bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline differences in characteristics of a racially diverse group of men electing active surveillance.
Authors: Feibus Allison H. , Haney Nora M. , Liu James , Chiang Jason H , Ledet Elisa M. , Boxberger John , Levy Justin , Moparty Krishnarao , Lewis Brian E. , Thomas Raju , Sartor Oliver , Silberstein Jonathan L. 
Published: March 2017

103 Background: To date, large populations of men from European ancestry have been prospectively evaluated on Active Surveillance (AS), a strategy reserved for low risk prostate cancer (PCa). African Americans (AA) deemed to be candidates for AS have yet to be fully characterized. We sought to determine the similarities and differences of our AS cohort stratified by race. Methods: We identified 308 men from our multi-institutional, prospective AS database were analyzed. Inclusion criteria was PSA < 20ng/mL, Gleason score ≤ 7, and clinical stage ≤ T2a. Men who sought treatment for their PCa or refused subsequent imaging and biopsy were excluded. Univariate analysis was done to analyze racial differences in demographic, clinical and pathologic variables. Results: We identified 308 men, 131 (43%) AA and 177 nonAA (57%). The groups were not significantly different with respect to age; 65 years, BMI 28.4, family history of PCa (22%), prior negative biopsy (21%) and clinical staging (87% T1c). Median follow-up is 25 months (IQR 12-44). Significant differences between the AA and nonAA cohorts did exist at baseline with respect to overall health, suggesting AA having worse overall health. More AA had diabetes (29 vs 14%; p = .03), were smokers (55 vs 29%; p < .01), cardiovascular disease (21 vs 9%) and erectile dysfunction (43 vs 18%; p < .01). Social characteristics also differed within the groups, with AA less likely to be married (47 vs 51%; p = .01). Despite a lack of difference with respect to biopsy Gleason score, AA had higher PSA (5.7 vs 5.0 ng/mL; p = 0.02), lower testosterone levels (250 vs 334 ng/dL; p = 0.05), greater PSA density (0.15 vs 0.12; p < 0.01), and greater linear length of cancer per biopsy core (16 vs 13mm; p < 0.01) at time of diagnosis and initiation of AS. Conclusions: Within our AS cohort, AA have worse overall health and more aggressive PCa features despite meeting inclusion criteria and selecting AS. Further prospective study is needed to determine how these competing factors may impact long term outcomes.
Application of stable isotopic tracing in an ex-vivo system to reveal heterogeneous patterns of androgen metabolism in localized, hormone-naïve prostate cancer.
Authors: Dai Charles , Sharifi Nima , Chung Yoon-Mi , Klein Eric A. 
Published: March 2017

109 Background: The 5α-androstanedione (5α-dione) pathway is the demonstrated route through which adrenal precursor steroids bypass testosterone (T) to form dihydrotestosterone (DHT) in metastatic castration-resistant prostate cancer (mCRPC). However, accessible pathways of DHT synthesis are less clear in localized, hormone-naïve prostate cancer (HNPCa), where steroidogenic enzyme expression may differ and circulating T and adrenal steroids could act as competing substrates for 5α-reductase. We employed a dual substrate, ex-vivo system with selective stable isotopic labeling of DHT precursors to better understand alterations in androgen synthesis that occur in the transition of HNPCa to mCRPC. Methods: Under IRB approval and patient consent, tumor and adjacent benign prostate tissues were procured from radical prostatectomy specimens of men with HNPCa (n = 16). Tissues were grossly homogenized and incubated ex-vivo in serum-free media spiked with 1 µM of 13C3-AD +/- equimolar unlabeled T. Media was collected over 48 hours and subjected to liquid-liquid extraction to capture free and glucuronidated steroid metabolites for analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Both AD and T were readily 5α-reduced in treated prostate tissues. 13C labeling revealed DHT originating from metabolism of AD. Co-incubation with T did not dramatically alter the efficiency of AD metabolism. Minimal differences were found in metabolism between PZ and TZ tissue. No glucuronidated steroid was detected in media, in contrast to in prostate cancer cell lines and xenograft tumor tissue. Considerable heterogeneity was observed in measurements of reaction efficiency across different patients. Conclusions: AD is an active substrate for 5α-reductase comparable to T in HNPCa. Adrenal steroids may therefore contribute to DHT in HNPCa via the 5α-dione pathway. Metabolic heterogeneity may reflect currently unappreciated genotypic differences in patient tumors.
Characterization of circulating tumor cells in patients with localized high risk prostate cancer, post-prostatectomy.
Authors: Friedlander Terence W. , Anantharaman Archana , Welty Christopher , Zejnullahu Kreshnik , Hough Jeffrey , Edwards Matthew , Jendrisak Adam , Lee Jerry , Greene Stephanie , Ontiveros Priscilla , Graf Ryon , Rodriguez Angel , Suraneni Mahipal , Wang Yipeng , Landers Mark Andrew , Cooperberg Matthew R. , Carroll Peter , Dittamore Ryan Vance , Paris Pamela 
Published: March 2017

