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Background: Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies., Methods: We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated., Results: Thirty-three patients (18 male; median age, 5 years) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n = 10, 30%). Most tumors were in the cerebral hemispheres (n = 22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3% ± 8.3%; the 5-year overall survival (OS) rate was 96.4% ± 4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6% ± 15.2% (P < .01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways., Conclusions: pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking., Methods: A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed., Results: Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n = 22), occurred in the youngest patients (median age = 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (p = 0.0043, p = 0.00013). EFS and OS were not different between IHG and LGG (p = 0.95, p = 0.43). Imaging review showed IHGs are associated with circumscribed margins (p = 0.0047), hemispheric location (p = 0.0010), and intratumoral hemorrhage (p = 0.0149)., Conclusions: HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment., Methods: We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC)., Results: The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function., Conclusions: We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes., Methods: We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses., Results: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash., Conclusions: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset., Methods: Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation., Results: One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%-98.4% vs 59.3%-87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021)., Conclusion: A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hippocampal avoidance has been suggested as a strategy to reduce short-term memory decline in adults receiving whole-brain radiation therapy (RT). The purpose of this study was to determine whether the hippocampal dose in children and adolescents undergoing RT for low-grade glioma was associated with memory, as measured by verbal recall., Methods: Eighty patients aged at least 6 years but less than 21 years with low-grade glioma were treated with RT to 54 Gy on a phase II protocol. Patients underwent age-appropriate cognitive testing at baseline, 6 months posttreatment, yearly through 5 years posttreatment, year 7 or 8, and year 10 posttreatment. Random coefficient models were used to estimate the longitudinal trends in cognitive assessment scores., Results: Median neurocognitive follow-up was 9.8 years. There was a significant decline in short-delay recall (slope = -0.01 standard deviation [SD]/year, P < 0.001), total recall (slope = -0.09 SD/y, P = 0.005), and long-delay recall (slope = -0.01 SD/y, P  = 0.002). On multivariate regression, after accounting for hydrocephalus, decline in short-delay recall was associated with the volume of right (slope = -0.001 SD/y, P = 0.019) or left hippocampus (slope = -0.001 SD/y, P = 0.025) receiving 40 Gy (V40 Gy). On univariate regression, decline in total recall was only associated with right hippocampal dosimetry (V40 Gy slope = -0.002, P = 0.025). In children <12 years, on univariate regression, decline in long-delay recall was only associated with right (V40 Gy slope = -0.002, P = 0.013) and left (V40 Gy slope = -0.002, P = 0.014) hippocampal dosimetry., Conclusion: In this 10-year longitudinal study, greater hippocampal dose was associated with a greater decline in delayed recall. Such findings might be informative for radiation therapy planning, warranting prospective evaluation., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed "DNET-like neoplasms of the septum pellucidum." Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series., Methods: We collected 20 of these tumors for a comprehensive study of their clinical, radiological, and pathological features. RNA sequencing or targeted DNA sequencing was undertaken on 18 tumors, and genome-wide DNA methylation profiling was possible with 11 tumors. Published cases (n = 22) were also reviewed for comparative purposes., Results: The commonest presenting symptoms and signs were related to raised intracranial pressure; 40% of cases required cerebrospinal fluid diversion. Epilepsy was seen in approximately one third of cases. All patients had an indolent disease course, despite metastasis within the neuraxis in a few cases. Radiologically, the septum verum/septal nuclei were involved in all cases and are the proposed site of origin for septal DNET (sDNET). Septal DNET showed a high frequency (~80%) of mutations of platelet derived growth factor receptor A (PDGFRA), and alterations in fibroblast growth factor receptor 1 (FGFR1) and neurofibromatosis type 1 (NF1) were also identified. In a genomic DNA methylation analysis alongside other neural tumors, sDNETs formed a separate molecular group., Conclusions: Genetic alterations that are different from those of cerebral DNETs and a distinct methylome profile support the proposal that sDNET is a distinct disease entity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG., Methods: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization., Results: Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%., Conclusion: Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this study was to evaluate amifostine for protection from cisplatin-induced serious hearing loss in patients with average-risk medulloblastoma by extending a previous analysis to a much larger sample size. In addition, this study aimed to assess amifostine with serious hearing loss in patients with high-risk medulloblastoma treated with cisplatin., Methods: Newly diagnosed medulloblastoma patients (n = 379; ages 3-21 years), enrolled on one of 2 sequential St. Jude clinical protocols that included 4 courses of 75 mg/m(2) cisplatin, were compared for hearing loss by whether or not they received 600 mg/m(2) of amifostine immediately before and 3 hours into each cisplatin infusion. Amifostine administration was not randomized. The last audiological evaluation between 5.5 and 24.5 months following protocol treatment initiation was graded using the Chang Ototoxicity Scale. A grade of ≥ 2b (loss requiring a hearing aid or deafness) was considered a serious event., Results: Among average-risk patients (n = 263), amifostine was associated with protection from serious hearing loss (adjusted OR, 0.30; 95% CI, 0.14-0.64). For high-risk patients (n = 116), however, there was not sufficient evidence to conclude that amifostine prevented serious hearing loss (OR, 0.89; 95% CI, 0.31-2.54)., Conclusions: Although patients in this study were not randomly assigned to amifostine treatment, we found evidence in favor of amifostine administration for protection against cisplatin-induced serious hearing loss in average-risk but not in high-risk, medulloblastoma patients., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Children treated for posterior fossa tumors experience reduced cognitive processing speed and, after imaging, show damage to white matter (WM) tracts in the brain. This study explores relationships between white matter microstructure, assessed by fractional anisotropy (FA), and speed of cognitive processing using tract-based spatial statistics (TBSS). At 36 months after treatment with radiotherapy and chemotherapy, 40 patients completed an MRI examination and neuropsychological evaluation. Patients were matched with healthy control subjects based on age, sex, and race. Individual FA values were extracted from examinations for all voxels identified as having significant association between processing speed and FA using TBSS. The regions were labeled anatomically, and fiber tracts were grouped into larger fiber bundle categories based on their anatomical and functional associations. Analyses were performed between mean skeletal FA values in each of the fiber bundles and each of the cognitive processing scores controlling for age. Children 3 years after treatment for posterior fossa brain tumors demonstrate significantly lower processing speed associated with decreased FA, compared with their healthy peers. Commissural fibers in the corpus callosum were negatively affected by disease and therapy with detrimental consequence on patients' cognitive processing. Diffusion tensor imaging of the white matter tracts in the brain is relevant to determining potential mechanisms underlying clinically meaningful change in cognitive performance. Neuroprotective strategies are needed to preserve critical functions.