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Background: Postoperative recurrence risk for pediatric low-grade gliomas (pLGGs) is challenging to predict by conventional clinical, radiographic, and genomic factors. We investigated if deep learning (DL) of magnetic resonance imaging (MRI) tumor features could improve postoperative pLGG risk stratification., Methods: We used a pretrained DL tool designed for pLGG segmentation to extract pLGG imaging features from preoperative T2-weighted MRI from patients who underwent surgery (DL-MRI features). Patients were pooled from 2 institutions: Dana Farber/Boston Children's Hospital (DF/BCH) and the Children's Brain Tumor Network (CBTN). We trained 3 DL logistic hazard models to predict postoperative event-free survival (EFS) probabilities with (1) clinical features, (2) DL-MRI features, and (3) multimodal (clinical and DL-MRI features). We evaluated the models with a time-dependent Concordance Index (Ctd) and risk group stratification with Kaplan-Meier plots and log-rank tests. We developed an automated pipeline integrating pLGG segmentation and EFS prediction with the best model., Results: Of the 396 patients analyzed (median follow-up: 85 months, range: 1.5-329 months), 214 (54%) underwent gross total resection and 110 (28%) recurred. The multimodal model improved EFS prediction compared to the DL-MRI and clinical models (Ctd: 0.85 (95% CI: 0.81-0.93), 0.79 (95% CI: 0.70-0.88), and 0.72 (95% CI: 0.57-0.77), respectively). The multimodal model improved risk-group stratification (3-year EFS for predicted high-risk: 31% versus low-risk: 92%, P < .0001)., Conclusions: DL extracts imaging features that can inform postoperative recurrence prediction for pLGG. Multimodal DL improves postoperative risk stratification for pLGG and may guide postoperative decision-making. Larger, multicenter training data may be needed to improve model generalizability., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Introduction: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor group, currently regarded as a chronic disease. On 23 April 2024, the U.S. FDA approved a new type II RAF inhibitor, tovorafenib (OJEMDA TM ), previously known as DAY101, for the treatment of patients aged 6 months and older with relapsed or refractory (R/R) pLGG harboring a BRAF fusion or rearrangement, or BRAF V600E mutation., Areas Covered: This article aims to review the pharmacological properties of tovorafenib and evaluate its efficacy and safety in the treatment of R/R pLGG. We conducted a systematic search of PubMed and Web of Science databases for English-language publications related to tovorafenib, including journal articles and conference abstracts, up through 20 August 2024., Expert Opinion: As the first and only FDA-approved medicine for children with BRAF fusions or rearrangements, which are the most common molecular alteration in pLGG, tovorafenib shows superior central nervous system penetration without the paradoxical activation of the MAPK pathway reported for type I BRAF inhibitors. Phase 1 and the pivotal phase 2 trials have demonstrated that tovorafenib monotherapy is generally well-tolerated and exhibits encouraging signs of meaningful, rapid and sustained clinical activity in children and young adults with BRAF-altered pLGG.