110 Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, many of these patients will recur despite definitive therapy. Better predictive biomarkers could allow for earlier detection of recurrence and change surveillance paradigms. The role of circulating tumor cells (CTCs) as biomarkers in this context is not well defined. Here, we evaluate the ability to detect CTCs from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples from 31 patients with high risk, localized PCa were obtained 2-4 months post RP and sent to Epic Sciences on an IRB approved protocol. Nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N-terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. Cytokeratin expressing (CK+) CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transitions (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were detected in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in this population using a novel platform. We observed a trend toward shorter PFS in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa.
Racial variation in the reliability of prostate cancer indicators in men undergoing subsequent prostate biopsy.
Authors: Libby Robert Scott , Nguyen Hoang MT , Kramer Jordan J. , Feibus Allison H. , Thomas Raju , Silberstein Jonathan L. 
Published: March 2017

115 Background: Many men with an initial negative prostate biopsy have a persistently elevated prostate specific antigen (PSA) prompting physicians to perform repeat biopsies. African American men (AA) are at particular risk as they have a greater prostate cancer (PCa) incidence and mortality, yet traditional PSA testing may be less reliable in this cohort. We sought to determine the predictors of PCa and PCa severity in a racially diverse population on subsequent biopsy following an initial benign biopsy. Methods: Upon receiving Institutional Review Board approval, a retrospective analysis was performed on men with repeat prostate biopsies at Tulane Medical Center and Southeast Louisiana Veterans Health Care Services in New Orleans, Louisiana from 2003-2015. Inclusion criteria included patients with a benign initial prostate biopsy and underwent subsequent repeat prostate biopsy within 5 years. Race, age, serum PSA, PSA density (PSAD), and prostate volume by transrectal ultrasound (TRUS) were evaluated to determine if they correlate with the presence and severity of PCa. Aggressive PCa was defined as Gleason score >6. Results: A total of 209 men were included; 127 (61%) were AA, and 82 (39%) were Caucasian American men (CA). The two groups were similar with respect to PSA, PSAD, and TRUS. More AA (25.2% vs. 17.1%) had a repeat biopsy showing any PCa. Of those with PCa, 28.1% of AA and 28.6% of CA had aggressive PCa. PSAD positively correlated with any PCa (p=.015). TRUS negatively correlated with any PCa (p=.008). PSA levels (p<.001) and PSAD (p<.001) positively correlated with aggressive PCa in CA but not in AA. Conclusions: The goal of prostate biopsy particularly for those with a prior negative biopsy is to detect aggressive PCa. PSA and PSAD positively correlated with finding any PCa in both AA and CA but not with aggressive PCa in AA. PSA and PSAD are less accurate predictors of aggressive PCa in AA, and novel biomarkers are needed. [Table: see text]
Predicting late fecal incontinence risk after RT for prostate cancer: External independent validation.
Authors: Cicchetti Alessandro , Avuzzi Barbara , Palorini Federica , Rancati Tiziana , Stucchi Claudio , Fellin Giovanni , Gabriele Pietro , Vavassori Vittorio , Degli Esposti Claudio , Cozzarini Cesare , Fiorino Claudio , Valdagni Riccardo 
Published: March 2017

