Pediatric Central Nervous System Tumors Research Articles

Pediatric neuropathology practice in a low- and middle-income country: capacity building through institutional twinning

BackgroundAccurate and precise diagnosis is central to treating central nervous system (CNS) tumors, yet tissue diagnosis is often a neglected focus in low- and middle-income countries (LMICs). Since 2016, the WHO classification of CNS tumors has increasingly incorporated molecular biomarkers into the diagnosis of CNS tumors. While this shift to precision diagnostics promises a high degree of diagnostic accuracy and prognostic precision, it has also resulted in increasing divergence in diagnostic and management practices between LMICs and high-income countries (HICs). Pathologists and laboratory professionals in LMICs lack the proper training and tools to join the molecular diagnostic revolution. We describe the impact of a 7-year long twinning program between Canada and Pakistan on pathology services.MethodsDuring the study period, 141 challenging cases of pediatric CNS tumors initially diagnosed at Aga Khan University Hospital (AKUH), Karachi, were sent to the Hospital for Sick Children in Toronto, Canada (SickKids), for a second opinion. Each case received histologic review and often immunohistochemical staining and relevant molecular testing. A monthly multidisciplinary online tumor board (MDTB) was conducted to discuss the results with pathologists from both institutions in attendance.ResultsDiagnostic discordance was seen in 30 cases. Expert review provided subclassification for 53 cases most notably for diffuse gliomas and medulloblastoma. Poorly differentiated tumors benefited the most from second review, mainly because of the resolving power of specialized immunohistochemical stains, NanoString, and targeted gene panel next-generation sequencing. Collaboration with expert neuropathologists led to validation of over half a dozen immunostains at AKUH facilitating diagnosis of CNS tumors.ConclusionsLMIC-HIC Institutional twinning provides much-needed training and mentorship to pathologists and can help in infrastructure development by adopting and validating new immunohistochemical stains. Persistent unresolved cases indicate that molecular techniques are indispensable in for diagnosis in a minority of cases. The development of affordable alternative molecular techniques may help with these histologically unresolved cases.

The importance of basic and translational research in caring for children with malignant solid tumors in Latin America.

Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.

Identifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors.

Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to the low prevalence of pediatric CNS tumors, major advances in targeted therapies have been lagging compared to other adult tumors. We collect single nuclei RNA-seq data from 84,700 nuclei of 35 pediatric CNS tumors and three non-tumoral pediatric brain tissues and characterize tumor heterogeneity and transcriptomic alterations. We distinguish cell subpopulations associated with specific tumor types including radial glial cells in ependymomas and oligodendrocyte precursor cells in astrocytomas. In tumors, we observe pathways important in neural stem cell-like populations, a cell type previously associated with therapy resistance. Lastly, we identify transcriptomic alterations among pediatric CNS tumor types compared to non-tumor tissues, while accounting for cell type effects on gene expression. Our results suggest potential tumor type and cell type-specific targets for pediatric CNS tumor treatment. Here we address current gaps in understanding single nuclei gene expression profiles of previously under-investigated tumor types and enhance current knowledge of gene expression profiles of single cells of various pediatric CNS tumors.

Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors

Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.

Clinical, pathologic, and genomic characteristics of two pediatric glioneuronal tumors with a CLIP2::MET fusion

Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.

Atypical Teratoid/Rhabdoid Tumor with Retained SMARCB1 (INI1) Expression and Rare SMARCA4 Gene Mutation: A Case Report of a Pediatric Patient

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive tumors of the central nervous system (CNS), accounting for 1–3% of all pediatric CNS tumors. In general, AT/RTs are associated with biallelic inactivation of SMARCB1, resulting in the loss of expression of the integrase interactor 1 (INI1) protein. In this report, we describe the clinical course of an infant patient who presented with fatigue, postprandial vomiting, and disability of left side movement. Histological examination revealed classical features indicative of rhabdoid tumors, yet an atypical immunohistochemical profile with preserved INI1 expression was observed. Molecular diagnostics further elucidated the presence of a heterozygous frameshift variant, SMARCA4 c.2693del, p.(Asn898Thrfs*12), underscoring the distinctive genetic foundations of the case. Surgical resection of the tumor was administered with subsequent chemotherapy to the patient, but the condition worsened dynamically, and a decision was made to give the patient palliative therapy. We report on a patient with AT/RT caused by a rare mutation of the SMARCA4 gene and an aggressive course of disease to provide more information and characteristics of these tumors.