Introduction: Machine learning (ML) shows promise for the automation of routine tasks related to the treatment of pediatric low-grade gliomas (pLGG) such as tumor grading, typing, and segmentation. Moreover, it has been shown that ML can identify crucial information from medical images that is otherwise currently unattainable. For example, ML appears to be capable of preoperatively identifying the underlying genetic status of pLGG., Methods: In this chapter, we reviewed, to the best of our knowledge, all published works that have used ML techniques for the imaging-based evaluation of pLGGs. Additionally, we aimed to provide some context on what it will take to go from the exploratory studies we reviewed to clinically deployed models., Results: Multiple studies have demonstrated that ML can accurately grade, type, and segment and detect the genetic status of pLGGs. We compared the approaches used between the different studies and observed a high degree of variability throughout the methodologies. Standardization and cooperation between the numerous groups working on these approaches will be key to accelerating the clinical deployment of these models., Conclusion: The studies reviewed in this chapter detail the potential for ML techniques to transform the treatment of pLGG. However, there are still challenges that need to be overcome prior to clinical deployment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Radiotherapy is a highly effective treatment for pediatric low-grade glioma, serving as the standard for evaluating progression-free and overall survival, as well as vision preservation. Despite its proven efficacy, concerns about treatment complications have led to increased use of chemotherapy and targeted therapy, which are associated with poorer progression-free survival outcomes., Methods: This review by Indu Bansal and Thomas E. Merchant examines the indications, timing, and results of radiotherapy for pediatric low-grade glioma. The authors provide a comprehensive analysis of clinical management strategies, addressing the controversies surrounding the use and timing of radiotherapy compared to other therapies., Results: The review highlights that while radiotherapy is essential for certain patients, particularly those who are not candidates for complete resection due to the tumor's infiltrative nature or location, it is often deferred in favor of systemic therapies. This deferral can lead to significant morbidity, including poor visual outcomes. Reports indicate that systemic therapy negatively impacts progression-free survival in patients who eventually undergo radiotherapy. Newer radiotherapy techniques have been developed to minimize complications, offering potential benefits over traditional methods., Discussion: The evolving clinical management of pediatric low-grade glioma involves balancing the benefits of radiotherapy with concerns about its side effects. Although systemic therapies are increasingly favored, their associated inferior progression-free survival and potential for significant morbidity underscore the need for careful consideration of radiotherapy, particularly in older children, adolescents, or those with progressive disease post-systemic therapy. The emerging role of targeted therapy presents additional challenges, including uncertainties about long-term side effects and its interaction with radiotherapy. Further research is needed to optimize treatment strategies and improve outcomes for pediatric patients with low-grade glioma., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Understanding the molecular and cellular mechanisms driving pediatric low-grade glioma (pLGG)-the most prevalent brain tumor in children-is essential for the identification and evaluation of novel effective treatments. This review explores the intricate relationship between the mitogen-activated protein kinase (MAPK) pathway, oncogene-induced senescence (OIS), the senescence-associated secretory phenotype (SASP), and the tumor microenvironment (TME), integrating these elements into a unified framework termed the MAPK/OIS/SASP/TME (MOST) axis. This integrated approach seeks to deepen our understanding of pLGG and improve therapeutic interventions by examining the MOST axis' critical influence on tumor biology and response to treatment. In this review, we assess the axis' capacity to integrate various biological processes, highlighting new targets for pLGG treatment, and the need for characterized in vitro and in vivo preclinical models recapitulating pLGG's complexity to test targets. The review underscores the need for a comprehensive strategy in pLGG research, positioning the MOST axis as a pivotal approach in understanding pLGG. This comprehensive framework will open promising avenues for patient care and guide future research towards inventive treatment options., (© 2024. The Author(s).)

Purpose: Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) in pLGG is the most important prognostic factor. There are multiple intraoperative tools to optimize the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the surgical treatment of pLGG., Methods: The tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers., Results: We included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep-seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (chi-square test, p < 0.01)., Conclusion: iUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long-term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent and iMRI if locally available., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Periventricular pediatric low-grade gliomas (pLGG) present a surgical challenge due to their deep-seated location, accessibility, and relationship with the subcortical network connections. Minimally invasive parafascicular approaches with tubular brain retractors (port brain surgery) have emerged, in recent years, as an alternative to conventional microsurgical and endoscopic approaches for removal of periventricular tumors., Objectives: To describe the minimally invasive approach with tubular brain retractors for periventricular pLGG, its technique, applications, safety, and efficacy., Methods: In this article, we describe the port brain surgery techniques for periventricular pLGG as performed in different centers, with different commercialized tubular retractor systems. Illustrative cases followed by a literature review are analyzed, with a detailed description of different approaches or techniques, comparing their advantages and disadvantages with contemporary microsurgical and endoscopic approaches., Conclusions: The port brain surgery with micro-exoscopic vision and endoscopic assistance, for the treatment of deep-seated lesions such as periventricular pLGG, is an alternative for achieving a functionally safe-gross total or subtotal-tumor resection, obtaining adequate tissue for pathological examination. This technique could offer a new dimension for a less-invasive, safe, and effective access to deep-seated tumors, offering the possibility to lower morbidity in experienced hands., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- and therapy-related morbidity in affected patients. Recent in-depth molecular profiling and studies of the genetic landscape of PLGGs led to the discovery of the paramount role of frequent upregulation of RAS/MAPK and mTOR signaling in tumorigenesis and progression of these tumors. Beyond, the subsequent unveiling of RAS/MAPK-driven oncogene-induced senescence in these tumors may shape the understanding of the molecular mechanisms determining the versatile progression patterns of PLGGs, potentially providing a promising target for novel therapies. Recent in vitro and in vivo studies moreover indicate a strong dependence of PLGG formation and growth on the tumor microenvironment. In this work, we provide an overview of the current understanding of the multilayered cellular mechanisms and clinical factors determining the natural progression patterns and the characteristic biological behavior of these tumors, aiming to provide a foundation for advanced stratification for the management of these tumors within a multimodal treatment approach.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods : Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results : A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Introduction: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge., Methods: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model., Results: Of the tested models, only a BRAF V600E -driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro., Conclusion: Taken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation., (© 2024. The Author(s).)

