Selenium Based Chemoprevention - HGPIN

描述（由申请人提供）：Larry Clark博士在1996年报告的临床试验提供了强有力的基于人类的证据，证明硒补充剂可以预防前列腺癌。 克拉克博士的研究小组（JRM）的持续随访继续表明，硒补充剂的风险在统计学上显著降低，尽管略有降低。 虽然这些结果令人鼓舞，但前列腺癌只是克拉克博士考虑的几个终点之一，他研究的人是非黑色素瘤皮肤癌患者，生活在饲料硒水平极低的地区。 显然，克拉克博士的工作需要后续跟进。 我们建议完成硒在男性中的随机临床试验，这些男性由于被诊断患有高级别前列腺上皮内瘤变，患前列腺癌的风险大大增加。 每例受试者在基线时接受活检，在可行的程度上，最大限度地减少未诊断癌症的概率，并指定每例受试者接受3年随访活检。 活检数据由前列腺病理学家（WS）集中审查，他是HGPIN研究的领导者。 到目前为止，超过280名男性已经注册，200人已经随机分配到我们的研究目标465随机。 主要研究终点是PC，通过六分仪或更大的前列腺活检确定。 第二个终点是毒性，通过患者症状报告确定。 我们在获得足以分别用于增殖和凋亡的Ki-67和TUNEL分析的样本块方面遇到了困难，但在本研究期结束时将完成这些次要终点生物标志物的发育评价。 我们打算编写一份单独的提案，以支持对这些标志物的额外分析。 我们建议继续我们的机器视觉分析的前列腺导管和腺体的基底细胞层的退化和核染色质模式的分泌细胞核。 这项研究有望成为迄今为止规模最大、方法学上最严格的HGPIN研究，HGPIN被广泛认为是前列腺癌的关键癌前病变。

DESCRIPTION (provided by applicant): The clinical trial reported in 1996 by Dr. Larry Clark provided strong, human-based evidence that selenium supplementation protects against prostate cancer. Continued follow-up of Dr. Clark's study group (by JRM), continues to indicate a statistically significant, though slightly diminished, decrease in risk with selenium supplementation. While these results are encouraging, prostate cancer was only one of several endpoints considered by Dr. Clark, and the people he studied were nonmelanoma skin cancer patients living in a region with extremely low forage selenium levels. Clearly, Dr. Clark's work demands follow-up. We propose to complete our randomized clinical trial of selenium among men who, by virtue of having been diagnosed with high-grade prostatic intraepithelial neoplasia, are at substantially increased risk of prostate cancer. Each subject at baseline receives a biopsy that, to the degree practicable, minimizes the probability of undiagnosed cancer, and each subject is designated to receive a 3-year follow-up biopsy. Biopsy data is reviewed centrally by a prostate pathologist (WS), who is a leader in HGPIN research. To date, over 280 men have been registered, and 200 have been randomized toward our study goal of 465 randomizations. The primary study endpoint is PC, identified by sextant or greater prostatic biopsy. The second endpoint is toxicity, identified by patient symptom report. We have experienced difficulty obtaining sample blocks adequate for Ki-67 and TUNEL analysis of proliferation and apoptosis, respectively, but will have completed developmental evaluation of these secondary endpoint biomarkers by the end of the present study period. We intend to write a separate proposal for support of additional analyses of those markers. We propose to continue our machine vision analysis of the degradation of the basal cell layer of prostatic ducts and glands and of nuclear chromatin patterns in secretory cell nuclei. This study promises to be the largest and most methodologically rigorous to date of HGPIN, which is widely believed to be the key premalignant lesion for prostate cancer.