bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of survival in patients with metastatic prostate cancer by single nucleotide polymorphisms of cancer-associated genes.
Authors: Inoue Takamitsu , Tsuchiya Norihiko , Matsui Shigeyuki , Kamba Tomomi , Mitsuzuka Koji , Hatakeyama Shingo , Horikawa Yohei , Ohyama Chikara , Saito Seiichi , Arai Yoichi , Ogawa Osamu , Habuchi Tomonori 
Published: February 2017

177 Background: Individual genetic variations may have a significant influence on the survival of metastatic prostate cancer (PCa) patients. We aimed to identify target genes and their variations involved in the survival of PCa patients using a single nucleotide polymorphism (SNP) panel. Methods: A total of 185 PCa patients with bone metastasis at initial diagnosis were analyzed. Each patient was genotyped using a Cancer SNP panel that contained 1421 SNPs in 408 cancer-related genes. SNPs associated with the survival were screened by log rank test. A prognostic scoring index using selected SNPs was developed by incorporating the difference in their effect sizes to classify high-risk and low-risk groups and its predictive accuracy was assessed. Results: Fourteen SNPs in six genes, XRCC4, PSM1, GATA3, IL13, CASP8, and IGF1, were identified to have statistically significant association with the cancer-specific survival. The cancer-specific survivals of patients grouped according to the number of risk genotypes of 6 SNPs selected from the 14 SNPs differed significantly (0-1 vs 2-3 vs 4-6 risk genotypes, P = 7.20×10−8). The predictive model using the 14 SNPs showed a statistically significant cross-validated accuracy in predicting the groups at high and low risk groups for poor survival (P = 0.0050). The high-risk group was independently associated with the survival in a multivariate analysis that included conventional clinicopathological variables (P = 0.0060). Conclusions: Using a panel of the SNPs, the prediction of the survival and optimization of the individualized treatment for patients with advanced PCa may be possible.
Predictive biomarkers in circulating tumor cells (CTC) from patients with castration-resistant prostate cancer (CRPC) through genomic analysis.
Authors: Danila Daniel Costin , Anand Aseem , Yao Jianchao , Gierszewska Magdalena , Kramer Melissa , Muller Stephanie , Fleisher Martin , McCombie William R. , Scher Howard I. 
Published: February 2017

179 Background: Although designed to retain activity against known androgen receptor (AR) mutants, it is predicted that new MDV3100-resistant mutations may predict for sensitivity to the drug in clinic. To predict for tumor sensitivity to treatment with novel AR targeted therapies, we explored the frequency of mutation detection and copy number alteration in CTC isolated from patients with CRPC enrolled on a trial with MDV3100. Methods: We used fluorescence-activated cell sorting (FACS) methodology to enrich EpCAM+, CD45−, DAPI− cells. For mutation detection and genomic copy number alteration in CTC in low number of cancer cells found in clinical samples, we optimized next-gen deep sequencing by Illumina. Results: In patients with progressive CRPC, >10 or >50 EpCAM+ events (EPE) were isolated by FACS in 88% or 58% of patients, in whom 32% and 10% had unfavorable (>5 cells/7.5 ml) CTC counts using CellSearch. EPE, expressing prostate-specific mRNAs, provide sufficient high quality DNA for genomic sequencing and copy number analysis. Adequate coverage was obtained from as few 50 EPE, with a recovery rate of 89% from FACS sorted samples. The detection threshold of a mutation was established at 1:4 alleles. To further expand genomic profiling in CTC, we optimized Nimblegen exome mutation detection by deep sequencing on HiSeq PE101. Our initial analysis established the polymorphism frequency detection thresholds in heterogeneous cell populations, and confirmed the sequencing coverage. Somatic missense mutations in AR, APC and TP53 found in CTC but not in paired WBC were confirmed by Sanger sequencing. In parallel, copy number alterations in CTC are studied. Conclusions: Somatic mutations detected in CTC isolated from patients with CRPC can serve as predictive markers of tumor sensitivity to targeted therapies. We established standard operating procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection thresholds in heterogeneous cell population. Currently we are proceeding to clinical samples to study the associations between specific molecular alterations in CTC as predictive markers of sensitivity and clinical outcomes.
Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer.
Authors: Fong Lawrence , Weinberg Vivian K. , Corman John M , Amling Christopher L , Stephenson Robert A , Formaker Carl , Chan Stephen E , Simko Jeffrey , Sims Robert Brownell , Carroll Peter , Small Eric Jay 
Published: February 2017

