Childhood Leukemia: Oxidative Stress, Cognitive Changes & Academic Outcomes

儿童白血病：氧化应激、认知变化

• 批准号: 8440207
• 负责人: Ida Marie, DNSc Moore
• 金额: $ 50.9万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440207
• 关键词: 12 year old; 15 year old; 5 year old; Acute Lymphocytic Leukemia; Acute leukemia; Address; Adolescent; Adverse effects; Age; Antioxidants; Area; Biological; Brain; Cancer Survivorship; Cells; Central Nervous System Diseases; Ceramides; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Children' s Oncology Group; Clinical Trials Cooperative Group; Cognitive; Cognitive deficits; Diagnosis; Diagnostic; Disease-Free Survival; Dose; Education; Employment Opportunities; Enrollment; F2-Isoprostanes; Funding; Future; Gender; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Injury; Intervention; Intravenous; Knowledge; Lead; Learning; Lecithin; Literature; Long-Term Survivors; Malignant Childhood Neoplasm; Malignant Neoplasms; Maternal Age; Measures; Methotrexate; Modeling; Motor Skills; NIH Program Announcements; Neuraxis; Organ; Outcome; Oxidative Stress; Pathology; Pattern; Persons; Pharmaceutical Preparations; Reading; Reporting; Research; Sampling; Short-Term Memory; Site; Spinal Puncture; Survivors; Testing; Therapeutic; Time; Tissues; Treatment Protocols; United States; United States National Institutes of Health; Visuospatial; Vocabulary; base; brain tissue; cancer diagnosis; central nervous system injury; chemotherapy; cognitive change; comparative efficacy; experience; improved; leukemia; longitudinal design; motor learning; neuropsychological; prevent; programs; prospective; response; standardize measure; therapy design; visual motor; white matter

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and adolescents less than 15 years of age. Central nervous system (CNS) treatment with intrathecal and intravenous methotrexate is an essential part of ALL therapy because the brain is a sanctuary site for leukemia cells. Despite the importance of CNS treatment for long-term disease-free survival, declines in academic abilities, especially math and reading have been reported. Our preliminary findings demonstrate declines in specific cognitive abilities during the first two years of CNS treatment, while declines in academic abilities are evident after 3 years of treatment. Early changes in specific cognitive abilities may be important predictors of academic outcomes. Methotrexate increases oxidative stress in several organs, including the brain. White matter and the hippocampus are known to be vulnerable to oxidative stress, and are important for cognitive abilities, such as working memory, learning, visual-spatial and visual-motor skills. Oxidative stress as a mechanism of methotrexate-induced CNS injury that may lead to cognitive declines and academic outcomes has not been studied. The long-term goal is to increase knowledge about mechanisms of methotrexate-induced CNS injury, and to develop interventions that will prevent or minimize tissue damage, cognitive declines, and academic problems that are significant challenges for long-term survivors of childhood ALL. The purpose is to explicate relationships among oxidative stress, cognitive abilities, and academic outcomes among children with ALL who receive aggressive CNS treatment with methotrexate. Specific Aims are to: 1. Describe changes in oxidative stress during CNS treatment with methotrexate. 2. Describe changes in cognitive abilities during CNS treatment with methotrexate. 3. Describe relationships among oxidative stress, cognitive abilities, and academic outcomes. A prospective longitudinal design enrolling 80 children with ALL between 3 and 12 years of age will be used. Verbal and non-verbal cognitive abilities will be assessed within 1 month after diagnosis, and then annually for 3 years. Academic abilities will be assessed 3 years after ALL diagnosis. CSF samples will be obtained during diagnostic and therapeutic lumbar punctures for measuring oxidative stress. Aims 1 and 2 will be addressed using mixed model ANOVAs. Aim 3 will be addressed using correlations and multiple regression. Ancillary analyses will be conducted to describe the potential influence of covariates (total amount of methotrexate received, subject gender and age, and maternal education) on oxidative stress, cognitive abilities, and academic outcomes. This is the first study of oxidative stress as a mechanism of methotrexate-induced CNS injury that could be associated with early declines in cognitive abilities and academic outcomes among children with ALL. Findings will provide the basis for future studies of biological and cognitive interventions designed to prevent or minimize CNS tissue injury, and improve cognitive abilities and academic outcomes among the ever increasing number of long-term survivors of childhood leukemia.

