bluuebunny/crossref_metadata_2025_split huggingface dataset:
Satisfying the fatty acid demand of prostate cancer: De novo synthesis versus uptake as alternative and potentially cooperative prostate cancer phenotypes.
Authors: Gaston Sandra Marlene , Kearns James , Adams George W. , Rais-Bahrami Soroush , Nix Jeffrey , Kolettis Peter N , Bryant James E , Otali Dennis , Grizzle William E. 
Published: March 2017

107 Background: Malignant transformation increases cellular demand for fatty acids (FA). Many cancers show increased expression of fatty acid synthase (FASN); FASN catalyzes the de novo synthesis of the FA palmitate. While research has focused on FASN and de novo tumor FA synthesis, observations suggest that alternate mechanisms for FA acquisition are also important, including studies showing that cancer cells can be rescued from FASN inhibition by exogenous palmitate. Using a biopsy-based approach, we identified a PrCa subtype with outlier (>10 fold) overexpression of fatty acid binding protein 5 (FABP5). FABP5 facilitates the utilization of palmitate and other FAs from outside the cell; a FABP5 overexpression phenotype may confer a selective advantage when dietary FAs are abundant or when FASN is targeted as a therapy. Methods: 244 prostate biopsy patients were prospectively enrolled. Tissue prints were collected from each core for RNA and DNA preparation. mRNA was analyzed using Affymetrix arrays and TaqMan qrtPCR assays. Immunohistochemistry (IHC) was performed using archival radical prostatectomy (RP) specimens. Results: mRNA analyses revealed a PrCa subtype with >10 x overexpression of FABP; this phenotype was observed in 7% of 268 cores with Gleason sum (GS) 7-10 PrCa. We also observed a second subtype with >10 x overexpression of FASN in 9% of GS 7-10 cores. With few exceptions these two PrCa subtypes showed an “either-or” pattern with top-quartile overexpression of FABP5 or FASN but not both (Spearman r = - 0.385; P < 0.0001). IHC confirmed variable expression, including “patchwork” PrCas with high Gleason pattern (GP) areas overexpressing FABP5 next to low GP areas overexpressing FASN. The net result may be a selective advantage for the high grade cancer if FABP5 allows it to exploit the FA being synthesized by the adjacent low grade focus Conclusions: Identification of a PrCa subtype with high levels of FABP5 overexpression suggests a previously unrecognized mechanism by which some PrCas can increase FA supply without de novo synthesis; such a PrCa subtype might be particularly sensitive to dietary interventions and relatively insensitive to FASN inhibitors.
A metastatic biology gene expression assay to predict the risk of distant metastases in patients with localized prostate cancer treated with primary radical treatment.
Authors: Jain Suneil , Lyons Ciara , Walker Steven M. , McQuaid Stephen , Hynes Sean , Mitchell Darren M. , Pang Brendan , Logan Gemma E , McCavigan Andrena , O'Rourke Declan , Davidson Catherine Joan , Knight Laura A , Berge Viktor , Neal David , Pandha Hardev S. , Harkin Paul D , James Jacqueline , Kennedy Richard D. , O'Sullivan Joe M. , Waugh David J. 
Published: March 2017

