Low-grade diffusely infiltrative tumors (LGDITs), SMARCB1-mutant, are a newly recognized subset of rare pediatric brain tumors characterized by microscopic infiltrative growth, low proliferative index, and potential progression to atypical teratoid/rhabdoid tumors (ATRT)-MYC. Previous case reports described radiographic solitary tumors at diagnosis in all cases. We report the first case of LGDIT with extensive involvement of supratentorial and infratentorial structures, including the brainstem, associated with a novel somatic SMARCB1 loss-of-function (LoF) mutation and copy-neutral loss of heterozygosity (cnLOH) on chromosome 22. An 8-year-old boy presented with progressive cranial nerve III palsy, ataxia, and facial weakness. MRI revealed non-enhancing T2/FLAIR hyperintensity involving the hypothalamus, right thalamus, cerebral peduncle, deep gray nuclei, and frontal lobe. Biopsied tumor demonstrated a gliomatosis-like infiltrative neuroepithelial tumor with absent vascularity and necrosis, low proliferative index (Ki67 <5%), rare atypical cells, and loss of INI1 immunoreactivity. Molecular testing identified a SMARCB1 frameshift variant (NM_003073.5:c.351dup, p.Thr118fs) and cnLOH spanning chr22:16054712–51213826, where SMARCB1 is located. Germline testing for SMARCB1 was negative. Additional findings included chromosomal imbalances and variants of uncertain significance in NF1 and KIT. The diagnosis of LGDIT, SMARCB1-mutant, was made. The patient received radiation therapy, with initial improvement followed by recurrence and dissemination within six months of completing radiation. Patient is alive with slow progressive disease at 21 months after diagnosis. This case is notable for its unique clinical presentation with cranioneuropathy from tumor infiltration of brainstem, disseminated tumor consistent with gliomatosis, and a novel somatic SMARCB1 LoF mutation with cnLOH rather than large deletions commonly reported in prior cases. This report expands the known clinical and molecular spectrum of LGDITs and supports the hypothesis that the combination of SMARCB1 LoF and cnLOH may represent an alternative two-hit mechanism. It underscores the need to consider LGDIT in pediatric patients with brainstem or centrally-located infiltrative tumors and to pursue molecular characterization to confirm this rare diagnosis.

BACKGROUND:Diffuse invasion remains a primary cause of treatment failure in pediatric high-grade glioma (pHGG). Identifying cellular driver(s) of pHGG invasion is needed for anti-invasion therapies. METHODS:Ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG were subjected to isolation of matching pairs of invasive (HGGINV) and tumor core (HGGTC) cells. RESULTS:pHGGINV cells were intrinsically more invasive than their matching pHGGTC cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57+CD133- cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57+CD133- > CD57+CD133+ > CD57-CD133+ > CD57-CD133- cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57+CD133- cells in the HGGINV front (HGGINV/CD57+CD133- cells) mediated by NANOG and SHH over-expression. Direct implantation of CD57+ (CD57+/CD133- and CD57+/CD133+) cells into mouse brains reconstituted diffusely invasion, while depleting CD57+ cells (i.e., CD57-CD133+) abrogated pHGG invasion. CONCLUSION:We revealed significantly increased invasive capacities in HGGINV cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57+CD133- and CD57+CD133+ cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells.

Background Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. Methods In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. Findings We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8.9 years (IQR 5.9-12.6), and median follow-up from diagnosis was 7.2 years (3.6-14.8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1.9 years (IQR 0.8-3.9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0.0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0.0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0.0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. fInterpretation The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Abstract BACKGROUND Surveillance of patients with medulloblastoma includes magnetic resonance imaging of the brain and spine and cerebrospinal fluid (CSF) cytology evaluation. Certain protocols require frequent CSF cytology evaluations off-therapy while others perform CSF cytology only at the time of radiographic relapse. We wanted to determine the incidence of isolated CSF positivity at the time of recurrence and the outcome of these patients. METHODS We performed a retrospective analysis of patients with relapsed medulloblastoma treated at Texas Children’s Hospital between 1997 and 2023. RESULTS Out of 223 patients with medulloblastoma, 45 patients developed recurrences. Twenty-five (55.5%) patients underwent lumbar puncture for CSF cytology at the time of relapse. The radiographic distribution of recurrences was focal (n=7), focal and disseminated (n=6), disseminated (n=11), and negative imaging (n=1). Seven out of the 25 (28%) patients had positive CSF cytology for malignant cells at initial relapse. All seven patients succumbed secondary to disease progression. Among 18 patients who had negative CSF cytology at recurrence, three infant patients at initial diagnosis were disease-free following craniospinal radiation at recurrence. Only one among 25 patients had positive CSF cytology without radiographic evidence of relapse. Among ten patients with focal disease at the time of relapse, seven had negative CSF cytology for malignant cells, and three did not have CSF cytology evaluated at the time of relapse. DISCUSSION Frequent evaluation of CSF cytology to detect recurrence may not be necessary in addition to imaging studies. In our study, it did not influence the outcome of patients with recurrence. Prospective studies are necessary to support periodic CSF surveillance to detect ctDNA, which may allow for early interventions that may influence outcomes in patients with recurrent medulloblastoma who have poor outcomes.