Comparative Analysis of Surgical Site Infections in Pediatric Brain Tumor Patients: Hygiene Practices, Risk Factors, and Implications for Healthcare Costs and Mortality

Surgical site infections (SSIs) significantly impact pediatric central nervous system tumor outcomes. We present our data of SSIs and their influence on outcomes of pediatric brain tumor patients treated between January 2011 till December 2022. This study utilized retrospective data from patients' medical records. Chi-squared test was used for correlational analysis. Independent sample t-test was used for equality of means. Linear and logistic regression was done to review impact of independent variables on dependent variable. Survival analysis was done using Kaplan–Meier curves. Between 2011 and 2022, 336 pediatric patients (202 males, 134 females) were diagnosed with brain tumors. Majority patients (279; 83%) underwent surgery (91% elective). Commonest tumor site was cerebellum (84/279; 30%). Tumor resection status was gross total resection (29/279; 46%), subtotal resection (59/279; 21%), near total resection (48/279; 17%), and partial resection (20/279; 7%); while 32/279 patients (11%) had a biopsy only. Hydrocephalus was present in 166/279 patients (59%); while majority (160/166; 96%) underwent a cerebrospinal fluid (CSF) diversion procedure. SSI developed in 23/279 patients (8%), leading to delayed postoperative management in majority (15/23; 65%). SSIs were significantly associated with lower age of presentation (p = 0.01), less duration between symptoms and diagnosis (p = 0.00), performance of CSF diversion procedure (p = 0.04), increase in hospital stay (p = 0.00), delay in postoperative management (15/23; 65%) (p = 0.01), decline in treatment completion (p = 0.01), and poor survival (p = 0.01). Majority (171/279) of patients (61%) completed treatment. The overall survival of our cohort was 84.9% with a median follow-up time of 11 (interquartile range [IQR]: 36, 1) months. Survival was significantly lower (56.5%) in patients with SSI (p = 0.01). Median time to death was 18 months. Progression-free survival was 77.4% with a median progression-free time of 8 (IQR: 28, 1) months. Median time to progression was 9 (IQR: 24, 4.5) months. The incidence of SSIs in our cohort closely resembled that of high-income countries. Risk factors for SSIs included younger age, a shorter time between symptom onset and surgery, undertaking of CSF diversion procedures. Adverse effects of SSIs included increased costs, delays in postoperative management, incomplete treatment, and higher mortality rates. This study emphasizes the substantial impact of SSIs on healthcare resources and patient well-being.

New CNS tumor classification: The importance in pediatric neurosurgical practice.

The management of the central nervous system (CNS) tumors in the pediatric population is crucial in neurosurgical practice. The World Health Organization (WHO) has evolved its classification of CNS tumors from the 19th century to the 5th edition, published in 2021, incorporating molecular advancements. This transition from morphology to molecular characterization is ongoing. This manuscript analyzes the modifications introduced in the 5th edition of WHO's CNS tumor classification, particularly focusing on pediatric tumor families. The paper integrates clinical, morphological, and molecular information, aiming to guide pediatric neurosurgeons in their daily practice and interdisciplinary discussions. The 5th edition of the WHO classification introduces a hybrid taxonomy that incorporates both molecular and histological components. The terminology shifts from "entity" to "type" and "subtype," aiming to standardize terminology. Tumor grading experiences changes, integrating molecular biomarkers for prognosis. The concept of integrated layered diagnosis is emphasized, where molecular and histological information is combined systematically. The 5th edition of the WHO CNS classification signifies a paradigm shift toward molecular characterization. The incorporation of molecular advances, the layered diagnostic approach, and the inclusion of clinical, morphological, and molecular information aim to provide comprehensive insights into pediatric CNS tumors. This classification offers valuable guidance for pediatric neurosurgeons, aiding in precise diagnosis and treatment planning for these complex neoplasms.

