Analysis of MTOPS Tissue Study Data

MTOPS 组织研究数据分析

• 批准号: 8051802
• 负责人: Kathleen C. Torkko
• 金额: $ 11.36万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051802
• 关键词: Adrenergic Antagonists; Age; Aging; American; Ancillary Study; Apoptosis; Benign; Benign Prostatic Hypertrophy; Biological Markers; Biopsy; Biopsy Specimen; CD34 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Density; Cell Proliferation; Cells; Chronic; Cicatrix; Clinical; Clinical Data; Clinical Trials; Colorado; Combined Modality Therapy; Computer-Assisted Image Analysis; Consent; Controlled Clinical Trials; Data; Data Analyses; Databases; Development; Diagnostic; Disease; Disease Progression; Double-Blind Method; Doxazosin; Drug usage; Epidemiologist; Epithelial; Epithelium; Finasteride; Funding; Future; Goals; Grant; Histologic; Histological Techniques; Human Resources; Hyperplasia; Image; Image Analysis; Incontinence; Infiltration; Inflammation; Inflammatory; Laboratories; Lead; Link; Literature; Location; Measures; Medical; Medical center; National Institute of Diabetes and Digestive and Kidney Diseases; Nodule; Nomograms; Oxidoreductase; PTPRC gene; Paper; Participant; Pathologic; Pathologist; Peripheral; Phase; Placebo Control; Placebos; Prostate; Prostatic; Prostatic Diseases; Publishing; Request for Proposals; Research; Research Personnel; Risk; Sampling; Smooth Muscle; Societies; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Testing; Therapeutic; Tissue Banks; Tissues; United States National Institutes of Health; Universities; Urinary Retention; Urine; Urodynamics; Wages; Work; angiogenesis; base; caspase-3; density; design; digital imaging; experience; inhibitor/antagonist; macrophage; men; morphometry; novel; prevent; prostate enlargement; public health relevance; urinary; urologic

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（申请人提供）：良性前列腺肥大，简称BPH（良性前列腺增生），是老年男性的常见疾病，会导致尿失禁、尿潴留等问题。前列腺症状药物治疗 (MTOPS) 研究由 NIH/NIDDK 资助，是一项双盲、安慰剂对照临床试验，在 3,000 多名男性中进行，测试药物治疗是否可以预防有症状的 BPH 男性的疾病进展。该研究于 2002 年结束，发现非那雄胺和多沙唑嗪联合使用最能预防疾病进展。 MTOPS 研究包括一项仍在进行中的组织子研究，其中约三分之一的参与者在基线和研究结束时获得了前列腺活检。此项资助的共同研究员 Lucia 博士是 MTOPS 的首席病理学家，并参与了 MTOPS 前列腺样本分析 (mPSA) 联盟的辅助研究阶段。作为组织研究的一部分，Lucia 博士和他在科罗拉多大学丹佛分校的研究小组对活检标本使用了免疫组织化学/组织学技术和先进的计算机成像技术，以确定与 BPH 进展相关的组织学变化。目标是评估活检的许多参数，并确定它们与症状、临床表现和疾病进展的关联。我们的新技术用于量化每个活检标本的组织成分（即基质、上皮、平滑肌）、细胞凋亡（使用活化的 caspase-3）和增殖 (Ki67) 水平、微血管密度 (CD34) 和总炎症量(CD45)，特别强调巨噬细胞 (CD68) 和 T 淋巴细胞 (CD4、CD8)。我们假设，前列腺增生症进展的男性在基线活检中会表现出更高水平的这些生物标志物。如果能够识别出这种联系，可能会带来额外的治疗选择，专门针对 BPH 组织成分的病理变化、微血管密度 (MVD) 程度以及男性 BPH 炎症成分的特征，并更好地了解 BPH 患者的症状。谁有可能进步。剩下的就是完成数据分析。由于早期人员变动的困难以及 MTOPS/mPSA 统计核心的资金短缺及其随后的关闭，组织数据与临床数据库的合并和分析从未完成。在此提案中，我们请求为具有前列腺疾病经验的流行病学家提供工资支持，以完成分析。我们预计这项工作将产生至少四篇论文：1）与临床发现和进展相关的 BPH 组织的基线和纵向成分分析，2）与临床发现和 BPH 进展相关的慢性炎症； 3) 细胞更新（增殖和凋亡）和血管生成 (MVD) 与 BPH 进展风险的关系，以及 4) 开发列线图，利用这些组织研究的结果结合已建立的临床数据来确定谁有疾病进展的风险因素。 公共健康相关性：前列腺症状医学治疗 (MTOPS) 临床试验着眼于使用药物治疗 BPH（良性前列腺增生或前列腺肿大），BPH 是老年男性的常见疾病，会导致许多泌尿问题，如失禁和尿潴留。 MTOPS 包括一项子研究，其中男性进行前列腺活检以收集组织，以识别与 BPH 恶化相关的变化，这些变化可用于将来更好地治疗该疾病。由于 MTOPS 在数据分析完成之前结束，因此该提案要求提供资金来完成分析并将结果发布在科学文献中。

项目成果

Prostate Biopsy Markers of Inflammation are Associated with Risk of Clinical Progression of Benign Prostatic Hyperplasia: Findings from the MTOPS Study.

前列腺活检炎症标志物与良性前列腺增生临床进展的风险相关：MTOPS 研究的结果。

• 发表时间: 2015-08
• 作者: Torkko, Kathleen C;Wilson, R Storey;Smith, Elizabeth E;Kusek, John W;van Bokhoven, Adrie;Lucia, M Scott
• 通讯作者: Lucia, M Scott