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Purpose: Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations. Methods: We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases. Results: Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1–84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations. Conclusion: DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201. [ABSTRACT FROM AUTHOR]

Diffuse midline glioma of the brain is a rare but very aggressive and resistant glial tumor. This pathology is characterized by impossibility of radical surgical treatment, radioresistance, resistance to drug treatment, high morbidity in children, low quality of life of the patients, frequent complications in the form of neurologic deficit, and unfavorable prognosis. The absence of effective treatment scheme for diffuse midline glioma requires identification of other methods (oncolytic virus therapy, immunotherapy) but there is not enough data on this topic leading to the necessity of its further investigation.

The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states. [ABSTRACT FROM AUTHOR]

Abstract Background Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia. Results We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies. Conclusions We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

Abstract Background This review explores how diffuse intrinsic pontine glioma (DIPG) diagnosis and treatment have evolved and are improving. Main body Authors used various sources from 2000 to present time to compile information on diffuse intrinsic pontine glioma in the pediatric population. The following topics were included: diagnosis procedure, molecular analysis, stereotactic biopsy, radiation therapy and other treatments. Historically, diffuse intrinsic pontine glioma’s anatomical proximity to crucial brain stem structures prevented biopsy thus limiting diagnostic and molecular analysis. However, with the optimistic rise of the stereotactic biopsy technique, identifying genetic and other biological markers for targeted treatments is more feasible. Previous investigations have identified a histone mutation that appears in 80% of DIPG cases and there is plenty of exploration into how to unravel the effects of the resulting chromatin modification. For example, new pharmaceuticals like Panobinostat and ONC201 show promise. Conclusion Advances in stereotactic biopsy technology have resulted in more accurate diagnosis opening more avenues for molecular analysis and thus, targeted treatments. DIPG requires more exploration to improve outcomes for patients.

Background: This review explores how diffuse intrinsic pontine glioma (DIPG) diagnosis and treatment have evolved and are improving. Main body: Authors used various sources from 2000 to present time to compile information on diffuse intrinsic pontine glioma in the pediatric population. The following topics were included: diagnosis procedure, molecular analysis, stereotactic biopsy, radiation therapy and other treatments. Historically, diffuse intrinsic pontine glioma's anatomical proximity to crucial brain stem structures prevented biopsy thus limiting diagnostic and molecular analysis. However, with the optimistic rise of the stereotactic biopsy technique, identifying genetic and other biological markers for targeted treatments is more feasible. Previous investigations have identified a histone mutation that appears in 80% of DIPG cases and there is plenty of exploration into how to unravel the effects of the resulting chromatin modification. For example, new pharmaceuticals like Panobinostat and ONC201 show promise. Conclusion: Advances in stereotactic biopsy technology have resulted in more accurate diagnosis opening more avenues for molecular analysis and thus, targeted treatments. DIPG requires more exploration to improve outcomes for patients. [ABSTRACT FROM AUTHOR]

Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as “cold”, several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy [ABSTRACT FROM AUTHOR]

We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMGH3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201. [ABSTRACT FROM AUTHOR]

Medulloblastoma, neuroblastoma, and pediatric glioma account for almost 30% of all cases of pediatric cancers. Recent evidence indicates that pediatric nervous system tumors originate from stem or progenitor cells and present a subpopulation of cells with highly tumorigenic and stem cell-like features. These cancer stem cells play a role in initiation, progression, and resistance to treatment of pediatric nervous system tumors. Histone modification, DNA methylation, chromatin remodeling, and microRNA regulation display a range of regulatory activities involved in cancer origin and progression, and cellular identity, especially those associated with stem cell features, such as self-renewal and pluripotent differentiation potential. Here, we review the contribution of different epigenetic mechanisms in pediatric nervous system tumor cancer stem cells. The choice between a differentiated and undifferentiated state can be modulated by alterations in the epigenome through the regulation of stemness genes such as CD133, SOX2, and BMI1 and the activation neuronal of differentiation markers, RBFOX3, GFAP, and S100B. Additionally, we highlighted the stage of development of epigenetic drugs and the clinical benefits and efficacy of epigenetic modulators in pediatric nervous system tumors. [ABSTRACT FROM AUTHOR]

Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the 2016 World Health Organization classification of CNS tumors, molecular profiling has become an indispensable step in the diagnosis, prediction of prognosis, and treatment of pediatric as well as adult CNS tumors. These molecular data are changing diagnosis, leading to new guidelines, and offering novel molecular targeted therapies. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) makes practical recommendations using recent advances in CNS tumor classification, particularly in molecular discernment of these neoplasms as morphology-based classification of tumors is being replaced by molecular-based classification. In this article, we summarize recent knowledge to provide an overview of pediatric gliomas, which are major pediatric CNS tumors, and describe recent developments in strategies employed for their diagnosis and treatment.

