Survival and functional outcomes in paediatric thalamic and thalamopeduncular low grade gliomas.

BACKGROUND: Childhood thalamopeduncular gliomas arise at the interface of the thalamus and cerebral peduncle. The optimal treatment is total resection but not at the cost of neurological function. We present long-term clinical and oncological outcomes of maximal safe resection. METHODS: Retrospective review of prospectively collected data: demography, symptomatology, imaging, extent of resection, surgical complications, histology, functional and oncological outcome. RESULTS: During 16-year period (2005-2020), 21 patients were treated at our institution. These were 13 girls and 8 boys (mean age 7.6 years). Presentation included progressive hemiparesis in 9 patients, raised intracranial pressure in 9 patients and cerebellar symptomatology in 3 patients. The tumour was confined to the thalamus in 6 cases. Extent of resection was judged on postoperative imaging as total (6), near-total (6) and less extensive (9). Surgical complications included progression of baseline neurological status in 6 patients, and 5 of these gradually improved to preoperative status. All tumours were classified as low-grade gliomas. Disease progression was observed in 9 patients (median progression-free survival 7.3 years). At last follow-up (median 6.1 years), all patients were alive, median Lansky score of 90. Seven patients were without evidence of disease, 6 had stable disease, 7 stable following progression and 1 had progressive disease managed expectantly. CONCLUSION: Paediatric patients with low-grade thalamopeduncular gliomas have excellent long-term functional and oncological outcomes when gross total resection is not achievable. Surgery should aim at total resection; however, neurological function should not be endangered due to excellent chance for long-term survival.

MICROSURGICAL MANAGEMENT OF LOW-GRADE SPINAL CORD ASTROCYTOMA IN ADULTS: A PERSONAL CASE SERIES REPORT AND BRIEF LITERATURE REVIEW.

Astrocytoma is the second most common intramedullary tumor of predominantly low-grade malignancy in adult patients. Adult astrocytomas have better-quality prognosis compared with astrocytomas in children. Although a standardized surgical management protocol for spinal cord glioma is currently unavailable, surgery of low-grade astrocytoma should be aimed at gross total resection to preserve neurological function and to improve the outcome. Herein, we present a personal case series of four consecutive adult spinal cord astrocytoma patients who were operated on during the last few years. Tumor resection was performed in all patients utilizing microsurgical technique and intraoperative neurophysiologic monitoring. We also provide a literature review of the treatment of intramedullary astrocytoma in adults and discuss contemporary surgical management and prognosis.

Clinical characteristics, long-term complications and health-related quality of life (HRQoL) in children and young adults treated for low-grade astrocytoma in the posterior fossa in childhood.

INTRODUCTION: Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge concerning its long-term outcome is sparse. The aim of the study was to investigate if children treated for low-grade pilocytic astrocytoma in the posterior fossa had complications affecting physical and psychological health, cognitive functions, learning difficulties and HRQoL. METHODS: A descriptive single-centre study, where 22 children and young adults out of 27 eligible patients (81%) treated for pilocytic astrocytoma, with a mean follow-up time of 12.4 years (5-19 years) participated (14 adults, two by telephone interviews and eight children). The study included a review of medical records, an interview, neurological investigation, screening tools for psychiatric symptoms (Beck Depression and Anxiety Inventories and Beck Youth Inventory Scales) and HRQoL measures (RAND-36). RESULTS: Motor complications were most common, reported in 12 patients and mainly affecting fine-motor skills. Seven patients reported cognitive difficulties affecting performance in school. Educational support was given in the period immediately after treatment but not after primary school. None had elevated levels of psychiatric symptoms and the level of HRQoL as well as their psychosocial and educational situation was in correspondence with Swedish norms. The HRQoL score for vitality (VT) almost reached statistical significance. CONCLUSIONS: The long-term functional outcome for children treated for low-grade astrocytoma is favourable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programmes including interventions in school.

Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma.

Epithelioid glioblastoma (E-GBM) is a rare variant of glioblastoma (GBM), characterized by epithelioid cells with eosinophilic round cytoplasm devoid of stellate cytoplasmic processes. A number of studies have demonstrated that more than half of E-GBMs harbor a valine to glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E). However, there are no previous reports on E-GBM with telomerase reverse transcriptase (TERT) promoter mutation in addition to BRAF V600E mutation. Here, we report an E-GBM case in an 18-year-old man with BRAF V600E and TERT promoter mutations. The tumor composed of 80% E-GBM and 20% diffuse astrocytoma-like components, and BRAF V600E and TERT promoter mutations were detected in both. E-GBM generally arises as a primary lesion; however, a few previous cases have been demonstrated to accompany low-grade areas. Demonstration of concurrent BRAF V600E and TERT promoter mutations in low- and high-grade lesions strongly suggested their identical origin, and acquisition of each mutation may be an early event, possibly playing a pivotal role in the genesis and subsequent progression to E-GBM.

