Abstract：
Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.
摘要：
自从发现BRAF突变和融合在儿童低级别神经胶质瘤发展中的关联以及随后认识到大多数儿童低级别神经胶质和神经胶质细胞肿瘤通过RAS/RAF/MAP激酶途径具有异常信号传导以来，这些肿瘤的概念化方式发生了巨大的变化。这些肿瘤中存在的许多融合和突变与分子靶标有关，有正在开发或已经在临床使用的药物。各种代理商，包括MEK抑制剂,BRAF抑制剂,MTOR抑制剂和，在NTRK抑制剂的小亚群患者中，已成功用于治疗复发性疾病的儿童，在常规方法如手术或化疗失败后。与新诊断的神经胶质瘤和神经胶质肿瘤儿童的分子靶向治疗相比，化疗的相对益处正在研究中。在新诊断的BRAF-V600E突变的低度神经胶质瘤和神经胶质肿瘤儿童中，MEK抑制剂和BRAF抑制剂的组合已显示优于常规化疗（卡铂和长春新碱）。然而,这种分子靶向治疗的长期效果尚不清楚.分子靶向治疗在早期治疗中的潜在用途使得在开始治疗之前必须知道大多数低级别神经胶质和神经胶质细胞肿瘤的分子组成。该规则的主要例外是患有1型神经纤维瘤病的儿童，根据定义,有NF1损失；然而，即使在这个人群中，出现在儿童晚期和青春期或对常规治疗无反应的胶质瘤可能是活检的候选人，尤其是在进入分子靶向治疗试验之前。