11 Background: Approximately 20% of patients with organ confined prostate cancer (PCa) will develop disease recurrence following radical treatment (surgery or external beam radiotherapy (EBRT)). We hypothesized that a molecular subgroup of early PCa may have metastatic potential at presentation, resulting in disease recurrence. Methods: Using unsupervised hierarchical clustering of gene expression from a PCa dataset we identified a novel molecular subgroup with a transcriptional profile similar to metastatic disease. We developed a 70 gene expression assay to prospectively identify patients within the subgroup from formalin fixed and paraffin embedded tissue (FFPE). Initial assessment found the assay to be prognostic in three independent publicly available prostatectomy datasets. We therefore assessed the prognostic value of the assay in FFPE clinical samples collected from multiple international sites. FFPE tumor resections and tumor biopsy specimens were obtained from 322 surgical patients and 248 patients treated with EBRT. Regions of highest Gleason grade were identified for macrodissection, RNA extraction and gene expression analysis. Samples were dichotomized as metastatic biology assay positive or negative using a pre-specified cut-off. The association of assay results with biochemical failure (BF) and distant metastases (DM) was tested on multivariate (MVA). Results: The assay was significantly associated with BF on MVA (HR 1.67 [1.16-2.38]; p = 0.0059), (HR 2.26 [1.26-4.04]; p = 0.0062) and DM on MVA (HR 3.39 [1.88-6.12]; p = 0.0001), (HR 3.26 [1.27-8.30]; p = 0.0137) for surgery and EBRT cohorts respectively. Importantly, in a combined model, the assay demonstrated additional information to the commonly used CAPRA clinical tool for prediction of DM, HR 2.72 [2.10-3.51]; p < 0.0001, and HR 2.72 [1.42-5.20]; p = 0.0026 (Prostate Metastatic Assay combined with CAPRA-S and CAPRA respectively). Conclusions: The metastatic biology assay predicts BF and DM in PCa patients treated with surgery or EBRT. The assay may help to select patients at risk of metastatic disease for additional treatment aimed at preventing disease recurrence.
Informed decision making (IDM) for prostate cancer (PCa) screening in a high-risk population.
Authors: Dhillon Puneet , Grivas Petros , Raska Paola , Hickman Devon , Elson Paul , Awadalla Ann , Abraham Jame , Smolenski Kathy N. , Zhu Hui , Schalcosky Thomas , Modlin Charles , Bell Kimberly , Abraksia Samir 
Published: March 2017

112 Background: PCa incidence and mortality in African Americans (AA) is higher than in Caucasians. Health-education programs and culturally appropriate outreach to high-risk groups in accordance with American Cancer Society IDM guidelines can reduce disparities. Data show that it is hard to provide comprehensive unbiased education about screening to patients (pts). This study aims to examine whether IDM guidelines in a large high risk group setting can improve knowledge on PCa and screening decision, and whether such education program is overall beneficial to pts. Methods: Pts were included in one-day outreach event and were given a 15-question pre and post- test focused on standard informative educational PowerPoint and then were offered screening (PSA + DRE). Components of IDM were reviewed during this educational intervention. Demographics and family history was collected and UCSF 10-year mortality index was assessed to help IDM. Pre- and post- test number of correct answers were compared (Wilcoxon signed rank); pts were surveyed on their opinion on the program. The decision regarding screening after the intervention was tracked as well as the % of PCa diagnosed. Pts were tracked via an established navigation system to ensure follow up care. Results: 106 pts were included in the current analysis. Median number of correct answers at pre and post test was 8 and 11 (p < 0.001). Overall, 86% responded that they wanted screening. Of those, 92% were AA and 21% had family history of PCa; 21 pts had PSA only, 60 had PSA + DRE. 13 pts (16%) had abnormal PSA per NCCN guidelines, 5 (8%) had abnormal DRE. 5 PCa were biopsy-diagnosed, 4 had abnormal DRE + PSA; 1 had only abnormal DRE. Overall, 82% pts favored IDM before screening, 18% would prefer screening without IDM. 75% of all pts found the information “very helpful” in decision-making (within a 5-point Likert scale). Conclusions: Our education-based IDM led to significant improvement in knowledge about PCa screening. Most pts preferred education prior to screening. Our approach paired with the use of navigation program is feasible and was positively received by a large high risk group. Project is ongoing with more pts and follow up, and further validation is pending. Clinical trial information: NCT02419846.
Effect of heparin bridged transrectal prostate biopsy on the risk of hemorrhage in patients requiring temporary discontinuation of warfarin.
Authors: Hamano Itsuto , Hatakeyama Shingo , Yoneyama Tohru , Tobisawa Yuki , Soma Osamu , Matsumoto Teppei , Yamamoto Hayato , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: March 2017