132 Optimizing Success Rates of CSF Liquid Biopsy Examined With Next Generation Sequencing in Pediatric Central Nervous System Tumors

INTRODUCTION: Cerebrospinal fluid (CSF) liquid biopsy presents an attractive option for minimally invasive diagnosis and follow up for pediatric brain tumors. Best practice for obtaining appropriate cfDNA for next generation sequencing (NGS) is not currently known. METHODS: CSF was collected from patients under a prospective study to evaluate diagnostic utility of NGS. Samples were collected from control (non-tumor) and CNS tumor patients. CSF was collected at the dura opening, immediate ventricular catheter (IVC) from CSF divergent procedures, or ventricular shunt taps. Data was gathered on demographics, pathological diagnosis, tumor location, volume of CSF extraction, and DNA yield. RESULTS: CSF was extracted from 72 CNS tumor patients and 20 controls (48 female, 44 male). Of the CNS tumors, there were forty low-grade tumors (40/72) and thirty-two high-grade tumors (32/72). CSF collection location included dura opening (57), ventricular catheter (23), and shunt taps (12). cfDNA yield (ng) for CNS tumors displayed a mean of 135.5 ng (±353.4) and controls displayed a mean of 95.6 ng (±241.0). CNS tumor patients generated a significantly higher (p < 0.0001) DNA concentration (ng/cc) with a mean of 18.9 ng/cc (±82.7) compared to 0.5 ng/cc (±0.7) mean for controls. High grade tumors demonstrated a significantly greater amount of cfDNA concentration with a mean of 33.6 ng/cc (±116.6) whereas low grade tumors had a mean of 4.2 ng/cc (±5.0). CSF acquisition was 90.2% successful for NGS with a mean volume of 4.9 cc. In addition, infratentorial tumors revealed a 96% success rate with a mean volume of 5 cc. CONCLUSIONS: Extracting 4.9 cc of CSF had an 90.2% success rate for NGS. CSF may be acquired from either ventricular catheter or dura opening. High grade tumors had significantly higher cfDNA yield and concentration in CSF compared to low grade.

Registration, incidence patterns, and survival trends of central nervous system tumors among children in Germany 1980-2019: An analysis of 40years based on data from the German Childhood Cancer Registry.

Tumors of the central nervous system (CNS) are the second most common type of pediatric cancer in Germany. We aimed to describe registration practice, incidence, and survival patterns for childhood CNS tumors in Germany for the past 40years. Including all CNS tumor cases in children diagnosed at ages 0-14years registered at the German Childhood Cancer Registry (GCCR) in 1980-2019 (for survival analysis 1980-2016), we calculated age-specific and age-standardized incidence rates (ASIR) over time, average annual percentage changes (AAPC), and 1- and 5-year overall survival. While we observed a pronounced increase in ASIR after the establishment of the GCCR during the 1980s, ASIR for all pediatric CNS tumors combined continued to increase markedly from 28.6 per million in 1990-1999 to 43.3 in 2010-2019 (AAPC=2.7% in 1991-2010, AAPC=0.3% in 2010-2019). The 5-year overall survival from CNS tumors improved from 63% in the 1980s, 70% in the 1990s to 79% in 2010-2016. These improvements have occurred across all age groups. Children diagnosed with ependymomas and choroid plexus tumors experienced the strongest increase (from 54% to 81%). Observed increases in incidence rates for pediatric CNS tumors are likely only partially caused by actual increasing case numbers. The majority is a function of improved registration and, to a minor extent, improvements in diagnostics. Survival from pediatric CNS tumors has, by and large, improved consistently, leading to a growing population of childhood cancer survivors with diverse health biographies and risk of lifelong adverse impact on health and wellbeing.

Abstract 6372: Germline pathogenic variants are enriched in pediatric central nervous system tumor patients and associate with somatic functional consequences

