tbuckley/cabot-search huggingface dataset:
EXTH-59. POTENT, SELECTIVE, AND BRAIN PENETRANT INHIBITORS OF EXTRACELLULAR DOMAIN EGFR ONCOGENIC MUTANTS EXPRESSED IN GBM DEMONSTRATE EFFICACY IN AN INTRACRANIAL PATIENT DERIVED XENOGRAFT MODEL
Authors: Matthew O’Connor, Matt Lucas, Darlene Romashko, Sara Rasmussen, Raffaele Fiorenza, Tai-An Lin, Nigel Waters, George Trainor, Alexander Flohr, Giorgio Ottaviani, Christopher Roberts, Elizabeth Buck, Theodore Nicolaides, David Raleigh, Tomoko Ozawa, Luca Arista
Journal: Neuro-Oncology (2020)

Abstract EGFR mutations identified in glioblastomas (GBM) occur nearly exclusively at the allosteric extracellular domain (ECD) and constitutively activate oncogenic signaling. Despite wide success in treating tumors expressing EGFR catalytic site mutants, no drug has demonstrated clinical utility against tumors expressing the extracellular domain EGFR mutants. We demonstrate that the family of ECD mutations are not only co-expressed in GBM, but that they all activate the oncogene through a similar disulfide bond-mediated receptor dimerization mechanism. This dimerization occurs independent of ligands and renders the Locked-dimer (LoDi)-EGFR insensitive to agents that target the EGFR kinase domain mutants in NSCLC. The kinase conformation induced by these ECD mutations seen in glioblastomas is both oncogenic and altered from kinase domain mutations, thus necessitating a new approach to targeting. By screening against cells expressing LoDi-EGFR mutants, we have identified the first inhibitors that potently and selectively target LoDi-EGFR mutants versus both canonical active site oncogenic mutants and wild type EGFR. Through an optimization effort, we have identified a novel family of potent and selective LoDi-EGFR mutant inhibitors that effectively penetrate the blood brain barrier (BBB) following oral dosing in preclinical studies. A leading exemplar, BDTX-GBM-001, inhibits the 5 major LoDi-EGFR mutants expressed in GBM with antiproliferative potency of ~10 nM while showing favorable selectivity versus the human kinome. When dosed orally in the intracranial GBM6 patient derived xenograft model at 50, 30, and 15 mg/kg, a dose responsive decrease in tumor growth, as well as a statistically significant increase in survival, were observed. These data support the continued evaluation of rationally designed BBB penetrant inhibitors selectively targeting the common LoDi-EGFR mutants and enable the first chance to fully test the clinical hypothesis of EGFR driver mutants in GBM.
PPARγ-p53-Mediated Vasculoregenerative Program to Reverse Pulmonary Hypertension
Authors: Jan K. Hennigs, Aiqin Cao, Caiyun G. Li, Minyi Shi, Julia Mienert, Kazuya Miyagawa, Jakob Körbelin, David P. Marciano, Pin-I Chen, Matthew Roughley, Matthew V. Elliott, Rebecca L. Harper, Matthew A. Bill, James Chappell, Jan-Renier Moonen, Isabel Diebold, Lingli Wang, Michael P. Snyder, Marlene Rabinovitch
Journal: Circulation Research (2020)

Rationale: In pulmonary arterial hypertension (PAH), endothelial dysfunction and obliterative vascular disease are associated with DNA damage and impaired signaling of BMPR2 (bone morphogenetic protein type 2 receptor) via two downstream transcription factors, PPARγ (peroxisome proliferator-activated receptor gamma), and p53. Objective: We investigated the vasculoprotective and regenerative potential of a newly identified PPARγ-p53 transcription factor complex in the pulmonary endothelium. Methods and Results: In this study, we identified a pharmacologically inducible vasculoprotective mechanism in pulmonary arterial and lung MV (microvascular) endothelial