The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states.

Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as “cold”, several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy.

We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201.

BackgroundPediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level.MethodsDNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes.ResultsWe identified 33 putatively pathogenic germline variants among 31 patients (11.1%) which were located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N = 9/63). Five variants were located in tumor protein 53 (TP53), of which 4 were identified among patients with glioblastoma (6.3%, N = 4/63). The next most frequently mutated gene was neurofibromatosis 1 (NF1), in which putatively pathogenic variants were identified in 4 patients with astrocytoma not otherwise specified. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (odds ratio, 32.8, P = 8.04 × 10-7).ConclusionA considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.

Background: BRAFV600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAFV600E kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAFV600E mutant brain tumors. Results: Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUC0-∞median) was 604 mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550 mg/m2, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has promising anti-tumor activity in recurrent BRAF V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.

Tremendous success using CAR T therapy in hematological malignancies has garnered significant interest in developing such treatments for solid tumors, including brain tumors. This success, however, has yet to be mirrored in solid organ neoplasms. CAR T function has shown limited efficacy against brain tumors due to several factors including the immunosuppressive tumor microenvironment, blood-brain barrier, and tumor-antigen heterogeneity. Despite these considerations, CAR T-cell therapy has the potential to be implemented as a treatment modality for brain tumors. Here, we review adult and pediatric brain tumors, including glioblastoma, diffuse midline gliomas, and medulloblastomas that continue to portend a grim prognosis. We describe insights gained from different preclinical models using CAR T therapy against various brain tumors and results gathered from ongoing clinical trials. Furthermore, we outline the challenges limiting CAR T therapy success against brain tumors and summarize advancements made to overcome these obstacles. • Antigenic targets of CAR T-cell treatment ofbrain tumors vary by molecular subtype. • Delivery methods of CAR T-cells impact T-celllocalization, efficacy, and toxicity. • The tumor microenvironment is a major focus fordeveloping more effective CARs. [ABSTRACT FROM AUTHOR]

Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

Abstract Background Glioma is one of the central nervous system (CNS) tumors in children, accounting for 80% of malignant brain tumors. Nucleotide excision repair (NER) is a vital pathway during DNA damage repair progression. Xeroderma pigmentosum group D (XPD) or excision repair cross‐complementing group 2 (ERCC2) is a critical factor in the NER pathway, playing an indispensable role in the DNA repair process. Therefore, the genetic variants in XPD may be associated with carcinogenesis induced by defects in DNA repair. Methods We are the first to conduct a multi‐center case‐control study to investigate the correlation between XPD gene polymorphisms and pediatric glioma risk. We chose three single nucleotide polymorphisms and genotyped them using the TaqMan assay. Results Although there is no significant association of these genetic variations with glioma susceptibility, the stratified analysis revealed that in the subtype of astrocytic tumors, the rs13181 TG/GG genotype enhanced glioma risk than the TT genotype, and carriers with two to three genotypes also elevated the tumor risk than 0‐1 genotypes. Conclusion In conclusion, our findings provided an insight into the impact of XPD genetic variants on glioma risk.

Pediatric high-grade gliomas (pHGG) accounts for approximately 8–12% of primary brain tumors in children. Prognosis is poor, with a median survival of 9–15 months. Insulin-like growth factor 1-receptor (IGF-1R) gene amplifications have been identified in high-grade gliomas and may contribute to its highly aggressive phenotype, but the effect of IGF inhibitors on pHGG is yet to be determined. In the present study, we analyzed the response of patient-derived pediatric high-grade glioma cells to a novel IGF-1R inhibitor, the IGF-Trap. Using immunohistochemistry, we found that IGF-1R was localized to both the nucleus and cell membrane in different pHGG patient-derived xenograft (PDX) lines under basal conditions. In response to ligand binding, nuclear levels of the receptor increased, and this was associated with the transcriptional upregulation of both the receptor and cyclin D1, suggesting that IGF-1R could regulate its own expression and cell cycle progression in these cells. Insulin-like growth factor-1 (IGF-1) increased the proliferation of the pHGG cells DIPG13 and SGJ2, and this could be blocked by the addition of the IGF-Trap. The IGF-Trap reduced the colony formation of these cells in an optimal growth medium and impeded the ability of IGF-1 to rescue DIPG13 cells from starvation-induced apoptosis. Collectively, these results implicate the IGF-1 axis in the regulation of cell cycle progression, cellular proliferation, and cell survival in pHGG, and identify the IGF-axis as a target and the IGF-Trap as a potential inhibitor of this axis in pHGG. [ABSTRACT FROM AUTHOR]