Abstract The genetic contribution of rare pathogenic germline variation to central nervous system (CNS) tumor formation in pediatric patients without a family history of cancer remains unclear. We sought to characterize the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in 838 patients profiled in the Pediatric Brain Tumor Atlas (PBTA) by whole genome sequencing (n=821) or whole exome sequencing (n=17). Rare variants in 214 CPGs were annotated as pathogenic (P) or likely pathogenic (LP) consistent with American College of Medical Genetics criteria using AutoGVP, our open-source automated pathogenicity assessment tool. To assess enrichment of P/LP variants in the PBTA, we compared the frequency of CPG P/LP variants in cases to a tumor-free control cohort from Penn Medicine BioBank (PMBB; n=6,295). Somatic alterations, mutational signatures, and gene set enrichment analyses from matched tumor sequencing were integrated to characterize functional consequences associated with germline pathogenic variation. We observed 215 germline P/LP variants within 76 distinct CPGs in 189 (22.6%) PBTA patients. CPG P/LP variants were most prevalent among patients with a plexiform neurofibroma diagnosis (9/14, 64.3%), and least prevalent among patients with craniopharyngioma (3/39, 7.8%). We detected syndrome-associated P/LP variants in 45/58 (77.6%) patients with a clinically reported cancer predisposition syndrome and incidentally in another 37 patients. CPG P/LP variants were significantly enriched in the PBTA cohort relative to the PMBB control cohort (OR=2.0, p=1.0E-12, CI=1.6-2.4), and NF1 harbored the most significant excess P/LP variant burden (OR=30.7, p=4.57E-13, CI=11.2-105.1). We observed a significant enrichment of mismatch repair (MMR) gene P/LP variants in patients with high-grade gliomas (HGG) and tumors from MMR P/LP carriers exhibited significantly higher MMR-deficiency mutational signature exposures relative to tumors from non-carrier HGG patients (SBS14: W=478, p=1.71E-05). Overall, 90/215 (41.9%) of identified germline P/LP variants co-occurred with at least one corresponding somatic alteration in matched tumors, including oncogenic SNV (n=5), copy number variation (n=28), loss of heterozygosity (n=54), differential gene expression (n=23), and proximal alternative splicing (n=19). In summary, rare germline P/LP variants are enriched in PBTA patients and are associated with somatic events in the same gene, resulting in gene- and pathway-specific functional consequences. Our work emphasizes a role for pathogenic germline variation in pediatric CNS tumor development and frequent under-identification of cancer predisposition syndromes, underscoring the importance of germline sequencing in personalized patient care strategies. Citation Format: Ryan J. Corbett, Rebecca Kaufman, Shelly W. McQuaid, Zalman Vaksman, Saksham Phul, Miguel A. Brown, Jennifer L. Mason, Heena Desai, Ryan Hausler, Ammar S. Naqvi, Antonia Chroni, Zhuangzhuang Geng, Bo Zhang, Chuwei Zhong, Yuankun Zhu, Allison P. Heath, Marilyn Li, Penn Medicine BioBank, Phillip B. Storm, Adam C. Resnick, Kara N. Maxwell, Miriam Bornhorst, Kristina A. Cole, Angela J. Waanders, Suzanne P. MacFarland, Jo Lynne Rokita, Sharon J. Diskin. Germline pathogenic variants are enriched in pediatric central nervous system tumor patients and associate with somatic functional consequences [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6372.

MiR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression.

Medulloblastoma (MB), a prevalent pediatric central nervous system tumor, is influenced by microRNAs (miRNAs) that impact tumor initiation and progression. However, the specific involvement of miRNAs in MB tumorigenesis remains unclear. Using single-cell RNA sequencing, we identified ROR2 expression in normal human fetal cerebellum. Subsequent analyses, including immunofluorescence, quantitative real-time PCR (qRT-PCR), and Western blot, assessed ROR2 expression in MB tissues and cell lines. We investigated miR-124-3p and miR-194-5p and their regulatory role in ROR2 expression through the dual-luciferase reporter, qRT-PCR, and western blot assays. Mechanistic insights were gained through functional assays exploring the impact of miR-124-3p, miR-194-5p, and ROR2 on MB growth in vitro and in vivo. We observed significantly reduced miR-124-3p and miR-194-5p expression and elevated ROR2 expression in MB tissues and cell lines. High ROR2 expression inversely correlated with overall survival in WNT and SHH subgroups of MB patients. Functionally, overexpressing miR-124-3p and miR-194-5p and inhibiting ROR2 suppressed in vitro malignant transformation and in vivo tumorigenicity. Mechanistically, miR-124-3p and miR-194-5p synergistically regulated the ROR2/PI3K/Akt pathway, influencing MB progression. Our findings indicate that miR-124-3p and miR-194-5p function as tumor suppressors, inhibiting MB progression via the ROR2/PI3K/Akt axis, suggesting a key mechanism and therapeutic targets for MB patients.

Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, established new approaches to both CNS tumor nomenclature and grading, emphasizing the importance of integrated diagnoses and layered reports. This edition increased the role of molecular diagnostics in CNS tumor classification while still relying on other established approaches such as histology and immunohistochemistry. Moreover, it introduced new tumor types and subtypes based on novel diagnostic technologies such as DNA methylome profiling. Over the past decade, molecular techniques identified numerous key genetic alterations in CSN tumors, with important implications regarding the understanding of pathogenesis but also for prognosis and the development and application of effective molecularly targeted therapies. This review summarizes the major changes in the 2021 fifth edition classification of pediatric CNS tumors, highlighting for each entity the molecular alterations and other information that are relevant for diagnostic, prognostic, or therapeutic purposes and that patients' and oncologists' need from a pathology report.

Recurrence Patterns and Surveillance Imaging in Pediatric Brain Tumor Survivors.

Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in pediatric central nervous system (CNS) tumors. The frequency of neuroimaging surveillance varies without a standardized approach. A single-institutional retrospective cohort study evaluated the frequency of recurrences. This study included 476 patients with the majority diagnosed with low-grade glioma (LGG) (n=138, 29%), high-grade glioma (HGG) (n=77, 16%), ependymoma (n=70, 15%), or medulloblastoma (n=61, 13%). LGG, HGG, and ependymoma patients more commonly had multiply recurrent disease ( P =0.08), with ependymoma patients demonstrating ≥2 relapses in 47% of cases. Recurrent disease was identified by imaging more often than clinical symptoms (65% vs. 32%; P =<0.01). Patients diagnosed with meningioma demonstrated the longest mean time to first relapse (74.7mo) whereas those with atypical teratoid rhabdoid tumor and choroid plexus carcinoma tended to have the shortest time to relapse (8.9and 9mo, respectively). Overall, 22 patients sustained first relapse >10 years from initial diagnosis. With a higher tendency toward detection of tumor recurrence/progression on MRI surveillance in comparison to clinical progression, surveillance imaging is necessary in routine follow up of pediatric CNS tumor survivors. With some relapses >10 years from initial diagnosis, imaging beyond this time point may be useful in particular tumor types. While the study is limited in outcome analysis, earlier detection of recurrence would lead to earlier initiation of treatment and implementation of salvage treatment regimens which can impact survival and quality of life.

Abstract A014: ClpP drives efficacy and mediates acquired resistance with imipridones ONC201 and ONC206 in glioma in vitro

Abstract A014: ClpP drives efficacy and mediates acquired resistance with imipridones ONC201 and ONC206 in glioma <i>in vitro</i>

Influencing factors, surgical management, and predictors of posterior fossa tumors with hydrocephalus in children

Background: Hydrocephalus is a common disease in neurosurgery. In pediatric central nervous system tumors, the proportion of posterior fossa tumors (PFTs) in children is high, hydrocephalus is often the first manifestation, and some cases have de novo or aggravated hydrocephalus after surgery. Objective: To conclude some controversies about the treatment methods and timeline of PFT with hydrocephalus. Methods: This article reviews the latest progress in the literature and practical problems encountered in clinical practices. Results: For most children, surgical drainage is the most effective treatment; however, medical treatment can be performed before surgery or a definite diagnosis is made. In children with PFT, the risk of hydrocephalus can be initially predicted according to the condition of the child, which has clear clinical significance for the selection of treatment methods and the evaluation of related prognosis. Conclusion: PFT is a common site for CNS tumors in children, and its clinical manifestations are often hydrocephalus-related. According to the condition of pediatric patients, early prediction of the risk of hydrocephalus has clear clinical significance for the selection of treatment methods and the evaluation of related prognoses.

Characterization of pediatric non-hematopoietic tumor metastases to the central nervous system: A single institution review.