cells in response to DNA damage and oxidant stress regulated in part by a BMPR2 dependent transcription factor complex between PPARγ and p53. Chromatin immunoprecipitation sequencing and RNA-sequencing established an inducible PPARγ-p53 mediated regenerative program regulating 19 genes involved in lung endothelial cell survival, angiogenesis and DNA repair including, EPHA2 ( ephrin type-A receptor 2 ), FHL2 ( four and a half LIM domains protein 2 ), JAG1 ( jagged 1 ), SULF2 ( extracellular sulfatase Sulf-2 ), and TIGAR ( TP53-inducible glycolysis and apoptosis regulator ). Expression of these genes was partially impaired when the PPARγ-p53 complex was pharmacologically disrupted or when BMPR2 was reduced in pulmonary artery endothelial cells (PAECs) subjected to oxidative stress. In endothelial cell-specific Bmpr2 -knockout mice unable to stabilize p53 in endothelial cells under oxidative stress, Nutlin-3 rescued endothelial p53 and PPARγ-p53 complex formation and induced target genes, such as APLN ( apelin ) and JAG1 , to regenerate pulmonary microvessels and reverse pulmonary hypertension. In PAECs from BMPR2 mutant PAH patients, pharmacological induction of p53 and PPARγ-p53 genes repaired damaged DNA utilizing genes from the nucleotide excision repair pathway without provoking PAEC apoptosis. Conclusions: We identified a novel therapeutic strategy that activates a vasculoprotective gene regulation program in PAECs downstream of dysfunctional BMPR2 to rehabilitate PAH PAECs, regenerate pulmonary microvessels, and reverse disease. Our studies pave the way for p53-based vasculoregenerative therapies for PAH by extending the therapeutic focus to PAEC dysfunction and to DNA damage associated with PAH progression.
PATH-33. EPIGENOMIC ANALYSIS OF SPINAL EPENDYMOMA
Authors: Erika Yamazawa, Shota Tanaka, Nagae Genta, Meguro Hiroko, Takayoshi Umeda, Taijun Hana, Toshihiro Takami, Yuta Nakanishi, Makoto Taniguchi, Keisuke Takai, Takashi Komori, Kouichi Ichimura, Kohei Fukuoka, Shunsaku Takayanagi, Hiroyuki Aburatani, Nobuhito Saito
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Ependymomas commonly occur in the fourth ventricle and the spinal cord. Gross total resection, age and WHO grade are known prognostic factors. Ependymomas are currently classified into 9 distinct subgroups by DNA methylation profile analysis. Spinal cord ependymoma is distinct from other subgroups. To investigate heterogeneity within spinal cord ependymoma, we examined DNA methylation profiles. MATERIALS AND METHODS We used Infinium MethylationEPIC array (illumina) to obtain DNA methylation data from frozen specimens of spinal ependymoma resected at the University of Tokyo, Osaka City University, and Tokyo Metropolitan Neurological Hospital. Japan Pediatric Molecular Neuro-Oncology Group provided methylation data for 11 reported cases. Cluster analysis was performed using Cluster3.0. RESULTS We analyzed 34 patients, 21 male and 13 female, aged from 18 to 76 years (median 50.5 years), including 2 cases with neurofibromatosis type 2. WHO grade was grade_3 in 2 cases and grade_2 in others. Clustering of the DNA methylation data showed that WHO grade_3 cases tended to be classified into a subgroup distinct from other cases. CONCLUSION This is the largest DNA methylation profiling study on spinal cord ependymoma to date. The study may suggest a new subgroup correlated with higher WHO grade.
Natural killer cell-based immunotherapy for acute myeloid leukemia
Authors: Jing Xu, Ting Niu
Journal: Journal of Hematology & Oncology (2020)

Abstract Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.