125 Background: Safety of heparin bridging therapy for transrectal ultrasound-guided prostate (TRUS) biopsy in patients requiring temporary discontinuation of antithrombotic therapy is unknown. This study aimed to assess the relationship between heparin bridging therapy and the incidence of complications after TRUS biopsy. Methods: From January 2005 to November 2015, we performed 1307 consecutive TRUS biopsies on 1134 patients in our hospital. The patients were assigned to two groups: those without heparin bridging (the control group) and those with temporary discontinuation of antithrombotic agents with heparin bridging therapy (the bridging group). A 10–12-core TRUS biopsy was performed; the patients were evaluated for bleeding-related complications. Results: Of 1134 patients, 1109 (1281 biopsies) and 25 (26 biopsies) were assigned to the control and bridging group, respectively. Patient background did not significantly differ between the control and bridging groups, except for age, history of diabetes, cardiovascular diseases, and CHADS2 scores. Compared with the control group, the bridging group showed a significantly higher rate of complication for any complication (35% vs. 8.3%, P < 0.001), bleeding-related complications (27% vs. 4.4%), and urinary tract infection (7.7% vs. 1.2%). No thromboembolic event was observed in the present study. Multivariate logistic analysis showed that heparin bridging therapy was a significant risk factor for the incidence of any complication and bleeding-related complications. Conclusions: Heparin bridging therapy with temporal discontinuation of antithrombotic agents may increase the risk of complications after TRUS biopsy. Further, large-scale studies are required to clarify the safety of heparin bridging therapy.
Single cell phenogenomic subtyping of circulating tumor cells (CTCs) identify intercellular tumor heterogeneity (het) and multiple resistance mechansisms in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Graf Ryon , Jendrisak Adam , Schreiber Nicole A. , McLaughlin Brigit , Greene Stephanie , Rodriguez Angel , Fleisher Martin , Lee Jerry , Kelvin James , Wang Yipeng , Landers Mark Andrew , Dittamore Ryan Vance 
Published: March 2017

139 Background: Genomic profiling of metastatic tumors can identify mCRPC pts w/ “actionable” targets. However, responses from this approach are infrequent and not durable, broadly attributed to intra-tumor and intrer-cellular het. We sought to understand relationships between single CTC phenotypic and genomic patterns present when starting ARSi or taxane therapy (Tx) to develop more effective biomarker-directed treatment approaches. Methods: 9225 CTCs from 319 blood samples from 179 mCRPC pts were detected and digital phenotypically profiled using the Epic Sciences platform. Unsupervised clustering revealed 15 phenotypic CTC subtypes based on digital pathology features (Type ‘A’-‘O’). Phenotypic diversity was determined by a Shannon index of these subtypes in pt samples. Next, 856 CTCs representing each subtype were individually whole genome sequenced for copy number variation and genomic instability, to define phenogenomic single cell profile and taxonomy. Tx outcomes were associated with CTC profiles. Results: Pre-therapy identification of certain CTC phenotypic subtypes was associated with poor overall survival (OS) following ARSi and/or taxanes. 5/15 subtypes existed primarily in pts w/ high CTC het (84-94%, Bonferroni adjusted p < 0.05, permutation test), and linked to amp of AR and cMYC, and loss of TP53 and PTEN. Clusters of genomic events were linked to phenotypic features (i.e. small cell CTC w/AuroraK & nMYC amp) and provide single cell phenogenomic associations with pathways such as AR/PTEN feedback and DNA repair machinery. Conclusions: Presence ofspecific CTC subtypes was associated w/ poor survival on ARSi and/or taxanes and may inform Tx selection. Identifying CTC subtypes present in high het samples can provide insight into individual pt disease evolution and potential approaches to maximize benefit. Longitudinal monitoring of CTC phenogenomics is being studied in novel Tx trials.[Table: see text]
Rapid, ultra-low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hovelson Daniel H. , Liu Chia-Jen , Wang Yugang , Kang Qing , Haakenson Christine , Langmore John , Kamberov Emmanuel , Ramnath Nithya , Krauss John C. , Talpaz Moshe , Chugh Rashmi , Hyland David , Tuck Missy , Herman Kirk , Husain Hatim , Tewari Muneesh , Chinnaiyan Arul M. , Mills Ryan , Morgan Todd Matthew , Tomlins Scott A. ,   Rubicon Genomics
Published: March 2017

