Benign prostate enlargement, referred to as BPH (benign prostatic hyperplasia), is a common disease in aging men causing problems such as incontinence and urinary retention. The Medical Therapy of Prostatic Symptoms (MTOPS) study, funded by the NIH/NIDDK, was a double-blind, placebo-controlled clinical trial in over 3,000 men that tested if medical therapy could prevent disease progression in men with symptomatic BPH. The study ended in 2002 and found that finasteride and doxazosin worked best in combination to prevent disease progression. The MTOPS study included a tissue sub-study, still in progress, in which prostate biopsies were obtained at baseline and end-of-study from approximately a third of the participants. The co-investigator of this grant, Dr. Lucia, was the lead pathologist for MTOPS and has participated in the ancillary studies phase with the MTOPS Prostate Samples Analysis (mPSA) consortium. As part of the tissue studies, Dr. Lucia and his research group at the University of Colorado Denver used immunohistochemical/histological techniques and advanced computer imaging on biopsy specimens to identify histologic changes associated with BPH progression. The goal was to evaluate a number of parameters on biopsies and determine their association with symptomology, clinical findings, and disease progression. Our novel techniques were used to quantify each biopsy specimen for tissue composition (i.e. stroma, epithelium, smooth muscle), apoptosis (using activated caspase-3) and proliferation (Ki67) levels, microvessel density (CD34), and the amount of total inflammation (CD45) with specific emphasis on macrophages (CD68) and T-lymphocytes (CD4, CD8). We hypothesized that men who had progression of their BPH would demonstrate higher levels of these biomarkers on baseline biopsies. If such links can be identified, this could lead to additional therapeutic options that specifically target pathologic changes in the tissue composition of BPH, degree of microvessel density (MVD), and characterization of inflammatory components for men with BPH, and to a better understanding about who is likely to progress. All that remains is to complete the data analysis. Due to earlier difficulties with personnel changes and lapses in funding with the MTOPS/mPSA statistical core and its subsequent closure, tissue data merger and analysis with the clinical database was never completed. In this proposal we are requesting funds for salary support of an epidemiologist with experience in prostatic diseases to complete the analyses. We expect that at least four papers will result from this effort: 1) baseline and longitudinal compositional analysis of BPH tissue related to clinical findings and progression, 2) chronic inflammation in relation to clinical findings and BPH progression;3) cell turnover (proliferation and apoptosis) and angiogenesis (MVD) in relation to risk of BPH progression, and 4) development of a nomogram to determine who is at risk for disease progression employing the results from these tissue studies in combination with established clinical factors.
The Medical Therapy of Prostatic Symptoms (MTOPS) clinical trial looked at using drugs to treat BPH (benign prostatic hyperplasia or prostate enlargement), a common disease in aging men that causes many urinary problems like incontinence and urinary retention. MTOPS included a sub-study in which men had a prostate biopsy to collect tissue for the identification of changes associated with worsening of BPH that could be used in the future to better treat the disease. Because MTOPS ended before the data analysis was completed, this proposal asks for funds to complete the analysis and publish the results in the scientific literature.
|Torkko, Kathleen C; Wilson, R Storey; Smith, Elizabeth E et al. (2015) Prostate Biopsy Markers of Inflammation are Associated with Risk of Clinical Progression of Benign Prostatic Hyperplasia: Findings from the MTOPS Study. J Urol 194:454-61|