bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early assessment of PSA response in CRPC patients treated with enzalutamide (Enza) or abiraterone (Abi).
Authors: Guccione Jeffrey R. , Ledet Elisa M. , Stolten Michael D. , Steinberger Allie E. , Chow Lydia D. , Cotogno Patrick , Lewis Brian E. , Sartor A. Oliver 
Published: February 2017

249 Background: Abi and Enza are used in treating metastatic CRPC. Primary resistance is well described but little data exists for early treatment responders. Further characterization of patients with early PSA declines was the goal of this study. Methods: Single institution, retrospective reviews were performed on 84 CRPC patients (pts) treated with Abi or Enza. PSAs were recorded for the duration of treatment. The primary end point was to describe receiver operating characteristics (ROC) of early PSA changes, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥ 50% decrease in PSA from baseline). 12 additional clinical covariates were also evaluated as treatment response predictors. Results: 30/63 pts in the Abi treatment group and 12/44 pts in the Enza treated group had a PSA treatment response at some point. Among the “eventual” Abi responders, some achieved a response early; 16/30 at 4 weeks and 22/30 at 8 weeks. Of Enza “eventual” responders, 7/12 achieved response at 4 weeks. For early responders (either 4 or 8 weeks), Abi pts median treatment time was 336 days. Enza early responders median treatment was time 303 days. For ROC analysis of PSA changes at 4 & 8 weeks, in terms of predicting ‘eventual’ responders, the Abi group had an area under the curve (AUC) of 0.86 ± 0.07 and 0.93 ± 0.08, respectively. Enza ROC analysis of PSA change at 4 weeks had an AUC of 0.97 ± 0.03. Sensitivities and specificities were also described for various PSA change thresholds in each group. Ideal cut-off points for Abi at 4 weeks was a 37% decrease in PSA (sensitivity: 0.74, specificity: 0.97) and at 8 weeks was a 33% decrease (0.82, 0.97). For Enza ideal cut-off at 4 weeks was a 31% PSA decrease (0.82, 0.93). Covariate analysis of the Abi pts indicated that metastasis at diagnosis (P = 0.048) and prior taxanes predicted resistance to treatment (P = 0.019), as measured by < 50% decline in PSA. All covariates in the Enza pts failed to reach significance. Conclusions: Results suggest that early PSA changes for both Enza and Abi may be a reliable way for clinicians to predict long-term PSA response. This may allow for earlier modifications to be made in patient management for those not achieving an early PSA response.
Gene expression in prostate tissue according to frequency of ejaculation.
Authors: Rider Jennifer R. , Sinnott Jennifer A , Mucci Lorelei A. 
Published: February 2017

25 Background: Long-term prospective data from within the Health Professionals Follow-up Study (HPFS) suggest more frequent ejaculation throughout adult life may be protective against future development of prostate cancer (PCa). Compared to men with an average monthly ejaculation frequency (EF) of 4-7 times/month during adulthood, men who ejaculated at least 21 times per month were 30% less likely to be diagnosed with PCa after adjustment for a number of potential confounders and PCa screening. We sought to explore mechanisms through which EF may influence PCa development utilizing gene expression data assessed on tumor and adjacent normal tissue. Methods: In 1992, 31,925 HPFS participants were questioned on their average monthly EF at ages 20-29, 40-49, and in the previous year; 3,839 of these men were later diagnosed with PCa. Expression of 20,254 genes was available from archival tumor tissue from 156 cases; 84 of these cases also had data from adjacent normal tissue. We regressed each gene expression value as a continuous outcome on EF, age at diagnosis, and year at diagnosis. We calculated the p value associated with the coefficient for the EF variable as a measure of the strength of the trend test. We then used t values for the coefficients to rank the genes, and ran a gene set enrichment analysis to identify pathways with genes associated with EF. Results: We observed that while there was not much signal in the tumor tissue, there was enrichment of smaller p values in the adjacent normal tissue. EF in the time period most proximal to diagnosis is most strongly associated with gene expression in normal tissue. Focusing on the association between gene expression in normal tissue and EF in the year prior to the questionnaire (1991), the top six differentially expressed genes were OR4K1, CCDC138, SERPINA9, TRMT61B, ZNF302, and ASB4. Gene set enrichment analysis revealed a substantial number of pathways differentially expressed at the FDR <0.05 threshold. Conclusions: Identifying changes in gene expression associated with EF in normal prostate tissue provides further support for a biological role of ejaculation frequency in the etiology of PCa. Notably, pathways downregulated with increasing ejaculation frequency were primarily immune related.
Comparison of abiraterone acetate (Abi) versus ketoconazole (Keto) in chemotherapy-naive patients (CN-pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: Peer Avivit , Neumann Avivit , Sella Avishay , Rosenbaum Eli , Neiman Victoria , Gottfried Maya , Kuchuk Iryna , Kovel Svetlana , Sarid David , Gez Eliahu , Mermershtain Wilmosh , Rouvinov Keren , Carducci Michael Anthony , Eisenberger Mario A. , Sinibaldi Victoria J. , Berger Raanan , Keizman Daniel 
Published: February 2017