Background: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use., Methods: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m 2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate., Discussion: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG., Trial Registration: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022., (© 2024. The Author(s).)

The most common childhood central nervous system (CNS) tumor is pediatric low-grade glioma (pLGG), representing 30%-40% of all CNS tumors in children. Although there is high associated morbidity, tumor-related mortality is relatively rare. pLGG is now conceptualized as a chronic disease, underscoring the importance of functional outcomes and quality-of-life measures. A wealth of data has emerged about these tumors, including a better understanding of their natural history and their molecular drivers, paving the way for the use of targeted inhibitors. While these treatments have heralded tremendous promise, challenges remain about how to best optimize their use, and the long-term toxicities associated with these inhibitors remain unknown. The International Pediatric Low-Grade Glioma Coalition (iPLGGc) is a global group of physicians and scientists with expertise in pLGG focused on addressing key pLGG issues. Here, the iPLGGc provides an overview of the current state-of-the-art in pLGG, including epidemiology, histology, molecular landscape, treatment paradigms, survival outcomes, functional outcomes, imaging response, and ongoing challenges. This paper also serves as an introduction to 3 other pLGG manuscripts on (1) pLGG preclinical models, (2) consensus framework for conducting early-phase clinical trials in pLGG, and (3) pLGG resistance, rebound, and recurrence., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pediatric low-grade glioma (PLGG) is a heterogeneous group of primary central nervous system malignancies which represent the most frequent brain tumors in children. Although diagnosis and treatment of PLGG have been improved recently, the molecular mechanisms underlying the oncogenesis and progression of PLGG remain elusive. Studies have revealed critical roles of long non-coding RNAs (lncRNAs) in brain tumor progressions. Here, we aimed to investigate the clinical roles and molecular mechanisms of lncRNA PVT1 in PLGG. Expression of PVT1 was significantly upregulated in PLGG tissues compared with normal brain tissues. Blocking PVT1 effectively suppressed the glucose metabolism of PLGG-derived cells. MicroRNA-187-3p was detected to be remarkedly downregulated in PLGG tissues. Moreover, miR-187-3p is negatively correlated with PVT1 in PLGG tissues. We identified PVT1 sponged miR-187-3p to block its expression in PLGG cells. This association was further verified by RNA pull-down and luciferase assay. Subsequently, rescue experiments validated that inhibition of miR-187-3p in PVT1-silenced PLGG cells successfully overcame the low-PVT1-induced miR-187-3p upregulation and glucose metabolism. In summary, this study reports critical roles and molecular mechanisms of the lncRNA PVT1-accelarated glucose metabolism of PLGG cells.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in young children. While they are typically associated with good overall survival, children with these central nervous system tumors often experience chronic tumor- and therapy-related morbidities. Moreover, individuals with unresectable tumors frequently have multiple recurrences and persistent neurological symptoms. Deep molecular analyses of pLGGs reveal that they are caused by genetic alterations that converge on a single mitogenic pathway (MEK/ERK), but their growth is heavily influenced by nonneoplastic cells (neurons, T cells, microglia) in their local microenvironment. The interplay between neoplastic cell MEK/ERK pathway activation and stromal cell support necessitates the use of predictive preclinical models to identify the most promising drug candidates for clinical evaluation. As part of a series of white papers focused on pLGGs, we discuss the current status of preclinical pLGG modeling, with the goal of improving clinical translation for children with these common brain tumors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We aimed to develop machine learning models for prediction of molecular subgroups (low-risk group and intermediate/high-risk group) and molecular marker (KIAA1549-BRAF fusion) of pediatric low-grade gliomas (PLGGs) based on radiomic features extracted from multiparametric MRI., Methods: 61 patients with PLGGs were included in this retrospective study, which were divided into a training set and an internal validation set at a ratio of 2:1 based on the molecular subgroups or the molecular marker. The patients were classified into low-risk and intermediate/high-risk groups, BRAF fusion positive and negative groups, respectively. We extracted 5929 radiomic features from multiparametric MRI. Thereafter, we removed redundant features, trained random forest models on the training set for predicting the molecular subgroups or the molecular marker, and validated their performance on the internal validation set. The performance of the prediction model was verified by 3-fold cross-validation., Results: We constructed the classification model differentiating low-risk PLGGs from intermediate/high-risk PLGGs using 4 relevant features, with an AUC of 0.833 and an accuracy of 76.2% in the internal validation set. In the prediction model for predicting KIAA1549-BRAF fusion using 4 relevant features, an AUC of 0.818 and an accuracy of 81.0% were achieved in the internal validation set., Conclusions: The current study demonstrates that MRI radiomics is able to predict molecular subgroups of PLGGs and KIAA1549-BRAF fusion with satisfying sensitivity., Trial Registration: This study was retrospectively registered at clinicaltrials.gov (NCT04217018)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving Food and Drug Administration (FDA) approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children's Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups., (© 2023 Wiley Periodicals LLC.)

