Upper Gastrointestinal Cancer Studies

上消化道癌症研究

• 批准号: 8157902
• 负责人: Sanford M Dawsey
• 金额: $ 124.96万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157902
• 关键词: Malignant neoplasm of gastrointestinal tract

BACKGROUND: Gastric cancer and esophageal cancer are the second and sixth most common causes of cancer death worldwide. Both of these upper gastrointestinal tract (UGI) cancers have a very poor prognosis, largely because symptoms usually do not occur until late in the disease. Significant reduction in UGI cancer mortality will probably require development of new prevention strategies based on identification of new modifiable risk factors and development of new methods to diagnose and treat more cases at earlier, more curable stages of disease. PURPOSE: The aims of this project are (1) to examine hypotheses relating to the etiology and prevention of upper gastrointestinal cancers, and (2) to develop successful clinical strategies for the early detection and treatment of these cancers. METHODS: Both etiologic and early detection studies are most efficiently done in high-risk populations, so many of the studies in this project are performed in such populations. (1) Etiologic studies: (a) China: Between 1985 and 1991, we conducted two randomized nutrition intervention trials (NIT), in Linxian, China, a county where cumulative death rates due to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) exceed 20%. These trials, with a combined enrollment of nearly 33,000 people, evaluated the effect of supplementation with several vitamin/mineral combinations on UGI cancers and found significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium, beta-carotene and vitamin E. Since 1991, we have followed the NIT participants as a cohort, and have performed nested studies evaluating the association between baseline characteristics and later development of UGI cancers. In addition, we have performed other etiologic studies specifically designed to evaluate individual exposures such as polycyclic aromatic hydrocarbons (PAHs), acetaldehyde, human papillomavirus (HPV), and Helicobacter pylori (H. pylori). (b) Iran: We have recently performed two etiologic studies in Golestan Province, Iran, another population with very high rates of ESCC. Between 2003 and 2007, the Golestan Case-Control Study enrolled 300 ESCC cases, 571 neighborhood controls and 300 clinic controls, and between 2004 and 2008 the Golestan Cohort Study enrolled 50,000 participants. Comparing results from high-risk populations in Iran and China, which are quite distinct geographically, ethnically and culturally, should give us insight into which environmental and genetic risk factors are most important for the development of this disease. (c) Brazil: We have begun preliminary studies evaluating PAH exposure in a high ESCC risk population in southern Brazil; (d) Kenya: We have begun a feasibility study for a case-control study of ESCC in western Kenya, which has high rates of this disease and the unusual occurrence of 8% of the cases in individuals younger than 30 years old. (2) Early Detection of Esophageal Cancer: This part of the project includes four studies: (a) the Cytology Sampling Study (CSS), to develop practical and accurate primary screening tests for esophageal squamous dysplasia and early ESCC; (b) the Mucosal Staining Study (MSS), to develop methods for endoscopic localization of squamous and