bluuebunny/crossref_metadata_2025_split huggingface dataset:
HSD3B1 and resistance to androgen deprivation therapy in prostate cancer.
Authors: Hearn Jason W.D. , AbuAli Ghada , Magi-Galluzzi Cristina , Reddy Chandana A. , Chang Kai-Hsiung , Klein Eric A. , Sharifi Nima 
Published: February 2017

156 Background: The somatic mutation HSD3B1(1245A>C) has been mechanistically linked to castration-resistant prostate cancer by encoding a mutant enzyme that augments intratumoral dihydrotestosterone synthesis. Given the HSD3B1(1245C) allele is also frequently found in the germline, we hypothesized men inheriting this variant allele would exhibit resistance to androgen deprivation therapy (ADT), as manifested by worse clinical outcomes. Methods: We used a prospectively maintained prostate cancer registry to identify men treated with ADT for biochemical failure in the post-prostatectomy setting who were without evidence of metastatic disease at the time of ADT initiation. We analyzed progression-free survival, distant metastasis-free survival, and overall survival according to HSD3B1 genotype using Kaplan-Meier methods. Cox proportional hazards regression was performed to evaluate potential gene-dosage effects, with homozygous wild-type men serving as the reference group. Demographic and treatment characteristics were compared across genotypes to assess for possible confounders using Fisher’s exact test and Kruskal-Wallis analysis of variance. Results: Of 118 men genotyped, 37% were homozygous wild-type, 53% were heterozygous, and 10% were homozygous variant. Demographic and treatment characteristics did not differ across groups. Median progression-free survival diminished as a function of the number of variant alleles inherited (6.6 years in homozygous wild-type men, 4.1 years in heterozygotes, and 2.5 years in homozygous variant men; P=0.01). Median distant metastasis-free survival likewise decreased according to the number of variant alleles inherited (9.1 years in homozygous wild-type men, 6.8 years in heterozygotes, and 3.6 years in homozygous variant men; P=0.01). Finally, overall survival also diminished with the number of variant alleles inherited (5-year and 10-year overall survival: 82% and 55% in homozygous wild-type men, 74% and 35% in heterozygotes, and 58% and 0% in homozygous variant men; P=0.006). Conclusions: Inheritance of the variant HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis may predict resistance to ADT for prostate cancer. These findings require validation.
Can mpMRI predict biochemical recurrence after radical prostatectomy? Implications for preoperative staging and surgical planning.
Authors: Ho Richard , George Arvin Koruthu , Frye Thomas P , Abboud Steven , Chelluri Raju , Fascelli Michele , Shakir Nabeel Ahmad , Walton-Diaz Annerleim , Sankineni Sandeep , Merino Maria J , Turkbey Baris , Choyke Peter L. , Pinto Peter A. 
Published: February 2017