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors. [Display omitted] • Both N-terminal fusion partner and NTRK variant influence tumor aggressiveness and biology • Tyrosine kinase inhibition prolongs survival, but persister cells lead to recurrence • Resistance-associated point mutations influence response to therapy in vivo • MEK inhibition leads to a significant growth inhibition in vivo Here, Schmid et al. develop a series of NTRK fusion-driven GEMMs of pediatric-type glioma. Treatment with TRK kinase inhibitors significantly prolongs survival, but tumors eventually recur due to treatment-resistant persister cells. These tumors upregulate the Ras-Raf-MEK-ERK and PI3K-AKT-mTOR pathways, and MEK inhibition by itself leads to a significant growth inhibition. [ABSTRACT FROM AUTHOR]

Background/Aim: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusionpositive solid tumors. Patient and Methods: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. Results: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. Conclusion: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse. [ABSTRACT FROM AUTHOR]

Since high grade gliomas are aggressive brain tumors, intensive search for new treatment options is ongoing. For adult patients with newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM), low intensity intermediate frequency alternating electric fields, known as tumor treating fields (TTFields) have been established as a new treatment modality. Tumor treating fields significantly increase survival rates in combination with adjuvant temozolomide (TMZ) in adult and GBM patients. Here, we report about feasibility and safety of treatment on a pediatric patient with diffuse midline glioma who is receiving TTFields therapy in combination with temozolomide. [ABSTRACT FROM AUTHOR]

Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Develop a time-dependent deep learning model to accurately predict the prognosis of pediatric glioma patients, which can assist clinicians in making precise treatment decisions and reducing patient risk., Study Design: The study involved pediatric glioma patients from the Surveillance, Epidemiology, and End Results (SEER) Registry (2000-2018) and Tangdu Hospital in China (2010-2018) within specific time frames. For training, we selected two neural network-based algorithms (DeepSurv, neural multi-task logistic regression [N-MTLR]) and one ensemble learning-based algorithm (random survival forest [RSF]). Additionally, a multivariable Cox proportional hazard (CoxPH) model was developed for comparison purposes. The SEER dataset was randomly divided into 80 % for training and 20 % for testing, while the Tangdu Hospital dataset served as an external validation cohort. Super-parameters were fine-tuned through 1000 repeated random searches and 5-fold cross-validation on the training cohort. Model performance was assessed using the concordance index (C-index), Brier score, and Integrated Brier Score (IBS). Furthermore, the accuracy of predicting survival at 1, 3, and 5 years was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and the area under the ROC curves (AUC). The generalization ability of the model was assessed using the C-index of the Tangdu Hospital data, ROC curves for 1, 3, and 5 years, and AUC values. Lastly, decision curve analysis (DCA) curves for 1, 3, and 5-year time frames are provided to assess the net benefits across different models., Results: A total of 9532 patients with pediatric glioma were included in this study, comprising 9274 patients from the SEER database and 258 patients from Tangdu Hospital in China. The average age at diagnosis was 9.4 ± 6.2 years, and the average survival time was 96 ± 66 months. Through comprehensive performance comparison, the DeepSurv model demonstrated the highest effectiveness, with a C-index of 0.881 on the training cohort. Furthermore, it exhibited excellent accuracy in predicting the 1-year, 3-year, and 5-year survival rates (AUC: 0.903-0.939). Notably, the DeepSurv model also achieved remarkable performance and accuracy on the Chinese dataset (C-index: 0.782, AUC: 0.761-0.852). Comprehensive analysis of DeepSurv, N-MTLR, and RSF revealed that tumor stage, radiotherapy, histological type, tumor size, chemotherapy, age, and surgical method are all significant factors influencing the prognosis of pediatric glioma. Finally, an online version of the pediatric glioma survival predictor based on the DeepSurv model has been established and can be accessed through https://pediatricglioma-tangdu.streamlit.app., Conclusions: The DeepSurv model exhibits exceptional efficacy in predicting the survival of pediatric glioma patients, demonstrating strong performance in discrimination, calibration, stability, and generalization. By utilizing the online version of the pediatric glioma survival predictor, which is based on the DeepSurv model, clinicians can accurately predict patient survival and offer personalized treatment options., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Pediatric high-grade gliomas (pHGGs) are a deadly and heterogenous subgroup of gliomas for which the development of innovative treatments is urgent. Advances in high-throughput molecular techniques have shed light on key epigenetic components of these diseases, such as K27M and G34R/V mutations on histone 3. However, modification of DNA compaction is not sufficient by itself to drive those tumors. Here, we review molecular specificities of pHGGs subcategories in the context of epigenomic rewiring caused by H3 mutations and the subsequent oncogenic interplay with transcriptional signaling pathways co-opted from developmental programs that ultimately leads to gliomagenesis. Understanding how transcriptional and epigenetic alterations synergize in each cellular context in these tumors could allow the identification of new Achilles' heels, thereby highlighting new levers to improve their therapeutic management. [ABSTRACT FROM AUTHOR]