[Pediatric brain tumors]. / Kindliche Hirntumoren.

Brain tumors differ between children and adults both in histology and localization. Malignant gliomas and meningiomas predominate in adults while medulloblastomas and low-grade astrocytomas are the most frequent brain tumors in children. More than one half (50-70%) of pediatric brain tumors have an infratentorial location but only approximately 30% in adults. Brain tumors can be recognized in sonography, cranial computed tomography (CCT) and magnetic resonance imaging (MRI) by their space-consuming character and by their divergent density and intensity in comparison to normal brain parenchyma. They can grow extrusively, even infiltrate the parenchyma or originate from it. Besides clinical symptoms and diagnostics this article describes the most common pediatric brain tumors, i.e. astrocytoma, medulloblastoma, brainstem glioma, craniopharyngioma, neurofibromatosis and ganglioglioma. The most important imaging criteria are outlined.

Prognostic value of the extent of resection in supratentorial WHO grade II astrocytomas stratified for IDH1 mutation status: a single-center volumetric analysis.

Current evidence supports a maximized extent of resection (EOR) in low-grade gliomas (LGG), regardless of different histological subtypes and molecular markers. We therefore evaluated the prognostic impact of extensive, mainly intraoperative (i)MRI-guided surgery in low-grade astrocytomas stratified for IDH1 mutation status. Retrospective assessment of 46 consecutive cases of newly diagnosed supratentorial WHO grade II astrocytomas treated during the last decade was performed. IDH1 mutation status was obtained for all patients. Volumetric analysis of tumor volumes was performed pre-, intra-, early postoperatively and at first follow-up. Survival analysis was conducted with uni-and multivariate regression models implementing clinical parameters and continuous volumetric variables. Median EOR was 90.4 % (range 17.5-100 %) and was increased to 94.9 % (range 34.8-100 %) in iMRI-guided resections (n = 33). A greater EOR was prognostic for increased progression-free survival (HR 0.23, p = 0.031) and time to re-intervention (TTR) (HR 0.23, p = 0.03). In IDH1 mutant patients, smaller residual tumor volumes were associated with increased TTR (HR 1.01, p = 0.03). IDH1 mutation (38/46 cases) was an independent positive prognosticator for overall survival (OS) in multivariate analysis (HR 0.09, p = 0.002), while extensive surgery had limited impact upon OS. In a subgroup of patients with ≥40 % EOR (n = 39), however, initial and residual tumor volumes were prognostic for OS (HR 1.03, p = 0.005 and HR 1.08, p = 0.007, respectively), persistent to adjustment for IDH1. No association between EOR and neurologic morbidity was found. In this analysis of low-grade astrocytomas stratified for IDH1, extensive tumor resections were prognostic for progression and TTR and, in patients with ≥40 % EOR, for OS.

Is Upregulation of Aquaporin 4-M1 Isoform Responsible for the Loss of Typical Orthogonal Arrays of Particles in Astrocytomas?

The astrocytic endfoot membranes of the healthy blood-brain barrier-contacting the capillary-are covered with a large number of the water channel aquaporin 4 (AQP4). They form orthogonal arrays of particles (OAPs), which consist of AQP4 isoform M1 and M23. Under pathologic conditions, AQP4 is distributed over the whole cell and no or only small OAPs are found. From cell culture experiments, it is known that cells transfected only with AQP4-M1 do not form OAPs or only small ones. We hypothesized that in astrocytomas the situation may be comparable to the in vitro experiments expecting an upregulation of AQP4-M1. Quantitative Real-time PCR (qRT-PCR) of different graded astrocytomas revealed an upregulation of both isoforms AQP4 M1 and M23 in all astrocytomas investigated. In freeze fracture replicas of low-grade malignancy astrocytomas, more OAPs than in high-grade malignancy astrocytomas were found. In vitro, cultured glioma cells did not express AQP4, whereas healthy astrocytes revealed a slight upregulation of both isoforms and only a few OAPs in freeze fracture analysis. Taken together, we found a correlation between the decrease of OAPs and increasing grade of malignancy of astrocytomas but this was not consistent with an upregulation of AQP4-M1 in relation to AQP4 M23.

