P53 AND DNA PLOIDY IN BARRETT'S METAPLASIA

Barrett 化生中的 P53 和 DNA 倍体

• 批准号: 6689567
• 负责人: Mamoun Younes
• 金额: $ 25.4万
• 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/6689567
• 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：这项研究的目标是确定是否准确和 以检测为目的的内窥镜监测方案的成本效益 Barrett化生(BM)患者的早期恶变可以 通过以下方面得到改进：1)检验P53蛋白积累、DNA 非整倍体和G0G1或G2M组分的增加更准确和客观 Barrett化生(Barrett‘s食道)恶性潜能的标志物 而不是常规的不典型增生的形态评估，2)确定 活组织检查和细胞学检查结合起来比活组织检查或细胞学检查更有用 单独地，3)确定从出现 LGD/Ind、P53蛋白积聚和DNA倍体异常 高度不典型增生(HGD)和腺癌(CA)的发展，以及4) 执行成本分析，以确定监视计划是否可以 其中活组织检查和细胞学检查与P53结合使用 和DNA倍体测定，而且比目前的监测成本更低 程序。 将对P53积聚和DNA倍体研究进行评估 最初和后续的活组织检查和刷检细胞学材料至少有200份 Barrett化生(BM)患者。活检的步骤切片(Bx)将是 苏木精-伊红染色，Feulgen染色进行DNA定量； P53蛋白免疫染色，将进行P53基因突变分析 通过对显微解剖的组织进行直接测序。然后将对每个案例进行分析 对于异型增生，图像分析显示DNA倍体类型，P53积聚和 基因突变。细胞学制剂(Cy)也将被评估 异型增生、DNA倍体图像分析、P53积聚。这个 数据将每两年汇编一次，并与患者的预后相关， 在单独的分析中使用HGD和CA的发展作为终点，以及 采用单变量和多变量分析进行评价。敏感度 这些指标的特异性、阳性预测值和阴性预测值 将确定作为HGD和CA发展预测因子的标志物 分别在由Bx、Cy以及由Bx和Cy组合检测的标记上。这些 将进行比较以确定Bx和Cy在 对BM患者的随访优于单纯Bx或Cy。两者之间的时间 其中一种标志物的出现和肿瘤的发展也将 进行研究，以确定近距离内窥镜检查的时间段 监测既有临床依据，又有成本效益。P53基因突变 将其与P53蛋白积累量、DNA倍体和患者进行比较 结果以确定是否有特定的突变与 DNA非整倍体与CA的研究进展一个多步递进模型将是 在此基础上，将提出一个新的监视计划。一种代价 然后将进行分析以确定分子基础是否 监控计划将比目前的计划更具成本效益 根据异型增生的形态分级。