Cancer cells need nutrients to grow and proliferate. During nutrient stress in the microenvironment, it is unclear if or how cancer cells can adopt alternative resources to re-wire and survive in patients. We discovered a 6-factor-secretome remarkably sustains a critical cell mass during nutrient stress in a pediatric embryonal brain tumor, atypical teratoid rhabdoid tumor (ATRT). Specific ATRT subtypes emerged as secretome-enriched, matching macrophage-enrichment patterns and were high-relapse-risk subtypes. The secretome alters drug response, protects against cell death, and provides pro-survival niches to rescue drugged cells. Secretome-grown tumor cells rearrange into a web-like architecture-stable during drug exposure, suggesting a mechanism for therapy resistance. Secretome prevents tumor cell death in aggressive tumor models, and in cerebrospinal dissemination, suggesting a role in tumor resistance/relapse. Our results unravel, a previously unexplored role of a specific 6-factor-secretome, providing an alternative fuel to sustain cancer cells during nutrient stress, and implications in relapse subtypes.

Background. Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin. Methods. We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI). Results. Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range: 3.1-21.1). The mean cochlear dose (Dmc) (+/- SD) was 31.5 +/- 8.5 Gy, and the cumulative cisplatin dose was 295 +/- 50 mg/m(2). Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range: 4-22) with a median audiogram follow-up of 49 months (range: 6-177). Twenty-seven patients (34%) had grades 3-4 HL. In adjusted Cox models, only higher Dmc (HR = 1.12, 95% CI:1.06-1.18) was associated with grades 3-4 HL. The predicted 3-year incidence of grades 3-4 HL was 40.0% (95% CI: 21.3-66.3) and 66.7% (95% CI: 35.4-93.7) for children with Dmc >= 36 Gy and age at radiotherapy >= 7 and <7 years, respectively (P = .042). It was 8.9% (95% CI: 2.3-31.6) and 15.6% (95% CI: 5.3-41.1) for children with Dmc <36 Gy and age at radiotherapy >= 7 and <7 years, respectively (P = .78). Conclusions. Children <7 years at radiotherapy with a Dmc >= 36 Gy are at higher risk for HL.

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.

BACKGROUND:The role of neoadjuvant chemotherapy in treating patients with metastatic central nervous system (CNS) germinoma is controversial.METHODS:We compared the relapse-free survival (RFS) of different treatment modalities by performing a meta-analysis using published data. We summarized all data using standard descriptive statistics. We used the Kaplan-Meier method to estimate RFS and their corresponding 95% confidence intervals (CIs). We used the log-rank test for the comparison of survival functions.RESULTS:We identified 97 patients with a median age at presentation of 15 years (range: 7-38). Sites of metastasis were cerebrospinal fluid (CSF) disease only (n = 12), brain parenchyma (n = 18), spinal cord (n = 9), ventricular and CSF (n = 10), ventricular only (n = 31), and other (n = 17). The 3-year RFS among patients who received any form of radiotherapy was 89% (95% CI: 83-96) compared with 0% for patients who received a chemotherapy-only regimen (p = .001). Five-year RFS among patients who received craniospinal irradiation (CSI) was 92% (95% CI: 84-100) compared with 76.4% (95% CI: 63-90) in the non-CSI group (with or without neoadjuvant chemotherapy) (p = .014). Five-year RFS of patients who received CSI less than 24 Gy with neoadjuvant chemotherapy was 100% compared with 92% (95% CI: 83-100) CSI dose greater than or equal to 24 Gy alone (p = .3).CONCLUSIONS:Our analysis does not support avoiding spinal irradiation among patients with radiographic metastatic CNS germinoma. Future studies are needed to confirm whether neoadjuvant chemotherapy will allow a reduction of irradiation dose without compromising survival.

