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Abstract: Altered signaling pathways resulting from aberrant changes in epigenetic parameters may play a pivotal role in carcinogenesis. To identify biological pathways likely to be affected by methylation-mediated alterations in gene expression in prostate cancer, we performed a genome-wide methylation analysis of 27,578 CpG sites, corresponding to 14,495 genes on a pooled sample of 12 pairs of prostate tumor and adjacent normal tissues. In all, 972 CpG sites were significantly hypermethylated while 209 sites were hypomethylated in prostate tumor tissue (FDR adjusted p-value<0.05; fold change⩾2) corresponding to 1043 unique genes, which is consistent with genome-wide gene-specific hypermethylation patterns previously observed in multiple cancer models. Global hypomethylation in prostate tumor was also detected by measuring methylation changes in ALU repeat sequences. Pathway analysis of the genes with altered methylation patterns identifies the involvement of a cancer related network of genes whose activity may be heavily regulated by TNF-α in prostate tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to TNF-α-dependent apoptosis and electrophile detoxification may be intimately involved in prostate carcinogenesis. These findings may lend credence to the possibility of using tumor-specific alterations in methylation patterns as biomarkers in estimating prognosis and assessing treatment options for prostate cancer. [Copyright &y& Elsevier]

Given the heterogeneity of prognoses in patients with castrate metastatic prostate cancer, the ability to accurately predict survival is vital for optimal patient counseling, selection of treatments, clinical trial design, and interpretation of clinical data. Over the past 20 years, several prognostic models have been developed in an attempt to refine the clinician''s predictive ability. Early models were based on patients with more advanced disease. They included variables that are no longer regularly encountered today and involved cumbersome calculations that were not practical for everyday use in the clinic. Recently, 2 point-based nomograms have been developed based on pretreatment variables measured on a routine basis. These models provide a user-friendly format in which to make sophisticated predictions of survival. These models have improved our ability to predict the outcomes of patients with castrate metastatic disease. However, further work to identify novel prognostic markers to improve the accuracy of these predictions is needed. [Copyright &y& Elsevier]

Over the last decade, an increasing number of novel therapies have been tested in prostate cancer. Although each agent has potential to affect the natural history of the disease, how we should proceed, select, and test these agents to show a clinical benefit remains a dilemma. Because prostate cancer is a heterogeneous disease, an understanding of the disease states is required to screen and test novel agents. Only with the appropriate selection of disease state, trial design, and endpoints will we be able to select the most promising regimens to move forward. [Copyright &y& Elsevier]

Androgen deprivation therapy, alone or in combination with androgen signaling inhibitors, is a treatment option for patients with advanced prostate cancer (PC). When making treatment decisions, health care providers must consider the long-term effects of treatment on the patient's overall health and well-being. Herein, we review the effects of these treatments on the musculoskeletal and cardiovascular systems, cognition, and fall risk, and provide management approaches for each. We also include an algorithm to help health care providers implement best clinical practices and interdisciplinary care for preserving the overall well-being of PC patients. [ABSTRACT FROM AUTHOR]

Elderly patients (≥65 yr) with advanced prostate cancer and cardiovascular disease (CVD) conditions are often excluded from clinical trials of abiraterone acetate (AA) or enzalutamide (ENZ). Consequently, little is known about the effects of these medications on these vulnerable patients. To assess the short-term outcomes of AA and ENZ in patients with pre-existing CVDs. A population-based retrospective study. The Surveillance, Epidemiology, and End Results-Medicare–linked database was used to identify prostate cancer patients using AA or ENZ. The primary endpoint was 6-mo all-cause mortality, analyzed using modified Poisson regression modeling of relative risk (RR) adjusted for confounders and comorbidities. Among eligible patients (2845 with AA and 1031 with ENZ), 67% had at least one pre-existing CVD. Compared with those without pre-existing CVDs, having one to two pre-existing CVDs was associated with 16% higher 6-mo mortality (RR = 1.16, 95% confidence interval [CI]: 1.00–1.36), and the risk increased further among those having three or more CVDs (RR = 1.56, 95% CI: 1.29–1.88). Most of the differences in survival of patients with pre-existing CVD condition occurred within the first 6 mo of treatment. After treatment with AA or ENZ, elderly prostate cancer patients with pre-existing CVDs experienced higher short-term mortality than otherwise similar patients without CVDs. Mortality associated with CVDs did not depend on having received AA versus ENZ. Patients with pre-existing cardiovascular diseases (CVDs) experienced higher short-term mortality after abiraterone acetate or enzalutamide than those without pre-existing CVDs. It is recommended that a multidisciplinary team, including a cardiologist, evaluate patients having pre-existing CVDs in the process of making treatment decisions and monitoring potential side effects. Pre-existing cardiovascular conditions are associated with higher short-term mortality after abiraterone acetate or enzalutamide. The survival benefit observed in the pivotal clinical trials might not hold for patients with significant pre-existing cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Objectives: To describe the 5-year outcomes of patients with high-risk localized prostate cancer treated with neoadjuvant estramustine and vinblastine followed by concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT).Methods: A total of 23 patients completed therapy consisting of two 8-week cycles of vinblastine, weekly as 4 mg/m2, followed by 8 weeks of concomitant chemotherapy and 3D-CRT. Estramustine was given daily at 10 mg/kg in three divided doses. 3D-CRT consisted of a total dose of 7560 cGy.Results: Assessable patients include 9 with Stage T3 or greater tumors and 5 with lymph node metastasis at diagnosis. All patients had a Gleason score 7 or greater. The median follow-up was 60 months. Of the 23 assessable patients, 15 (65%) experienced biochemical relapse by American Society for Therapeutic Radiology Oncology criteria. The median time to prostate-specific antigen relapse was 12 months (range 7 to 16). Five patients (22%) developed metastases. The median time to metastasis had not been reached by last follow-up. Of the 23 assessable patients, 11 (48%) received no additional therapy and had noncastrate testosterone levels. Six patients had no evidence of disease and 9 patients were receiving androgen blockade. Three patients died (one of prostate cancer and two of other diseases).Conclusions: A substantial proportion of patients with unfavorable-risk localized prostate cancer achieved long-term disease control with estramustine and vinblastine and concurrent 3D-CRT, no significant long-term toxicities were seen and 48% underwent no further therapy after RT. These long-term findings support the continued study of chemotherapy combined with RT as a potential alternative to prolonged androgen deprivation. [Copyright &y& Elsevier]