161 Background: Multiparametric magnetic resonance imaging (mpMRI) used in conjunction with MR/TRUS fusion-guided biopsy has improved detection and localization of clinically significant prostate cancer. We aim to evaluate the utility of preoperative MRI characteristics to predict biochemical recurrence (BCR) following radical prostatectomy. Methods: Patients who underwent robotic assisted radical prostatectomy (RARP) between 2007-2014 at the National Institutes of Health were reviewed. We identified patients with BCR defined following the guidelines of the AUA Localized Prostate Cancer Update Panel report (serum PSA ≥0.2 ng/ml with a subsequent confirmatory value). Bivariate analysis and logistic regression were used to determine the association of mpMRI and preoperative patient characteristics with BCR. Results: Of 365 patients who had RARP, 21 met criteria for BCR with a median follow up of 19 months (IQR: 10-34). Mean preoperative PSA (ng/mL) [p<0.001], high MRI suspicion level [p=0.016], presence of extracapsular extension (ECE) on MRI [p=0.003], and total prostate volume by MRI (cc) [p<0.001] were associated with BCR. Increasing MRI suspicion corresponded to increases in rates of BCR within suspicion levels (2.22% of low, 3.88% of moderate, and 10.64% of high). The rates of BCR were significantly greater in men with ECE on final pathology [p<0.001]. Gleason grade trended toward significance [p=0.058]. Controlling for potentially confounding preoperative variables on multivariate analysis, MRI suspicion score, ECE on MRI, and total prostate volume by MRI remained significantly associated with predicting BCR. Conclusions: MRI suspicion score, ECE on mpMRI, and total prostate volume were associated with BCR in patients undergoing RARP. Preoperative mpMRI characteristics aid in risk stratification, patient counseling, and modification of surgical technique in those with high risk imaging features for BCR. The integration of mpMRI characteristics into a comprehensive model of BCR may provide robust tools for preoperative staging and surgical planning.
Validation of the Decipher prostate cancer classifier in intermediate to high-risk men treated with radical prostatectomy but without additional therapy upon PSA rise.
Authors: Ross Ashley , Yousefi Kasra , Trock Bruce J. , Choeurng Voleak , Lam Lucia L.C. , Fedor Helen L. , Ghadessi Mercedeh , Buerki Christine , Glavaris Stephanie , Sundi Debasish , Tosoian Jeffrey , Han Misop , Humphreys Elizabeth B. , Partin Alan W. , Netto George J. , Davicioni Elai , Schaeffer Edward M. 
Published: February 2017

173 Background: Radical prostatectomy (RP) is a primary treatment option for men with intermediate and high risk prostate cancer. Though many will be effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic findings and clinical disease recurrence. The Decipher test has been previously shown to predict metastatic progression in cohorts that included adjuvant and salvage therapy after RP. Here we evaluate Decipher in a natural history cohort of at risk men who received no additional treatment until the time of metastatic progression. Methods: Men with NCCN intermediate or high risk localized prostate cancer treated with RP at the Johns Hopkins Medical Institute (1992-2010) with at least 5 years of post-operative follow up were identified. Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis detection were included (n=765). A case-cohort design was used to randomly sample the cohort. The highest Gleason grade cancer tissue was used for RNA extraction and Decipher genomic classifier (GC) scores were calculated with a locked 22-biomarker signature and algorithm. Results: GC results were obtained for 260 patients, 28% had positive margins, 77% had EPE, 28% had SVI, 20% had lymph node invasion and 36% had Gleason ≥8 disease. Median follow up was 9 (IQR 6-12) years and at 15 years post RP the cumulative incidence of BCR, metastasis and prostate cancer specific death was 38%, 21% and 9%. Median GC score was 0.34 (IQR: 0.22-0.52) and was significantly higher among men experiencing metastatic progression during follow up (0.47 vs 0.28 respectively p<0.001). In UVA and MVA (adjusting for clinical covariates), GC had an HR of 1.48 (95% CI: 1.30-1.69, p<0.001) and 1.37 (95% CI: 1.21-1.55, p<0.001) per 10% increase, respectively. Conclusions: The majority of the men in this study had excellent long-term outcomes with surgery alone. Elevated Decipher scores correlated with metastatic events, independent of clinical risk factors. Use of Decipher may allow for selection of candidates for immediate vs. delayed adjuvant or salvage therapy following prostatectomy.
Androgen receptor (AR) based biomarker association with response to abiraterone acetate/prednisone (AA/P) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Wang Liguo , Sicotte Hugues , Qin Rui , Carlson Rachel , Eckel-Passow Jeanette , Tan Winston , Wu Kevin , Dehm Scott , Eiken Patrick W , Jimenez Rafael E. , Cernigliaro Joseph , Quevedo Fernando , Costello Brian Addis , Pitot Henry Clement , Moynihan Timothy J. , Ho Thai Huu , Dronca Roxana Stefania , Bryce Alan Haruo , Wang Liewei 
Published: February 2017

174 Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]
Cytoreductive radical prostatectomy in patients with prostate cancer and low-volume skeletal metastases: Results of a feasibility and case-control study.
Authors: Heidenreich Axel , Porres Daniel , Kuru T , Pfister David J. K. P. 
Published: February 2017