116 Background: To validating a predictive model for late fecal incontinence (FI) on a recent population (pop) of prostate cancer patients (pts) treated with radical radiotherapy. NTCP model was derived from literature. Methods: Pop included 267 pts treated with IMRT in 2010-2014. Prescribed dose was between 68 and 80 Gy with conventional and hypo-fractionated (HF, from 2.2 to 2.8 Gy) treatment. Rectal toxicity was scored using the LENT/SOMA. Follow-up (FU) was considered up to 2 years. We chose to validate a model for prediction of chronic FI through multiple measures during FU. Mean FI was defined as the average score during the FU period after RT (Mean incontinence > 1). Literature based multivariate model included: mean rectal dose (Dmean), previous diseases of colon (COLO) and previous abdominal surgery (SURG). Dose distributions were corrected EQD in 2 Gy fractions. Results: 186 pts were available. Mean grade > 1 FI was scored in 18 patients (〜10%). Univariate logistic analysis confirmed the risk factors reported in literature. Similar Odds Ratios (OR) were found for Dmean (1.04vs1.05) and SURG (1.90vs1.50). COLO was not a risk factor for this pop. As consequence, NTCP models including Dmean and Dmean+SURG were evaluated through calibration plot. The models showed a clear trend (increasing observed toxicity rates with predicted risk), but the observed toxicity rates were underestimated (slope〜3, R2〜0.7). Including HF (OR = 2.20, 8.6% vs 17.6%) as a variable into the previous model the calibrations improved significantly (slope〜1, R2〜0.9). Conclusions: The study confirms formerly published results on effect of abdominal surgery and dose to large rectal volumes as potential risk factors for late FI. The overfitting in calibrations could be due to an effect of HF, not included in previous models developed on normofractionated treatments. This effect goes beyond the applied standard correction using LQ model for late effects and also beyond the time recovery correction (slope〜2, R^2〜0.8). Probably we should found a more suitable alpha/beta value for the longitudinal definition (toxicity starting in acute phase and persisting during follow-up) instead of using the assumption settled on incidence of late peak events.
The impact of pretreatment MRI on genitourinary and gastrointestinal toxicity after radiation therapy in patients with localized prostate cancer.
Authors: Kilinski Kyle , Naghavi Arash , Abuodeh Yazan Asad , Echevarria Michelle , Yamoah Kosj 
Published: March 2017

119 Background: MRI has several advantages relative to other imaging modalities in evaluating, diagnosing, and planning treatment for prostate cancer yet it is rarely ordered for localized disease. While the diagnostic abilities have been studied, little has been done to associate clinical outcomes with prostate cancer patients who received MRI. We evaluated the effect of pre-treatment MRI on genitourinary (GU) and gastrointestinal (GI) toxicity in prostate cancer patients who received definitive radiation treatment. Methods: We retrospectively analyzed prostate cancer patients who underwent definitive radiation treatment at our facility between January 01, 1999 and July 31, 2014. All patients who underwent MRI of the pelvis or prostate within 5 years prior to treatment were included in the MRI cohort. The American Urological Symptom Score (AUA) and Rectal Assessment Scale (RAS) were used to measure GU and GI toxicity, respectively. We compared the toxicity profile of patients in our MRI cohort to a comparable cohort of patients who did not receive pre-treatment MRI. Results: 1085 patients (211 with MRI) were analyzed. Median follow-up was 30 months. Mean increase from baseline in AUA scores at 6 months was 3.58 for the MRI cohort and 5.04 for the comparison cohort (p = 0.017). RAS scores were not significantly different between the MRI and comparison cohorts at 6 months (mean increase: 0.62 vs. 0.77, p = 0.662). AUA scores returned to baseline after 6 months in the MRI cohort and after 12 months in the comparison cohort. RAS scores returned to baseline after 12 months in the MRI cohort but never returned to baseline in the comparison cohort. Biochemical failure rates were not significantly different between the MRI cohort and comparison cohort (86.3% vs. 91.1%, p = 0.083). Conclusions: Pre-treatment MRI was associated with significantly less GU and GI toxicity. These results may be influenced by more advanced disease and higher use of hormonal therapy in the MRI cohort. Future prospective studies in a risk-matched cohort are required to validate these findings.
Results from a phase II trial (NTC01902680) of ultrafocal brachytherapy for low/intermediate risk prostate cancer.
Authors: Graff-Cailleaud Pierre , Malavaud Bernard , Portalez Daniel , Brun Thomas , Aziza Richard , Lusque Amellie , Khalifa Jonathan , Filleron Thomas , Bachaud Jean-Marc 
Published: March 2017