Supplementary Figure S1-S3 Figure S1. Anti-proliferative effects of MLN8237 on pGBM cell lines. Paired monolayer (Mono) and neurosphere (NS) of IC-4687GBM, IC-3752GBM and ICR0315GBM were seeded at 2,000 cells/well and exposed to MLN8237 (1 - 4,000 nM) and anti-proliferative effect was assessed by staining with 250 µg/mL of MTT for 4 hrs at day 11. Viable cells were stained with dark colored intracellular crystal. (Bar=100 µm) Figure S2. FCM analysis of cell cycle distribution in vitro and in vivo. A. In vitro analysis was performed in paired monolayer (Mono) and neurosphere (NS) cells of IC-4687GBM, IC-3752GBM and IC-R0315GBM. Both dose-responses (on day 7) (left panel) and time-course change (at 62.5 nM) (right panel) were examined and presented as percentages of G0 /G1 , S and G2 /M phase in alive cells. € P<0.05, *P<0.01 compared to the untreated (0 nM) cells. B. In vivo changes of cell cycle distribution were analyzed in IC-4687GBM cells treated by MLN8237 (30 mg/kg/day for 12 days by gavage). In addition to the recurrent tumors (Recurrent) harvested when the mice became moribund in the survival group, a separate group of tumors harvested 1 hr post the last treatment of MLN8237 (30 mg/kg/day for 12 days by gavage) (End of Treatment samples) were also included. DNA/RNA were stained with Hoechst 33342/Pyronin Y followed by mouse antibody cocktail staining (to gate out mouse cells) and analyzed by FCM. Representative DNA/RNA profiles (upper panel) and percentage of G0 , G1 , S and G2 /M phase in cell cycle (lower panel) were presented. Figure S3. Representative images of IHC of ARUKA. A. Representative images of AURKA in IC-4687GBM xenograft showing the cells with different staining intensity (arrow) (Magnification: x40). B. AURKA protein expression in IC-R0315GBM in the vehicle treated control and in the recurrent tumor (magnification: x40).

Background Preclinical studies have suggested that mTOR pathway signaling may be a potential therapeutic target for childhood ependymoma. Methods A phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that mTOR pathway inhibition would result in tumor responses for children with recurrent and/or progressive ependymomas. Results Eleven subjects [sex: 4 females (36.4%); median age: 8 years (range: 2-15 years); race: 9 white; prior therapies: median 6 (range: 3-9)] were enrolled on the study. Ten primary tumors were located in the posterior fossa and one primary tumor was located in the spinal cord. Eight of 9 tumors were PF-A subtype epenydmomas. All subjects were treated with oral everolimus 4.5 mg/m(2)/day (each cycle = 28 days) that was titrated to achieve serum trough levels of 5-15 ng/ml. Overall, everolimus was well tolerated; except for a single event of grade 3 pneumonia, all adverse events were grade 1-2. No objective tumor responses were observed. Participating subjects experienced tumor progression and discontinued therapy after a median of 2 cycles of therapy (1 cycle = 2; 2 cycles = 6; 3, 4, and 8 cycles = 1 each). Conclusions Everolimus does not appear to have activity for children with recurrent or progressive PF-A ependymoma.

Figure S1 from Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups

Supplementary Figure 2 from Genome-Wide Allelic Imbalance Analysis of Pediatric Gliomas by Single Nucleotide Polymorphic Allele Array