176 Background: Androgen deprivation (ADT) represents the standard treatment for PCA with osseous metastases. We explored the role of cytoreductive radical prostatectomy in PCA with low volume skeletal metastases in terms of a feasibility study. Methods: 32 patients with biopsy proven PCA, minimal osseous metastases (≤ 3 hot spots on bone scan), absence of visceral or extensive lymph node metastases and PSA decrease to < 1.0 ng/ml after neoadjuvant ADT were included in the feasibility study. 38 men with metastatic PCA who were treated by ADT without local therapy served as control group (group B). Surgery-related complications, biochemical progression-free, symptomatic-free, cancer-specific and overall survival were analyzed using descriptive statistical analysis. Results: Mean age was 61 (42-69) and 64 (47-83) years in group A and B, respectively, with similar patient characteristics in terms of initial PSA, biopsy Gleason score, clinical stage, extent of metastatic disease. The mean follow-up was 40.6 (3-71) and 44 (24-96) months in group A and B, respectively. Pathohistology revealed vital PCA with metastatic potential in all 32 patients despite neoadjuvant ADT. 12% of pts in group A developed Clavien grade III complications. According to the ICSmaleSF questionnaire 30/32 (93.7%) pts were continent. Patients in group A experienced significantly better bPFS (36.8 versus 23.1 months, p=0.042), clinical PFS (38.6 versus 26.5 months, p=0.032) and cancer specific survival rate (95.6% versus 84.2%, p=0.043) whereas the overall survival was similar. 0% and 29% of men in group A and B, respectively, underwent palliative surgical procedures for locally progressing PCA. Conclusions: CRP is feasible with good functional and oncological results in well selected men with metastatic PCA who respond well to neoadjuvant ADT. These men have a long life expectancy and CRP reduces the risk of locally recurrent PCA and local complications. CRP might be a treatment option in the multimodality management of PCA with minimal osseous metastases.
Urokinase plasminogen activator receptor (uPAR) as a novel biomarker in prostate cancer.
Authors: Lippert Solvej , Berg Kasper Drimer , Iversen Peter , Høyer-Hansen Gunilla , Christensen Ib Jarle , Brasso Klaus , Røder M. Andreas 
Published: February 2017

183 Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated plasma samples with two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs). Results: Plasma uPAR(I-III) + uPAR(II-III) and uPAR(I) were significantly higher in hormone naïve patients and CRPC patients compared to patients with localized disease (see table). Quantification of intact uPAR(I-III) revealed no significant differences between the three groups. Conclusions: Our findings suggest that uPAR(I-III) + uPAR(II-III) and uPAR(I) are associated with higher tumor stage as well as advanced PCa disease. These associations suggest that uPAR domains in plasma harbour prognostic value for PCa patients. Further studies are warranted to validate the use of uPAR forms as biomarkers for PCa. [Table: see text]
Epigenetic field effects: Potential applications for detection of occult high-grade prostate cancer.
Authors: Gaston Sandra Marlene , Grizzle William E. , Van Neste Leander , Bigley Joseph , Yen James , Adams George W , Kearney Gary P 
Published: February 2017