260 Background: Abi is a standard treatment (tx) in CN-pts with mCRPC. It is a potent and selective CYP 17 inhibitor. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17. Clinical data (Peer et al, Prostate 2014) suggests that in docetaxel (D) refractory mCRPC, the outcome of abi tx may be superior to keto. However, there are limited clinical data comparing both agents in CN-pts with mCRPC. We aimed to compare the clinical effectiveness of abi vs keto in CN-pts with mCRPC, who were treated after the year 2004 (approval of D for the tx of mCRPC). Methods: Records from 72 CN-pts with mCRPC treated with abi in 5 Israeli centers were reviewed retrospectively, and matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012) to pts treated with keto 200 - 400 mg 3x day (international database, n = 156, from 4 centers across the US and Israel). We compared the PSA response (decrease ≥ 50% from baseline), biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. Results: The groups were matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012), based on pretreatment NLR and PSA doubling time, and the prior response to a gonadotropin-releasing hormone agonist. The groups were balanced regarding age (72 abi vs 70 keto), time from primary tx to disease relapse, gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), and ECOG PS. In the groups of abi vs keto, PSA response was 75% vs 47% (OR 3.8, p = 0.04), median biochemical PFS 12 vs 6 months (HR 0.62, p = 0.03), median radiological PFS 16 vs 8 months (HR 0.54, p = 0.01), median OS not reached after a median follow-up time of 18 months vs 26 months, and tx interruption d/t adverse events 10% vs 22% (0R 0.65, p = 0.05). Conclusions: In CN-pts with mCRPC, the outcome of pts treated with abi may be superior to keto.
Phase I/II study of stereotactic ablative radiotherapy including regional lymph node irradiation for patients with high-risk prostate cancer (SATURN): Early results.
Authors: Musunuru Hima Bindu , D'Alimonte Laura , Davidson Melanie , Ho Ling , Cheung Patrick , Vesprini Danny , Liu Stanley K. , Chu William , Chung Hans T. , Ravi Ananth , Deabreu Andrea , Bhounr Zeeba , Zhang Liying , Commissso Kristina , Loblaw Andrew 
Published: February 2017

264 Background: Dose escalation using five-fraction stereotactic ablative radiotherapy (SABR) is gaining popularity in the treatment of prostate cancer. This has not been extensively tested in the context of pelvic radiation for high-risk groups. The objectives of study are to report early toxicity and quality of life outcomes in patients following 5-fraction prostate and pelvic radiation. Methods: A phase I/II study was performed where high-risk prostate cancer patients (T3a-3b or Gleason score ≥ 8 or PSA > 20ng/ml) received 40Gy to prostate and 25Gy to pelvis and seminal vesicles in 5 weekly fractions, on a gantry-based platform. A 3mm planning target volume margin to the prostate and a 6mm margin to the lymph nodes was applied. Image guidance was performed using gold seed fiducials and cone beam computerized tomography. Androgen deprivation therapy (ADT) was used for 12-18 months. Common Terminology Criteria for Adverse Events version 3.0 was used to assess toxicities at 3- and 6-months. Quality of life data (QOL) was captured using EPIC questionnaire. A minimally clinically important change (MCIC) definition was triggered if the EPIC QOL score decreases > 0.5 SD, where SD is the standard deviation of baseline scores. Results: Thirty patients completed the planned treatment with a median follow up of 11.9 months (IQR 8.3, 13.0). The following toxicities were observed: grade 2 genitourinary (GU): 50% at 3 months and 34.5% at 6 months; grade 2 gastrointestinal (GI): 3.3% at 3months and 6.9% at 6 months. No ≥ grade 3 toxicities were observed. Mean (95% Confidence Interval) EPIC urinary QOL scores were 86.6 (81.9-91.3), 87.1(81.4-92.6) and 86.1(80.2-92.0) at baseline, 3 months and 6 months and the bowel scores were 94.1(91.3-97.0), 93.2(89.1-97.2) and 93.2(89.5-96.8), respectively. Proportion of patients experiencing MCIC at 3 months and 6 months were 27.8% and 31.8% for urinary domain, 23.5% and 28.6% for bowel domain; respectively. Conclusions: This gantry-based novel fractionation schedule incorporating pelvic radiation for high-risk prostate cancer in combination with ADT is feasible and well tolerated in the acute setting. Clinical trial information: NCT 01953055.
Changes in T cell immunity in patients with metastatic castration resistant prostate treated with Radium-223 treatment.
Authors: Kim Joseph W. , Kang Youna , Shin Min , Deshpande Hari Anant , Hurwitz Michael E. , Roberts John D. , Cardinale Joseph G. , Narayana Ashwatha , Kang Insoo , Petrylak Daniel Peter 
Published: February 2017