124 Background: Biology suggests that the most significant focus drives the natural history of prostate cancer. We assessed the feasibility of ultrafocal brachytherapy (BT) of the index tumor. Methods: In a 2-step Simon’s design (&=0.1, ß=0.1), 17 patients were needed to assess that 100% of clinical target volume (CTV) - gross tumor volume on T2-MRI plus 2mm margin - received ≥95% of the prescribed dose (primary objective: D100≥152Gy). Pre-inclusion:EAU guidelines for Surveillance [PSA <10ng/mL, cT1c-cT2a, Gleason sum on referring biopsies ≤6(3+3), ≤3 positive biopsies, ≤50% of cancer] and for BT [IPSS <10, no TURP, prostate <60mL, >10yr life expectancy]. Inclusion:when mpMRI detected a PIRADS≥3 focal lesion, confirmed as Gleason sum ≤7a (3+4) cancer on elastic fusion registration (EFR) biopsies (Koelis). Procedure:EFR was used to insert trans-rectally a US-visible marker (Bard SourceLink) within CTV before biplanar TRUS for BT. Dose distribution was optimized by inverse planning (Variseed v7.2) before ultrafocal implantation of I-125 seeds (Bard Pro-Link). 1ary objective:Doses delivered within the first 30d to CTV were assessed by Variseed rigid registration between pre-implant MRI and d30 CT-Scan. 2ary objectives: GI, GU CTCAE toxicity & QoL (IPSS, IIEF5, QLQc30) were prospectively accrued. Protocol biopsies of GTV and rest of the gland were obtained by EFR 1yr post-implantation. Results: 27 patients failed confirmatory biopsies (multifocal n=10; aggressive 11; no cancer 6). Of 17 included (10/2013-8/2016), only 3 did not meet the primary objective (D100: 76, 105, 132 Gy) and the trial was deemed successful. Mean CTV was 0.74±0.31mL that is 1.9±1.1% of the gland. Prescribed dose was delivered to 14.5±6.4% of the gland, in line with the ultrafocal nature of the treatment. To date 11 patients, including the previous 3, received 1yr biopsies. No in-field recurrences (GTV) were observed, 5 non-clinically significant cancers were found in the contralateral lobe. No grade>2 toxicity was observed. QoL evaluation is in process. Conclusions: As shown by optimal dosimetry in 14/17(82.4%), minimal toxicity in all, and no in-field recurrences (0/11), ultrafocal BT is a promising avenue in focal treatment. Clinical trial information: NCT01902680.
The long tail of significantly mutated genes in prostate cancer.
Authors: Armenia Joshua , Mullane Stephanie Anne , Gao JianJiong , Chakravarty Debyani , Kundra Ritika , Huang Franklin W. , Han G. Celine , Robinson Dan , Garraway Levi A. , Nelson Peter , Rubin Mark A. , Taplin Mary-Ellen , Abida Wassim , Sawyers Charles L. , Chinnaiyan Arul M. , Kantoff Philip W. , De Bono Johann S. , Schultz Nikolaus , Van Allen Eliezer Mendel 
Published: March 2017