BRAFV600E is a common finding in glioma (about 10-60% depending on histopathologic subclassification). BRAFV600E monotherapy shows modest preclinical efficacy against BRAFV600E gliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAFV600E inhibition in glioma. Furthermore, we investigate BRAFV600E/MEK combination therapy that overcomes intrinsic resistance to BRAFV600E inhibitor and also prevents BRAFV600E inhibitor induced secondary malignancies. Immunoblotting and Human Phospho-Receptor Tyrosine Kinase Array assays were used to interrogate MAPK pathway activation. The cellular effect of BRAFV600E and MEK inhibition was determined by WST-1 viability assay and cell cycle analysis. Flanked and orthotopic GBM mouse models were used to investigate the in vivo efficacy of BRAFV600E/MEK combination therapy and the effect on secondary malignancies. BRAFV600E inhibition leads to recovery of ERK phosphorylation. Combined BRAFV600E and MEK inhibition prevents reactivation of the MAPK signaling, which correlates with decreased cell viability and augmented cell cycle arrest. Similarly, mice bearing BRAFV600E glioma showed reduced tumor growth when treated with a combination of BRAFV600E and MEK inhibitor compared to BRAFV600E inhibition alone. Additional benefit of BRAFV600E/MEK inhibition was reflected by reduced cutaneous squamous-cell carcinoma (cSCC) growth (a surrogate for RAS-driven secondary maligancies). In glioma, recovery of MAPK signaling upon BRAF inhibition accounts for intrinsic resistance to BRAFV600E inhibitor. Combined BRAFV600E and MEK inhibition prevents rebound of MAPK activation, resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development.

Pediatric gliomas (PGs) are the most common brain tumors in children and the leading cause of childhood cancer-related death. The understanding of the immune microenvironment is essential for developing effective antitumor immunotherapies. Transcriptomic data from 495 PGs were analyzed in this study, with 384 as a training cohort and 111 as a validation cohort. Macrophages were the most common immune infiltrates in the PG microenvironment, followed by T cells. PGs were classified into 3 immune subtypes (ISs) based on immunological profiling: “immune hot” (IS-I), “immune altered” (IS-II), and “immune cold” (IS-III). IS-I tumors, characterized by substantial immune infiltration and high immune checkpoint molecule (ICM) expression, had a favorable prognosis and were more likely to respond to anti-PD1 and anti-CTLA4 immunotherapies, whereas IS-III tumors, characterized by weak immune infiltration and low ICM expression, had a dismal prognosis and poor immunotherapy responsiveness. IS-II tumors represented a transitional stage. Immune classification was also correlated with somatic mutations, copy number alterations, and molecular pathways related to tumorigenesis, metabolism, and immune responses. Three predictive classifiers using eight representative genes were generated by machine learning methods for immune classification. This study established a reliable immunological profile-based classification system for PGs, providing implications for further immunotherapy strategies.

We conducted a systematic review on pediatric intraventricular gliomas to survey the patient population, tumor characteristics, management, and outcomes. PubMed, Scopus, Web-of-Science, and Cochrane were searched using PRISMA guidelines to include studies reporting pediatric patients with intraventricular gliomas. A total of 30 studies with 317 patients were included. Most patients were male (54%), diagnosed at a mean age of 8 years (0.2–19), and frequently exhibited headache (24%), nausea and vomiting (21%), and seizures (15%). Tumors were predominantly located in the fourth (48%) or lateral ventricle (44%). Most tumors were WHO grade 1 (68%). Glioblastomas were rarely reported (2%). Management included surgical resection (97%), radiotherapy (27%), chemotherapy (8%), and cerebrospinal fluid diversion for hydrocephalus (38%). Gross total resection was achieved in 59% of cases. Cranial nerve deficit was the most common postsurgical complication (28%) but most were reported in articles published prior to the year 2000 (89%). Newer cases published during or after the year 2000 exhibited significantly higher rates of gross total resection (78% vs. 39%, P < 0.01), lower rates of recurrence (26% vs. 47%, P < 0.01), longer average overall survival time (42 vs. 21 months, P = 0.02), and a higher proportion of patients alive (83% vs. 70%, P = 0.03) than in older cases. Pediatric intraventricular gliomas correlate with parenchymal pediatric gliomas in terms of age at diagnosis and general outcomes. The mainstay of management is complete surgical excision and more recent studies report longer overall survival rates and less cranial nerve complications. [ABSTRACT FROM AUTHOR]