e14001 Background: KIF11, a mitotic kinesin, is responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11 to enhance tumor proliferation. Many cancers overexpress KIF11, including medulloblastoma (MB), the most common malignant brain tumor in children. MB is molecularly classified into 4 molecular subtypes: sonic-hedgehog (SHH)-activated MB, Wingless (WNT)-activated, and less characterized Group 3 and 4 subtypes. Group 3 and 4 MBs are the most aggressive subtypes and Group 3 MBs have the worst survival outcome. p53 mutation defines a high-risk group in MB patients. We evaluated the efficacy of a Phase I/II KIF11 inhibitor, ispinesib on MB. Methods: We employed in-vitro proliferation assays (CCK), flow cytometry (Annexin V, Propidium Iodide), western blot, Hoechst staining, and two patient-derived orthotopic xenograft (PDOX) mouse models for in-vivo drug testing. Results: Ispinesib effectively inhibited proliferation at nanomolar concentrations for all 5 MB cell lines. A comparison of IC 50 (day 4) indicated that p53-mutational-status did not influence sensitivity to ispinesib. In all five cell lines, regardless of p53 mutational status, ispinesib led to G2/M arrest. However, different p53-mutational-status led to different modes of cell death. High levels of necrotic cell death were observed in p53-mutant, while apoptosis was the predominant mode of cell death in p53-wildtype, on flow cytometry. Apoptotic nuclei were more significantly observed in p53-wildtype (p = 0.002) while p53-mutant cell line demonstrated more micronuclei (p = 0.0302) and multi-nucleation (p= 0.0161), compared to respective DMSO-control cells on Hoechst staining. Ispinesib has demonstrated effective blood brain barrier penetration in brain xenografts. We compared 2 PDOX models of MB. Ispinesib significantly improved survival outcome of Group 3 MB (Control=6, Treated=7, Log-rank p=0.0003), but worsened the survival outcome of p53-mutant SHH MB (Control=14, Treated=11, Log-rank p=0.169). This differential efficacy of ispinesib was recapitulated in the matched 3D-neurosphere cultures of both PDOX models. Cancer-stem-cell (CSC)-enriched neurospheres derived from aggressive Group 3 subtype demonstrated susceptibility to 7-day in-vitro treatment with ispinesib (AUC=0.7743). Monolayer tumor cells demonstrated similar susceptibility (AUC=0.7757). Area under curve (AUC)>0.7 was the significant cut-off. In contrast, both CSC-enriched neurospheres (AUC=0.379) and monolayer tumor cells (AUC=0.491) derived from p53-mutant SHH MB did not demonstrate susceptibility to ispinesib, consistent with matching PDOX models. Conclusions: Preclinically, our results indicate feasibility of ispinesib treatment in MB, specifically aggressive Group 3 MB. Importantly, p53-mutant SHH MB represents a poor molecular-subtype candidate for ispinesib therapy.

Abstract PURPOSE To evaluate the incidence and risk factors for hearing loss (HL) among children with medulloblastoma treated with proton irradiation and cisplatin. METHODS We identified children with medulloblastoma ≥3 years of age treated at Texas Children’s Hospital between 2007-2022. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale (SIOP-Boston). Time to grade ≥3 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS Seventy-eight patients (65.4% male) were treated with craniospinal irradiation (CSI) at a median age of 7.6 years (range: 3-21). The mean cochlear irradiation dose was 31.5±9 Gy, and the cumulative cisplatin dose was 295±50 mg/m2. Fifty-six patients (72%) received amifostine. Patients completed a median of 9 audiograms (range: 4-22) with a median audiogram follow-up of 49 months (range: 3-177). Grade ≥3 HL was documented in 25 patients (32%). In adjusted Cox models, mean cochlear dose (HR=1.12, 95% CI: 1.06-1.18) and the age at CSI (HR=0.81, 95% CI: 0.68-0.98) were associated with grade ≥3 HL. Among children who received irradiation after or at 7 years of age, the estimated probability of grade ≥3 HL at three years post-CSI was 12.6% (95% CI: 4.1-34.6) in children exposed to <36 Gy cochlear irradiation and 35.6% (95% CI: 17.4-63.6) in children exposed to >36 Gy cochlear irradiation. Among children who received irradiation before 7 years of age, the estimated probability of grade ≥3 HL at three years post-CSI was 16.5% (95% CI: 5.6-43) in children exposed to <36 Gy cochlear radiation and 66.7% (95% CI: 35.4-93.7) in children exposed to >36 Gy cochlear irradiation. CONCLUSION Long-term follow-up shows that children who received a cochlear dose ≥36 Gy before 7 years of age are at higher risk for HL, regardless of the amifostine and the cisplatin dose.

Background Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It’s capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM. Materials and methods 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 10 5 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 10 11 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage. Results PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times. Conclusion A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.

Supplementary Tables 1-2 from Genome-Wide Allelic Imbalance Analysis of Pediatric Gliomas by Single Nucleotide Polymorphic Allele Array