181 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To better understand the immunologic effects of sipuleucel-T, an open-label Phase 2 study (P07‐1; NCT00715104 ) of sipuleucel-T prior to radical prostatectomy (RP) was undertaken in patients with localized prostate cancer. Methods: Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to RP. Prostate biopsies (pre-treatment) and tissue from RP (post-treatment) were assessed for the presence of lymphocytes by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP infusions of sipuleucel-T. To date, tissue IHC analysis has been completed in 19 patients. Treatment-related AEs were manageable and reversible. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (>2‐fold) in CD3+ and CD4+ T cells populations were observed at the tumor rim (where benign and malignant glands interface), compared with the pre-treatment biopsy (ANOVA post hoc Newman-Keuls test: p=0.0002, 0.0002, respectively). CD8+ T cells or CD56+ cells were not significantly increased at the tumor rim compared with benign biopsy regions. Conclusions: Neoadjuvant sipuleucel-T treatment appears to result in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. These data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.
Pain control and delay in time to skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA): Long-term follow-up.
Authors: Basch Ethan M. , De Bono Johann Sebastian , Scher Howard I. , Molina Arturo , Sternberg Cora N. , Fizazi Karim , North Scott A. , Chi Kim N. , Jones Robert J. , Goodman Oscar B. , Mainwaring Paul N. , Farr Amanda M. , Rothman Margaret , Hao Yanni , Liu Cameron S. , Kheoh Thian San , Haqq Christopher M. , Efstathiou Eleni , Logothetis Christopher 
Published: February 2017

183 Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increased overall survival in mCRPC post-docetaxel (D) in both interim and updated analyses at 552 and 775 events, respectively. Interim data also showed a significant benefit of AA on patient (pt) reported pain. We present long-term outcomes of the effect of AA on pain and SREs. Methods: In this international randomized double blind study of AA (1 g QD) + prednisone (P) (5 mg BID) vs placebo + P in mCRPC post-D, pain was assessed at baseline and each treatment cycle until treatment discontinuation using the BPI-SF questionnaire. Palliation/progression of pain intensity (P-INT) and pain interference (P-INF) were evaluated using a priori definitions. P-INT palliation was defined as ≥ 30% improvement in pt reported “worst pain in last 24 h” (on 0-10 numerical rating scale) durable for ≥ 28 d without increased analgesic use (by WHO criteria) in eligible pts (those with significant baseline pain). Conversely, P-INT progression was defined as ≥ 30% deterioration, or increased analgesic use, over ≥ 28 d. Results: 797 pts were randomized to AA + P, 398 to placebo + P. Median follow-up was 20.2 mos. Median time to SRE was 25.0 mos (AA + P) vs 20.3 mos (placebo + P), p = 0.0001. Pain data were available for most patients; the cumulative amount of missing data ranged from 5% at Cycle 1 to 7% at Cycle 20. AA + P improved P-INT outcomes (Table); P-INF benefits were similar and also highly significant. Conclusions: Benefits of AA + P observed in the interim analysis, including superior and more durable pain relief and delay of pain progression and SREs, were maintained with longer follow-up. Additional analyses of the potential relationships between pain/SREs and other outcomes, as well as of prednisone’s effect on pain palliation in the control arm, are ongoing. [Table: see text]
Biochemical, pathologic, toxicity, and quality-of-life outcomes in a five-fraction hypofractionated accelerated radiotherapy treatment using standard linear accelerators and gold seed fiducials.
Authors: Loblaw D. Andrew , Cheung Patrick , Tang Colin I , Quon Harvey Charles , Pang Geordi , Morton Gerard , Mamedov Alexandre , D'Alimonte Laura , Deabreu Andrea , Tirona Romeo , Jain Suneil 
Published: February 2017