Objective: A case of low-grade glioma in which 5-aminolevulinic acid (5-ALA) fluorescence was visualized by a digital exoscope is presented., Case Presentation: A 14-year-old girl with recurrent paroxysmal episodes of a strange smell and nausea underwent magnetic resonance imaging (MRI) for further investigation. The MRI showed a tumor with an enhanced nodule in the right temporal lobe. The patient received 5-ALA preoperatively, and intraoperative observation using a 4 K-3-dimension digital exoscope (Olympus ORBEYE) showed that the tumor was fluorescent, which was useful in determining the extent of tumor removal. Postoperative MRI showed that the tumor was completely removed. The histopathological diagnosis was pleomorphic xanthoastrocytoma. She was discharged without any complications., Conclusions: 5-ALA-fluorescence-guided resection of low-grade glioma using the ORBEYE was useful for determining the extent of removal., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors., Methods: We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing., Results: Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival., Conclusions: These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Despite advancements in molecular and histopathologic characterization of pediatric low-grade gliomas (pLGGs), there remains significant phenotypic heterogeneity among tumors with similar categorizations. We hypothesized that an unsupervised machine learning approach based on radiomic features may reveal distinct pLGG imaging subtypes., Methods: Multi-parametric MR images (T1 pre- and post-contrast, T2, and T2 FLAIR) from 157 patients with pLGGs were collected and 881 quantitative radiomic features were extracted from tumorous region. Clustering was performed using K-means after applying principal component analysis (PCA) for feature dimensionality reduction. Molecular and demographic data was obtained from the PedCBioportal and compared between imaging subtypes., Results: K-means identified three distinct imaging-based subtypes. Subtypes differed in mutational frequencies of BRAF (p < 0.05) as well as the gene expression of BRAF (p<0.05). It was also found that age (p < 0.05), tumor location (p < 0.01), and tumor histology (p < 0.0001) differed significantly between the imaging subtypes., Conclusion: In this exploratory work, it was found that clustering of pLGGs based on radiomic features identifies distinct, imaging-based subtypes that correlate with important molecular markers and demographic details. This finding supports the notion that incorporation of radiomic data could augment our ability to better characterize pLGGs., 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 © 2022. Published by Elsevier Inc.)

Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8-5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location., (© 2022. The Author(s).)