144 Background: Although cell free DNA (cfDNA) profiling by next generation sequencing (NGS) holds great promise for precision oncology, the inability to estimate tumor content a priori typically results in ultra-deep sequencing (e.g. 10,000x) based approaches—often at limited loci—to ensure accurate assessment of cfDNA samples where tumor content can be < 0.1%. However, a large subset of patients with advanced cancers, where most precision oncology is applied, have much greater cfDNA tumor content. Methods: Here we demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) on benchtop sequencers as a precision medicine screening strategy based on ultra-low coverage (~0.005x) tumor content determination through genome-wide copy number alteration (CNA) profiling using 48 plasma cfDNA samples from patients with advanced cancer. Results: Using this approach, we identified therapeutically relevant focal CNAs in 13 of 48 (27%) cfDNA samples from patients with metastatic cancer, including 11 of 36 (31%) from patients with mCRPC. We further show that PRINCe is effective at whole genome coverages as low as 0.005x. Combining PRINCe with targeted multiplexed-PCR NGS of the same cfDNA enables mutation and CNA assessment using effective coverage as low as 25x based on calibrating sequencing depth to cfDNA tumor content. Lastly, PRINCe identifies pre-treatment cfDNA copy number profiles that can be used for inexpensive disease monitoring. Conclusions: Taken together, our screening approach enables broadly applicable cfDNA based precision oncology for patients with advanced cancer through rapid, inexpensive identification of therapeutically relevant CNAs and pre-treatment genomic profiles for disease monitoring, while also guiding additional cfDNA profiling approaches to reserve costly ultra-deep approaches for patients with very low cfDNA tumor content.
Estimating the incidence of oligorecurrent and potentially salvageable prostate cancer on 18F-Choline PET-CT: Screening phase of the STOMP randomized phase II trial.
Authors: Ost Piet , De Bruycker AurÃ©lie , Claeys Tom , Delrue Louke , De Meerleer Gert , De Vos Filip , Decaestecker Karel , De Man Kathia , Fonteyne Valerie , Lumen Nicolaas , Ameye Filip , Billiet Ignace , Joniau Steven , Lambert Bieke 
Published: March 2017

153 Background: To identify sites and patterns of prostate cancer (PCa) recurrence following primary PCa treatment with 18F-choline PET/CT and estimate the number of patients potentially eligible for metastasis-directed therapy (MDT, defined as patients with up to 3 metastatic lesions). Methods: Between 7/7/2011 and 7/6/2016, 229 patients underwent a 18F-choline PET/CT for a biochemical PCa recurrence for potential inclusion in a randomized phase II-trial (STOMP). The trial randomizes patients with oligorecurrent (Orec) PCa between active surveillance (AS) and MDT. Patients were eligible for the trial in case of biochemical recurrence following primary prostate cancer treatment, up to 3 extracranial metastases and testosterone > 50 ng/ml. Patterns of recurrence were classified as local (prostate or prostate bed), distant (N1, M1a/b/c) or a combination of both. The number of lesions were counted per scan and patients with up to 3 distant lesions with or without a local recurrence were considered as ORec vs > 3 lesions as polyrecurrent (PRec). Results: A total number of 229 patients underwent 277 choline PET-CTs, resulting in 208 patients (91%) with a recurrence and 21 patients (9%) without any detectable recurrence. Twenty-two men (10%) had a local recurrence and 186 men (81%) had a distant recurrence, which was combined with a local recurrence in 17 men. Of the 186 patients, 131 (57%) were considered as ORec and 55 (24%) as PRec at median PSA values of 3.4 and 5.4 ng/ml, respectively (p < 0.003). ORec were categorized as N1: 16%, M1a: 8%, M1b: 13%, M1c: 2% or a combination of sites: 17% (Figure 1). Fifty-eight patients had 1 lesion (25%), 39 2 lesions (17%) and 34 3 lesions (15%). Men with ORec PCa were treated with AS, MDT or palliative ADT in respectively 27%, 27% and 1% of the cases. Sixty-two of ORec men (27%) agreed to be randomized in the STOMP-trial. PRec were categorized as N1: 2%, M1a: 1%, M1b: 3%, M1c: 1% or a combination: 17% (Figure 1). Thirteen patients had 4 lesion (6%), 9 5 lesions (4%) and 33 > 5 lesions (18%) Conclusions: Two out of three PCa recurrences on 18F-choline PET-CT are potentially salvageable with local therapy and/or metastasis-directed therapy. Clinical trial information: NCT01558427.
First-line chemotherapy (CT) versus anti-androgen therapy (AT) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Individual patient analysis of the Veterans Health Administration (VHA) dataset.
Authors: Sonpavde Guru , Huang Ahong , Wang Li , Baser Onur , Miao Raymond 
Published: March 2017