Primary brain tumors are the most common solid neoplasms in children and a leading cause of mortality in this population. MRI plays a central role in the diagnosis, characterization, treatment planning, and disease surveillance of intracranial tumors. The purpose of this review is to provide an overview of imaging methodology, including conventional and advanced MRI techniques, and illustrate the MRI appearances of common pediatric brain tumors. [ABSTRACT FROM AUTHOR]

IntroductionThe treatment of pediatric optic pathway gliomas (OPG) is challenging. At present, most centers provide individualized treatment to maximize progression free survival (PFS) and minimize morbidity. We aim to report our experience in the management of pediatric OPG, and investigate factors associated with an increased duration of remission after treatment.MethodsThis is a single-institution study approved by the hospital ethics board. A retrospective review of consecutive OPGs managed from 2000 to 2020 was performed. Patients were divided into those managed with monomodality treatment (MT) and those who received combined therapy (CT). MT included various forms of surgery, chemotherapy and radiotherapy given alone, while CT involves a combination of surgery and adjuvant chemotherapy and/or radiotherapy.ResultsTwenty-two patients were selected for this study. They had 40 treatment cycles; and a total follow up duration of 194.8 patient-years. Most of them were male (63.6%) and presented with visual deficits (72.7%). The mean age at initial presentation was 65 months and majority (86.4%) had their tumors arising directly from the optic chiasm, with 77.3% with hypothalamic extension. One patient had Neurofibromatosis type I (4.5%). The most common histological diagnosis was pilocytic astrocytoma (90.9%), followed by pilomyxoid astrocytoma (9.1%). The 5- and 10- year PFS were 46.2% and 36.4% respectively, while the 5- and 10-year OS were both 100%. When accounting for treatment type, there were 24 treatment cycles with MT (60.0%) and 16 CT (40.0%). After adjustment, treatments with MT were shown to have a shorter mean duration of remission (MT: 45 ± 49, CT: 84 ± 79 months; p = 0.007). Cox regression curve plotted after adjusting for patient’s age at treatment demonstrated a significantly longer PFS in the CT group (p = 0.037).ConclusionsOur results suggest a significant survival benefit of CT over MT for affected patients due to the prolonged the duration of disease remission, for both primary and subsequent treatments. Nonetheless, we acknowledge that our study reflects the outcomes of treatment strategies that have evolved over time. We emphasize the need for collective efforts from a dedicated multidisciplinary team and international collaborations for better disease understanding.

Oligodendroglioma represents a distinctive neoplasm in adults but similar neoplasms occur rarely in children. We studied 20 cases of pediatric oligodendroglioma by SNP array (median age 9 years, range 1-19; 15 grade II and 5 grade III). Cytogenetic abnormalities were present in 8 (53%) grade II and all five anaplastic oligodendrogliomas. Most changes were in the form of deletion and copy neutral loss of heterozygosity (LOH). The most common abnormality was 1p deletion (n = 5). Whole arm 1p19q co-deletion was present in three cases from adolescent patients and 9p loss in 3, including one low-grade oligodendroglioma with CDKN2A homozygous deletion. Common losses were largely limited to the anaplastic subset (n = 5) and included 3q29 (n = 3), 11p (n = 3), 17q (n = 3), 4q (n = 2), 6p (n = 2), 13q (n = 2), 14q (n = 2), 17p (n = 2) and whole Ch 18 loss (n = 2). Gains were non-recurrent except for whole Ch 7 (n = 2) and gain on 12q (n = 2) including the MDM2 locus. Possible germ line LOH (or uniparental disomy) was present in seven cases (35%), with one focal abnormality (22q13.1-13.2) in two. BRAF-KIAA1549 fusions and BRAF p.V600E mutations were absent (n = 13 and 8). In summary, cytogenetic alterations in pediatric oligodendrogliomas are characterized mostly by genomic losses, particularly in anaplastic tumors.

