Quantitative MR measure of MTX neurotoxicity in children

描述(申请人提供)：急性淋巴细胞白血病(ALL)是 最常见的儿童癌症，每个约有3,500个新病例 在美国的一年。当癌症治疗特别针对 大脑不成熟，就像儿童ALL一样，治疗疗效必须 要与慢性神经毒性的可能性相平衡。估计为 儿童三年无事件存活率，目前ALL约为90 %，越来越多的注意力集中在将晚期神经毒性降至最低 在这一特别脆弱的人群中。中枢神经系统最常用的方法 儿童ALL的预防包括大剂量甲氨蝶呤(HDMTX)。然而， 多项研究表明，高密度脂蛋白甲氨蝶呤与 神经毒性。因此，治疗引起的神经毒性是一种重要的 儿科肿瘤学中的临床相关问题。我们自己的研究已经 证实在多达75%的人中可以观察到白质脑病 在使用HDMTX治疗期间的患者，即使那些没有癫痫发作或其他 急性神经毒性症状。我们的研究建立在这样一个假设之上： 由HDMTX引起的白质脑病跨越了一系列严重的疾病 使用无创性磁共振技术可靠地进行探测。 300多名儿童将在我们的五年计划中接受全部治疗 接受治疗的机构，包括2.5或5.0克/平方米的五个疗程 在诱导和巩固阶段的HDMTX。拟议中的项目 将是第一个使用基于定量成像的措施(混合神经 网络分段；T1和T2松弛时间)以进行调查 一组受试者在治疗过程中出现的治疗引起的白质脑病 足够大，足以检验以下假设：1) 治疗早期白质脑病预示较晚的脑白质 变化；2)治疗期间白质脑病与 暴露于HDMTX；以及3)治疗期间白质脑病是可预测的 治疗诱导的神经认知结果将直接影响 儿童急性淋巴细胞白血病未来临床试验的设计。最终目标是使用 这些定量的磁共振成像方法可以检测早期治疗诱导的 神经毒性，通过治疗调整可能是可逆的 针对个人的其他神经行为和药物干预 孩子们。

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer with approximately 3,500 new cases each year in the United States. When cancer treatment specifically targets the immature brain, as is the case for children with ALL, treatment efficacy must be balanced against the potential for chronic neurotoxicity. With estimated three-year event-free survival for children with ALL now at approximately 90 percent, increasing attention is directed toward minimizing late neurotoxicity in this particularly vulnerable population. The most common method of CNS prophylaxis for pediatric ALL includes high-dose methotrexate (HDMTX). However, several studies have shown a significant association between HDMTX and neurotoxicity. Thus, treatment-induced neurotoxicity is an important and clinically relevant problem in pediatric oncology. Our own studies have confirmed that leukoencephalopathy can be observed in as many as 75 percent of patients during treatment with HDMTX, even those without seizures or other symptoms of acute neurotoxicity. Our research builds on the hypothesis that leukoencephalopathy resulting from HDMTX spans a continuum of severity that can be probed reliably using noninvasive MR technology. More than 300 children will be treated for ALL on a five-year protocol at our institution with therapy that includes five courses of either 2.5 or 5.0 g/m2 of HDMTX during the induction and consolidation phases. The proposed project will be the first to use quantitative imaging-based measures (hybrid neural network segmentation; T1 and T2 relaxation times) to investigate treatment-induced leukoencephalopathy during therapy in a group of subjects sufficiently large to adequately test the following hypotheses: 1) that leukoencephalopathy early in therapy is predictive of later white matter changes; 2) that leukoencephalopathy during therapy is proportionate to exposure to HDMTX; and 3) that leukoencephalopathy during therapy is predictive of treatment-induced neurocognitive outcome will have a direct impact on the design of future clinical trials for pediatric ALL. The ultimate goal is to use these quantitative MR imaging measures to detect early therapy-induced neurotoxicity, which is potentially reversible through therapy adjustments of other neurobehavioral and pharmacological interventions for individual children.