急性淋巴细胞白血病（ALL）是儿童和青少年中最普遍的癌症 年龄。中枢神经系统（CNS）用鞘内和静脉甲氨蝶呤治疗是一种 所有疗法的重要组成部分，因为大脑是白血病细胞的避难所。尽管很重要 中枢神经系统治疗可长期无病生存，学术能力的下降，尤其是数学和 读书已有报道。我们的初步发现表明，在特定的认知能力下的下降 CNS治疗的头两年，尽管经过3年的治疗，但学术能力的下降是显而易见的。 特定认知能力的早期变化可能是学术成果的重要预测指标。甲氨蝶呤 在包括大脑在内的几个器官中增加氧化应激。白质和海马是 已知容易受到氧化压力的影响，对于诸如工作记忆， 学习，视觉空间和视觉运动技能。氧化应激作为甲氨蝶呤诱导的中枢神经系统的机制 可能导致认知能力下降和学术成果的伤害尚未被研究。长期目标是 增加有关甲氨蝶呤诱导的中枢神经系统损伤机制的知识，并发展干预措施 这将防止或最大程度地减少组织损害，认知能力下降以及重要的学术问题 童年的长期幸存者面临的挑战。目的是说明之间的关系 氧化压力，认知能力以及所有接受的儿童的学术成果 甲氨蝶呤侵略性的中枢神经系统治疗。具体目的是：1。描述氧化的变化 甲氨蝶呤治疗中枢神经系统治疗期间的应力。 2。描述CNS期间认知能力的变化 用甲氨蝶呤治疗。 3。描述氧化应激，认知能力和 学术成果。一个前瞻性纵向设计，招募了80名3至12岁之间的儿童 将使用年龄。口头和非语言认知能力将在1个月内评估 诊断，然后每年3年。所有诊断后3年将评估学术能力。 CSF 在测量氧化应激的诊断和治疗性腰椎穿刺过程中，将获得样品。 目标1和2将使用混合模型方差分析来解决。 AIM 3将使用相关性和 多重回归。将进行辅助分析以描述协变量的潜在影响（总数 接受氧化压力的甲氨蝶呤的数量，受试者性别和年龄以及孕产妇教育的数量， 认知能力和学术成果。这是对氧化应激的首次研究 甲氨蝶呤诱导的中枢神经系统损伤可能与认知能力的早期下降有关 所有人的学术成果。调查结果将为未来的生物学研究提供基础 以及旨在预防或最大程度减少中枢神经系统组织损伤并提高认知能力的认知干预措施 以及不断增加的儿童白血病长期幸存者的学术成果。

项目成果

Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia.

儿童白血病治疗期间氧化防御、细胞凋亡和认知能力的变化。

• DOI: 10.1177/1099800418763124
• 发表时间: 2018
• 期刊: Biological research for nursing
• 影响因子: 2.5
• 作者: Moore,IdaMKi;Koerner,KariM;Gundy,PatriciaM;Montgomery,DavidW;Insel,KathleenC;Harris,LynnetteL;Taylor,OlgaA;Hockenberry,MarilynJ
• 通讯作者: Hockenberry,MarilynJ

Fatigue and Oxidative Stress in Children Undergoing Leukemia Treatment.

• DOI: 10.1177/1099800416647794
• 发表时间: 2016-10
• 期刊: Biological research for nursing
• 影响因子: 2.5
• 作者: Rodgers C;Sanborn C;Taylor O;Gundy P;Pasvogel A;Moore IM;Hockenberry MJ
• 通讯作者: Hockenberry MJ

Evaluation of Biomarkers of Oxidative Stress and Apoptosis in Patients With Severe Methotrexate Neurotoxicity: A Case Series.

严重甲氨蝶呤神经毒性患者氧化应激和细胞凋亡生物标志物的评估：病例系列。

• DOI: 10.1177/1043454214563409
• 发表时间: 2015
• 期刊: Journal of pediatric oncology nursing : official journal of the Association of Pediatric Oncology Nurses
• 作者: Taylor,OlgaA;Hockenberry,MarilynJ;McCarthy,Kathy;Gundy,Patricia;Montgomery,David;Ross,Adam;Scheurer,MichaelE;Moore,IdaM
• 通讯作者: Moore,IdaM