The brain tumor microenvironment contains numerous distinct types of nonneoplastic cells, which each serve a diverse set of roles relevant to the formation, maintenance, and progression of these central nervous system cancers. While varying in frequencies, monocytes (macrophages, microglia, and myeloid-derived suppressor cells), dendritic cells, natural killer cells, and T lymphocytes represent the most common nonneoplastic cellular constituents in low- and high-grade gliomas (astrocytomas). Although T cells are conventionally thought to target and eliminate neoplastic cells, T cells also exist in other states, characterized by tolerance, ignorance, anergy, and exhaustion. In addition, T cells can function as drivers of brain cancer growth, especially in low-grade gliomas. Since T cells originate in the blood and bone marrow sinuses, their capacity to function as both positive and negative regulators of glioma growth has ignited renewed interest in their deployment as immunotherapeutic agents. In this review, we discuss the roles of T cells in low- and high-grade glioma formation and progression, as well as the potential uses of modified T lymphocytes for brain cancer therapeutics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion., Methods: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery., Results: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation., Conclusions: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement., (© 2021. The Author(s).)

Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4-23.4 years), at death was 13.0 years (1.9-43.2 years), and the overall survival was 7.2 years (0.0-33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

First-line treatment of pediatric low-grade glioma using surgery, radio- or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP-LGG 2004 study (2004-2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98%/96% at 5/10 years, 15% neurofibromatosis type 1 [NF1]). During follow-up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment-lines, accompanied by up to 4 tumor-reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first-line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (<1 year) at start of treatment, tumor dissemination or progression within 18 months after start of chemotherapy. Progression-free survival rates declined with subsequent treatment-lines, yet remaining higher for patients with NF1. In non-NF1-associated tumors, vinblastine monotherapy vs platinum-based chemotherapy was noticeably less effective when used as second-line treatment. Yet, for the entire cohort, results did not favor a certain sequence of specific treatment options. Rather, all can be aligned as a portfolio of choices which need careful balancing of risks and benefits. Future molecular data may predict long-term tumor biology., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Clinical trials of MEK inhibitors are underway in pediatric low-grade glioma (PLGG) with BRAF oncogene mutations and recurrent/refractory disease. Cognitive and behavioral impacts of MEK inhibitors, such as trametinib, are unknown as these outcomes have not yet been studied. This case series compared cognition and behavior in eight PLGG cases prior to and while on treatment with trametinib compared to four PLGG controls. Intelligence in the trametinib cases was mainly unchanged while on treatment, with mild decline in one of seven cases with complete data. Parent-reported depression symptoms increased in five of eight trametinib cases relative to one of four controls., (© 2020 Wiley Periodicals LLC.)

Introduction: A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy., Methods: In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity., Results: We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2-4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%)., Conclusions: Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

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

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior - in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.

Background: Little is known about cognition and predictors of neuropsychological outcomes in pediatric low-grade glioma (PLGG) survivors treated without radiation therapy. This research expands upon our previous work by further identifying the cognitive profile of PLGG patients treated without radiation therapy, investigating the specific medical and demographic variables that predict functioning, and examining white matter structure and its relationship to neuropsychological performance., Procedure: Nineteen PLGG patients (11-19 years) were administered the Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale, and subtests from the Woodcock-Johnson Tests of Cognition (visual matching, rapid picture naming, and pair cancellation) and Cambridge Neuropsychological Test Automated Battery (pattern recognition memory, delayed matching to sample, intra-extra dimensional set shift, motor screening task, rapid visual information processing, and spatial span)., Results: The sample had normative weaknesses in verbal working memory, brief attention/vigilance, psychomotor speeded output, visual perception and matching, overall cognition, working memory, and processing speed. Increased surgeries or subtotal resections, hydrocephalus, shunting procedures, chemotherapy, NF1, and supratentorial location were predictive of cognitive deficits. Broad white matter involvement of the frontal, temporal, parietal, and occipital lobes as well as the cerebellum, as inferred from diffusion tensor imaging indices of decreased fiber orientation and increased water diffusion, was related to many cognitive difficulties., Conclusions: This study comprehensively examines cognitive functioning in PLGG patients treated without radiation therapy, predictors of cognition, and its relation to white matter structure. Our findings indicate that medical and demographic variables other than radiation therapy can lead to cognitive late effects with diffuse white matter involvement., (© 2019 Wiley Periodicals, Inc.)