glandular dysplasia of the esophagus and stomach; (c) the Endoscopic Therapy Pilot Study (ETPS), to evaluate new techniques for endoscopic treatment of high-grade squamous dysplasia and early ESCC; and (d) the Chemoregression Study (CRS), to test chemoprevention strategies to reduce progression and increase regression of low-grade esophageal squamous dysplasia. PROGRESS: (1) Etiologic studies: (a) China: Recent follow-up through 10 years after the end of the Linxian General Population Nutrition Intervention Trial has shown continued significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium, beta-carotene and vitamin E, especially among those who were less than the median age (55 years) at the beginning of the trial. Results from nested studies in the NIT cohort have shown: (i) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (ii) no relation between serum carotenoids and risk of UGI cancers; (iii) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (iv) a strong association between low tissue zinc levels and increased ESCC risk; (v) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (vi) no association between positive serology for HPV 16, HPV 18, or HPV 73 and ESCC, gastric cardia cancer or non-cardia gastric cancer; (vii) no relation between fumonisin exposure and ESCC risk; (viii) an association between tooth loss and risk of UGI cancers; (ix) an association between self-reported goiter and non-cardia gastric cancer; and (x) associations between several genetic polymorphisms and risk of ESCC and/or gastric cardia cancer. We also found no evidence of HPV DNA or HPV oncogene activity in fresh-frozen tumor samples from 272 consecutive ESCC resection specimens in Linxian. (b) Iran: Results from the Golestan Case-Control Study have shown an significant associations between case status and tobacco use, opium use or both; poor oral hygiene; drinking hot-temperature black tea; and various measures of low socioeconomic status. Comparison of normal esophageal tissue biopsies from cases and controls has shown a striking dose-response relationship between PAH exposure in the esophageal tissue (measured by intensity of immunohistochemical staining with anti-PAH antibodies) and case status, consistent with a causal role for PAH exposure in ESCC carcinogenesis. The accrual for the Golestan Cohort Study has also now been completed, and the subjects are being followed annually for vital status and cancer endpoints. (c) Brazil: Recent results from southern Brazil have show an association between urinary 1-hydroxypyrene glucuronide (a PAH metabolite) and consumption of mate, a local tea which has consistently been associated with ESCC risk. Laboratory analysis of dry mate leaves and mate beverages have shown high levels of PAHs in both. (d) Kenya: We have recently begun a feasibility study for the Thinker case-control study of ESCC in western Kenya. (2) Early Detection of Esophageal Cancer: (a) CSS: We recently analyzed a CSS study in which 720 asymptomatic Linxian adults were examined by one of two esophageal balloon samplers, followed by blood collection and endoscopy. The sensitivity/specificity of the two samplers for identifying biopsy-proven esophageal squamous dysplasia or cancer were 39%/85% and 46%/84%, insufficient for general use as a primary screening test for these lesions. (b) CRS: We recently completed the analysis of our first chemoregression study. This study randomized 267 Linxian patients with biopsy-proven mild or moderate squamous dysplasia to one of four treatment groups: selenomethionine 200ug once/day, celecoxib 200mg twice/day, both agents, or neither. Endoscopy was performed at baseline (T0) and after 10 months of intervention (T10). The primary endpoint was change in each patients worst dysplasia grade between T0 and T10 (regression/stable disease/progression). 