bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of β-hydroxy-β-methylbutyrate (HMB) on muscle strength in older men with prostate cancer (Pca) started on androgen deprivation therapy (ADT): Preliminary results of an open-label, randomized trial.
Authors: Bylow Kathryn A. , Kilari Deepak , Riese Matthew John , Burfeind John , Stolley Melinda , Prost Robert W , Musto Kaylinn , Neilson Raquel , Szabo Aniko , Thomas James P. , Ng Alexander V. 
Published: February 2018

258 Background: ADT causes muscle weakness and wasting within 3 months (mo), causing older men on ADT to experience functional impairments and falls. HMB, a leucine metabolite which decreases muscle protein breakdown, improves strength, fat-free mass and function in older patients when given with arginine (A) and glutamine (G). Use of HMB +AG in older men with PCa starting on ADT to improve muscle loss and function has not been reported. Methods: Men age ≥ 60 with Pca starting on ADT were eligible. 42 men to date have been randomized to receive HMB + AG (Juven) twice daily for 3 mo vs no supplement. Physical performance measures using the Short Physical Performance Battery (SPPB) and hand dynamometer measurements were done at baseline and 3 mo. Both of these validated tests predict morbidity and mortality in older patients. Information on primary outcome, body composition, will be reported in the future according to study plan. Interim results are reported here to describe functional geriatric outcomes. Results: 42 men (mean age 70.2) with Pca (42.4% localized, 27.3% biochemical recurrence, 30.3% metastatic) have enrolled to date. Change in SPPB score favored HMB group: 12.6% of HMB vs 23.1% of controls had decline of ≥ 1point (pt) and 56.3% of HMB vs 15.4% of controls had increase of ≥ 1 pt (p = 0.045). The change in timed chair stand portion of SPPB (measures quadriceps strength) trended in favor of HMB group: -1.5 ± 2.9 seconds (sec) for HMB vs +0.4 ± 2.5 sec for controls, p = 0.073. 41.2% of HMB vs 15.4% of controls experienced an improvement in chair stand score. Change in hand grip strength also favored HMB group: 52.9% of HMB vs 84.6% of controls lost strength and 29.4% of HMB vs 0 controls gained strength, p = 0.047. No significant side effects were reported in HMB group. Conclusions: These are preliminary results of an ongoing trial. HMB is well tolerated in men with PCa on ADT. There is a trend in all measures of muscle function in favor of the HMB group. A much higher than expected % of men on HMB experienced improvement in measures of muscle function despite being on ADT. Further studies are ongoing to clarify the role of HMB in older men on ADT. Clinical trial information: NCT01607879.
Cosegregation of cfDNA AR amplifications and mutations in relation to BRAF and MYC in CRPC.
Authors: Christensen Bryce Raymon , Ledet Elisa , Moses Marcus Marie , Chapman Lynne , Steinwald Peter , Shahbandi Ashkan , Cotogno Patrick , Schiff Joshua , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver 
Published: February 2018

261 Background: cfDNA can be utilized to evaluate androgen receptor (AR) alterations in metastatic castrate resistant prostate cancer (mCRPC) patients. Given the role of androgen receptors in the pathophysiology of PC, mutations in the AR gene can have important implications regarding prognosis and treatment. The goal of this research was to evaluate associations between certain PC treatments and AR mutations. Methods: Treatment and demographic data from 121 patients diagnosed with PC was collected including genetic data derived from the Guardant360 test (Guardant Health, Redwood City, CA). AR alterations were compared among race, treatment history, and other somatic alterations. Results: 52.9% (n = 64) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 43.8% (n = 28) had AR amplification (amps), 37.5% (n = 24) had AR mutations (muts), and 18.8% (n = 12) had both. AR muts included: T878A (n = 15), H875Y (n = 8), W742C (n = 11), AR L702H (n = 7), and others. AR alterations comprised on average about 7% of tumoral cfDNA. To better understand the relationship between AR alterations and other commonly detected cfDNA aberrations, associations between BRAF (27.3%), TP53 (44.6%), and MYC (19.0%) and AR were assessed. Among these genes, P53 alterations were all Muts. MYC (n = 21) and BRAF (n = 27) alterations were predominantly amps though muts were also detected in MYC (n = 3) and BRAF (n = 9). P53 muts were not significantly associated with AR alterations. BRAF and MYC alterations significantly associated with AR alterations (p = 0.0012 and p = 0.0223). Pts were re-tested upon disease progression; among these patients, 52.2% (n = 24) had an increase in overall mut burden. Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR, BRAF, and MYC alterations may also have significant prognostic and therapeutic implications. Further research, a larger sample size, and longitudinal assessment are needed to further elucidate associations between disease progression and treatment response to the development of somatic alterations over time in mCRPC.
Incidence, patterns of treatment, and survival among men newly diagnosed with advanced prostate cancer: An analysis of SEER-Medicare data.
Authors: Beebe-Dimmer Jennifer Lynn , Ruterbusch Julie J. , Cooney Kathleen A. , Schwartz Kendra L. , Bolton Adam , Heath Elisabeth I. 
Published: February 2018

