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BRAF$^{V600E}$ represents the most common BRAF mutation in all human cancers. Among central nervous system (CNS) tumors, BRAF$^{V600E}$ is mostly found in pediatric low-grade gliomas (pLGG, ~20%) and, less frequently, in pediatric high-grade gliomas (pHGG, 5-15%) and adult glioblastomas (GBM, ~5%). The integration of BRAF inhibitors (BRAFi) in the treatment of patients with gliomas brought a paradigm shift to clinical care. However, not all patients benefit from treatment due to intrinsic or acquired resistance to BRAF inhibition. Defining predictors of response, as well as developing strategies to prevent resistance to BRAFi and overcome post-BRAFi tumor progression/rebound growth are some of the main challenges at present in the field. In this review, we outline current achievements and limitations of BRAF inhibition in gliomas, with a special focus on potential mechanisms of resistance. We discuss future directions of targeted therapy for BRAF$^{V600E}$ mutated gliomas, highlighting how insights into resistance to BRAFi could be leveraged to improve outcomes.

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15-39 years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages.

Diencephalic syndrome is usually associated with tumors in the hypothalamic region, rarely occurring in patients with neurofibromatosis type 1 (NF1)-associated gliomas. We describe the clinical presentation and response to treatment in 3 patients with NF1 presenting with diencephalic syndrome as first symptom of optic pathway/hypothalamic glioma (OPHG). Because of the rarity of this constellation, knowledge about the clinical course and best treatment options for patients with NF1-associated OPHG and diencephalic syndrome is still limited. All 3 patients showed good response to treatment with normalization of body mass index and decrease in tumor volume within 6 months.

BRAFV600E represents the most common BRAF mutation in all human cancers. Among central nervous system (CNS) tumors, BRAFV600E is mostly found in pediatric low-grade gliomas (pLGG, ~20%) and, less frequently, in pediatric high-grade gliomas (pHGG, 5-15%) and adult glioblastomas (GBM, ~5%). The integration of BRAF inhibitors (BRAFi) in the treatment of patients with gliomas brought a paradigm shift to clinical care. However, not all patients benefit from treatment due to intrinsic or acquired resistance to BRAF inhibition. Defining predictors of response, as well as developing strategies to prevent resistance to BRAFi and overcome post-BRAFi tumor progression/rebound growth are some of the main challenges at present in the field. In this review, we outline current achievements and limitations of BRAF inhibition in gliomas, with a special focus on potential mechanisms of resistance. We discuss future directions of targeted therapy for BRAFV600E mutated gliomas, highlighting how insights into resistance to BRAFi could be leveraged to improve outcomes.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

The cerebellum is the most common site of presentation of central nervous system tumors in children but exceedingly rare in adults. Children often present with acute symptoms related to increased intracranial pressure, requiring urgent surgical intervention. The differential diagnosis is broad and includes a variety of benign and malignant entities. Cerebellar low-grade gliomas are the most common and benign, slow-growing tumors, for which surgical resection alone is curative. Embryonal tumors, on the other hand - most commonly medulloblastomas - are highly aggressive and treatment includes intensive postsurgical radiotherapy and chemotherapy. Driven by multiple genomewide profiling studies, the field of neuro-oncology is making great strides towards understanding how different tumors develop and embarking on a new generation of molecularly informed clinical trials.