Pediatric high-grade gliomas (pHGG) accounts for approximately 8–12% of primary brain tumors in children. Prognosis is poor, with a median survival of 9–15 months. Insulin-like growth factor 1-receptor (IGF-1R) gene amplifications have been identified in high-grade gliomas and may contribute to its highly aggressive phenotype, but the effect of IGF inhibitors on pHGG is yet to be determined. In the present study, we analyzed the response of patient-derived pediatric high-grade glioma cells to a novel IGF-1R inhibitor, the IGF-Trap. Using immunohistochemistry, we found that IGF-1R was localized to both the nucleus and cell membrane in different pHGG patient-derived xenograft (PDX) lines under basal conditions. In response to ligand binding, nuclear levels of the receptor increased, and this was associated with the transcriptional upregulation of both the receptor and cyclin D1, suggesting that IGF-1R could regulate its own expression and cell cycle progression in these cells. Insulin-like growth factor-1 (IGF-1) increased the proliferation of the pHGG cells DIPG13 and SGJ2, and this could be blocked by the addition of the IGF-Trap. The IGF-Trap reduced the colony formation of these cells in an optimal growth medium and impeded the ability of IGF-1 to rescue DIPG13 cells from starvation-induced apoptosis. Collectively, these results implicate the IGF-1 axis in the regulation of cell cycle progression, cellular proliferation, and cell survival in pHGG, and identify the IGF-axis as a target and the IGF-Trap as a potential inhibitor of this axis in pHGG.

Ongoing rapid advances in molecular diagnostics, precision imaging, and development of targeted therapies have resulted in a constantly evolving landscape for treatment of pediatric cancers. Radiotherapy remains a critical element of the therapeutic toolbox, and its role in the era of precision medicine continues to adapt and undergo re-evaluation. Here, we review emerging strategies for combining radiotherapy with novel targeted systemic therapies (for example, for pediatric gliomas or soft tissue sarcomas), modifying use or intensity of radiotherapy when appropriate via molecular diagnostics that allow better characterization and individualization of each patient's treatments (for example, de-intensification of radiotherapy in WNT subgroup medulloblastoma), as well as exploring more effective targeted systemic therapies that may allow omission or delay of radiotherapy. Many of these strategies are still under investigation but highlight the importance of continued pre-clinical and clinical studies evaluating the role of radiotherapy in this era of precision oncology. [ABSTRACT FROM AUTHOR]

Ongoing rapid advances in molecular diagnostics, precision imaging, and development of targeted therapies have resulted in a constantly evolving landscape for treatment of pediatric cancers. Radiotherapy remains a critical element of the therapeutic toolbox, and its role in the era of precision medicine continues to adapt and undergo re-evaluation. Here, we review emerging strategies for combining radiotherapy with novel targeted systemic therapies (for example, for pediatric gliomas or soft tissue sarcomas), modifying use or intensity of radiotherapy when appropriate via molecular diagnostics that allow better characterization and individualization of each patient’s treatments (for example, de-intensification of radiotherapy in WNT subgroup medulloblastoma), as well as exploring more effective targeted systemic therapies that may allow omission or delay of radiotherapy. Many of these strategies are still under investigation but highlight the importance of continued pre-clinical and clinical studies evaluating the role of radiotherapy in this era of precision oncology.

Oligodendrogliomas are an important adult form of diffuse gliomas with a distinctive clinical and genetic profile. Histologically similar tumors occurring rarely in children are incompletely characterized. We studied 50 patients with oligodendrogliomas (median age at diagnosis 8 y, range 7 mo to 20 y). Tumors resembling dysembryoplastic neuroepithelial tumors or pilocytic astrocytomas or those having a "mixed" histology were excluded. Tumors at first diagnosis were low grade (n=38) or anaplastic (n=12). Histologic features included uniform round cells with perinuclear halos (100%), secondary structures (predominantly perineuronal satellitosis) (90%), calcifications (46%), and microcysts (44%). Sequential surgical specimens were obtained in 8 low-grade oligodendroglioma patients, with only 1 progressing to anaplasia. Studies for 1p19q performed in 40 cases demonstrated intact 1p19q loci in 29 (73%), 1p19q codeletion in 10 (25%), and 1p deletion with intact 19q in 1 (2%). Except for 2 young patients (3 and 11 y of age), patients with 1p19q codeletion were older than 16 years at diagnosis. Mutant IDH1 (R132H) protein immunohistochemistry was positive in 4 (of 22) (18%) cases, 3 of which also had 1p19q codeletion, whereas 1p19q status was not available on the fourth case. There was a nonsignificant trend for worse overall survival in grade III tumors, but no significant association with age, extent of resection, or 1p19q status. In summary, oligodendrogliomas with classic histology occur in the pediatric population but lack 1p19q codeletion and IDH1 (R132H) mutations in most instances. They are predominantly low grade, recur/clinically progress in a subset, but demonstrate a relatively low frequency of histologic progression.

