Phenotype-Genotype Associations with Symptoms During Childhood Leukemia Treatment

儿童白血病治疗期间表型-基因型与症状的关联

• 批准号: 8348584
• 负责人: Marilyn J Hockenberry
• 金额: $ 62.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8348584
• 关键词: 18 year old; Adolescent; Adverse effects; Adverse event; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Biochemical; Biochemical Genetics; Biochemical Pathway; Biological Markers; Characteristics; Child; Childhood Leukemia; Clinical; Cognition; Diagnosis; Disease; Dose; Exhibits; F2-Isoprostanes; Failure; Fatigue; Foundations; Funding; Future; Genetic Variation; Genome; Genotype; Individual; Inflammatory; Interleukin-6; Interleukin-7; Interleukins; Intervention; Lead; Malignant Neoplasms; Measures; Memory; Mental Depression; Methodology; Modeling; Molecular; Nausea; Neoadjuvant Therapy; Outcome; Oxidative Stress; Pain; Pathway interactions; Patients; Pattern; Pharmacogenetics; Phase; Phenotype; Physical activity; Principal Investigator; Production; Quality of life; Relative (related person); Research; Research Design; Risk; Science; Severities; Sleep; Sleep disturbances; Spinal Puncture; Subgroup; Survival Rate; Symptoms; System; Therapeutic; Time; Toxic effect; Tumor Necrosis Factor-alpha; Variant; base; cancer therapy; caspase-3; clinical practice; cytokine; experience; genetic variant; high risk; improved; leukemia; programs; response; tool; treatment planning

DESCRIPTION (provided by applicant): The focus on cure for childhood leukemia over the last three decades has resulted in increased survival rates of > 80%. However, efforts to manage leukemia treatment symptoms have not kept pace with new therapies that promote cure. Symptom toxicity during treatment can result in complications, treatment delays and therapy dose reductions. Compromise in therapy can negatively influence quality of life and even more notably, jeopardize chances for long-term survival. This study examines biologic mechanisms that influence symptom toxicities caused by increased oxidative stress or cytokine production or actual failure of the anti-oxidant and anti-inflammatory defense systems due to genetic variation. A repeated measures research design is used to evaluate the number and severity of treatment symptoms experienced by 400 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. Symptoms include fatigue, sleep disturbance, pain, depression, nausea, physical activity changes, as well as memory and cognition deficits. CSF oxidative stress and cytokine biomarkers will be obtained with all therapeutic lumbar punctures occurring at four time points during post-induction therapy. Linear mixed models (LMM) will be used to determine the influence that symptom clusters have on quality of life. LMM also will be used to determine the effect CSF oxidative stress and cytokine biomarkers have on symptom clusters. We will also evaluate whether patients with genetic variants associated with the oxidative stress and inflammatory pathways have higher risk of developing symptom clusters than those without these genetic variants. This study is the first of its kind to search for genetic variants associated with the oxidative stress and inflammatory pathways as well as explore CNS oxidative stress and cytokine biomarkers, and their relationships with symptom clusters. Understanding symptom clusters during leukemia treatment will pave the way for future interventions that decrease toxicity and minimize delays and dose reductions in therapy that may compromise a child's best chance for cure. PUBLIC HEALTH RELEVANCE: Childhood leukemia survival rates have greatly decreased over the last three decades. However, symptoms experienced during treatment often result in complications, treatment delays and may jeopardize chances for long-term survival. This study examines mechanisms that influence symptom toxicities during the most intensive phase of childhood leukemia treatment.

描述（由申请人提供）：在过去的三十年中，关注儿童白血病治疗的重点导致生存率提高> 80％。但是，管理白血病治疗症状的努力并没有与促进治疗的新疗法保持同步。治疗过程中的症状毒性会导致并发症，治疗延迟和降低剂量。治疗中的妥协可能会对生活质量产生负面影响，甚至更明显地危害了长期生存的机会。这项研究研究了由于遗传变异而导致的氧化应激或细胞因子产生或抗氧化剂和抗炎防御系统的实际失败引起的症状毒性的生物学机制。一项重复的措施研究设计用于评估400名3-18岁儿童和青少年经历的治疗症状的数量和严重程度，并在最激烈的治疗阶段诊断为白血病。症状包括疲劳，睡眠障碍，疼痛，抑郁，恶心，体育锻炼变化以及记忆和认知缺陷。在诱导后治疗期间，将在四个时间点发生的所有治疗性腰椎穿刺，将获得CSF氧化应激和细胞因子生物标志物。线性混合模型（LMM）将用于确定症状簇对生活质量的影响。 LMM还将用于确定CSF氧化应激和细胞因子生物标志物对症状簇的影响。我们还将评估与没有这些遗传变异的患者相比，与氧化应激和炎症途径相关的遗传变异患者是否具有发展症状簇的风险。这项研究是第一个寻找与氧化应激和炎症途径相关的遗传变异，并探索CNS氧化应激和细胞因子生物标志物以及它们与症状簇的关系。在白血病治疗期间了解症状簇将为将来的干预措施铺平道路，从而减少毒性并最大程度地减少治疗的延迟和剂量减少，这可能会损害儿童治愈的最佳机会。 公共卫生相关性：在过去的三十年中，儿童白血病的存活率大大下降。但是，治疗期间经历的症状通常会导致并发症，治疗延迟，并可能危害长期生存的机会。这项研究研究了在儿童白血病治疗最密集的阶段影响症状毒性的机制。