Central nervous system (CNS) metastases represent a small portion of pediatric CNS neoplasms and data surrounding this condition with high morbidity is scarce. Single institutional archival institutional pathology records between 1999 and 2022 were searched for patients over 21 years old and younger with CNS, dura, cranial nerve, CSF, or leptomeningeal metastases; 41 cases were identified. We documented primary tumor types and locations, metastasis locations, types of invasion (direct extension vs distant metastasis), times from imaging or pathologic diagnosis to CNS involvement, and outcomes. Distant metastasis was the most common mechanism of metastasis (n = 32, 78%). Interval times to CNS metastasis varied by both tumor type and primary tumor location. In this cohort, osteosarcoma portended the shortest survival following CNS metastasis. This study highlights the diverse mechanisms and locations of CNS involvement in pediatric CNS metastases and illuminates a need for varied monitoring strategies when considering primary tumor type and anatomic location.

Imaging of supratentorial intraventricular masses in children: a pictorial review-part 2.

This article is the second in a two-part series aimed at exploring the spectrum of supratentorial intraventricular masses in children. In particular, this part delves into masses originating from cells of the ventricular lining, those within the septum pellucidum, and brain parenchyma cells extending into the ventricles. The aim of this series is to offer a comprehensive understanding of these supratentorial intraventricular masses, encompassing their primary clinical findings and histological definitions. We conducted a review and analysis of relevant epidemiological data, the current genetics/molecular classifications as per the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5), and imaging findings. Each supratentorial intraventricular mass was individually evaluated, with a detailed discussion on its clinical and histological features. This article covers a range of supratentorial intraventricular masses observed in children. These include colloid cysts, subependymal giant cell astrocytomas, ependymomas, gangliogliomas, myxoid glioneuronal tumors, central neurocytomas, high-grade gliomas, pilocytic astrocytomas, cavernous malformations, and other embryonal tumors. Each mass type is characterized both clinically and histologically, offering an in-depth review of their individual imaging characteristics. The WHO CNS5 introduces notable changes, emphasizing the vital importance of molecular diagnostics in classifying pediatric central nervous system tumors. These foundational shifts have significant potential to impact management strategies and, as a result, the outcomes of intraventricular masses in children.

Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors.

Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an "in-house" gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine.

10152-PEDT-5 JAPANESE SUBGROUP ANALYSIS OF A PHASE II TRIAL OF DABRAFENIB PLUS TRAMETINIB (D+T) IN BRAF V600-MUTANT PEDIATRIC LOW-GRADE GLIOMA (PLGG) AND RELAPSED/REFRACTORY (R/R) BRAF V600-MUTANT PEDIATRIC HIGH-GRADE GLIOMA (PHGG)

Abstract BACKGROUND pLGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. pHGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. The result of a phase II global clinical trial (NCT02684058) of D+T vs carboplatin + vincristine (C+V) in first-line BRAF V600-mutant pLGG and single arm D+T in relapsed/refractory (r/r) BRAF V600-mutant pHGG has already been described. Briefly, the primary endpoint was the independently assessed overall response rate, ORR (CR+PR) using RANO criteria. The ORR was 47% (95% CI, 35%-59%) with D+T vs 11% (95% CI, 3%-25%) with C+V (P&amp;lt;.001; odds ratio, 7.2 [95% CI, 2.3-22.4]) in pLGG and 56.1% (95% CI, 39.7%-71.5%) in pHGG. Safety was consistent with the established profile of D+T in other indications. We report results for the Japanese subgroup. RESULTS A total of 6 Japanese pts were included in pLGG (D+T; n=4, C+V; n=2). And a total of 11 Japanese pts with diverse WHO Grade III/IV gliomas were included in r/r pHGG. The best overall response assessed by independent reviewer were as followed; D+T; SD 75% (n=3), PD 25% (n=1), C+V; CR 50% (n=1), PD 50% (n=1) in pLGG and CR 9.1% (n=1), PR 27.3% (n=3), SD 9.1% (n=1), PD 36.4% (n=4) in r/r pHGG. Treatment-related grade &amp;gE;3 adverse events were D+T; 25% (n=1) and C+V; 100% (n=2) in pLGG and 27.3% (n=3) in r/r pHGG. DISCUSSION AND CONCLUSIONS Treatment with D+T showed encouraging efficacy in Japanese pLGG and r/r pHGG. Profile of AEs was similar or consistent which is reported in other adult cohorts. Thus, these results suggest that D+T may represent a critical treatment advance for pLGG and r/r pHGG Japanese pts with BRAF V600-mutant.