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

• 批准号: 8893907
• 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
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893907
• 关键词: Accounting; Address; Affect; Age; Anthracyclines; Atherosclerosis; Blood Vessels; Cancer Patient; Cancer Survivor; Candidate Disease Gene; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; 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 Intervention; 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 information; genetic risk factor; genetic variant; genome-wide; genome-wide analysis; hematopoietic cell transplantation; high risk; improved; information gathering; interest; mortality; novel; patient oriented; patient registry; programs; skills; trait

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、以患者为中心的研究者，专注于了解影响癌症幸存者的代谢和心血管 (CV) 并发症。结果研究和遗传流行病学方面严格的教学和指导计划将为申请人提供全面检查癌症治疗后影响心血管疾病的治疗、环境和宿主因素的基础。具体来说，他建议研究造血细胞移植（HCT）后不良CV后期效应的决定因素。 HCT 的改进导致长期幸存者数量不断增加，并且需要更好地描述除复发和慢性移植物抗宿主病 (GVHD) 之外的该人群发病和死亡的原因。幸存者出现高血压、血脂异常和糖尿病等不良后期影响的风险似乎增加，所有这些都会导致心血管发病率和死亡率增加。据称的危险因素包括：1）移植前蒽环类药物和放射治疗暴露，这些与晚期心肌病、瓣膜和血管损伤有关； 2) 慢性 GVHD 和全身照射 (TBI)，推测它们会导致内皮损伤和动脉粥样硬化。先前的研究受到选择和回忆偏差、样本量小以及在不考虑遗传决定因素的情况下对主要临床因素进行评估的限制。来自集中登记处的数据包含较大样本，但通常缺乏详细的 HCT 前治疗、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) 接受治疗的近 5000 名 e2 年 HCT 幸存者的队列。该队列的优势在于 FHCRC 拥有出色的临床研究数据库，随访损失率<1%，并且可以提供出院和死亡记录以及记录与 CV 相关的医疗、环境和家族史的患者调查问卷 疾病。该队列改善了心血管结果的表型特征，辅以丰富的环境和家族史，将有助于对该人群中易患心血管疾病的危险因素进行更深入的分析（通过嵌套病例队列设计），包括对遗传变异进行有意义的研究。 FHCRC 收集的现有全基因组变异数据将用于识别新基因座并复制先前发表的关联。总体而言，这些结果将有助于对晚期心血管疾病风险增加的个体进行更好的分类，并为临床医生和患者提供调整治疗和/或通过早期干预进行更有针对性的 HCT 后监测的机会。这项研究还与接受类似治疗的更多癌症幸存者群体有直接关系。完成这些目标将为候选人提供启动独立研究计划所需的技能、经验和初步数据。