20 Background: Needle biopsy (Bx) pathology is central to the diagnosis and management of prostate cancer (PCa), but Bx sampling error can result in an underestimate of Gleason grade (GS). Epigenetic DNA hypermethylation markers associated with PCa are commonly observed in histologically benign tissue adjacent to a cancer focus. Such field effects are the basis for a diagnostic test in which the absence of GSTP1, APC and RASSF1 hypermethylation in benign Bxs is associated with a low risk of “missed” PCa. Relatively low methylation thresholds are used for the current epigenetic test (ConfirmMDx) that is designed to be sensitive to any occult cancer, regardless of GS. We are evaluating new prototype epigenetic tests that are designed to be sensitive to the GS of an occult PCa. Methods: DNA was extracted from prostate bx tissue prints and used for quantitative methylation-specific PCR for GSTP1, APC and RASSF1. Results were computed as levels of marker methylation relative to a common reference gene. Each of 12 cores was tested from a series of 102 Bx patients: 20 diagnosed with no cancer (Group 1), 46 with GS 6 PCa (Group 2) and 36 with GS 7 PCa (Group 3). Results: For all 3 markers, we observed a positive correlation between the highest level of hypermethylation in the benign cores and in the same-patient cancer cores. This correlation was strongest for APC (P <0.0001). For GSTP1 and APC, hypermethylation intensity in the benign cores was also positively correlated with the overall GS. Interestingly, for each marker, the GS 6 cores from Group 3 (overall diagnosis GS 7) showed significantly higher levels of hypermethylation than the GS 6 cores from Group 2 (overall GS 6). The strongest correlation between the level of GS 6 core hypermethylation and overall GS was observed for GSTP1(P=0.0002). Conclusions: For GSTP1, APC and RASSF1, the intensity of field effect hypermethylation in benign Bx cores was positively correlated with the level of hypermethylation present in the cancer cores from the same patient. In GS 6 cancer cores, the intensity of hypermethylation is higher in subjects who also have cores of GS 7 than in subjects with GS 6 cores only. Both findings support the feasibility of an epigenetic test that is sensitive to the GS of an occult PCa.
Stage at presentation and survival outcomes of patients with Gleason 8 to 10 prostate cancer and low PSA.
Authors: Falchook Aaron David , Martin Neil E. , Chen Ronald C. 
Published: February 2017

21 Background: Low prostate specific antigen (PSA) levels among men with Gleason 8-10 prostate cancer may be a result of cellular de-differentiation rather than low disease burden. We hypothesized that men with Gleason 8-10 prostate cancer and low PSA have increased risk for advanced disease and worse survival outcomes. Methods: Men diagnosed from 2004-2006 with Gleason 8-10 prostate adenocarcinoma in the Surveillance Epidemiology & End-Results (SEER) database were included. Patients were stratified by PSA at diagnosis: 0.1-3.9 ng/mL, 4.0-9.9 ng/mL, 10.0-19.9 ng/mL, and ≥ 20.0 ng/mL. Outcomes examined by PSA group included: clinical TNM stage, pathologic stage (for patients who received prostatectomy), and overall survival (for patients with N0 and M0 disease). Results: 18,491 patients were included. Men with PSA <4 were more likely than PSA 4-9.9 to present with clinical T3-4 disease (26 vs. 22%, p<.001), nodal (6 vs. 4%, p<.001) and distant (6 vs. 3%, p<.001) metastasis (Table). For patients who underwent radical prostatectomy, PSA <4 was more likely than PSA 4-9.9 to have pathologic nodal metastasis (10 vs. 7%, p<.001). With a median follow-up of 6 years, 6 year OS was 89.8% (PSA<4) vs. 92.3% (PSA 4-9.9) for prostatectomy patients (Logrank p=.02), and 73.6% vs. 79.3% for radiotherapy (p= 0.01). Conclusions: Patients with Gleason 8-10 cancer and PSA<4 have a more aggressive presentation and worse survival than those with PSA 4-9.9; these low PSA cancers behave more like those with PSA >10. Further study is needed to evaluate any biologic basis for inferior outcomes among men with high Gleason score and low PSA. [Table: see text]
Oligometastatic prostate cancer: An evaluation of stereotactic body radiotherapy (SBRT) as an alternative to palliative androgen deprivation therapy.
Authors: Henderson Daniel Robert , Tree Alison , Taylor Helen , Khoo Vincent , Van As Nicholas John 
Published: February 2017