HGG-43. CONGENITAL GLIOBLASTOMA MULTIFORME: A CASE REPORT OF A RARE PEDIATRIC BRAIN TUMOR, MOLECULAR ANALYSIS, AND REVIEW OF THE LITERATURE
Authors: Christina Amend, James Stadler, Shahriar Salamat, Erik Dedekam, Angela Waanders, Nitin Wadhwani
Journal: Neuro-Oncology (2020)

Abstract Congenital brain tumors are rare, accounting for less than 4% of all pediatric brain tumors. Congenital glioblastoma multiforme (GBM) is rarer still, accounting for 3–15% of congenital brain tumors. There is literature to suggest that these tumors differ from pediatric and adult GBM clinically and molecularly, and as such should be treated as their own distinct entity. Our case is a 4 week old male who initially presented to his pediatrician for enlarging head circumference and upward gaze palsy. An MRI was obtained revealing a right parietal mass. He underwent gross total resection the following day with pathology revealing glioblastoma, WHO grade IV. Further analysis revealed ATRX retained, p53 immunoreactivity in 15–20% of nuclei, IDH1 and IDH2 wildtype, MGMT promoter not methylated, H3K27M wildtype, no 1p and/or 19q deletion/codeletion. Interestingly, RNA analysis of his tumor detected the PPP1CB-ALK fusion transcript as well as amplification of the ALK gene. Co-occurrence of these mutations has been reported in a small number of pediatric glioblastoma patients and PPP1CB-ALK fusions are one of the most common receptor tyrosine kinase fusions in infantile gliomas. ALK rearrangements and amplifications suggest a potential therapeutic target with tyrosine kinase inhibitors in glioblastoma. This patient serves as an example of a rare congenital glioblastoma with unique molecular features that may suggest novel treatment opportunities. We present his clinical course along with a pertinent review of the literature.
RBIO-06. IMPLEMENTATION OF HUMAN INDUCED PLURIPOTENT STEM CELL DERIVED CEREBRAL ORGANOIDS TO MODEL NORMAL TISSUE RADIORESPONSE
Authors: Lawrence Bronk, Sanjay Singh, Riya Thomas, Luke Parkitny, Mirjana Maletic-Savatic, Radhe Mohan, Frederick Lang, David Grosshans
Journal: Neuro-Oncology (2020)

Abstract Treatment-related sequelae following cranial irradiation have life changing impacts for patients and their caregivers. Characterization of the basic response of human brain tissue to irradiation has been difficult due to a lack of preclinical models. The direct study of human brain tissue in vitro is becoming possible due to advances in stem cell biology, neuroscience, and tissue engineering with the development of organoids as novel model systems which enable experimentation with human tissue models. We sought to establish a cerebral organoid (CO) model to study the radioresponse of normal human brain tissue. COs were grown using human induced pluripotent stem cells and a modified Lancaster protocol. Compositional analysis during development of the COs showed expected populations of neurons and glia. We confirmed a population of microglia-like cells within the model positive for the makers Iba1 and CD68. After 2-months of maturation, COs were irradiated to 0, 10, and 20 Gy using a Shepard Mark-II Cs-137 irradiator and returned to culture. Subsets of COs were prepared for immunostaining at 30- and 70-days post-irradiation. To examine the effect of irradiation on the neural stem cell (NSC) population, sections were stained for SOX2 and Ki-67 expression denoting NSCs and proliferation respectively. Slides were imaged and scored using the CellProfiler software package. The percentage of proliferating NSCs 30-days post-irradiation was found to be significantly reduced for irradiated COs (5.7% (P=0.007) and 3.4% (P=0.001) for 10 and 20 Gy respectively) compared to control (12.7%). The reduction in the proliferating NSC population subsequently translated to a reduced population of NeuN-labeled mature neurons 70 days post-irradiation. The loss of proliferating NSCs and subsequent reduction in mature neurons demonstrates the long-term effects of radiation. Our initial results indicate COs will be a valuable model to study the effects of radiation therapy on normal and diseased human tissue.