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

Pediatric low-grade gliomas (PLGGs) have relatively favorable prognosis and some resectable PLGGs, such as cerebellar pilocytic astrocytoma, can be cured by surgery alone. However, many PLGG cases are unresectable and some of them undergo tumor progression. Therefore, a multidisciplinary approach is necessary to treat PLGG patients. Recent genomic analysis revealed a broad genomic landscape underlying PLGG. Notably, the majority of PLGGs present MAPK pathway-associated genomic alterations and MAPK signaling-dependent tumor progression. Following preclinical evidence, many clinical trials based on molecular target therapy have been conducted on PLGG patients, some of whom exhibited durable response to target therapy. Here, we provide an overview of PLGG genetics and the evidence supporting the application of molecular target therapy in these patients.

In pediatric low-grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low-toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow-up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment-limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Pediatric low-grade gliomas (PLGG) are the most common primary central nervous system tumor in children. Patients in whom gross total resection can be achieved have an excellent overall (OS) and event-free survival (EFS) and do not require adjuvant therapy. However, children with unresectable tumors often experience multiple progressions and require additional treatment., Conventional Chemotherapy: Radiotherapy results in long-term tumor control, but it is associated with significant toxicity, making chemotherapy the preferred therapeutic option. Several chemotherapy combinations have been found to be successful in PLGG, but 5-year EFS has been below 60 % with most of them., Molecular-Based Treatment: Recent molecular advances have led to a better understanding of the molecular pathways involved in the biology of LGG, allowing the development of promising tumor-specific, molecularly targeted therapies.

The majority of brain tumors arising in children are low-grade gliomas. Although historically categorized together as pediatric low-grade gliomas (PLGGs), there is significant histologic and genetic diversity within this group. In general, prognosis for PLGGs is excellent, and limitation of sequelae from tumor and treatment is paramount. Advances in high-throughput genetic sequencing and gene expression profiling are fundamentally changing the way PLGGs are classified and managed. Here, we review the histologic subtypes and highlight how recent advances in elucidating the molecular pathogenesis of these tumors have refined diagnosis and prognostication. Additionally, we discuss how characterizing specific genetic alterations has paved the way for the rational use of targeted therapies that are currently in various phase clinical trials., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