Pediatric high-grade gliomas (pHGGs) are a deadly and heterogenous subgroup of gliomas for which the development of innovative treatments is urgent. Advances in high-throughput molecular techniques have shed light on key epigenetic components of these diseases, such as K27M and G34R/V mutations on histone 3. However, modification of DNA compaction is not sufficient by itself to drive those tumors. Here, we review molecular specificities of pHGGs subcategories in the context of epigenomic rewiring caused by H3 mutations and the subsequent oncogenic interplay with transcriptional signaling pathways co-opted from developmental programs that ultimately leads to gliomagenesis. Understanding how transcriptional and epigenetic alterations synergize in each cellular context in these tumors could allow the identification of new Achilles’ heels, thereby highlighting new levers to improve their therapeutic management.

Primary brain tumors are the most common solid neoplasms in children and a leading cause of mortality in this population. MRI plays a central role in the diagnosis, characterization, treatment planning, and disease surveillance of intracranial tumors. The purpose of this review is to provide an overview of imaging methodology, including conventional and advanced MRI techniques, and illustrate the MRI appearances of common pediatric brain tumors.

The bHLH transcription factor, OLIG2, is universally expressed in adult human gliomas and, as a major factor in the development of oligodendrocytes, is expressed at the highest levels in low-grade oligodendroglial tumors. In addition, it is functionally required for the formation of high-grade astrocytomas in a genetically relevant murine model. The pediatric gliomas have genomic profiles that are different from the corresponding adult tumors and accordingly, the expression of OLIG2 in non-oligodendroglial pediatric gliomas is not well documented within specific tumor types. In the current study, the pattern of OLIG2 expression in a spectrum of 90 non-oligodendroglial pediatric gliomas varied from very low levels in the ependymomas (cellular and tanycytic) to high levels in pilocytic astrocytoma, and in the diffuse-type astrocytic tumors (WHO grades II-IV). With dual-labeling, glioblastoma had the highest percentage of OLIG2 expressing cells that were also Ki-67 positive (mean = 16.3%) whereas pilocytic astrocytoma WHO grade I and astrocytoma WHO grade II had the lowest (0.9 and 1%, respectively); most of the Ki-67 positive cells in the diffuse-type astrocytomas (WHO grade II-III) were also OLIG2 positive (92-94%). In contrast to the various types of pediatric astrocytic tumors, all ependymomas WHO grade II, regardless of site of origin, showed at most minimal OLIG2 expression, suggesting that OLIG2 function in pediatric gliomas is cell lineage dependent.

Chimeric Antigen Receptor (CAR) T cell therapy has recently begun to be used for solid tumors such as glioblastoma multiforme. Many children with pediatric malignant brain tumors develop extensive long-term morbidity of intensive multimodal curative treatment. Others with certain diagnoses and relapsed disease continue to have limited therapies and a dismal prognosis. Novel treatments such as CAR T cells could potentially improve outcomes and ameliorate the toxicity of current treatment. In this review, we discuss the potential of using CAR therapy for pediatric brain tumors. The emerging insights on the molecular subtypes and tumor microenvironment of these tumors provide avenues to devise strategies for CAR T cell therapy. Unique characteristics of these brain tumors, such as location and associated morbid treatment induced neuro-inflammation, are novel challenges not commonly encountered in adult brain tumors. Despite these considerations, CAR T cell therapy has the potential to be integrated into treatment schema for aggressive pediatric malignant brain tumors in the future.

Chimeric Antigen Receptor (CAR) T cell therapy has recently begun to be used for solid tumors such as glioblastoma multiforme. Many children with pediatric malignant brain tumors develop extensive long-term morbidity of intensive multimodal curative treatment. Others with certain diagnoses and relapsed disease continue to have limited therapies and a dismal prognosis. Novel treatments such as CAR T cells could potentially improve outcomes and ameliorate the toxicity of current treatment. In this review, we discuss the potential of using CAR therapy for pediatric brain tumors. The emerging insights on the molecular subtypes and tumor microenvironment of these tumors provide avenues to devise strategies for CAR T cell therapy. Unique characteristics of these brain tumors, such as location and associated morbid treatment induced neuro-inflammation, are novel challenges not commonly encountered in adult brain tumors. Despite these considerations, CAR T cell therapy has the potential to be integrated into treatment schema for aggressive pediatric malignant brain tumors in the future. [ABSTRACT FROM AUTHOR]

