P53 AND DNA PLOIDY IN BARRETT'S METAPLASIA

Barrett 化生中的 P53 和 DNA 倍体

• 批准号: 6667047
• 负责人: Mamoun Younes
• 金额: $ 0.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-09 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667047
• 关键词: Barretts esophagus; adenocarcinoma; aneuploidy; clinical research; diagnosis design /evaluation; endoscopy; gastrointestinal imaging /visualization; human subject; immunocytochemistry; metaplasia; neoplasm /cancer diagnosis; neoplasm /cancer genetics; p53 gene /protein

DESCRIPTION: The goal of this study is to determinewhether the accuracy and cost-effectiveness of endoscopic surveillance protocols aimed at detecting early malignant transformation in patients with Barrett's metaplasia (BM) can be improved by: 1) testing the hypothesis that p53 protein accumulation, DNA aneuploidy, and increased G0G1 or G2M fractions are more accurate and objective markers of malignant potential in Barrett's metaplasia (Barrett's esophagus) than the routine morphologic evaluation of dysplasia, 2) determining whether biopsy and cytology combined are more useful than either biopsy or cytology alone, 3) determining the time period that elapses between the appearance of LGD/IND, p53 protein accumulation, and DNA ploidy abnormalities, and between the development of high grade dysplasia (HGD) and adenocarcinoma (CA), and 4) perform cost-analysis to determine whether a surveillance program can be constructed in which biopsy and cytology are utilized in conjunction with p53 and DNA ploidy determination, and is less costly than current surveillance programs. Evaluation of p53 accumulation and DNA ploidy studies will be performed on initial and follow-up biopsies and brush cytology material from at least 200 patients with Barrett's metaplasia (BM). Step sections of biopsies (Bx) will be stained with hematoxylin and eosin, Feulgen stain for DNA quantitation, and immunostained for p53 protein, p53 gene mutational analysis will be performed by direct sequencing on microdissected tissues. Each case will be then analyzed for dysplasia, DNA ploidy patterns by image analysis, and p53 accumulation and gene mutation. Cytologic preparations (Cy) will be also evaluated for dysplasia, DNA ploidy patterns by image analysis, and p53 accumulation. The data will be compiled every two years and correlated with the patients outcome, using the development of HGD and CA as end points in separate analyses, and evaluated by univariate and multivariate analysis. The sensitivity, specificity, and positive and negative predictive value of each of these markers as predictors of HGD and of CA development will be determined separately on markers detected by Bx, Cy, and by the Bx and Cy combined. These will be compared to determine whether the use of both Bx and Cy in the follow-up of patients with BM is better than Bx or Cy alone. The time between the appearance of one of the markers and the development of carcinoma will also be studied, in order to identify a period of time in which close endoscopic surveillance is both clinically warranted and cost-effective. p53 mutations will be compared with p53 protein accumulation, and with DNA ploidy and patient outcome in order to determine if there are specific mutations associated with progression to DNA aneuploidy and CA. A multi step progression model will be constructed, upon which a new surveillance program will be proposed. A cost analysis will be then performed to determine whether a molecular based surveillance program would be more cost-effective than current program which is based on morphologic grading of dysplasia.

描述：本研究的目的是确定是否准确性和 旨在检测的内镜监测方案的成本效益 Barrett化生（BM）患者的早期恶变可 可以通过以下方法改进：1）检验p53蛋白积累、DNA 非整倍体和G 0 G1或G2 M分数增加更准确和客观 Barrett化生（Barrett食管）的恶性潜能标志物 比发育不良的常规形态学评价，2）确定是否 活检和细胞学检查相结合比活检或细胞学检查更有用 3）确定出现的时间间隔， LGD/IND、p53蛋白积聚和DNA倍体异常，以及 高度异型增生（HGD）和腺癌（CA）的发展，以及4） 进行成本分析，以确定监测计划是否可以 其中活检和细胞学与p53结合使用 和DNA倍性测定，并且比目前的监测成本更低 程序. p53蓄积和DNA倍性研究的评价将在以下研究中进行： 至少200例患者的初始和随访活检和刷检细胞学材料 Barrett化生（BM）患者。活检（Bx）的步骤切片将 用苏木精和伊红染色，用于DNA定量的Feulgen染色，和 对p53蛋白进行免疫染色，进行p53基因突变分析 通过对显微组织的直接测序。每一个案例都将被分析 对于异型增生，通过图像分析的DNA倍体模式和p53积累， 基因突变还将评价细胞学制剂（Cy）， 异型增生、图像分析的DNA倍体模式和p53积累。的 数据将每两年汇编一次，并与患者的结果相关联， 使用HGD和CA的发展作为单独分析的终点，以及 通过单变量和多变量分析进行评价。敏感性， 特异性，以及这些中的每一个的阳性和阴性预测值 将确定作为HGD和CA发展的预测因子的标志物 分别对由Bx、Cy以及由Bx和Cy组合检测的标记物进行检测。这些 将进行比较，以确定是否使用Bx和Cy在 BM患者的随访优于单纯Bx或Cy。之间的时间 其中一种标志物的出现和癌的发展也将 研究，以确定一段时间，其中关闭内窥镜 监测既有临床必要，又符合成本效益。p53突变 将与p53蛋白积累、DNA倍性和患者 结果，以确定是否有特定的突变与 发展为DNA非整倍体和CA。一个多步骤的发展模式将是 在此基础上，将提出一项新的监督计划。成本 然后将进行分析以确定基于分子的 监督计划将比目前计划更具成本效益， 根据发育不良的形态学分级