BACKGROUND: Optimal management of children with centrally located low-grade glioma (LGG) is unclear. A better understanding of the inherent risk factors along with the effects of interventions on long-term outcome can lead to reassessment of the current approaches to minimize long-term morbidity. Our goal was to reassess the current treatment strategies to gain a better understanding of the benefits and risks of different treatment approaches. A secondary goal was to determine whether BRAF-KIAA1549 (B-K) fusion is associated with a better PFS. METHODS: To reassess the current treatment strategies of centrally located LGG, we compared the long-term survival and morbidity of different treatment regimens. Medical records of patients primarily treated at Texas Children's Cancer and Hematology Center, Baylor College of Medicine between 1987 and 2008 were reviewed. Fluorescent in situ hybridization (FISH) for B-Kfusion/duplication was performed. RESULTS: Forty-seven patients with a median follow-up of 79 months were included in the analysis. The 5-year overall survival (OS) and progression-free survival (PFS) for all patients were 96% and 53%, respectively. The 5 year PFS for those treated initially with RT (12 patients, median age 11 years, range 3-15) and with chemotherapy (28 patients, median age 2 years, range 0-8) were 76% and 37%, respectively (log-rank test p = 0.02). Among children who progressed after chemotherapy, the 5-year PFS after salvage RT was 55%. Patients diagnosed at a younger age (<5yrs) were more likely to experience endocrine abnormalities (Fisher's Exact test, p < 0.00001). In 27 patients with qualified tissue sample, risk of progression is nearly 3 times higher with presence of B-K fusion/duplication compared to the absence of B-K fusion/duplication (HR 2.95, 95% CI: 0.83-10.51). CONCLUSIONS: Effective and durable tumor control was obtained with RT as initial treatment. In younger patients, chemotherapy can delay the use of RT; however, frequent progression and long-term morbidity are common. More effective and less toxic therapies are required in these patients, the majority of whom are long-term survivors. Our cohort confirmed the previous report of frequent B-K fusion in pilocytic astrocytoma, but did not find any significant association between this fusion and clinical outcomes. Molecular-targeting therapeutics for B-K fusion specifically or MAPK pathway are promising future treatment with potentially less toxic effect. SECONDARY CATEGORY: Clinical Neuro-Oncology.