131 Background: The mutational landscapes of primary and metastatic PCa have been robustly analyzed in multiple whole exome sequencing (WES) studies. We hypothesized that an aggregate, uniform analysis of all data generated to date would enable discovery of new significantly mutated genes and pathways not previously associated with PCa, and shed more light onto the genetic differences between primary and metastatic PCa. Methods: We assembled and uniformly analyzed a cohort of 1,021 tumor and matched germline primary and metastatic PCa whole exomes (686 primary, 335 metastatic), and performed mutational significance analysis using statistical and biological approaches to determine which genes and pathways are recurrently altered. Results: We identified 117 significantly mutated genes (Mutsig q<0.1) in PCa, which included many novel genes and pathways. These include epigenetic modifiers [KMT2C (6%), KMT2D (6%), and KDM6A (2.7%)], regulators of the SWI/SNF complex [SMARCA1 (1.1%), ARID1A (1.5%), ARID1B (1.3%), ARID2 (1.3%), and PBRM1 (0.7%)], and the splicing pathway [SF3B1 (1.1%) and U2AF1 (0.5%)]. In addition, we identified mutations in FUBP1 (0.4%), a splicing regulator involved in the regulation of MDM2 splicing. We also found truncating mutations in SPEN, a hormone inducible transcriptional repressor, in 2.8% of samples, similar to the frequency observed in breast tumors. Finally, a comparison of primary and metastatic samples enabled discovery of a genetic profile associated with metastatic disease, including AR amplifications and mutations, and loss of TP53, PTEN, and RB1. At lower frequency, metastatic tumors showed enrichment in mutations in MLLs (KMT2C/D), APC, CDK12, BRCA2, CTNNB1, and amplifications of MYC and CCND1. Conclusions: Through aggregation and uniform genomic analysis, we refined the map of somatic mutations in PCa and identified cancer genes and pathways not previously associated with this disease. Our findings may inform patient stratification and translational investigation.
A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 in patients with mCRPC.
Authors: Kolinsky Michael Paul , Rescigno Pasquale , Bianchini Diletta , Zafeiriou Zafeiris , Mehra Niven , Mateo Joaquin , Riisnaes Ruth , Crespo Mateus , Figueiredo Ines , Flohr Penelope , Tunariu Nina , Banerji Udai , Raynaud Florence I. , Swales Karen E , Tovey Holly , Porta Nuria , Slade Rachel , Leonard Lorna , Hall Emma , De Bono Johann S. 
Published: March 2017

135 Background: Activation of the PI3K/AKT/mTOR pathway may contribute to resistance to androgen receptor targeted therapies in metastatic CRPC (mCRPC). The phase I/II RE-AKT trial (NCT02525068) investigates the safety and activity of enzalutamide (enza) in combination with the AKT inhibitor, AZD5363, in patients (pts) with mCRPC. Results of the phase I run-in are reported. Methods: mCRPC pts progressing after 1-2 lines of taxane chemotherapy and at least 12 weeks (wks) of abiraterone or enza were treated with enza (160mg od) and AZD5363 bid 4-days on, 3-days off, in a 3+3 dose escalation design. Co-primary endpoints were to assess toxicity (CTCAE), and identify the recommended phase II dose (RP2D) of AZD5363; antitumour activity and pharmacokinetics (PK) were secondary endpoints. Response was assessed by PSA, RECIST v1.1 and circulating tumor cell (CTC) conversion. Pts were considered evaluable for response if they completed 12 wks of treatment. Results: 16 pts were enrolled between 12/2014 & 04/2016 with 15 receiving treatment. At the AZD5363 320mg dose 3 pts were treated with no dose limiting toxicity (DLT). At the AZD5363 480mg dose, 5 pts were treated with 2 DLTs of grade (G) 3 maculopapular rash (MPR) related to AZD5363. An intermediate dose level of AZD5363 400mg was selected with 7 pts treated. 1 pt withdrew consent prior to completing the DLT window. 1 DLT of G3 MPR occurred and this dose was selected as the RP2D. Non-DLT treatment related (TR) G3/4 adverse events (AEs) were hyperglycaemia (n = 4, 26.7%), neutropenia (n = 1, 6.7%) & diarrhea (n = 1, 6.7%). All other TR AEs were G1 or G2, with diarrhea (n = 9, 60%), anorexia (n = 8, 53.3%) & nausea (n = 7, 46.7%) being most common. Of the 10 pts who completed 12 wks of treatment, 3 met at least one of the criteria for response. 1 pt (AZD5363 320mg) who had previously progressed on enza exhibited RECIST v1.1 partial response, > 50% PSA response, and CTC conversion by wk 13. Enza decreased AZD5363 PK exposure; robust modulation of pS6, pGSK3b and pPRAS40 was demonstrated. Conclusions: AZD5363 at the RP2D of 400mg bid 4 days on, 3 days off combined with enza 160mg od is safe and tolerable. Antitumor activity is reported, suggesting that AZD5363 may be able to overcome resistance to enza. Clinical trial information: NCT02525068.