bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pelvic lymph node metastases in prostate cancer: Preoperative detection with dynamic contrast-enhanced magnetic resonance imaging compared with postoperative pathologic result of pelvic lymph node dissection.
Authors: Hwang Jinho , Kim Jung Jun , Oh Jong Jin , Jeong Chang Wook , Lee Sang Eun , Byun Seok-Soo , Lee Sangchul 
Published: February 2018

171 Background: To evaluate the accuracy of preoperative magnetic resonance imaging (MRI) in patients who underwent pelvic lymph node dissection (PLND). Methods: The data of 1528 patients who underwent radical prostatectomy and PLND from 2003 to 2017 in our institution were retrospectively reviewed. We evaluated the various clinicopathologic variables including preoperative MRI and pathologic lymph node metastasis (LNmet). The prediction model for pathologic lymph node (LNmet) was assessed using logistic regression analyses and the areas under receiver operating characteristic curves (AUCs) were evaluated. Results: The mean age of our cohort was 66.4 ± 6.7 years. Positive preoperative MRI finding was observed in 9.4% (145/1528) of patients. 5.3% (81/1528) of patients accompanied confirmed final pathologic LNmet. Sensitivity and specificity of preoperative MRI were 30.8% and 91.7%, respectively. Multivariate analysis showed that preoperative MRI findings, clinical stage, and biopsy Gleason score were independent predictors for pathologic LNmet. Preoperative PSA, which was significantly related to pathologic LNmet in univariate analysis, failed to achieve independent predictor status in multivariate analysis. A better prediction model with greater accuracy was achieved by applying multivariate ROC analysis that included MRI findings, clinical stage, and biopsy Gleason score (AUC: 0.799 vs 0.613, p<0.01). The corresponding newer prediction model showed better sensitivity(77.78%) and specificity(70.74%) within threshold value range when it was compared with the predictor model using conventional Partin triad. Conclusions: Preoperative MRI findings for pathologic LNmet showed limited prediction power, yet the predicting power was significantly increased when additional factors such as clinical stage, and biopsy Gleason score were included in the analysis. [Table: see text]
Testosterone (T) suppression by weight and age groups in four pivotal trials of in-situ forming polymer-delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).
Authors: Tagawa Scott T. , McLane John A. , Atkinson Stuart , Boldt-Houle Debbie , Sartor A. Oliver 
Published: February 2018

172 Background: In-situ forming polymer-delivered, subcutaneous leuprolide acetate (SC-LA) has previously been shown to suppress serum T levels to ≤20ng/dL in advanced PCa patients. Currently, luteinizing hormone releasing hormone agonists are dosed independently of body weight (BW) or age. Reaching nadir T<20ng/dL within the first year of androgen deprivation therapy (ADT) is associated with improved clinical outcomes such as time to progression and disease specific survival (Klotz 2015). As maintaining castrate T levels during ADT is important, it is of interest to understand if factors such as BW or age should be considered when selecting a therapy. This study aims to determine if patient BW and age correlate with the pharmacodynamic profile of all SC-LA formulations. Methods: In 4 open-label, prospective single-arm, fixed dose, pivotal studies, 438 PCa patients were treated with either 7.5, 22.5, 30, or 45mg SC-LA lasting 1, 3, 4, or 6 months. Blood was sampled at screening, baseline, 2, 4, 8 hours post dosing, day 1, 2, 3, 7, and every other week until end of study and assayed for total T by radioimmunoassay. Results: Mean BW of 86 kg (range 49-146) and age of 73 years (range 40-86) was similar across the 4 studies. >90% of patients in all age groups (including 100% of those <60 years) and ≥92% of patients in all BW groups (including 97% of those ≥90 kg) achieved T≤50ng/dL by week 4. When pooled, all age and BW groups achieved median T≤20ng/dL by week 4 and maintained until the end of the study (Table). Conclusions: The results demonstrate that all SC-LA dose formulations consistently achieve and maintain T≤20ng/dL across all BW and age subgroups, including those with the highest BW (>90 kg) and youngest age (<70 years). BW and age do not appear to have an impact on consistent drug delivery and T suppression by SC-LA. Consistent achievement of T ≤20ng/dL may have implications for improved clinical outcomes and progression free survival in PCa patients. [Table: see text]
Germline variant in HSD3B1 (1245 A>C) and response to abiraterone acetate plus prednisone (AA) in men with new onset metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew W , Gill David Michael , Nussensveig Roberto , Poole Austin , Farnham James M. , Cannon-Albright Lisa A , Agarwal Neeraj 
Published: February 2018

