Determinants of late cardiovascular morbidity among survivors of hematopoietic ce

造血细胞癌幸存者晚期心血管发病的决定因素

基本信息

批准号：
8111884
负责人：
Eric Jessen Chow
金额：
$ 15.11万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111884
关键词：
Accounting Address Affect Age Anthracyclines Atherosclerosis Blood Vessels Cancer Patient Cancer Survivor Candidate Disease Gene Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Transplantation Cessation of life Chest Classification Clinical Clinical Investigator Clinical Research Computer Simulation Data Databases Death Records Development Diabetes Mellitus Dose Drug Metabolic Detoxication Dyslipidemias Early treatment Environmental Exposure Environmental Risk Factor Evaluation Family Family Characteristics Foundations Fred Hutchinson Cancer Research Center Future General Population Genetic Genetic Determinism Genetic Variation Genomics Goals Health Status Heart failure Hematopoietic Hospitals Hypertension Individual Injury Integration Host Factors Investigation Late Effects Life Style Long-Term Survivors Medical Mentors Metabolic Morbidity - disease rate Myocardial Ischemia Neuraxis Obesity Outcome Outcomes Research Overweight Patients Population Publishing Questionnaires Radiation therapy Recording of previous events Registries Relapse Relative (related person)Research Research Personnel Resources Risk Risk Factors Sample Size Sampling Stroke Surveys Survivors Transplantation Treatment Factor Validation Variant Whole-Body Irradiation adverse outcome cancer therapy cardiovascular disorder risk chronic graft versus host disease clinical practice cohort design drug metabolism experience follow-up genetic epidemiology genetic risk factor genetic variant genome wide association study genome-wide high risk improved information gathering interest mortality novel patient oriented patient registry programs skills trait

项目摘要

DESCRIPTION (provided by applicant): Dr. Chow's long-term goal is to become an independent, patient-oriented investigator focused on understanding the metabolic and cardiovascular (CV) complications affecting cancer survivors. A rigorous didactic and mentoring program in outcomes research and genetic epidemiology will provide the applicant the foundation to comprehensively examine treatment, environmental, and host factors that influence CV disease following cancer treatment. Specifically, he proposes to investigate determinants of adverse CV late effects following hematopoietic cell transplantation (HCT). Refinements in HCT have led to an increasing number of long-term survivors and a need to better characterize causes of morbidity and mortality in this population besides relapse and chronic graft versus host disease (GVHD). Survivors appear to be at increased risk of adverse late effects such as hypertension, dyslipidemia, and diabetes, all of which contribute to increased CV morbidity and mortality. Purported risk factors include: 1) pre-transplant anthracycline and radiotherapy exposure, which are associated with late cardiomyopathy, valvular and vascular injury; and 2) chronic GVHD and total body irradiation (TBI), which are hypothesized to cause endothelial injury and atherosclerosis. Previous studies have been limited by selection and recall biases, small sample size, and evaluation of primarily clinical factors without consideration of genetic determinants. Data from centralized registries contain larger samples, but often lack detailed pre-HCT treatment, environmental exposure, and genetic information. To address these limitations, Dr. Chow proposes to study a cohort of nearly 5000 e2 yr HCT survivors treated at the Fred Hutchinson Cancer Research Center (FHCRC) since 1969. This cohort has advantages of an exceptional clinical research database at FHCRC with <1% loss to follow-up, and availability of hospital discharge and death records, and patient questionnaires documenting medical, environmental, and family histories relevant to CV disease. This cohort, with improved phenotypic characterization of CV outcomes supplemented by enriched environmental and family histories, will facilitate more in-depth analyses (via a nested case-cohort design) of risk factors that predispose towards CV disease in this population, including meaningful investigation of genetic variation. Existing genome-wide variation data collected at FHCRC will be used to identify novel loci and to replicate prior published associations. Overall, these results will allow better classification of individuals who may be at increased risk of late CV disease and give clinicians and patients an opportunity to modify therapy and/or develop more targeted post-HCT surveillance with earlier intervention. This research also has direct relevance to the larger population of cancer survivors who receive similar treatment exposures. Completion of these aims will provide the candidate with the necessary skills, experience, and preliminary data to launch an independent research program.

描述（由申请人提供）：Chow博士的长期目标是成为一名独立的，以患者为导向的研究者，专注于了解影响癌症幸存者的代谢和心血管（CV）并发症。在结果和遗传流行病学方面进行的严格的教学和指导计划将为申请人提供基础，以全面检查癌症治疗后影响CV疾病的治疗，环境和宿主因素。具体而言，他建议研究造血细胞移植后不良CV后期作用（HCT）的决定因素。 HCT的改进导致了越来越多的长期幸存者，并且需要更好地表征该人群中发病率和死亡率的原因，除了复发和慢性移植与宿主疾病（GVHD）。幸存者似乎有增加不良后期影响的风险，例如高血压，血脂异常和糖尿病，所有这些都导致CV发病率和死亡率增加。声称的危险因素包括：1）移植前蒽环类和放射治疗暴露，与晚期心肌病，瓣膜和血管损伤有关； 2）慢性GVHD和全身辐照（TBI），这些（TBI）被认为会导致内皮损伤和动脉粥样硬化。先前的研究受到选择和召回偏见，样本量较小以及主要是临床因素的评估而受到限制，而无需考虑遗传决定因素。来自集中式注册表的数据包含较大的样本，但通常缺乏详细的HCT治疗，环境暴露和遗传信息。为了解决这些局限性，Chow博士建议研究自1969年以来在Fred Hutchinson癌症研究中心（FHCRC）治疗的近5000 e2年HCT幸存者。该同龄人在FHCRC上具有出色的临床研究数据库的优势，该数据库具有<1％的损失，并记录了医院的病人，并记录了病人的病情，并记录了病人的病情，并记录了病人，并记录了病人的病情，并记录了病人的病情，并记录了病人的病情。疾病。该队列具有改进的表型表征，以富集的环境和家庭历史补充的CV结果，将促进对危险因素的更深入的分析（通过嵌套的病例 - 库奥特设计），这些危险因素易于在该人群中易于CV疾病，包括对遗传变异的有意义的研究。在FHCRC收集的现有全基因组变异数据将用于识别新的基因座并复制事先已发布的关联。总体而言，这些结果将允许更好地分类患有CV晚期疾病风险的个体，并使临床医生和患者有机会修改治疗和/或在较早的干预下进行更有针对性的HCT后监测。这项研究还与较大的受到类似治疗暴露的癌症幸存者人群直接相关。这些目标的完成将为候选人提供必要的技能，经验和初步数据，以启动独立的研究计划。