Quantitative MR measure of MTX neurotoxicity in children

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是 最常见的儿童癌症，每种癌症约有3,500例新发病例 在美国的一年。当癌症治疗专门针对 不成熟的大脑，就像ALL儿童的情况一样，治疗效果必须 与慢性神经毒性的可能性相平衡。与估计 ALL儿童的3年无事件生存率现在约为90 %，越来越多的注意力集中在尽量减少晚期神经毒性上 在这个特别脆弱的群体中。CNS最常见的方法 儿童ALL的预防包括大剂量甲氨蝶呤（HDMTX）。然而，在这方面， 几项研究表明，HDMTX和 神经毒性因此，治疗诱导的神经毒性是一个重要的， 儿科肿瘤学中的临床相关问题。我们自己的研究 证实，白质脑病可以观察到多达75%的 在用HDMTX治疗期间的患者，即使那些没有癫痫发作或其他 急性神经毒性的症状。我们的研究建立在这样的假设之上， 由HDMTX引起的白质脑病的严重程度是连续的， 使用非侵入性MR技术进行可靠探测。 超过300名儿童将在我们的五年协议中接受ALL治疗。 治疗机构，包括5个疗程的2.5或5.0 g/m2 HDMTX在诱导和巩固阶段。拟建项目 将是第一个使用定量成像为基础的措施（混合神经 网络分段; T1和T2弛豫时间）进行调查 一组受试者在治疗期间发生治疗诱导的白质脑病 足够大以充分检验以下假设：1） 治疗早期出现白质脑病可预测后期出现白色物质 变化; 2）治疗期间的白质脑病与 暴露于HDMTX;和3）治疗期间的白质脑病是预测性的 治疗引起的神经认知结果将直接影响 未来儿科ALL临床试验的设计。最终目标是利用 这些定量磁共振成像措施，以检测早期治疗引起的 神经毒性，通过以下治疗调整可能可逆： 其他神经行为和药物干预， 孩子

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.