To analyze efficacy, functional outcome, and treatment toxicity of low-dose rate I-125 brachytherapy (SBT) alone or in combination with best safe resection (in case of larger tumor volumes) as first-line treatment for pediatric low-grade gliomas (PLGGs) not suitable for complete resection. Consecutively treated (2000-2014) complex located circumscribed WHO grade I/II PLGGs were included. For small tumors (≤4 cm in diameter) SBT alone was performed; for larger tumors best safe resection and subsequent SBT was chosen. Temporary Iodine-125 seeds were used (median reference dose: 54 Gy). Treatment response was estimated with the modified MacDonald criteria. Analysis of functional outcome included ophthalmological, endocrinological and neurological evaluation. Survival was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from proportional hazards models. Toxicity was categorized according to the Common Terminology Criteria for Adverse Events. Fifty-eight patients were included treated either with SBT alone (n = 39) or with SBT plus microsurgery (n = 19). Five-year progression-free survival was 87%. Two patients had died due to tumor progression. Among survivors, improvement/stabilization/deterioration of functional deficits was seen in 20/14/5 patients, respectively. Complete/partial response had beneficial impact on functional scores (P = 0.02). The 5-year estimated risk to receive adjuvant radiotherapy/chemotherapy was 5.2%. The overall early (delayed) toxicity rate was 8.6% (10.3%), respectively. No permanent morbidity occurred. In complex located PLGGs, early SBT alone or combined with best safe resection preserves/improves functional scores and results in tumor control rates usually achieved with complete resection. Long-term analysis is necessary for confirmation of these results., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pediatric low-grade gliomas (PLGGs), the most frequent pediatric brain tumor, comprise a heterogeneous group of diseases. Recent genomic analyses suggest that these tumors are mostly driven by mitogene-activated protein kinase (MAPK) pathway alterations. However, little is known about the molecular characteristics inherent to their clinical and histological heterogeneity., Methods: We performed gene expression profiling on 151 paraffin-embedded PLGGs from different locations, ages, and histologies. Using unsupervised and supervised analyses, we compared molecular features with age, location, histology, and BRAF genomic status. We compared molecular differences with normal pediatric brain expression profiles to observe whether those patterns were mirrored in normal brain., Results: Unsupervised clustering distinguished 3 molecular groups that correlated with location in the brain and histological subtype. "Not otherwise specified" (NOS) tumors did not constitute a unified class. Supratentorial pilocytic astrocytomas (PAs) were significantly enriched with genes involved in pathways related to inflammatory activity compared with infratentorial tumors. Differences based on tumor location were not mirrored in location-dependent differences in expression within normal brain tissue. We identified significant differences between supratentorial PAs and diffuse astrocytomas as well as between supratentorial PAs and dysembryoplastic neuroepithelial tumors but not between supratentorial PAs and gangliogliomas. Similar expression patterns were observed between childhood and adolescent PAs. We identified differences between BRAF-duplicated and V600E-mutated tumors but not between primary and recurrent PLGGs., Conclusion: Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAF genomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Children with pediatric low-grade gliomas (PLGG) are known to have excellent 10-year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG., Procedure: Four thousand and forty patients with either WHO grade I or II PLGG were identified and outcome data retrieved. Two analyses were performed to assess survival and risk of death from tumor. Competing risks analysis was conducted and cumulative incidence curves of death due to disease were generated. Cox proportional hazards regression was performed, with adjustment for non-disease death. Kaplan-Meier curves for overall cancer specific survival (OS) were also generated., Results: The 20-year OS was 87% ± 0.8% and the 20-year cumulative incidence of death due to glioma was 12% ± 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% ± 1.8%. Year of diagnosis, age of diagnosis, histology, WHO grade, primary site, radiation, and degree of initial resection were prognostic in univariate analysis, while the administration of radiation was the greatest risk of death in multivariate analysis of OS (hazard ratio = 3.9)., Conclusions: PLGGs are associated with an excellent long-term survival, with a low likelihood of PLGG related death in adult survivors. Treatment strategies for pediatric tumors should therefore aim for disease control during childhood and adolescence with an emphasis on minimizing long-term treatment induced toxicities., (© 2014 Wiley Periodicals, Inc.)

In the past decade significant advancements have been made in the discovery of targetable lesions in pediatric low-grade gliomas (pLGGs). These tumors account for 30-50% of all pediatric brain tumors with generally a favorable prognosis. The latest 2021 WHO classification of pLGGs places a strong emphasis on molecular characterization for significant implications on prognosis, diagnosis, management, and the potential target treatment. With the technological advances and new applications in molecular diagnostics, the molecular characterization of pLGGs has revealed that tumors that appear similar under a microscope can have different genetic and molecular characteristics. Therefore, the new classification system divides pLGGs into several distinct subtypes based on these characteristics, enabling a more accurate strategy for diagnosis and personalized therapy based on the specific genetic and molecular abnormalities present in each tumor. This approach holds great promise for improving outcomes for patients with pLGGs, highlighting the importance of the recent breakthroughs in the discovery of targetable lesions. [ABSTRACT FROM AUTHOR]

In recent years, it has been established that molecular biology of pediatric low-grade gliomas (PLGGs) is entirely distinct from adults. The majority of the circumscribed pediatric gliomas are driven by mitogen-activated protein kinase (MAPK) pathway, which has yielded important diagnostic, prognostic, and therapeutic biomarkers. Further, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) Steering Committee in their fourth meeting, suggested including a panel of molecular markers for integrated diagnosis in "pediatric-type" diffuse gliomas. However, a designated set of platforms for the evaluation of these alterations has yet not been mentioned for easier implementation in routine molecular diagnostics. Herein, we have reviewed the relevance of analyzing these markers and discussed the strategies and platforms best apposite for clinical laboratories. [ABSTRACT FROM AUTHOR]