EXTH-74. IND-ENABLING CHARACTERIZATION OF DUAL DRD2- AND ClpP-TARGETING AGENT ONC206 AS THE NEXT IMIPRIDONE FOR CLINICAL NEURO-ONCOLOGY
Authors: Varun Prabhu, Sara Morrow, Abed Rahman Kawakibi, Yulia Jitkova, Jinkyu Jung, Neel Madhukar, Mathew Garnett, Ultan McDermott, Cyril Benes, Robert Wechsler-Reya, Olivier Elemento, Sharon DeMorrow, Aaron Schimmer, Martin Stogniew, Brett Theeler, Mark Gilbert, Joshua Allen
Journal: Neuro-Oncology (2020)

Abstract ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and allosteric mitochondrial protease ClpP agonist, that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201, is also a bitopic DRD2 antagonist that exhibits enhanced non-competitive effects, nanomolar potency, and disruption of DRD2 homodimers. In these studies, a FITC-casein degradation assay revealed that ONC206 also acts as an agonist of human ClpP and has a 3-fold improved potency. GEPIA database analysis showed ClpP mRNA was overexpressed in glioblastoma cells relative to normal cells. Broad nanomolar efficacy of ONC206 (GI50 &amp;lt; 78-889nM, 72h) was observed in &amp;gt;1,000 GDSC cancer cell lines with the highest sensitivity in cell lines exhibiting high ClpP and/or DRD2+/DRD5- RNA expression signatures. Among solid tumors, nervous system related cell lines were particularly sensitive. ONC206 reduced the viability of normal human fibroblasts at higher doses (GI50 &amp;gt; 5µM), suggesting a wide therapeutic window. Antitumor efficacy without body weight loss was observed with 50 mg/kg weekly oral ONC206 in a subcutaneous xenograft model of DRD2-overexpressing, dopamine-secreting tumor cells. Oral ONC206 at 50mg/kg exhibited a ~12 µM plasma Cmax and ~6 hours terminal half-life in Sprague-Dawley rats. Additionally, 5–10 fold higher ONC206 concentrations were observed in adrenal gland, bile duct, brain and bone marrow relative to plasma. GLP toxicology studies with weekly oral ONC206 in Sprague-Dawley rats and beagle dogs revealed no dose-limiting toxicities. Mild and reversible body weight changes were observed at the highest evaluated dose in both species. The no-observed-adverse-effect level was ≥ 16.7 mg/kg in dogs and ≥ 50 mg/kg in rats that exceed efficacious doses. A 50 mg starting dose of ONC206 was selected for the first-in-human open label, dose escalation, and food effect Phase I study in biomarker-enriched adult recurrent primary CNS tumors.
EPID-22. CHARACTERIZATION OF RADIATION-INDUCED MENINGIOMAS IN A BRAIN TUMOR DATABASE
Authors: Nilan Vaghjiani, Andrew Schwieder, Sravya Uppalapati, Zachary Kons, Elizabeth Kazarian, Srikar Sattiraju, Charles Opalak, Timothy Harris, William Broaddus
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Radiation-induced meningiomas (RIMs) are associated with previous exposure to therapeutic irradiation. RIMs are rare and have not been well characterized relative to spontaneous meningiomas (SMs). METHODS 1003 patients with proven or presumed meningiomas were identified from the VCU brain tumor database. Chart review classified RIM patients and their characteristics. RESULTS Of the 1003 total patients, 76.47% were female with a mean ± SD age of 67.55 ± 15.50 years. 15 RIM patients were identified (66.67% female), with a mean ± SD age of 52.67 ± 15.46 years, 5 were African American and 10 were Caucasian. The incidence of RIMs was 1.49% in our data set. The mean age at diagnosis was 43.27 ± 15.06 years. The mean latency was 356.27 ± 116.96 months. The mean initiating dose was 44.28 ± 14.68 Gy. There was a significant difference between mean latency period and ethnicity, 258.3 months for African American population, and 405.2 months for Caucasian population (p = 0.003). There was a significant difference between the mean number of lesions in females (2.8) versus males (1.2; p = 0.046). Of the RIMs with characterized histology, 6 (55%) were WHO grade II and 5 (45%) were WHO grade I, demonstrating a prevalence of grade II tumors approximately double that found with SMs. RIMs were treated with combinations of observation, surgery, radiation, and medical therapy. Of the 8 patients treated with radiation, 4 demonstrated response. 8 of the 15 patients (53%) demonstrated recurrence/progression despite treatment. CONCLUSION RIMs are important because of the associated higher grade histology, gender, and ethnic incidences, and increased recurrence/progression compared to SMs. Despite the presumed contributory role of prior radiation, RIMs demonstrate a significant rate of responsiveness to radiation treatment.