186 Background: Biological dose escalation through hypofractionated image-guided radiotherapy (H-IGRT) holds the promise of improved patient outcomes, system capacity but decreased cost. In 2006 we initiated a prospective trial of H-IGRT of patients with low risk localized prostate cancer. In this report, we report the toxicities, quality of life (QOL), biochemical and pathologic outcomes of this cohort with more mature follow-up. Methods: A phase I/II study in which patients with T1-2b, Gleason≤6, and PSA≤10 ng/ml prostate cancer received 35 Gy in 5 fractions, once a week over 29 days. No patients received hormone therapy. Treatment was delivered with intensity modulated radiotherapy (IMRT) on standard linear accelerators, with daily image guidance using gold seed fiducials, and a 4 mm CTV-PTV margin. CTCAE v3.0 and RTOG late morbidity scores were used to assess acute and late toxicities, respectively. QOL was assessed by the Expanded Prostate Cancer Index Composite (EPIC). Biochemical control (BC) was defined by the Phoenix definition, adjusted for benign bounce. Results: As of September 2011, 83 patients have completed treatment with a median follow-up of 42 months (range 12–60 months). Median age was 67y (42 – 82y). 78 patients (92%) were T1a-c; all had Gleason 6 cancers; median PSA was 5.3 (0.8 – 9.9 ng/ml). 82 (99%) had BC; the remaining patient had a negative biopsy and a history of chronic prostatitis. The median PSA on last visit was 0.69 ng/ml (.02 – 2.6 ng/ml). Of 59 patients who have had a biopsy to date, 2 (3%) were positive but both are under BC. The following toxicities were observed: acute grade 3+: 0% GI, 1% GU, 0% fatigue; late grade 3+: 1% GI, 1% GU. Median transformed QOL scores at baseline (0.5 SD) and 36mo follow-up are: urinary – 95% (4.1), 93%; bowel – 96% (4.8), 96%; sexual – 65% (13.7), 51%; and hormonal – 95% (5.3), 95%. Conclusions: This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control. A randomized study versus standard fractionation should be performed.
Physical activity and prostate gene expression in men with low-risk prostate cancer.
Authors: Magbanua Mark Jesus Mendoza , Richman Erin L , Sosa Eduardo V , Jones Lee , Simko Jeffrey , Shinohara Katsuto , Haqq Christopher M. , Carroll Peter , Chan June M. 
Published: February 2017

189 Background: Physical activity (PA), in particular longer duration or higher intensity, may reduce the risk of PCa progression and PCa-specific mortality in men diagnosed with clinically localized PCa. However, the molecular mechanism(s) by which PA exerts its protective effect in the prostate remains unknown. We examined the correlation of PA and gene expression patterns in men with low risk prostate cancer who elected to undergo active surveillance. Methods: Morphologically normal prostate tissue was obtained from men who subsequently participated in a clinical trial focused on nutritional supplements (previously published microarray dataset #GSE27140). Of the original sample (n=84), 70 completed a brief PA questionnaire and were dichotomized based usual PA [e.g. any vigorous PA (yes/no), 3+ h/wk vigorous PA (yes/no)]. Differential expression and pathway (gene set) analyses between groups were performed using Significance Analysis of Microarrays. Genes and gene sets with a false discovery rate ≤0.10 and 0.20 were considered significant, respectively. Results: Gene expression analysis detected 184 significant genes that were differentially expressed between men who performed vigorous PA for 3+ h/wk (n=23) and those who did not (n= 47). Up-regulated genes included the known tumor suppressors, BRCA1 and BRCA2. Furthermore, pathway analysis revealed that cell cycle and DNA repair pathways were positively modulated in men who participated in 3+h/wk vigorous PA vs. not. Consistent with the data on vigorous PA and clinical outcomes in men with PCa, the duration of vigorous PA was important; there were no significant genes detected when comparing men who participated in any vigorous PA to men who did none. Conclusions: Prostate gene expression and pathway analyses revealed candidate genes and in vivo pathways that may be modulated by participating in 3+ h/wk of vigorous PA. These data provide mechanistic insight into how 3+ h/wk of vigorous PA may offer PCa-specific benefits. Furthermore, understanding the molecular mechanisms by which such PA affects normal prostate gene expression may aid the development of strategies to prevent or delay PCa progression.
The influence of physician densities and patient characteristics on the decision to treat prostate cancer patients with varying clinical benefit.
Authors: Yu James B. , Aneja Sanjay , Makarov Danil V. , Roberts Kenneth B , Gross Cary P. 
Published: February 2017

19 Background: Our study investigates whether regional variations in physician densities or patient populations influence the decision to treat patients with prostate cancer. Methods: Data from the NCI Surveillance, Epidemiology, and End Results (SEER) database was combined with the health system factors from the Area Resource File for Health Service Areas (HSA). Patients treated from 2004-2007 with low likelihood of benefit from treatment (Gleason 6, PSA <10.0, stage T1cN0M0, and age >75) or high likelihood of benefit (Gleason 8-10 or PSA >20.0 or stage T3N0M0, aged <60) were analyzed. Health system factors analyzed were; radiation oncologist, urologist, and primary care provider densities, % unemployment, and % with at least a high school education. Patient factors analyzed included race and marital status. A logistic regression model was built to test the association between variables and attempted curative therapy (radical prostatectomy, EBRT, and/or brachytherapy). Results: For the 2630 pts with the lowest likelihood of benefit, 56.1% underwent some form of attempted curative therapy. White pts and those residing in HSAs with better-educated populations were less likely to be treated, whereas married pts (OR 0.69 [SE 0.07, p<.001]) were more likely to receive treatment. For the 3207 pts with the highest likelihood of clinical benefit from treatment, 91.1% underwent curative therapy as first initial treatment. Being married was again associated with a higher odds of curative therapy (OR 1.68 [SE 0.22], p<.001) whereas being black was associated with a lower odds (OR 0.43 [SE 0.16], p=.02). Both radiation oncologist density and urologist density were not found to influence receipt of treatment in either group. Conclusions: Radiation oncologist and urologist densities do not seem to influence the decision to treat prostate cancer at the regional level, whereas marital status is a significant predictor of attempted treatment. Though health system factors may influence the receipt of proper therapy, a patient’s decision-to receive treatment is potentially more influenced by his interpersonal relationships.
VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC).
Authors: Eisner Joel Robert , Abbott David H , Bird Ian M , Rafferty Stephen W , Moore William R , Schotzinger Robert J 
Published: February 2017