156 Background: The outcomes of pts receiving first-line CT vs AT for mCRPC are unclear. Using the VHA dataset, we compared outcomes with first-line CT vs AT in pts with mCRPC and assessed the impact of prior androgen deprivation therapy (ADT) duration and known prognostic factors. Methods: Pts with mCRPC initiating first-line AT (abiraterone, enzalutamide) or CT (taxane) from Oct 2012 to Sept 2014 were identified. The impact of AT vs CT on overall survival (OS) and time to discontinuation (TTD) was assessed using Cox proportional hazard models, adjusting for prior ADT duration, known prognostic factors (hemoglobin [Hb], albumin [alb], alkaline phosphatase [ALP], prostate-specific antigen [PSA]), Charlson Comorbidity Index (CCI) and chronic disease score (CDS). Results: Overall, 1445 pts were evaluable; 1108 received AT (abiraterone 996, enzalutamide 112) and 337 received CT (docetaxel). The overall median duration of prior ADT was 464 days. On multivariable analysis, prior ADT duration, CCI, CDS, Hb, Alb, ALP and PSA were associated with OS, but AT vs CT was not (HR: 1.041 [95% CI: 0.853–1.270], p = 0.6943). PSA levels, prior ADT duration, and ALP was associated with TTD, and TTD was shorter for CT vs AT (HR: 2.339 [95% CI: 1.969–2.779], p < 0.0001). Longer prior ADT duration was associated with longer OS (HR: 0.566, p < 0.0001) and TTD (HR: 0.831, p = 0.0363) in the AT cohort, but not in the CT cohort. Treatment-free interval (TFI) (between first- and second-line treatment) was longer for CT vs AT (mean: 53 vs 39 days; p = 0.0303). Conclusions: To our knowledge, this is one of the largest mCRPC datasets analyzed at the individual pt level comparing first-line CT vs AT. OS was not significantly different for first-line CT vs AT after adjusting for key prognostic factors, despite shorter TTD with CT and longer TFI after first-line CT. Prior ADT duration ≤ 464 days was associated with shorter OS and TTD in the AT cohort, but not the CT cohort, suggesting that such pts may benefit from receiving CT over AT. The results are hypothesis-generating and prospective validation is required. Funding: Sanofi Genzyme
Multisite experience of fluciclovine (18F) PET/CT imaging in biochemically recurrent prostate cancer: Impact of clinical factors and intersite variation.
Authors: Zanoni Lucia , Nanni Christina , Bach-Gansmo Tore , Bogsrud Trond V , Nieh Peter , Kieboom Jesse , Korsan Katrine Andersen , Sletten Heidi , Tade Funmilayo I , Odewole Oluwaseun , Ward Penny , Chau Albert , Goodman Mark , Fanti Stefano , Schuster David M. , Willoch Frode 
Published: March 2017

163 Background: Fluciclovine (18F) is an FDA-approved positron emission tomography/computerized tomography (PET/CT) tracer in clinical use for the detection and localization of biochemically recurrent (BCR) prostate cancer. Here, we report the impact of clinical factors and study site on its performance. Methods: In total, 596 subjects with BCR prostate cancer underwent fluciclovine (18F) PET/CT scanning at four sites in Italy, Norway and USA. Detection Rates (DR), including region level analyses, were stratified by prostate specific antigen (PSA) levels, PSA doubling time (PSAdt), Gleason score (GS), and by investigator/site. Extra-prostatic disease was defined as all positivity outside of residual prostate, prostate bed and seminal vesicles. Results: Fluciclovine (18F) PET/CT was positive in 67.7% (403/595) of subjects. Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232/599) and 32.6% (194/596) of scans, respectively. Metastatic involvement outside the pelvis was found in 26.2% (155/591) of scans. Generally, DR increased with increasing baseline PSA (Table 1). While subject level DR did not vary significantly with PSAdt (DR = 60-69% across all categories), a positive extra-prostatic scan was more likely in patients with shorter PSAdt (DR = 52%, 48%, 37% and 28% for PSAdt <3, 3-<6, 6-<12 and >12 months, respectively). Among 361 subjects for whom baseline GS was available, scores ≥9 were associated with the highest extra-prostatic DR (55%) compared with 23% in patients with GS ≤6. Inter-site variations in acquisition protocols may have impacted DR at low baseline PSA values; with subject level DR at PSA >0.2-0.5 ng/ml = 20%, 38%, 46% and 73% at site A, B, C and D, respectively. Conclusions: Fluciclovine (18F) can detect and localize BCR prostate cancer in a wide range of subjects and, with appropriate imaging protocols, has a clinically useful DR at PSA <0.5 ng/ml. Clinical trial information: NCT02443571. [Table: see text]