265 Background: About 5% of men are newly-diagnosed with advanced stage prostate cancer (PCa) and experience far poorer survival compared to men diagnosed with local or regionally-advanced disease. PCa mortality is higher in African Americans (AA) compared to non-Hispanic whites (NHW), with a marginally higher proportion of AA men first diagnosed with advanced disease. Thus, we sought to describe recent trends in incidence, survival and patterns of treatment among men diagnosed with de novo AJCC stage IV PCa. Methods: SEER*Stat software was used to calculate age-adjusted rates and annual percent changes for PCa stratified by AJCC stage and race/ethnicity for men age 66 or older diagnosed 2004-2014. We then used the Surveillance, Epidemiology and End Results database linked to Medicare Claims files to identify men diagnosed with advanced PCa during same time period. We examined patterns of treatment among all eligible patients and by race/ethnicity. Results: Rates for AJCC stage I-III PCa among elderly men have significantly declined in recent years for both NHW and AA men (-5.8% APC, p<0.001 for both), while rates for AJCC stage IV increased for NHW men (+1.5% APC, p=0.011) and decreased for NHB men (-1.8% APC, p=0.008). Of the 8,828 eligible patients identified from the SEER-Medicare database, 13% were AA, with a median survival of 32 months among all patients and survival significantly poorer among AA (p < 0.0001). AA patients were also more likely to go without treatment (p < 0.0001) compared to NHW patients, even after accounting for early mortality and TNM stage. The frequency of nearly all forms of treatment was lower among AA patients with the exception of orchiectomy, which was significantly higher (10.1% vs. 6.1%), and among Medicare Part D enrollees, the progesterone Megace (24.6% vs. 15.0%). Conclusions: Results from this study of Medicare patients diagnosed with advanced stage PCa suggest less aggressive treatment may contribute to the poorer survival observed in AA men. Understanding drivers of treatment-related decisions are critical in reducing racial disparities in survival among men with advanced PCa.
Evaluating changes in circulating tumor cell count in prostate cancer patients during androgen deprivation plus chemotherapy by using AxonDx enumeration device.
Authors: Brobey Reynolds , Amato Robert J. , Smith Jeff , Dehghani Mehdi , Murphy Kent , Wang Yue 
Published: February 2018