238 patients (89%) completed the trial. Analysis showed that celecoxib treatment did not influence dysplasia grade (p=0.78). Selenomethionine had no effect in patients who began the trial with moderate dysplasia (p=1.00), but showed a significant improvement in dysplasia grade in patients who began with mild dysplasia (p=0.02).

背景：胃癌和食管癌是全球癌症死亡的第二和第六大最常见原因。这两种上胃肠道（UGI）癌症的预后都很差，这主要是因为症状通常直到疾病后期才发生。基于确定新的可修改风险因素和开发新方法以诊断和治疗更多病例的新预防策略的大幅度降低可能需要开发新的预防策略，以诊断和治疗更多的病例。目的：该项目的目的是（1）检查与上胃肠道癌的病因和预防有关的假设，以及（2）开发成功的临床策略，以早日检测和治疗这些癌症。方法：在高危人群中，病因学和早期检测研究都是最有效的，因此该项目中的许多研究都是在此类人群中进行的。 （1）病因研究：（a）中国：在1985年至1991年之间，我们进行了两项随机营养干预试验（NIT），在林克斯，中国，一个县，一个县，在该县中，食管食道鳞状细胞癌（ESCC）和胃部卡迪亚腺瘤（GCA）累积死亡率超过20％。这些试验的组合成立了近33,000人，评估了补充几种维生素/矿物质组合对UGI癌的补充的影响，并发现在1991年以来，在硒，β-胡萝卜素和维生素E的基本方面，我们的基本参与者遵循了nit nist and and and and and and and nist and and and and and and nist and and and and and and nist and and and and and and and nist and and nist and and and and nist and and and and and nist and，并且已经逐渐降低。后来开发UGI癌。此外，我们还进行了其他专门设计的病因研究，以评估单个暴露，例如多环芳烃（PAHS），乙醛，人乳头瘤病毒（HPV）和幽门螺杆菌（H. Pylori）。 （b）伊朗：我们最近在伊朗的戈莱斯坦省进行了两项病因学研究，ESCC率很高。在2003年至2007年之间，Golestan病例对照研究招募了300例ESCC病例，571个邻里控制和300个临床对照，2004年至2008年，Golestan COHORT研究招募了50,000名参与者。 比较伊朗和中国的高风险人口的结果，这些结果在地理，种族和文化上是完全不同的，应该让我们深入了解哪些环境和遗传危险因素对于这种疾病的发展最为重要。 （c）巴西：我们已经开始评估巴西南部ESCC风险较高的PAH暴露的初步研究； （d）肯尼亚：我们已经开始了一项可行性研究，用于对肯尼亚西部ESCC进行病例对照研究，该研究的患病率很高，在30岁以下的个体中，这种疾病的发生率很高，并且发生了8％的病例。 （2）早期检测食管癌：该项目的这一部分包括四项研究：（a）细胞学抽样研究（CSS），以开发用于食管鳞状食管发育不良和早期ESCC的实用，准确的原发性筛查测试； （b）粘膜染色研究（MSS），开发了食管和胃的鳞状和腺体发育不良的内窥镜定位方法； （c）内窥镜治疗试验研究（ETP），以评估用于内窥镜治疗高级鳞状发育不良和早期ESCC的新技术； （d）化学进展研究（CRS），测试化学预防策略，以减少进展并增加低级食管鳞状发育不良的消退。进度：（1）病因研究：（a）中国：林克斯一般人口营养干预试验结束10年后的最新随访，表明，在硒，β-胡萝卜素和维生素E相结合的人中，总的总死亡率和胃癌死亡率的显着降低，尤其是在中位年龄（55岁）（55岁）（55岁）中的人（尤其是55岁）。 NIT队列中嵌套研究的结果表明：（i）低血清硒水平与ESCC和胃CADCADIA癌症的风险之间的牢固关联； （ii）血清类胡萝卜素与UGI癌的风险之间无关； （iii）低血清α-生育酚水平与ESCC风险增加之间的密切关联； （iv）低组织锌水平与ESCC风险增加之间的密切关联； （v）幽门螺杆菌血清学阳性的受试者中心脏病和非心脏胃癌的风险增加； （vi）HPV 16，HPV 18或HPV 73和ESCC，胃CADCADIA癌或非辣妹胃癌之间的阳性血清学之间没有关联； （vii）富莫尼菌素暴露与ESCC风险之间没有关系； （viii）牙齿癌的牙齿脱落与风险之间的关联； （ix）自我报告的甲状腺肿与非心脏胃癌之间的关联； （x）几种遗传多态性与ESCC和/或胃癌癌的风险之间的关联。我们还没有发现来自Linxian中272个连续ESCC切除标本的新鲜冻结肿瘤样品中HPV DNA或HPV癌基因活性的证据。 （b）伊朗：Golestan病例对照研究的结果表明，病例状态与烟草使用，鸦片使用或两者之间存在显着关联；口腔卫生差；喝热温红茶；以及各种社会经济地位低的措施。从病例和对照组中进行正常食管组织活检的比较表明，食管组织中PAH暴露在PAH暴露之间存在显着的剂量反应关系（通过抗PAH抗体的免疫组织化学染色的强度与病例状态相一致，与PAH在Escc CCC Caccineation中的作用相一致，这是一致的。 Golestan队列研究的应计研究也已完成，并且每年都在关注受试者，以确保至关重要的状态和癌症终点。 （c）巴西：巴西南部的最新结果显示，尿尿1-羟基苯甲酸葡萄糖醛酸（PAH代谢产物）与伴侣的消费之间存在关联，这是一种始终与ESCC风险相关的当地茶。干伴侣和伴侣饮料的实验室分析都显示出高水平的PAH。 （D）肯尼亚：我们最近开始对肯尼亚ESCC的思想家病例对照研究进行可行性研究。 （2）早期检测食管癌：（a）CSS：我们最近分析了一项CSS研究，其中有720名无症状的Linxian成年人由两个食管气球采样器之一检查，然后进行血液收集和内窥镜检查。两个样本者对鉴定活检证实的食管鳞状发育不全或癌症的敏感性/特异性为39％/85％和46％/84％，不足以作为这些病变的一般筛查测试的一般使用。 （b）CRS：我们最近完成了第一项化学收入研究的分析。这项研究随机分配了267例活检预先验证的轻度或中度鳞状发育不良的Linxian患者，与四个治疗组之一：硒甲米汀200倍，每天一次，塞来昔布200mg每天两次，两次药物，两种药物，或者都不是。内窥镜检查在基线（T0）和10个月的干预后进行（T10）。主要终点是每位患者在T0和T10之间最严重的发育不良等级（回归/稳定疾病/进展）。 238名患者（89％）完成了试验。分析表明，塞来昔布治疗不会影响发育不良级（p = 0.78）。素甲米氨酸对开始进行中度发育不良的试验的患者没有影响（P = 1.00），但在轻度发育不良的患者中表现出显着改善的发育不良级别（P = 0.02）。