To assess the early mortality in pediatric glioma and identify predictors of early mortality, which may provide insight into the therapeutic strategies for children with a high risk of early mortality. We used SEER∗Stat 8.3.5 software to extract data of pediatric glioma from the Surveillance, Epidemiology, and End Results database. Logistical regression to identify the independent factors in predicting early mortality. A total of 3035 male and 2741 female patients were enrolled in the present study. The death rates within 1 month and 3 months after diagnosis were 1.32% and 2.44%, respectively. Early mortality decreased significantly during the past 40 years. Our results showed that glioblastoma, anaplastic glioma, and oligodendroglioma were risk factors of early mortality for children diagnosed with glioma, whereas advanced age, gross total resection, radiation, and chemotherapy were associated with decreased early mortality. We found a decrease in early mortality during the past 40 years. The death rates within 1 month and 3 months after diagnosis were 1.32% and 2.44%, respectively. Age at diagnosis, histologic subtype, the extent of resection, chemotherapy, and radiation were associated with early mortality in pediatric glioma. [ABSTRACT FROM AUTHOR]

Pilomyxoid astrocytoma (PMA) is a rare brain tumour generally located in the chiasmatic-hypothalamic region. In comparison to pilocytic astrocytoma, PMA has distinct histopathological features, aggressive clinical behaviour, a high recurrence rate, and early cerebrospinal fluid dissemination. Only 14 cases of PMA have been reported in the spinal cord since its pathological description in 1999. Here, we report the 15th case in a 3-year-old girl who was treated with chemoradiotherapy and followed up for 5 years. In this report, we also present a review of spinal PMA including treatment options and prognosis. [ABSTRACT FROM AUTHOR]

We report a case of 2-year-old female with lateral ventricular glioma harboring both H3F3A K27M and BRAF V600E mutations. By the methylation analysis, the tumor was classified as a diffuse midline glioma H3 K27M mutant, WHO grade IV. However, the tumor was pathologically low-grade and likely localized rather than diffusely infiltrating. Further, the patient has survived more than 8 years after gross total resection of the tumor. Whereas both H3F3A K27M and BRAF V600E have been reported as poor prognostic markers in pediatric glioma, our case, along with several other reported cases, suggests that the coexistence of these two mutations might not indicate poor prognosis. The case emphasizes the importance of comprehensive assessment based on pathological, genetic and clinical findings and calls for further investigations of non-diffuse glioma with H3F3A K27M and glioma with H3F3A K27M and BRAF V600E. [ABSTRACT FROM AUTHOR]

Pilomyxoid astrocytoma is a variant of pilocytic astrocytoma and the clinical, histological and molecular data point to a very close relationship as well as a more aggressive biological behavior for the former. WHO 2016 classification does not provide a specific grade for these neoplasms, but there is sufficient evidence in the literature that pilomyxoid astrocytoma has slightly worse prognosis than typical pilocytic astrocytoma. There is increasing evidence that in addition to the MAPK pathway alterations, pilomyxoid astrocytomas harbor genetic alterations that distinguish them from typical pilocytic astrocytoma [ABSTRACT FROM AUTHOR]

The proto-oncogene tyrosine-protein kinase ROS1 (ROS1) is a tyrosine kinase that is closely related to anaplastic lymphoma kinase receptor (ALK). We describe a novel KLC1-ROS1 fusion identified in a case of pediatric low-grade glioma. This was detected by RNA sequencing and confirmed by reverse-transcription PCR and fluorescent in situ hybridization. Immunohistochemical staining for ROS1 was positive in the tumor cytoplasm. In vitro analysis demonstrated the oncogenic activity of this fusion, which was suppressed by the ALK/ROS1 inhibitor, crizotinib. Our case and others suggest that various ROS1 fusions might be present in a subset of pediatric gliomas, which could be targeted for therapy. [ABSTRACT FROM AUTHOR]

The mitogen-activated protein kinase (MAPK) pathway consists of the Ras/Raf/MEK/ERK signaling cascade, and its upregulation plays a major role in the pathogenesis of pediatric astrocytomas and molecular inhibitors of this pathway including trametinib and dabrafenib have been tested in early-phase clinical trials and used by pediatric oncologists in children with BRAF-mutated gliomas. We report a clinical case where a child with progressive BRAF-mutated glioma developed an uncommon and difficult to manage complication – pneumocephalus from intracranial air entry and trapping through dehisced surgical wounds and preexisting skull burr holes. The patient's wound breakdown coincided with skin toxicity from MEK inhibitor therapy. With increasing use of targeted molecular inhibitors in pediatric neuro-oncology, this case illustrates the potentially complicated course of MEK inhibitor therapy in patients with scalp surgical wounds and burr holes that were placed within few weeks from initiation of drug therapy, especially if patients have additional factors that can contribute to poor wound healing such as use of steroids and malnutrition. [ABSTRACT FROM AUTHOR]