266 Background: Circulating tumor cell (CTC) counts have clinical utility as a prognostic marker in cancer. For prostate cancer (PCa), CTC counts ≥5 CTC/7.5 ml using the FDA-approved CellSearch system convey a negative prognosis with respect to overall survival, but the significance of changes in CTC count during treatment is not fully understood. To determine whether longitudinal CTC counts can be used as a prognostic and/or predictive marker of clinical outcome in PCa patients undergoing androgen deprivation therapy (ADT) plus chemotherapy, we used the AxonDx nCyte non-enrichment-based CTC detection and enumeration system to evaluate CTC counts at baseline, during, and after therapy in 18 patients for up to 11 months. Methods: Whole blood was drawn from PCa patients on clinical trials for ADT plus chemotherapy at PSA evaluation (±radiographic reevaluation) into vacutainers containing K3-EDTA and processed within 6 hr. PBMC containing nucleated cells harvested from 6 ml of whole blood were fixed, permeabilized and blocked with BSA buffer, and stained using a proprietary antibody cocktail containing DAPI, an anti-cytokeratin mixture, the pan-leukocyte marker CD45, and markers selective for granulocytes and lymphocytes. Stained cells were drawn onto 1.2 µm pore filters, washed, placed on counting slides, and analyzed. CTCs are identified as cytokeratin-positive, nucleus-positive and leukocyte marker-negative. Results: CTCs were obtained from 12 patients for 2-9 months at 2-7 time points; from 2 patients for 11 months at 5-7 time points, and from 4 patients for 1 month at 1 time point. We detected time-dependent changes in CTC counts following treatment that did not necessarily correlate with patient’s local prostate specific antigen (PSA) levels but were early indicators of subsequent increase in tumor burden. Conclusions: The AxonDx nCyte system can reliably detect CTCs from PCa patient samples that trend along with other signs of disease progression. CTCs can be used longitudinally for clinical monitoring of patients with PCa prior to signs of progression via tumor markers or scans during ADT plus chemotherapy, providing a reliable biomarker for PCa.
Association of prostate-specific antigen (PSA) trajectories with risk for metastasis and mortality in non-metastatic castration-resistant prostate cancer (nmCRPC).
Authors: Li Sophia , Ding Zhijie , Lin Jennifer H , Behl Ajay S. , Pericone Chris , Macomson Brian , Shore Neal D. 
Published: February 2018

27 Background: Currently there is insufficient guidance for the management of nmCRPC. This study assessed patient risk of developing metastases and death based on their PSA levels over time. Methods: This was a retrospective study using the Optum electronic health record database (1/1/2007 – 4/30/2016) in men ≥18 years. nmCRPC was defined as a PC diagnosis, 2 rising PSA levels ≥1 week apart, testosterone < 50 ng/dL (post-PC diagnosis), and no ICD-9/10 code or therapy indicating metastasis. Patients were required to have ≥1 PSA record per 3-month period for 9 months following nmCRPC diagnosis. Group Based Trajectory Modeling (GBTM) was used to group patients based on similar PSA trends over 9 months. The association of these PSA groups with metastasis/mortality risk was measured using multivariate Cox proportional hazard regression models. An overall trend for metastasis and mortality across the groups was also tested. Results: From a total of 729 patients included, 4 distinct groups were identified: Group 1 (49% of patients), 2 (32%), 3 (14%) and 4 (5%). Group 1 had the lowest PSA (7 ng/mL) at nmCRPC diagnosis and steady PSA during the 9-month follow-up. In contrast, Groups 2, 3 and 4 had higher PSA at nmCRPC diagnosis (17, 61, 513 ng/mL respectively) and rising PSA during follow-up. There was a trend of increasing metastasis and mortality risk (p < 0.001 for both trends) with the higher PSA groups. For metastasis, Hazard Ratios (HRs) and 95% confidence intervals (CIs) were 1.7 (1.3-2.2), 3.5 (2.5-5.0), 1.8 (0.7-4.7) in Groups 2, 3 and 4, respectively, vs. Group 1. For mortality, HRs (95% CIs) were 1.9 (1.4-2.5), 2.6 (1.8-3.7), 4.5 (2.4-8.4) in Groups 2, 3 and 4, respectively, vs. Group 1. Metastasis-free survival (MFS) independently predicted mortality risk. Patients developing metastasis within 1 year had 4.4-fold greater risk for mortality (95% CI = 2.2-8.8) than those who remained MFS at year 3. Conclusions: A large proportion of nmCRPC patients with PSA increases during the follow-up period had significantly increased risk for metastasis and mortality, with MFS predicting mortality risk. Periodic measurement of PSA may better inform management of nmCRPC.
Novel method for rapid enrichment of high purity circulating tumor cells (CTCs) for prostate cancer (PCa) gene expression profiling.
Authors: Morrison Gareth , Jojo Nita , Cunha Alexander , Xu Yucheng , Robinson Peggy S. , Dorff Tanya B. , Quinn David I. , Goldkorn Amir 
Published: February 2018