295 Background: The bone seeking calcium mimetic, Radium223 (Ra223), emits high energy alpha particle that cause irreparable double strand DNA breaks in osseous metastases. Ra223 improves survival in patients with bone-predominant metastatic castration resistant prostate cancer (mCRPC). The effect of Ra223 on the host immune system, and T cell immunity in particular, is unknown. Methods: Eligible patients include men with mCRPC, osseous metastases and a clinical indication for Ra223 were eligible. Blood samples were collected at the following time points: prior to the first, second, and fourth treatments (tx) and 4 weeks after the sixth dose. Peripheral blood mononuclear cells (PBMCs) were purified and stained with a cocktail of antibodies to surface and effector immune molecules. Some PBMCs were stimulated and stained for intracellular cytokines (IFN-g, TNF-a, IL-13, IL-17, and IL-21). Stained cells were analyzed by flow cytometry. Results: A total seven patients completed at least two sample collections. The median number of prior lines of therapy was three. Median age was 71 (55-79). Median PSA was 78 (2-351). Effector memory (EM) CD8+ T cells were divided into two subsets expressing high and low levels of the IL-7 receptor alpha chain (IL-7Ra) with distinct cellular characteristics including perforin expression. The frequency of IL-7Rahigh and low EM CD8+ T cells expressing programmed death protein 1 (PD-1) was decreased after Ra223 treatment (pre vs. post, median (%) ± interquartile range, 14.3 ± 12.9 vs. 7.2 ± 20.9, P = 0.03; 16.7 ± 28.8 vs. 14.1 ± 37.8, P = 0.015 by Wilcoxon matched-pairs signed rank test). A similar finding was observed in the frequency of memory CD4+ T cells expressing PD-1 after the treatment (median (%) ± interquartile range, 7.2 ± 7.7 vs. 3.9 ± 3.4, P= 0.03). Conclusions: In this preliminary cohort of patients, Ra223 tx was associated with decrease in PD-1 expression by effector T cells. Further investigations of an immune mechanism of Ra223 mediated antitumor activity are warranted.
Differential gene expression in prostate tissue according to vasectomy.
Authors: Wilson Kathryn M , Gerke Travis , Ebot Ericka , Sinnott Jennifer A , Rider Jennifer R. , Mucci Lorelei A. 
Published: February 2017

298 Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.
PARPi in PCa results in decreased availability of DNA repair factors.
Authors: Schiewer Matthew Joseph , Knudsen Karen E. 
Published: February 2017

301 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).
The utility of serum CA9 in prognostication in prostate cancer.
Authors: Smith Alan D. , Truong Mathew , Bristow Rob , Wouters Bradley , Milosevic Michael F. , Joshua Anthony M. 
Published: February 2017

309 Background: Solid tumours are invariably less well-oxygenated than their normal tissue counterparts. Tumour hypoxia is important because it leads to resistance to radiotherapy and anticancer chemotherapy, and has been associated with prognosis in localized prostate cancer. Carbonic anhydrase IX (CA9), a member of a family of metalloenzymes that catalyze the reversible hydration of carbon dioxide, is considered to be one of the best biomarkers of cellular hypoxia. Although CA9 has been negatively correlated with survival in various cancers, no published data has demonstrated prognostic significance in prostate cancer. Methods: We retrospectively assessed CA9 in samples from 68 men with localized high-risk prostate cancer (LD) treated with radical prostatectomy (RP) or radiotherapy (RT), and twenty men with CRPC treated with docetaxel chemotherapy (DC). Samples were taken before treatment with RP and RT (in LD) or DC (in CRPC) from 2010 to 2012 at the Princess Margaret Cancer Center. Results: Of the 68 patients with LD, 57 patients underwent RP and 11 patients underwent RT. The proportion of patients with recurrence was 74% for RP and 55% for RT. Median CA9 for patients with LD and recurrence was 147 (range 60-1061) and 114 (range 48-1293) for those with no recurrence. Baseline CA9 was not associated with recurrence or PSA in these patients (p 0.79 and 0.09 respectively). Median follow-up for patients with CRPC was 14.1 months and 17 of 20 patients had confirmed death at the end of follow-up. The median CA9 level before DC was 155 pg/mL (range 38-1086). CA9 level before chemotherapy correlated with overall survival -0.41, however this did not reach statistical significance (p 0.10). There was no association between CA9 and PSA in CRPC (p 0.51). Conclusions: Absolute CA9 level negatively correlated with survival in men with CRPC, with a level that approached statistical significance in this small cohort. CA9 was not associated with recurrence of disease in men with LD, treated with either RP or RT. More data evaluating the relationship between hypoxia, CA9 and outcome in prostate cancer is needed before recommending its use as a biomarker in CRPC.
Urinary and bowel quality of life after image-guided, intensity modulated radiation therapy to the prostate bed.
Authors: Abuodeh Yazan , Naghavi Arash , Juan TzuHua , Ma Zhenjun , Wilder Richard 
Published: February 2017