Lipoastrocytoma: A rare case report and review of literature.

Lipoastrocytoma is an extremely rare tumor, with only a few cases described. We report a case of a low-grade astrocytoma occupying the right cortical lobe in the parafalcine location. The patient was admitted with headache, vomiting and altered sensorium for duration of 1 year. MRI revealed a large heterogeneous enhancing mass in the right fronto-parieto-temporal lobe with intratumoral fat along with cystic changes and calcification (correlated with CT) showing mass effect in the third ventricle. A gross total excision of the tumor was performed. Histologically, the tumor showed glial cells that contained lipid droplets coalescing into a single large droplet, similar in appeareance to adipocytes. Immunohistocemically, tumor cells strongly expressed GFAP and S-100 protein. Ki-67 labelling index was low. The patient remained in good neurological condition at 3 months follow-up. This case represents a rare variant of low-grade astrocytoma that is designated as lipoastrocytoma.

Surgical approaches for brainstem tumors in pediatric patients.

PURPOSE: To analyze the pathways to brainstem tumors in childhood, as well as safe entry zones. METHOD: We conducted a retrospective study of 207 patients less than 18 years old who underwent brainstem tumor resection by the first author (Cavalheiro, S.) at the Neurosurgical Service and Pediatric Oncology Institute of the São Paulo Federal University from 1991 to 2011. RESULTS: Brainstem tumors corresponded to 9.1 % of all pediatric tumors operated in that same period. Eleven previously described "safe entry zones" were used. We describe a new safe zone located in the superior ventral pons, which we named supratrigeminal approach. The operative mortality seen in the first 2 months after surgery was 1.9 % (four patients), and the morbidity rate was 21.2 %. CONCLUSIONS: Anatomic knowledge of intrinsic and extrinsic brainstem structures, in association with a refined neurosurgical technique assisted by intraoperative monitoring, and surgical planning based on magnetic resonance imaging (MRI) and tractography have allowed for wide resection of brainstem lesions with low mortality and acceptable morbidity rates.

Astrocytoma with high-grade features and MYBL1-MMP16 fusion.

Background: Gliomas represent the most common primary intraparenchymal brain tumors in adult and pediatric patients. Neuropathological work-up of these gliomas typically entails the determination of isocitrate dehydrogenase (IDH) mutational status, presence or absence of 1p/19q co-deletion, and O6 methylguanine-DNA methyl-transferase (MGMT) promoter methylation status. Case Description: We present here an unusual case of a posterior fossa tumor in a 51-year-old female, which was initially diagnosed as astrocytoma with some high-grade features that recurred, displaying even more aggressive features such as infiltration and increased proliferative activity. Both the initially resected and recurrent tumor revealed MYBL1-MMP16 fusion, which is much more commonly found in pediatric low-grade gliomas and, to our knowledge has not been described in the context of an adult glioma. Conclusion: The significance of MYBL1-MMP16 fusion in adult gliomas in relation to survival and likelihood of recurrence is, therefore, unknown and requires more extensive research.

Low-Grade Astrocytoma Causing Dural and Calvarial Destruction.

Most of the literature on intra-axial lesions causing calvarial and dural destruction comes from case reports for glioblastoma, lymphoma, metastasis, and aggressive meningioma. Destruction of dura and calvaria by low-grade gliomas is extremely uncommon; cases reported so far have been mostly oligodendrogliomas. This article describes the unusual case of a 23-year-old male patient with a left-sided intra and extracranial tumor involving the frontal lobe, destroying the overlying dura and calvaria, who underwent maximal safe resection. Histopathology showed the tumor to be a low-grade astrocytoma. The calvarial thinning or remodeling caused by low-grade gliomas is thought to result from their chronic mass effect, by displacing the overlying layer of cerebrospinal fluid and transmitting brain pulsations directly to the inner table of the skull. Pressure thinning of the inner table of the skull may be caused by Pacchionian granulations close to the midline. Although this is extremely uncommon, magnetic resonance imaging may include low-grade astrocytoma in the differential diagnosis in such cases.

Multi-joint steroid-induced avascular necrosis in a malignant brain tumor patient.