271 Background: CTC RNA analysis currently involves single cell recovery that is laborious and expensive, or alternatively lysis of preserved whole blood which yields RNA predominantly from leukocytes which vastly outnumber CTCs. To effectively characterize gene expression in large patient cohorts, new enrichment methodologies are needed that yield high purity CTC populations while preserving RNA integrity. Here we describe a simple yet robust method for enrichment of prostate CTCs for gene expression analysis. Methods: Blood was drawn with informed consent under an IRB-approved protocol. For initial optimization, CFSE-stained PCa cells were spiked into healthy blood and recovered using various combinations of 2 methods: microfluidic enrichment (Parsortix™ system) and CD45 depletion. For assay qualification, a prostate-specific multiplexed qRT-PCR gene expression panel was developed. Enrichment and gene expression were tested initially using PCa cell lines spiked into healthy blood, then metastatic castrate resistant prostate cancer (mCRPC) blood samples in parallel with CellSearch enumeration. Results: Optimal enrichment of live cells was achieved with CD45 depletion followed by microfluidic enrichment, resulting in an average spiked cell recovery of 30% and approximately 100 contaminating background leukocytes. Using this enrichment method, prostate specific genes were detectable by multiplexed qRT-PCR down to 25 cells spiked into 7.5 ml whole blood, and transcripts were not measurable in matched healthy blood controls. When applied to mCRPC patient blood containing CTCs by CellSearch, multiplexed qRT-PCR successfully detected prostate specific genes in all samples. Conclusions: We developed a novel enrichment method capable of rapidly and efficiently recovering live CTCs with high purity, free of magnetic beads and with very few background leukocytes. Captured cells yielded high-quality RNA with high sensitivity and specificity for prostate-specific transcripts. This approach is applicable to high throughput gene expression profiling assays and offers an alternative to laborious single cell recovery or non-cancer-specific whole blood fixation.
Validation of nuclear-localized AR-V7 on circulating tumor cells (CTC) as a treatment-selection biomarker for managing metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Graf Ryon P , Schreiber Nicole A. , Winquist Eric , McLaughlin Brigit , Lu David , Orr Sarah , Fleisher Martin , Lowes Lori , Anderson Amanda K. L. , Wang Yipeng , Dittamore Ryan Vance , Allan Alison L , Attard Gerhardt , Heller Glenn 
Published: February 2018

273 Background: A previous analysis of 161 patients (pts) tested for nuclear-localized AR-V7(+) CTCs showed a therapy interaction between AR-V7 positivity and improved overall survival (OS) on taxane chemotherapy vs. androgen receptor signaling inhibitors (ARSI). To validate the use of the biomarker result for physician decision making, we prospectively analyzed an independent, multicenter, blinded, cross-sectional cohort (n = 225) to confirm a therapy interaction with AR-V7. We corrected for possible pt selection bias by the treating physician by analyzing the association of therapy to OS in low and high risk groups defined by the test cohort. Methods: Two analyses were performed: (1) the validation of a therapy interaction between AR-V7 positivity and superior OS benefit for pts treated with taxanes in the context of use for 2nd+ line pts; and (2) as the choice between ARSI or taxanes was at the discretion of the attending physician, pt risk was incorporated into the predictive biomarker assessment. A pt-specific risk score was developed from line of therapy and other covariates to stratify pts as low and high risk, and the association of AR-V7 status and OS was performed within each risk group to correct for physician decision making and address possible confounding with treatment assignment. Results: (1) A therapy interaction between AR-V7(+) pts and lower risk of death on taxanes vs. ARSI (HR: 0.23, p = 0.003, 95% CI: 0.09 – 0.61) was validated. (2) In the validation cohort, high risk AR-V7(+) pts had an OS benefit when treated with taxanes (p = 0.02) and the AR-V7(-) pts had an improved OS with ARSI therapy (p = 0.02). AR-V7 incidence was low in the low risk pts, precluding the analysis for this sub-cohort. Conclusions: The results validate that the nuclear-localized AR-V7(+) biomarker has an interaction with therapy and improved survival on taxanes. Further, when adjusting for pt risk, the biomarker is predictive of OS in the high risk group. Nuclear-localized AR-V7 protein in CTCs can aid in the decision between ARSI and taxane chemotherapy in the 2nd or greater line of therapy for mCRPC.
Multi-parametric liquid biopsy analysis of circulating tumor cells (CTCs), cell-free DNA (cfDNA), and cell-free RNA (cfRNA) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Hodara Emmanuelle , Zainfeld Daniel , Morrison Gareth , Cunha Alexander , Xu Yucheng , Carpten John D. , Danenberg Peter V. , Dempsey Paul W. , Usher Joshua , DANENBERG KATHLEEN , Bischoff Farideh Z. , Khurana Aditi , Cotter Philip D. , Moore Mathew , Gunn Shelly , Dorff Tanya B. , Quinn David I. , Goldkorn Amir 
Published: February 2018