229 Background: Oligometastatic prostate cancer (OPC) can be defined as 1-3 sites of metastasis, typically occurring some years after radical treatment for primary disease. Standard treatment is long-term palliative androgen deprivation therapy (ADT). Although effective, this treatment can have a significant impact on quality of life. We hypothesized that ablative treatment with SBRT may delay disease progression, and therefore the need for palliative ADT. Methods: A single-institution case series 2011-present. Eligible patients had metachronous OPC diagnosed by F-choline PET/CT and were ADT-naïve in the palliative setting. Stereotactic body radiotherapy was given to a dose of 30 Gy in 3 fractions using a robotic radiosurgery system (Cyberknife). ADT-free survival was calculated as the time from completion of treatment for oligometastatic disease to initiation of ADT with palliative intent. Follow up with clinical review and PSA was undertaken at four weeks, then three monthly, with F-choline PET/CT restaging as indicated. Palliative ADT was initiated for metastatic disease not amenable to further SBRT. Results: Twenty one patients received SBRT for ADT-naïve OPC. Median time from primary treatment to oligometastatic relapse was 59.7 months. Median PSA doubling time was 4.1 months. Six patients received a short course (3-6 months) of ADT with SBRT. Sites treated: bone (8) and lymph node (20). At a median follow up of 16.7 months, 81% (17) remained ADT-free. Median ADT-free survival was 28 months (95% CI: 10 - 43 months). All but one patient had a PSA response, with a median reduction of 84%. There were no local failures. Incidence of grade 1 and 2 CTCAE toxicity was 29% (6) and 5% (1), respectively. No toxicity of grade 3 or above was observed. Conclusions: SBRT for OPC is well tolerated. A clinically significant delay in initiation of palliative ADT was observed in patients with ADT-naïve oligometastatic disease. In view of this potential to improve patients’ quality of life, randomised trials against a standard of care are justified.
The presence of intraductal carcinoma of the prostate in needle biopsy as a prognostic parameter for prostate cancer patients with distant metastasis.
Authors: Kato Masashi , Tsuzuki Toyonori , Kimura Kyosuke , Sassa Naoto , Yoshino Yasushi , Fukatsu Akitoshi , Kimura Tohru , Ishida Ryo , Gotoh Momokazu 
Published: February 2017

237 Background: The presence of intraductal carcinoma of the prostate (IDC-P) is an adverse prognostic factor for prostate-specific antigen (PSA) failure, progression-free survival, and cancer-specific survival (CSS) in localized prostate cancer patients. However, there is no data indicating whether the presence of IDC-P can influence outcome in prostate cancer patients with distant metastasis at presentation. We aimed to evaluate whether IDC-P in needle biopsies is also an adverse prognostic parameter for CSS in prostate cancer patients with distant metastasis. Methods: We retrospectively evaluated 159 prostate cancer patients with distant metastasis who presented at the hospitals that the authors are affiliated with between 2002 and 2012 and reviewed the slides prepared from prostate needle biopsy specimens. Data on the patient age, performance status, clinical T stage, serum PSA, C-reactive protein, alkaline phosphatase (ALP), hemoglobin (Hb), albumin, serum calcium, biopsy Gleason score (> 8 or not), the presence of Gleason pattern 5, the percent of the core involved with cancer, and the maximum percent of a core involved with cancer were analyzed. Patient characteristics were analyzed using the Fisher's exact test. Multivariate Cox proportional hazard regression models were developed to predict CSS. Results: Patient median age was 73 years (range 47–90 years). The median serum PSA was 290 ng/mL (range 4.18–10,992 ng/mL). The median follow-up period was 36 months (range 3–120 months). IDC-P component was detected in 103 (64.8%) patients. There were 82 patients who died of the disease and 6 patients who died of other causes. Using univariate analysis, IDC-P (p = 0.0001), the presence of Gleason pattern 5 (p = 0.005), the percent of the core involved with cancer (p = 0.002), Hb (p = 0.001), and high ALP (p = 0.002) were all shown to be significantly associated with CSS. In the multivariate analysis, only IDC-P (p = 0.016; hazard ratio, 2.187) was significantly associated with CSS. Conclusions: The presence of IDC-P in needle biopsy is a prognostic parameter for CSS in patients with distant metastasis at presentation.