Min , Theoret Marc Robert , Arlen Philip M. , Parnes Howard L. , Ojemuyiwa Michelle A. , Strauss Julius , Dawson Nancy Ann , McLeod David G. , Harold Nancy , Couvillon Anna , Cordes Lisa M , Chen Clara , Steinberg Seth M. , Sissung Tristan M. , Price Douglas K. , Gulley James L. , Figg William Douglas , Dahut William L. 
Published: February 2017

272 Background: AA pts experience greater prostate cancer (PC) incidence and mortality compared to Caucasian (C) pts but are underrepresented in clinical trials (CTs). Greater representation of AAs is required to explore differences in clinical benefit in advanced disease where recent data has reaffirmed the role of D. Methods: In a retrospective analysis, baseline characteristics, Gleason score (GS), ECOG PS, number of cycles (cys), maximum prostate-specific antigen (PSA) declines, radiographic responses, overall survival (OS) and progression-free survival (PFS) were captured in 2 recent D based CTs. Results: Of 136 pts, 28 (21%) self-identified as Black or AA. Median age of AA pts is 66 (50-78 yrs). Median GS is 8 (5-10). Median ECOG PS is 1 (0-2). 15 pts have bone and soft tissue disease; 13 pts have bone only disease. Median number of cys is 28.5 (1-63). Of 27 evaluable pts, 26 had PSA declines (-26 to -99%). Radiographic responses include 11 (39%) partial responses and 16 (57%) pts with stable disease. Median OS for AAs is 29.0 months (mos) (95% CI: 20.9-34.7 mos); median PFS is 21.5 mos (95% CI: 13.7-28.9 mos). Median OS for all non-AA pts is 24.8 mos (95% CI: 21.8-29.5 mos); median PFS is 16.1 mos (95% CI: 14.1-20.1 mos). The VEGF-634G > C SNP, associated with a more aggressive phenotype of PC, was evaluated in 54 pts. No evidence was found that genotype frequency varies between C and AA pts. Conclusions: In this analysis, AA pts did not have inferior OS (29 mos) or PFS (21.5 mos) outcomes compared to non-AA pts (24.8, 16.1 mos). Further analysis from larger studies is required to determine differential benefits of D for AA pts compared to non-AA pts. Clinical trial information: NCT00089609, NCT00942578.
Investigation of a frequently mutated transcriptional repressor in prostate cancer, in particular its role in modulating androgen signaling and its effects on TMPRSS2-ERG dependent tumor maintenance.
Authors: Bose Rohit , Abida Wassim , Iaquinta Phillip , Karthaus Wouter , Armenia Joshua , Wongvipat John , Doran Michael , Hieronymus Haley , Philip Watson , Liang Yupu , Schultz Nikolaus , Sawyers Charles L. 
Published: February 2017

274 Background: Recent genomic profiling of primary and metastatic prostate cancers revealed up to 27% of tumors contain putative loss-of-function point mutations or copy number deletions within the gene ERF, an ETS transcriptional repressor with a remarkably similar DNA-binding domain to the TMPRSS2-ERG gene product. Methods: Bioinformatic analysis of 450 patient tumors was obtained from the TCGA and SU2C datasets. Transcriptomic and cistromic analysis was achieved by RNA-seq and ChIP-seq on VCaP cells, as well as patient-derived organoid cultures of both normal and neoplastic prostates. Gene expression was inhibited by CRISPR or shRNA technology. Results: ERF copy number deletions are associated with Gleason 8+ primary disease (p = 0.0369), and ERF mRNA level inversely correlates with androgen-driven transcription (p < 0.0001) in the absence of androgen receptor amplification. Transient inhibition of ERG expression in TMPRSS2-ERG+ cancer models leads to a contraction of the androgen transcriptome. On the other hand, inhibition of ERF leads to an expansion of the androgen transcriptome, and moreover, supersedes the opposing effects of ERG. ERF and the TMPRSS2-ERG gene product have overlapping ETS cistromes that are associated with androgen-receptor binding sites; inhibition of one leads to occupancy at the vacated sites by the other. CRISPR-mediated inhibition of ERG in TMPRSS2-ERG+ models leads to a complete halt of growth, but concomitant loss of ERF partially restores cellular proliferation. Conclusions: ERF is a tumor suppressor with genomic loss-of-function mutations in up to 27% of prostate cancers, thereby expanding the concept of an ETS positive subtype. ERF occupies ETS sites of androgen-regulated genes and is an endogenous dampener of their transcription. Moreover, even in tumors lacking ERF mutations, upregulated ERG now occupies many of these same ETS sites, unmasking their transcriptional control by androgen. Thus, a key oncogenic activity of TMPRSS2-ERG is to antagonize endogenous ERF.
Clinical impact of 11C-Choline PET/CT in selection and outcome of salvage cryoablation in patients with recurrent prostate cancer after radiotherapy.
Authors: Vallinga Marleen Suzanne , Breeuwsma Anthonius , Rybalov Maxim , Pruim Jan , De Jong Igle J. 
Published: February 2017

276 Background: Salvage cryoablation is an effective but toxic treatment for local recurrent prostate cancer after primary radiotherapy. To assess the location of recurrent prostate cancer, an 11C-choline PET/CT can be used. We studied the clinical impact of 11C-choline PET/CT on the choice for and the results of salvage cryoablation. Methods: A total of 141 patients with a biochemical recurrence (BCR according to ASTRO-Phoenix criteria) after radiotherapy, and thus candidates for salvage cryoablation, were included. Patients were re-staged with an 11C-choline PET/CT, complementary prostate biopsies, when indicated a pelvic lymph node dissection and/or additional imaging. Change in choice of therapy was defined as major (no salvage cryoablation because of metastases or lack of local recurrence on PET/CT), minor (local salvage treatment was performed, but different technique of after additional diagnostics) or none (salvage cryoablation was performed). The impact of selection of patients for cryoablation with PET/CT on outcome was measured by time from cryoablation to BCR (according to Astro-Phoenix), first distant metastasis and start of hormonal therapy. Results: In 71 of 141 patients (51%) a change in therapy was implemented because of the result of 11C-choline PET/CT. A major impact was observed in 48 (34%) patients. In 83 patients, a salvage cryoablation was performed (59%). 18% of this group showed no PSA response. Of the remaining patients with PSA response, 37% developed a BCR after mean 25.7 months. 47% of patients are still in remission after a mean follow-up of 43 months. In 16 of 83 patients (19%) metastases were proven after mean 55.4 months (SD 26.3). 15 patients started with hormonal therapy, mean 29.5 months (SD 20.1) after cryoablation. Conclusions: 11C-choline PET/CT showed a significant impact on selection for salvage cryoablation. The choice for local salvage therapy was abandoned in 34% of patients. Of the men who underwent a salvage cryoablation, 47% stayed free of biochemical recurrence during mean 43 months follow-up.