312 Background: Majority of patients with adverse pathological features on radical prostatectomy do not receive post-prostatectomy radiation due to concerns of negative impact on their quality of life (QOL). The purpose of this study is to evaluate QOL after post-prostatectomy intensity modulated radiation therapy (IMRT) in the “adjuvant”(ADJ) setting for positive surgical margins, extraprostatic extension, or seminal vesicle invasion with a PSA < 0.2 ng/mL and a “salvage”(SAL) setting for a PSA ≥ 0.2 ng/mL at the start of IMRT. Methods: Between 2004 and 2013, 130 patients underwent IMRT to the prostate bed. Sexual Health Inventory for Men (SHIM), International Prostate Symptom Score (IPSS), and Expanded Prostate cancer Index Composite-26 for bowel (EPIC-26-bowel) scores were recorded before radiation and at 3-month intervals after completion of treatment to assess sexual, urinary, and rectal QOL, respectively. A mixed model for repeated measurements was used to compare QOL scores over time among various subgroups. Results: ADJ and SAL radiation were delivered to 48 (37%), 82 (63%) respectively. Total radiotherapy doses were 64.8-68.4 Gy using 1.8-Gy daily in 56 (43%) patients and 70.2-72.0 Gy in 74 (57%) patients. Androgen deprivation therapy (ADT) was given to 4/48 (8%) ADJ patients and 9/82 (11%) SAL patients. Fiducials were placed in prostate bed for image guidance in 42 (32%) patients. Median follow up was 46 months. Total radiation dose did not significalntly affect QOL. SAL IMRT was associated with worse mean SHIM scores (3 points, p = 0.002) and ADJ IMRT was associated with lower mean IPSS scores (2 points, p = 0.03). Mean EPIC-26-bowel scores were lower without fiducial markers (16 points, p < 0.0001). Conclusions: SAL IMRT was associated with worse sexual QOL, possibly due to less frequent usage of phosphodiesterase-5 inhibitors. ADJ IMRT was associated with worse urinary QOL, possibly due to a shorter post-operative recovery period. Fiducial marker resulted in better rectal QOL due to greater rectal sparing. Urinary and rectal QOL with post-prostatectomy, image-guided IMRT compare favorably with previous QOL reports involving three-dimensional conformal radiation therapy.
Duration of androgen deprivation therapy for high-risk prostate cancer: Application of randomized trial data in a tertiary referral cancer center.
Authors: Muralidhar Vinayak , Regan Meredith M. , Werner Lillian , Nakabayashi Mari , Evan Carolyn , Bellmunt Joaquim , Choueiri Toni K. , Elfiky Aymen , Harshman Lauren Christine , McKay Rana R. , Pomerantz Mark , Sweeney Christopher , Taplin Mary-Ellen , Kantoff Philip W. , Nguyen Paul L. 
Published: February 2017

33 Background: We wished to evaluate the incidence and predictors of the use of long-term (2-3 years) vs. shorter-term androgen deprivation therapy (ADT) in radiation-treated men with high-risk prostate cancer. Methods: We identified 302 patients from the Dana-Farber Cancer Institute patient registry diagnosed with high-risk prostate cancer (T3a or PSA > 20 ng/mL or Gleason score 8-10) between 1993 and 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate predictors of receiving shorter-course ADT than recommended by guidelines (< 2 years). Results: The course of ADT intended by physicians increased following the 2009 publication of trials showing the superiority of 2-3 years versus 4-6 months of ADT, with 43.5% intending ≥ 2 years before vs. 61.4% after (p=0.014). Starting in 2010, 49.4% of patients actually received less than 2 years of ADT. The most common reasons for receipt of shorter-course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on MRI only as the sole high-risk feature, or participation in a clinical trial. ACE-27 moderate to severe comorbidity (adjusted hazard ratio [AHR]=2.94), Gleason score less than 8 (AHR=5.66), and PSA < 20 ng/mL (AHR=4.19) all predicted receipt of shorter-course ADT (p<0.05 in all cases). Conclusions: In a tertiary-care setting, rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately half of patients continued to receive shorter-course ADT, often due to intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.