198 Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extragonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995–2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.
Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC).
Authors: Pond Gregory Russell , Armstrong Andrew J. , Wood Brian A. , Leopold Lance Howard , Galsky Matt D. , Sonpavde Guru 
Published: February 2017

204 Background: The efficacy of docetaxel following exposure to androgen synthesis inhibitors such as KC or abiraterone acetate (AA) is unknown. Given the emerging use of pre-docetaxel AA and docetaxel’s inhibition of androgen signaling, we retrospectively evaluated the efficacy of every 3 week docetaxel with prednisone (DP) in mCRPC previously exposed to KC as compared to KC-naïve patients. Methods: A randomized phase II trial of men with mCRPC treated with DP+AT-101 (bcl-2 inhibitor) vs. DP+placebo was analyzed (stratified for pain and performance status). Both arms were combined for analysis as no significant differences were seen. Overall survival [OS], progression-free survival [PFS], objective response [ORR], pain and PSA response rates were estimated with and without prior KC. Results: Of 220 evaluable men, 40 (18.2%) received prior KC (median duration=2.0 months, maximum=31.1 months). These 40 men had less visceral disease (15% vs 28%), more prior radiotherapy (70% vs 51%), and increased prior radiological (38% vs 21%) or bone scan progression (55% vs 41%). Efficacy outcomes were not statistically different (table). After adjusting for baseline stratum and treatment group, prior KC did not appear to significantly change OS with DP-based therapy (HR 1.34, 95%CI: 0.86–2.09, p=0.20). Conclusions: Similar outcomes were observed in mCRPC treated with DP-based therapy with or without prior KC. Given the marginally inferior survival with prior KC, evaluation of docetaxel outcomes following AA is of clinical importance, given its more potent CYP17 inhibition. [Table: see text]
The influence of daily localization during treatment of prostate cancer on acute toxicity.
Authors: Rossi Peter john , Cooper Sherrie , Jani Ashesh B. 
Published: February 2017

214 Background: Various localization techniques are used in clinical practice but little comparative effectivess data exists. The purpose of this investigation is to assess the impact of daily localization (L) of the prostate on toxicity during definitive treatment of prostate cancer with intensity modulated radiotherapy (IMRT). Methods: This study details an IRB approved retrospective review of three cohorts of patients treated for prostate cancer utilizing IMRT and different L technologies at four academic hospitals. Patients were treated with no technique (N), gold markers (G), or electromagnetic beacons [Calypso] (C) for daily L. Acute genitourinary (GU) and gastrointestinal (GI) toxicity was assessed according to RTOG toxicity criteria; toxicity rates between the groups were compared using the chi-square test. Ordered logit regression of all major demographic (age, race), disease (PSA, Gleason grade, and T-stage) and treatment (hormones, pelvic nodal treatment, total dose, and prior TURP) characteristics on GU and on GI toxicity were performed. Results: One hundred fifty four men who received definitive dose escalated IMRT (no brachytherapy or post-prostatectomy patients) for prostate cancer from 2006 to 2010 and were included (G: n=47; C: n=47; N: n=60). The cohorts were balanced except race (higher percentage of African Americans in the N group, due to hospital demographics) and higher grade and use of pelvic nodal treatment (which were more common in the G and C groups). Bladder V40 and V70 were higher in the N group (45.4%/24.3%) compared to C (27.9%/12.3%) and G (37.4%/18.4%) groups; however, rectal V40 and V70 were similar among all 3 groups. Toxicity results are shown in the Table; as shown the C and G groups had lower GU toxicity (p <0.001) respectively compared to the N group; no significant differences in GI toxicity were seen among the 3 groups. Ordered logit regression showed only daily L (p=0.041) reached significance in lowering GU toxicity, and only pelvic RT use (p =0.008) reached significance in increasing GI toxicity. Conclusions: In patients treated with IMRT, daily L was associated with lower acute GU toxicity but not acute GI toxicity.