Phenotype-Genotype Associations with Symptoms During Childhood Leukemia Treatment

描述(由申请人提供)：在过去的三十年里，对儿童白血病治疗的关注已经导致了80%的存活率的提高。然而，控制白血病治疗症状的努力并没有跟上促进治愈的新疗法的步伐。治疗期间的症状毒性可导致并发症、治疗延误和治疗剂量减少。治疗中的妥协可能会对生活质量产生负面影响，更值得注意的是，会危及长期生存的机会。这项研究考察了影响症状毒性的生物机制，这些症状毒性是由于基因变异导致的氧化应激或细胞因子产生增加或抗氧化和抗炎防御系统实际失效而引起的。采用重复测量研究设计，评估400名3-18岁的儿童和青少年在治疗最激烈阶段被诊断为白血病的治疗症状的数量和严重程度。症状包括疲劳、睡眠障碍、疼痛、抑郁、恶心、体力活动改变，以及记忆和认知障碍。脑脊液氧化应激和细胞因子生物标记物将通过所有治疗性腰椎穿刺术在诱导治疗后的四个时间点进行获得。将使用线性混合模型(LMM)来确定症状群对生活质量的影响。LMM还将用于确定脑脊液氧化应激和细胞因子生物标记物对症状群的影响。我们还将评估具有与氧化应激和炎症途径相关的基因变异的患者是否比那些没有这些基因变异的患者发展成症状群的风险更高。这项研究是第一次寻找与氧化应激和炎症途径相关的遗传变异，并探索中枢神经系统氧化应激和细胞因子生物标记物及其与症状群的关系。了解白血病治疗期间的症状群将为未来的干预铺平道路，这些干预措施将减少毒性，并将可能危及儿童最佳治愈机会的治疗延迟和剂量减少降至最低。

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.