Risk Stratification for and Early Detection of Liver Cancer

肝癌的风险分层和早期发现

基本信息

批准号：
10239079
负责人：
FASIHA KANWAL
金额：
$ 68.83万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-13 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239079
关键词：
African American Age Alcohols Algorithms Area Behavioral Genetics Biological Assay Biological Markers Biological Specimen Banks Blinded Blood Center for Translational Science Activities Cirrhosis Clinical Clinical/Radiologic Cohort Studies Collaborations DNA Markers Data Detection Development Early Detection Research Network Early Diagnosis Ethnic Origin Ethnic group Etiology Evaluation Funding Future Genetic Genetic Markers Goals Hepatitis C virus Hispanic Americans Hispanics Image Individual Infrastructure Laboratories Liver diseases Malignant neoplasm of liver Medical center Methods Mission Modernization Morbidity - disease rate Multicenter Studies Patients Performance Persons Phase Phenotype Plasma Prevention Primary carcinoma of the liver cells Race Recording of previous events Research Research Institute Research Personnel Resources Risk Sampling Screening for Hepatocellular Cancer Site Subgroup Testing Texas Time Tissues United States Department of Veterans Affairs Visit Work algorithm training alpha-Fetoproteins base blood-based biomarker cancer prevention case control cell free DNA clinical application clinical research site clinical risk cohort data harmonization design early detection biomarkers follow-up high risk improved indexing liquid biopsy liver imaging methylation biomarker mortality multidisciplinary non-alcoholic fatty liver disease novel novel marker phase 1 study phase 2 study phase 3 study phase 3 testing predictive modeling prospective racial and ethnic recruit risk prediction risk stratification sample collection translational impact translational scientist validation studies

项目摘要

The Translational Research Center (TRC) includes a multidisciplinary team of clinical and translational researchers that has a strong track record of collaborative work, with the collective mission of reducing the burden of HCC. At the center of the proposed TRC lie two unique active prospective (in-HCC surveillance) cohorts of patients with cirrhosis. One of the cohorts comes from a Cancer Prevention and Research Institute of Texas (CPRIT) funded ongoing prospective multicenter study (Texas HCC Consortium) that is on target to recruit > 3000 patients with cirrhosis (>12,000 surveillance episodes and 200 expected HCC cases) from diverse etiologies (including cured HCV and non-alcoholic fatty liver disease). These patients are under routine bi-annual surveillance at 5 medical centers in Texas. The second is a cohort of >700 patients (>1,300 visits surveillance episodes and 33 incident HCC cases as of September 2017) recruited from and prospectively followed at the Houston VA, most with cured HCV. The TRC will leverage, extend follow up, and harmonize data and samples from both cohorts, collectively resulting in a > 23,000 episodes of HCC surveillance (and > 300 expected HCC) with bio-banked specimens, clinical and radiological data for each episode, rendering it an invaluable resource for the proposed research and other trans-consortium projects. Using data from these cohorts, we will develop and test novel personalized risk stratification indices for predicting the future ‐ development to HCC in patients with cirrhosis across diverse etiologies (Aim 1). We will also develop and evaluate an early detection algorithm that combines existing HCC blood based biomarkers (e.g., AFP, AFP L3, DCP), their longitudinal changes over time and select host features (age, etiology) in a phase 3 study. We will also examine the performance of this algorithm in patients at different HCC risk strata (Aim 2). Our work will set the framework for incorporating other patient and liver disease related factors into (new) biomarker profiles, an area that is likely to remain highly relevant irrespective of the type of biomarker. We will evaluate highly promising methylated DNA markers (MDMs, liquid biopsy) as an independent test for HCC risk prediction in Aim 3. These markers have been identified in tissue case control phase 1 studies, reliable assays have been developed and they have excellent performance for HCC detection in phase 2 studies. We will validate individual markers in the study cohort and train an algorithm that combines the MDM to achieve maximum performance. In a phase 3 biomarker study, we will validate the algorithm in the test sample overall and in key subgroups based on HCC risk strata. Our approach (optimizing available markers while simultaneously maintaining a strong forward outlook) will have both an immediate and long-lasting impact on HCC related morbidity and mortality. The TRC will build on established and strong infra-structure and relationships to complete the proposed research. It also represents a new and exciting avenue for collaboration with other investigators within the U01 consortium.

翻译研究中心（TRC）包括一个临床和翻译的多学科团队具有协作工作的良好记录的研究人员，其集体使命是减少 HCC的负担。在拟议的TRC的中心，有两个独特的活跃前瞻性（在HCC监视）肝硬化患者队列。其中一个人群来自癌症预防和研究所德克萨斯州（CPRIT）资助了正在进行的前瞻性多中心研究（德克萨斯州HCC财团），该研究的目标是招募> 3000例肝硬化患者（>> 12,000例监视发作和200例HCC病例）多种病因（包括固化的HCV和非酒精性脂肪肝病）。这些患者常规德克萨斯州5个医疗中心的两年一次监视。第二个是> 700名患者的队列（> 1,300次就诊截至2017年9月，监视发作和33例HCC案件的33例HCC案件。紧随其后的是弗吉尼亚州的休斯顿，大多数是固化的HCV。 TRC将利用，扩展跟进并协调来自两个队列的数据和样本，共同导致了> 23,000次HCC监视（和>>） 300 HCC）带有生物银行标本，每个情节的临床和放射学数据，使其成为拟议的研究和其他跨性别项目的宝贵资源。使用这些数据队列，我们将开发和测试新颖的个性化风险分层指数，以预测未来 - 在潜水员病因的肝硬化患者中向HCC发育（AIM 1）。我们还将发展和评估一种结合现有HCC血液生物标志物的早期检测算法（例如，法新社，AFP L3， DCP），它们会随着时间的流逝而变化，并在3阶段研究中选择了宿主特征（年龄，病因）。我们将还要检查在不同的HCC风险地层患者中该算法的性能（AIM 2）。我们的工作将确定编码其他患者和肝病与（新）生物标志物概况的框架无论生物标志物的类型如何，都可能保持高度相关的区域。我们将高度评估有希望的甲基化DNA标记（MDMS，液体活检）作为HCC风险预测的独立测试 AIM 3。这些标记已在组织案例控制阶段1研究中鉴定出来，可靠的测定是在第二阶段研究中开发，它们在HCC检测方面具有出色的性能。我们将验证研究队列中的单个标记和训练结合MDM以达到最大的算法表现。在第三阶段生物标志物研究中，我们将验证总体测试样本中的算法和关键基于HCC风险层的亚组。我们的方法（同时优化可用标记保持强劲的前瞻性前景）将对相关HCC产生直接和持久的影响发病率和死亡率。 TRC将建立在建立和牢固的基础设施以及与完成拟议的研究。它还代表了与其他合作的新的令人兴奋的途径 U01财团内的调查人员。