173 Background: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, multiple reports validated the role of HSD3B1 (1245 A>C) variant in predicting response to androgen deprivation therapy (ADT) in castration sensitive prostate cancer. The objective of this study was to correlate HSD3B1 variantwith response AA in first-line therapy for men with mCRPC. Methods: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed as described by Hearn at al (Lancet Oncology, 2016). Primary endpoint was progression-free survival in first-line AA in men with mCRPC. We performed pre-specified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on PFS on AA (Table). Results: 76 men with mCRPC treated with first-line AA were included. In multivariate analysis, HSD3B1 (1245 A>C) did not predict response to first-line AA (Table). Conclusions: This hypothesis-generating data shows that inherited variant alleles in HSD3B1 do not predict response to first-line AA in mCRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling or our small sample size. [Table: see text]
Pharmacokinetic (PK) subgroup results from the phase 2 pharmacodynamic and bioequivalence study of abiraterone acetate fine particle formulation (AAFP) in patients with metastatic castration-resistant prostate cancer (mCRPC): The STAAR study.
Authors: Dunshee Curtis , Stein Cy Aaron , Nemeth Paul R. , Bosch Bill , Chapas-Reed Jillian , Dreicer Robert 
Published: February 2018

176 Background: AAFP, a novel formulation, showed therapeutic equivalence to originator abiraterone acetate (OAA) in the Phase 2 STAAR study (Stein et al. Urologic Oncol). A patient-subgroup analysis compared steady-state PK parameters between AAFP and OAA. Methods: This multicenter, open-label, active-controlled study enrolled men with progressive mCRPC treated 1:1 with 500 mg AAFP tablets QD + 4 mg methylprednisolone BID, or 1000 mg OAA tablets QD + 5 mg prednisone BID for 9 days. Study drug was taken 2 hours post morning meal. On day 9, plasma abiraterone blood samples were collected at predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hr time points. Results: PK samples were evaluable for 13 of 14 patients (n=5, AAFP; n=8, OAA). Mean age was 67.4 and 73.3 years, respectively. Twelve patients completed the 12-week study without clinical disease progression. One OAA patient died from MI in week 4. PK parameters (AUC, Cmax, Cmin), were numerically lower but not statistically significantly different for those treated with AAFP vs OAA (Table). Conclusions: Clinical benefit in this subgroup of patients was consistent with the overall study results. High PK variability was observed in both groups. PK parameters were not statistically different between AAFP and OAA. 24-hour PK Parameters at Steady State Clinical trial information: NCT02737332. [Table: see text]
Association of androgen receptor (AR) copy number gain with ARV7 expression and response to chemotherapy.
Authors: Iddawela Mahesh Y. , Pezaro Carmel Jo , Sluka Pavel , Kraska Jenna , Pereira Michelle , Joshi Sachin Subhashrao , Jamil Shafaet , Khattak Muhammad Adnan , Ng Siobhan , Davis Ian D. , Ziman Mel , Risbridger Gail , Gray Elin 
Published: February 2018