274 Background: Molecular profiling of prostate cancer using liquid biopsies such as CTC capture and cell-free nucleic acid analysis yield informative yet distinct datasets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We have conducted an initial proof of principle study aimed at piloting this multi-parametric approach. Methods: Blood was drawn under an IRB-approved protocol from 20 mCRPC patients. Samples were analyzed simultaneously for the following: CTC enumeration and single CTC and matched white blood cell capture for whole genome amplification and low-pass copy number variation; CTC DNA and matched cfDNA for somatic single nucleotide variant analysis; plasma cfRNA extraction and qRT-PCR for AR, AR-V7, and PCA3. When available, liquid biopsies were compared with matched tumor profiles. Results: Fifteen of 20 patients (75%) had detectable CTCs by CellSearch (range: 1-692/7.5mL, median: 16.5/7.5mL). Thirteen of 20 patients (65%) had detectable SSNVs in CTC DNA and/or matched cfDNA, including mutations in TP53, PIK3CA, HRAS, and EGFR. Matched CTC DNA and cfDNA demonstrated both shared and distinct SSNVs. Copy number analysis of single CTCs was performed in 2 patients, and both had CNVs in multiple cancer relevant genes. A majority of CNVs were present in matched solid tumor profiles, but some were exclusive to the liquid biopsies. Plasma PCA3 and AR transcripts were detected in 18/20 (90%) and AR-V7 in 4/20 (20%) cfRNA samples. Unique SSNVs were detected at second time points at disease progression (more are being collected). Conclusions: In this pilot cohort, simultaneous multi-parametric profiling was feasible for CTC DNA mutations and CNVs, and matched plasma cfDNA mutations and cfRNA gene expression. These disease-specific molecular profiles were often concordant with tumor tissues but also contained new, potentially actionable alterations unique to CTC DNA or cfDNA. Expanded studies will build upon this approach to optimally leverage liquid biopsies for molecularly directed patient management.
Enzalutamide and metformin combination therapy to overcome autophagy resistance in castration resistant prostate cancer (CRPC): Current results from a phase I study.
Authors: Parikh Mamta , Hyunh Jasmine C , Lara Primo , Pan Chong-xian , Robles Daniel , Evans Christopher P. 
Published: February 2018

281 Background: Preclinical models have shown that autophagy is a resistance mechanism of enzalutamide (enza), a small molecule suppressing the androgen pathway approved for treatment of CRPC. Metformin, an autophagy inhibitor, enhances preclinical therapeutic responses when combined with Enza, thus prompting a Phase I clinical trial evaluating the combination. We present results to date. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or metformin treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO qdaily and metformin 500 mg PO bid (DL1), with metformin dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL1. Primary objective was to establish the maximum tolerated dose (MTD), with secondary objectives of evaluating PSA response of ≥ 50%, PSA progression, and safety. Results: A total of 12 pts have been enrolled to date; mean age was 77 (range 60-95). No DLTs were observed at DL1; 1 DLT due to Grade 3 abdominal pain was observed at DL2, with an additional 6 pts subsequently enrolled in expansion. The only adverse effects ≥ Grade 3 were: syncope (1/12), hallucinations (1/12), and abdominal pain (2/12). One pt withdrew consent, 2 required dose reduction of metformin, and 1 died of progressive disease. Of 10 evaluable pts, PSA response was seen in 8 pts. Conclusions: The combination of enza 160 mg qdaily and metformin 1000 mg PO bid is safe and well-tolerated. Efficacy results to date support continued study of the combination in pts with CRPC. Clinical trial information: NCT02339168.