TBIO-08. BASE-RESOLUTION METHYLOMES OF GLIOMAS BEARING HISTONE H3.3 MUTATIONS REVEAL A G34 MUTANT-SPECIFIC SIGNATURE SHARED WITH BONE TUMORS
Authors: Yuhei Sangatsuda, Fumihito Miura, Hiromitsu Araki, Masahiro Mizuguchi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Takeo Amemiya, Yutaka Fujioka, Yasuhito Arai, Tatsuhiro Shibata, Koji Yoshimoto, Takashi Ito, Koji Iihara
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation was prevalent in bone tumors. In contrast to K27 mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42. Similarly, we analyzed seven and three gliomas harboring K27M and no mutations in H3F3A, respectively. These data were compared with those on bone tumors. RESULTS G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs compared with those bearing K27M and no mutations. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. These CGIs were hypermethylated in osteosarcomas with, but not without, the G34W mutation. In KNS-42 cells, CGIs with G34V-mutated histone H3.3 exhibited higher methylation levels than those with wild-type histone H3.3. This effect was also observed in the G34R-mutated glioma samples. CONCLUSIONS Gliomas bearing G34R/V mutations display characteristic methylomic alterations, some of which are shared by osteosarcomas with the G34W mutation. Deposition of G34 variants may lead to elevated methylation of otherwise hypomethylated, histone H3.3-bearing CGIs.
Abstract 11765: An Orally Available Novel Antagonist Against Corticotropin Releasing Hormone Receptor 2 Prevents Cardiac Dysfunction in Mouse Heart Failure Model
Authors: Mikito Takefuji, Hyi-Man Park, Ayako Tsuchihira, Masashi Ohmi, Akiyoshi Fujiuchi, Yumi Isogai, Toyoaki Murohara
Journal: Circulation (2019)

Introduction: In the heart, G protein-coupled receptors (GPCRs) regulate cardiac function in response to extracellular stimuli and play a pivotal role in cardiac dysfunction. GPCR antagonists are w...
Searching for the Optimal PEEP in Patients Without ARDS
Authors: Sarina K. Sahetya, Ewan C. Goligher, Arthur S. Slutsky
Journal: JAMA (2020)

Writing Committee and Steering Committee for the RELAx Collaborative Group; Anna Geke Algera, MD; Luigi Pisani, MD; Ary Serpa Neto, MD, MSc, PhD; Sylvia S. den Boer, MD; Frank F. H. Bosch, MD, PhD; Karina Bruin, RN; Pauline M. Klooster, MD; Nardo J. M. Van der Meer, MD, PhD; Ralph O. Nowitzky, MD; Ilse M. Purmer, MD; Mathilde Slabbekoorn, MD; Peter E. Spronk, MD, PhD; Jan van Vliet, MD; Jan J. Weenink, MD; Marcelo Gama de Abreu, MD, PhD; Paolo Pelosi, MD; Marcus J. Schultz, MD, PhD; Frederique Paulus, PhD
CSIG-14. COMBINING THE GLIOBLASTOMA CELL MEMBRANE-PERMEABILIZING EFFECT OF TUMOR TREATING FIELDS (TTFIELDS) WITH WITHAFERIN A (AND OTHER) CHEMOTHERAPY
Authors: Edwin Chang, Chirag Patel, Caroline Young, Thomas Flores, Yi Zeng, Lydia Joubert, Hamed Arami, Arutselvan Natarajan, Robert Sinclair, Sanjiv Gambhir
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Efforts are underway to uncover novel, unorthodox therapies against glioblastoma (GBM). Tumor treating fields (TTFields) disrupt mitotic spindle formation and inhibits tumor growth. Combining TTFields with Withaferin A and other therapeutics, synergistically inhibited proliferation. We describe relevant mechanisms. METHODS Human and murine GBM cells (GBM2, GBM39, U87-MG, KR158B) were isolated from primary tumors. Cells were engineered to stably express firefly luciferase (fLuc). Proliferation was assessed by bioluminescence imaging (using D-Luciferin as a substrate