180 Background: Emerging data suggests that ARV7 mRNA (ARV7+) expression and AR copy number gain/amplification (AR+) are associated with resistance to androgen deprivation therapy. Most studies thus far have evaluated either AR copy number or ARV7 mRNA, but not both markers. It is likely that both markers are indicators of genomic changes that are seen in the prostate cancer cells in response to tumour evolution or treatment. Here we developed a digital droplet PCR (ddPCR) based assay to evaluate plasma ARV7 mRNA expression in the same samples used for AR copy number analysis in castrate resistant prostate cancer (CRPC). This assay was use to evaluate the role of AR+ and ARV7+ in CRPC using samples collected from multiple centers and correlated with outcome. Methods: We collected plasma samples from patients with CRPC treated with chemotherapy (C) or next generation androgen targeted agents (NAR) to evaluate circulating tumour DNA (ctDNA) for AR and plasma mRNA for ARV7. Some patients had sequential samples and we correlated PSA response (reduction PSA≥50 confirmed 3wks later (RR)) with AR and ARV7 status and clinical features. Results: A total of 52 samples were included from 26 patients, with matched samples from some patients at different time points. Of the CRPC patients, AR+ was seen in 70% (18/26), AR- in 30% (8/26), ARV7+ in 67% (12/18) and ARV7- in 33% (6/18). 75% (9/12) patients with AR+ also had ARV7+. In matched samples: 3/7 had change in AR status, 2/7 had change in ARV7 status, including 1 patient where both changed; and interestingly there was a group with no AR or ARV7 detected. Number of patients expressing both markers AR+/ARV7+ in 50% (9/18), AR+/ARV7- in 17% (3/18), AR-/ARV7+ 17% (3/18) and AR-/ARV7- in 11% (2/18). RR to C or NAR was 63% (12/19) for AR+ and 75% (9/12) for ARV7+ patients. In AR+ patients, response to NAR was 58% (12/16) but response to chemotherapy was 100% (5/5). Conclusions: AR gain/amplification in CRPC was associated with ARV7+ expression and leads to lower response to NAR compared to C. This approach can be used to undertake integrated DNA and mRNA analysis, has wide-scale utility and may be used for analysis of a larger number of circulating biomarkers.
Multicenter extension and switch study evaluating the safety of long-term treatment with abiraterone acetate fine particle formulation (AAFP) in patients with metastatic castration-resistant prostate cancer (mCRPC): The STAAR-E study.
Authors: Levin Richard , Given Robert , Nemeth Paul R. , Bosch Bill , Chapas-Reed Jillian , Oh William K. 
Published: February 2018

181 Background: The STAAR-study results showed novel AAFP 500 mg is therapeutically equivalent to originator abiraterone acetate (OAA) 1000 mg in men with mCRPC (Stein et al. Urologic Oncol). This STAAR-extension study evaluates the safety of ≤ 1 year of additional AAFP treatment in men with mCRPC. Methods: Patients were enrolled in the extension if they had: 1) mCRPC; 2) successfully completed 84 days of treatment with either AAFP + methylprednisolone (MP) or OAA + prednisone (PDN) in the STAAR-study; and 3) received their last dose of STAAR-study treatment < 45 days of starting this extension study. All patients continued or switched to AAFP 500 mg QD + 4 mg MP BID. Serum testosterone and PSA levels are measured at 6 and 12 months. Safety evaluations include adverse event (AE) incidence, clinical laboratory test results, and vital signs. Results: 20 patients were enrolled in the ongoing study (11 were switched to AAFP from OAA and 9 continued on AAFP). Median age is 76.5 years, and median AAFP treatment duration (STAAR + STAAR-E) is 178 days as of 8/16/17. Ten patients have been treated with AAFP > 9 months; 3 of these for > 1 year. Three patients discontinued due to progressive disease (n=1), fatigue (n=1), and a fall (non-AAFP related) resulting in death (n=1). No adverse events related to liver enzyme or bilirubin increases have been reported (Table). Conclusions: In this extension study in men with mCRPC, the safety profile of AAFP, regardless of prior treatment with OAA or AAFP, is consistent with that of OAA reported in the literature. Based on these results, longer-term treatment with AAFP + MP has acceptable safety, and patients on OAA + PDN treatment can switch to AAFP + MP successfully. Clinical trial information: NCT02962284. [Table: see text]
Tumor suppressor aberrations and outcomes in localized and metastatic hormone sensitive prostate cancer (PrCa).
Authors: Hamid Anis , Gray Kathryn P. , Shaw Grace , MacConaill Laura E , Evan Carolyn , Bernard Brandon David , Choudhury Atish Dipankar , Sweeney Christopher 
Published: February 2018