Avascular necrosis (AVN) is a rare but serious adverse event associated with the use of corticosteroids for long durations or at high doses. This case report describes a 47-year-old female patient with low-grade astrocytoma who was initiated on low-dose dexamethasone for symptom management. The patient developed joint pain 1 year after steroid exposure, then was found to have AVN of the hip followed by multiple other joints. This case report highlights the extent to which AVN can occur in patients with brain tumors following a short course of low-dose corticosteroids. Careful evaluation of and monitoring for the development of AVN should occur frequently in patients with brain tumors given the frequent use of corticosteroids for symptom management in this population.

Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness.

BACKGROUND: Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis. METHODS: In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database. RESULTS: We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII-AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM. CONCLUSIONS: In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1mut AGII and AGIII progression towards secondary GBM.

A Simple Panel of IDH1 and P53 in Differential Diagnosis Between Low-Grade Astrocytoma and Reactive Gliosis.

BACKGROUND: Reactive gliosis is a response of glial tissue to different types of injury such as brain abscess, trauma, hemorrhage, or even neoplastic process. In some circumstances, especially when the tissue biopsy is small, there may be difficulty to discriminate this reactive condition with low-grade diffuse astrocytoma (World Health Organization [WHO] grade II) by conventional hematoxylin and eosin (H&E) slides, so some immunohistochemical and molecular markers have been introduced for this differential diagnosis. One of the important aspects of updated WHO classification in 2016 has been dividing some of the glial tumor according to IDH1 (isocitrate dehydrogenase 1) mutation. OBJECTIVES: In this study, we tried to evaluate IDH1 and P53 mutation by immunohistochemistry as a simple and highly specific and sensitive method to differentiate low-grade astrocytoma and reactive gliosis. MATERIAL AND METHODS: For 5 years (2013-2018), 50 cases of clinically documented reactive gliosis and 50 cases of low-grade astrocytoma were evaluated for the presence or absence of IDH1 and P53 mutation by immunohistochemistry. RESULTS: Isocitrate dehydrogenase 1 was positive in 92% and 4% of the astrocytoma and reactive gliosis cases and P53 was positive in 90% and 4% of the cases with the final diagnosis of astrocytoma and reactive gliosis, respectively. DISCUSSION AND CONCLUSION: Combination of P53 and IDH1 as an immunohistochemical panel showed specificity of 96% and sensitivity of 91% for differential diagnosis of reactive gliosis and low-grade astrocytoma. These 2 markers can be extremely helpful for this differential diagnosis.

Lipoastrocytoma: Case report and review of the literature.

Lipoastrocytoma is an extremely rare tumor, with only six cases described. We report the case of an astrocytoma involving the upper part of the cerebellar-pontine angle and the right portion of the clivus starting from the brainstem with a diffuse lipomatous component in a 39 year-old man. The patient was admitted with headache of 1 year's duration and diplopia over the previous 3 months. MRI revealed a ponto-cerebellar lesion that showed irregular enhancement after contrast administration. Subtotal excision of the tumor was accomplished. Adjuvant chemotherapy and radiation therapy were not administered. Histologically the tumor showed the classical histology of low-grade astrocytoma and a portion of the lesion was composed of lipid-laden cells. Immunohistochemistry for glial fibrillary acid and S-100 proteins clearly demonstrated the glial nature of these cells. Ki-67/Mib-1 labeling index was low (2%). The patient remains in good neurological conditions after 10 months. Our case has a benign postoperative behavior, also after subtotal excision, with restrictions due to the short follow-up. It is important to record each new case of this rare tumor to produce a better characterization of this lesion.

Prognostic factors and survival in low grade gliomas of the spinal cord: A population-based analysis from 2006 to 2012.

PURPOSE: Primary spinal cord tumors are rare, and evidence-based management of these patients remains a source of controversy. This study used a large cohort of low-grade spinal cord astrocytomas to determine the effectiveness of prognostic factors and survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify patients with WHO grade I-II primary spinal cord astrocytomas from 1973 to 2012; however, patients before 2006 were excluded due to ambiguity diagnosis. Univariate and multivariate Cox proportional hazard models were created to compare survival across covariates and summarized using the Kaplan-Meier method. RESULTS: A total of 561 patients with low-grade glioma (astrocytoma) were identified. Among these, 15.5% of patients received a gross total resection (GTR), 26.1% subtotal resection (STR), and 46.2% unidentified extent of resection. 59.4% did not receive any radiation therapy at any point of the treatment course, while 40.6% underwent radiation therapy. In our cohort, only patients with GTR demonstrated statistically improved survival (HR: 0.22, P < 0.001). Patients with STR had nearly identical survival compared to patients with no surgery (HR: 0.98), and radiotherapy was associated with increased odds of mortality (HR: 1.47, P < 0.001). Multivariate analysis demonstrated a significant survival benefit among patients with younger age, GTR and absence of radiotherapy. Histologic grade did not statistically impact survival. CONCLUSION: Our study suggests that GTR results in improved survival among patients with low-grade gliomas within the spinal cord. Future, considerable data research efforts will aim to better define the role of radiotherapy and tumor grading in this patient population.