for fLuc) or cell counting. Dextran-FITC binding and scanning electron microscopy (SEM) studies were used to probe effects on cellular membranes. RESULTS TTFields (200 kHz, 4 V/cm) significantly inhibited growth of cells (n=3/time point, p≤0.02; 2-way ANOVA, no TTFields vs. TTFields). Combination of Withaferin A or other chemotherapeutics with TTFields significantly inhibited growth of glioma cells synergistically beyond that of Withaferin A or TTFields alone (p&amp;lt; 0.01, at least n=3 experiments). Bioluminescence imaging suggested alterations in membrane configuration when cancer cells were exposed to TTFields. This was validated with observations of greater fluorescence of membrane-associating Dextran-FITC to U87-MG cells that were subjected to TTFields (p&amp;lt; 0.01, 2-way ANOVA, TTFields vs. no TTFields, n=3 experiments). SEM revealed significantly greater and larger number of holes on the membrane surface of TTFields-exposed U87-MG cancer cells (53.5±19.1 holes per field of view and mean size=240.6±91.7 nm2) compared to unexposed cells (23.9±11.0 holes per field of view and mean size=129.8±31.9 nm2, p&amp;lt; 0.005: TTFields exposed vs. non-exposed, n=3 samples, univariate Mann-Whitney test). CONCLUSION The findings suggest a novel combinatorial approach to treat GBM in a manner that is likely better than single treatment (drug or TTFields) alone and that is synergistic. Synergy is achieved through TTFields inducing increased permeability on membranes thus conferring greater accessibility to drug. Such a strategy is thus a promising candidate for future clinical translation in glioblastoma.
EPID-01. TRENDS OF INCIDENCE IN PEDIATRIC BRAIN TUMORS IN KUMAMOTO PREFECTURE, JAPAN
Authors: Takashi Itoyama, Naoki Shinojima, Takahiro Yamamoto, Kenji Fujimoto, Keishi Makino, Akitake Mukasa
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/PURPOSE One of the most problematic issues Japan has is a declining birthrate resulting in an aging society. There are some reports on the trends of incidence in brain tumors in the elderly, whereas few reports on those in the children. The aim of this study is to investigate the trends of incidence in childhood primary brain tumors. METHODS The population of children aged &amp;lt;15 years was available from Kumamoto Prefecture’s annual census between 1990 and 2017. During the period 301 childhood primary brain tumors (124 gliomas, including astrocytic tumors and ependymomas, 35 embryonal tumors, 34 germ cell tumors, 22 craniopharyngioma, and 86 others) were registered with the Kumamoto Brain Tumor Data Bank, and investigated. RESULTS The average of the annual incidence rate per 100,000 child populations was 3.90 for total brain tumors, 1.63 for gliomas, 0.44 for embryonal tumors, 0.42 for germ cell tumors, 0.26 for craniopharyngioma, and 1.15 for others. Divided into the first half from 1990 to 2003 and the second half from 2004 to 2017, there was no significant difference in the incidence of brain tumors aged &amp;lt;15 years between the two periods. However, the average of the annual incidence rate/100,000 child populations was 3.02 in the first half, while significantly increased in the second half of 4.78 (p=0.00075, t-test). DISCUSSION &amp; CONCLUSIONS The average number of children aged &amp;lt;15 years in Kumamoto Prefecture was 31,2737.9 from 1990 to 2003, while decreased remarkably to 251460.2 from 2004 to 2017. A decrease in the number of children may affect increasing the incidence rate of pediatric brain tumors.