184 Background: Aberrations of tumor suppressors (TS) TP53, PTEN and RB1 are recurrent genomic events in PrCa and associated with adverse clinical outcomes. Preclinical data suggest that cooperative functional loss of these genes drives development of even more aggressive disease phenotypes. Methods: We identified a retrospective cohort of men with PrCa who underwent DFCI Oncopanel targeted sequencing (NGS) on prostate gland (n = 230) or metastatic tissue (n = 7) for TP53, PTEN and RB1. Biomarker(BM)-positive was defined as copy number loss or likely deleterious mutation of ≥1 TS. For pts presenting with localized disease, Kaplan-Meier method estimated time from biopsy preceding local therapy to PSA relapse/metastasis/death (EFS), castration resistance (CRPC) and death (OS). Cox model assessed association of BM status and outcomes, adjusted for age, clinical stage and Gleason score in multivariate analyses (MVA). For M1 disease, time from ADT start to CRPC and death was estimated. We explored the association of cumulative BM-positive gene hits (0 vs 1 vs 2/3) with EFS (local disease) and OS (M1 disease). Results: Of pts presenting with localized disease (n = 205), 39% were BM-positive and 73 (36%) relapsed after median follow-up of 3.1 years. BM positivity was associated with significantly shorter EFS (driven by PSA relapse) (median 2.6 years, HR 1.95, 95% CI 1.22-3.13) and time to CRPC (HR 3.36, 95% CI 1.01-11.16). MVA confirmed the association with EFS (HR 1.84, p = 0.029). More gene hits lead to incremental risk of relapse (1 gene: HR 1.8, 95% CI 1.09-2.99; 2/3 genes: HR 2.68, 95% CI 1.27-5.63; both vs 0 hits) and this remained significant in MVA (1 gene: HR 1.75, p = 0.05; 2/3 genes: HR 2.74, p = 0.04). 43 patients had relapsed or de novo M1 disease. BM positivity (enriched at 63% of M1) was associated with poorer OS (10 deaths [of 27 BM-pos] vs 0 deaths [of 16 BM-neg] at median follow-up 3.3 years, HR not eval). A trend to incremental worse survival with cumulative gene hits was again observed. Conclusions: Deleterious TP53, PTEN and RB1 variants are associated with a short time to PSA relapse in localized disease, occur at a higher frequency in M1 disease and confer poorer OS. Worse outcomes are seen with cumulative gene hits.
Early versus delayed initiation of salvage androgen deprivation therapy and the risk of prostate cancer-specific mortality.
Authors: Mahal Brandon Arvin Virgil , Chen Ming-Hui , Renshaw Andrew A. , Kantoff Philip W. , D'Amico Anthony Victor 
Published: February 2018

189 Background: We sought to ascertain whether there is an association between prostate cancer (PC)-specific mortality (PCSM) and salvage androgen deprivation therapy (ADT) timing amongst men with short versus long prostate-specific antigen doubling times (PSA-DT)s. Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC who were randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. Fifty-four men who received salvage ADT for PSA failure after a median follow up of 18.72 years following randomization defined the study cohort. Fine-Gray competing risks regression analyzed whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (IQR 3.05 - 9.56) following salvage ADT 49 of the 54 men (91%) died, 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate was associated with a decreasing risk of PCSM (adjusted hazard ratio [AHR] 0.33, 95% CI 0.13, 0.82; P=0.02). Amongst men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA>12ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (AHR 8.84, 95% CI 1.99-39.27; P=0.004); whereas for men with a short (<6 months) PSA-DT (AHR 1.16, 95% CI 0.38-3.54; P=0.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA recurrence in men with a PSA-DT of 6 months or more may reduce the risk of PCSM, arguing against the unproven assumption that patients with a short PSA-DT are those most likely to benefit from early initiation of salvage ADT. Clinical trial information: NCT00116220.
What is the role of microRNA-301A expression as a diagnostic and predictive marker of biochemical recurrence for prostate cancer?
Authors: Dervishi Adnan , Rai Samarpit , Nguyen Kristy Doan , FitzGibbon Thomas Michael , Knoll Paul , Shaheen Saad , Damodaran Chendil , Ankem Murali 
Published: February 2018