Abnormal changes in voltage-gated sodium channels subtypes NaV1.1, NaV1.2, NaV1.3, NaV1.6 and CaM/CaMKII pathway in low-grade astrocytoma.

Epileptic seizures are the main clinical manifestation of low-grade astrocytoma. Voltage-gated sodium channels (VGSCs) play a crucial role in epilepsy. Until now, the role of VGSCs and the relationships between calmodulin (CaM)/CaM-dependent protein kinase II (CaMKII) and VGSCs in low-grade astrocytoma have not been demonstrated. In our study, the protein expression of NaV1.3, NaV1.6 and CaM was significantly increased in the tumor compared to control tissue, while the level of p-CaMKII/CaMKII was significantly decreased in the tumor group as determined by Western Blotting and immunohistochemistry. Furthermore, double-labeling immunofluorescence results showed that NaV1.3/NaV1.6 and CaM co-localization was significantly increased in the tumor group compared to control tissue. This study represents the first evidence of the abnormal changes in VGSCs subtypes and CaM/CaMKII pathway in human brain low-grade astrocytoma, providing new potential targets for molecular therapies of this disease.

Clinicopathological and imaging features of lipoastrocytoma: Case report.

Lipidized tumors of the central nervous system are very uncommon, with only a few cases described. We report a case of a 25-year-old woman with a tumor involving the left premotor area. She underwent gross total excision. Histologically, the tumor was composed of glial fibrillary acidic protein-positive glial cells with areas of lipidization. A diagnosis of lipoastrocytoma was rendered. At three-year follow-up she was doing well, supporting the presumed favorable prognosis of these uncommon tumors. Absence of xanthochromic appearance, mitotic activity, necrosis and poor reticulin activity are the differentiating features from the pleomorphic xanthoastrocytoma. We highlighted that these tumors involve the adult and pediatric population and distribute in both supratentorial and infratentorial compartments as well as in the spinal cord.

Subventricular zone predicts high velocity of tumor expansion and poor clinical outcome in patients with low grade astrocytoma.

OBJECTIVE: The aim of this study is to clarify the association between subventricular zone (SVZ) involvement and velocity of diametric expansion(VDE) in patients with low-grade astrocytoma and also assessed the clinical outcome of those patients. MATERIALS AND METHODS: A total of 168 adult patients with newly diagnosed supratentorial low-grade astrocytoma were studied retrospectively. RESULTS: There were 73 patients had SVZ involvement. Patients with SVZ involvement(7.16 ±â€¯6.53 mm/y) had a higher VDE than patients without SVZ involvement(4.38 ±â€¯5.35 mm/y). VDE was modeled as a categorical variable(＜4, ≥4 and, ＜8, ≥8 and, ＜12, ≥12 mm/y). Logistic regression showed that SVZ involvement was associated with high VDE after adjusting by confounding variables. On the univariate analysis, the results showed that tumor involved with SVZ, VDE ≥ 4 mm/y, VDE ≥ 8 mm/y, and VDE ≥ 8 mm/y were significant predictors of a shorter OS, progression-free survival (PFS) and malignant progression-free survival (MFS)(all p ＜0.05). The categorical variables of VDE (＜4 mm/y, ≥4 mm/y and, ＜8 mm/y, ≥8 mm/y and, ＜12 mm/y, ≥12 mm/y) were adjusted by confounding variables in multivariate analysis, respectively. The results indicated that VDE ≥ 8 mm/y, VDE ≥ 12 mm/y were worse prognostic factors for OS, while VDE ≥ 4 mm/y, VDE ≥ 8 mm/y and VDE ≥ 12 mm/y were related to shorter PFS and MFS. In addition, SVZ involvement was prognostic factors in predicting OS and PFS except MFS. CONCLUSION: Our results demonstrated that SVZ involvement predicted high VDE and worse clinical outcome, and high VDE was associated with poor prognosis in patients with low-grade astrocytoma.

A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas.

Background: Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA. Methods: A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF. Results: We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures. Conclusion: MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.