19 Background: Prostate specific antigen (PSA) screening for prostate cancer (PCa) remains controversial, due to its association with an increase in overdiagnosis of clinically insignificant PCa, and overtreatment. Hence, the need for more specific biomarkers to detect PCa and determine its prognosis. MicroRNA expression has previously been demonstrated as a biomarker to detect several malignancies. Studies suggest that microRNA-301a (miR-301a) inhibits the pro-apoptotic function of RUNX3, a transcription factor, and consequently activates ROCK1-mediated survival signaling in PCa. This study establishes the role of miR-301a as a reliable biomarker that can distinguish between patients with benign prostate hyperplasia (BPH) and PCa, and predict biochemical recurrence (BCR) after definitive treatment of PCa. Methods: Serum samples and tissue from prostate biopsies were collected from patients with an elevated PSA prospectively. The expression of miR- 301a was measured via reverse transcriptase-polymerase chain reaction. Additionally, miR-301a expression was retrospectively evaluated in prostatic tissue of 50 patients with PCa, including benign tissue, and correlated with clinico-pathological characteristics to predict BCR. Immunohistochemistry was performed to confirm the molecular target of miR-301a in cancerous tissue. Results: miR-301a demonstrated a significantly higher expression (p = 0.013) in both PCa tissue (Gleason 6 & 7 PCa) and serum samples (p = 0.011) when compared to BPH. Expression of miR-301a in Gleason 6 & 7 prostatectomy specimens positively correlated with patients who developed BCR when compared to patients who did not. When compared to the current nomogram for the prediction of PCa (i.e., PSA, age, race, Gleason score, and family history), incorporation of miR-301a was associated with a superior prediction of BCR at three years post-prostatectomy. Conclusions: miR-301a expression is a valuable tool for diagnosing PCa in patients with an elevated PSA. Combining miR-301a with PSA is associated with better risk stratification of PCa patients, and may help facilitate clinical decision making.
Influence of aggressive-variant prostate cancer (AVPC) features on outcome of metastatic hormone-sensitive prostate cancer (mHSPC) treated by chemohormonal therapy (CHT).
Authors: Koczka Kim , Vanhie James , Ibrahim Andrea , Bukhari Nedal , Reaume M. Neil , Sehdev Sandeep R. , Potvin Kylea R. , Sax Lori , Ernst D. Scott , Vickers Michael M. , Canil Christina M. , Winquist Eric , Ong Michael 
Published: February 2018

193 Background: Outcomes of patients (pts) undergoing CHT for mHSPC are heterogeneous, with some rapidly developing castration-resistance (CRPC). While AVPC ("anaplastic") features are described in CRPC, less is known in the mHSPC setting. In this multi-institutional cohort, we explored pre-treatment factors associated with poor outcome. Methods: De-novo mHSPC pts treated with CHT from June 2014 to July 2017 at The Ottawa Hospital Cancer Centre (TOHCC) and London Regional Cancer Centre (LRCC) were retrospectively identified. AVPC features (defined below) were collected and cumulatively scored (0, 1, or 2+), along with baseline, treatment and outcome data. Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with CRPC and survival. Results: 92 pts (58 TOHCC, 34 LRCC) met inclusion for study; 83 (90%) had "high-volume" disease (≥4 bone lesions; or ≥1 visceral metastasis), 69/73 (95%) prostate biopsies scored Gleason 8-10, and 55 (60%) had AVPC features: >5 cm nodal/pelvic mass (28), visceral metastases (21), lytic bone metastases (16), elevated LDH (12), low PSA (4), or neuroendocrine differentiation (2). Pre-docetaxel PSA fall of <50, 50-75, 75-90, and ≥90% baseline occurred in 12, 13, 19, and 56% respectively. Docetaxel was initiated a median of 66 days after androgen-deprivation, with 82% completing 5 or 6 cycles. 9 pts (10%) progressed during docetaxel, and 31 pts (34%) developed CRPC < 12 months. Median time to CRPC was 18.4, 14.0, and 11.0 months for 0, 1, and 2+ AVPC features (log rank p=0.009). CRPC was also associated with pre-docetaxel PSA fall <75% (p<0.001) and high alkaline phosphatase (p=0.016). At 18 months median follow-up, 16/55 (29%) with AVPC features have died versus 1/37 (3%) without (log rank p=0.001). In multivariable analysis, AVPC features and pre-docetaxel PSA fall were independently (p<0.05) associated with survival. Conclusions: In our study, mHSPC pts with AVPC features and suboptimal (<75%) pre-docetaxel PSA decline had poor prognosis. These features should be validated in larger cohorts to potentially identify mHSPC pts suitable for further study in clinical trials.