Central Nervous System Tumors In Children Research Articles

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.

Childhood and Adolescent Central Nervous System Tumours in Spain: Incidence and Survival over 20 Years: A Historical Baseline for Current Assessment.

Central nervous system (CNS) neoplasms are highly frequent solid tumours in children and adolescents. While some studies have shown a rise in their incidence in Europe, others have not. Survival remains limited. We addressed two questions about these tumours in Spain: (1) Is incidence increasing? and (2) Has survival improved? This population-based study included 1635 children and 328 adolescents from 11 population-based cancer registries with International Classification of Childhood Cancer Group III tumours, incident in 1983-2007. Age-specific and age-standardised (world population) incidence rates (ASRws) were calculated. Incidence time trends were characterised using annual percent change (APC) obtained with Joinpoint. Cases from 1991 to 2005 (1171) were included in Kaplan-Meier survival analyses, and the results were evaluated with log-rank and log-rank for trend tests. Children's survival was age-standardised using: (1) the age distribution of cases and the corresponding trends assessed with Joinpoint; and (2) European weights for comparison with Europe. ASRw 1983-2007: children: 32.7 cases/106; adolescents: 23.5 cases/106. The overall incidence of all tumours increased across 1983-2007 in children and adolescents. Considering change points, the APCs were: (1) children: 1983-1993, 4.3%^ (1.1; 7.7); 1993-2007, -0.2% (-1.9; 1.6); (2) adolescents: 1983-2004: 2.9%^ (0.9; 4.9); 2004-2007: -7.7% (-40; 41.9). For malignant tumours, the trends were not significant. 5-year survival was 65% (1991-2005), with no significant trends (except for non-malignant tumours). CNS tumour incidence in Spain was found to be similar to that in Europe. Rises in incidence may be mostly attributable to changes in the registration of non-malignant tumours. The overall malignant CNS tumour trend was compatible with reports for Southern Europe. Survival was lower than in Europe, without improvement over time. We provide a baseline for assessing current paediatric oncology achievements and incidence in respect of childhood and adolescent CNS tumours.

Pediatric low-grade glioma: State-of-the-art and ongoing challenges.

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.

1 Ototoxicity and Cognitive Outcomes among Children Treated for Brain Tumors in Infancy

Objective:Treatment of childhood central nervous system (CNS) tumors can lead to sensorineural hearing loss (SNHL), with prior research indicating associations between SNHL and cognitive difficulties. Infants (0-3 years) treated for CNS tumors are at particular risk for neurocognitive deficits due to increased vulnerability of the developing brain and missed developmental opportunities secondary to prolonged treatment. This study expands upon existing research by examining the association between treatment-related SNHL and later neurocognitive outcomes among infants.Participants and Methods:Serial audiology and neurocognitive assessments were conducted as part of a prospective, multisite, longitudinal trial (SJYC07). Children with newly diagnosed CNS tumors were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). SNHL was dichotomized based on hearing in the better ear as present versus not present (Chang grade ≥1a vs. <1a). Neurocognitive assessments included intellectual functioning (IQ), and parent ratings of executive functioning and behavioral functioning. Demographic and clinical variables investigated included: sex, age at diagnosis (years), treatment type (chemotherapy only vs. chemotherapy + RT), risk group (low vs. intermediate vs. high), and socioeconomic status (SES, continuous). Logistic regression models were used to identify factors associated with SNHL. Change point longitudinal models were used to examine the effect of each covariate individually and the potential impact of SNHL on trajectories of neurocognitive outcomes.Results:Of 135 patients (median age at diagnosis= 1.5 years), 67% had mild-to-severe SNHL as defined by Chang grade ≥1a at last follow-up. SNHL occurred early after treatment with a 1-year cumulative incidence 63.0% ±4.3%. SNHL was associated with age at diagnosis (p <.001) but not sex, treatment exposure or study risk arm (p >.10). At pretreatment baseline, IQ was associated with age at diagnosis (older age= higher IQ) and SES (higher SES= higher IQ) with a change in the trajectory of IQ after SNHL (stable prior to SNHL and declined 1.46 points/year after SNHL), which was impacted by tumor location (patients with supratentorial tumors stable prior to SNHL and declined 2.84 points/year after SNHL; whereas, patients with infratentorial tumors increased 1.93 points/year prior to SNHL and were stable after SNHL). At pre-treatment baseline, adaptive functioning was associated with age at diagnosis (older age= higher skills) with a change in adaptive functioning after SNHL that varied by age. There was a change in trajectory of attention problems (stable before SNHL and worsening 1.39 points/year after SNHL). SNHL was not associated with parent report of emerging executive functioning.Conclusions:Children with brain tumors experience SNHL and cognitive difficulties early in treatment that can worsen over time. Younger age at diagnosis is associated with greater risk for SNHL and cognitive difficulties. Analyses of the time course between the emergence of SNHL and cognitive late effects suggests even mild SNHL is associated with a clinically signficant decline in IQ and attention problems. These findings have notable implications with respect to refining monitoring guidelines, informing modifications to treatment, advocating for interventions, and helping educate parents, teachers, and providers about the significant impact of mild SNHL.

Evaluation of Neurofibromatosis Type 1 Associated Optic Pathway Gliomas

Background/Aims: Optic pathway gliomas (OPGs) are low-grade gliomas histologically represented by pilocytic astrocytoma (PA) in 90% of cases, can develop from any part of the visual pathways such as optic nerve, chiasm, optic tract, or optic radiations which frequently involve the hypothalamus. OPGs account for 3–5% of childhood central nervous system (CNS) tumors and about 2% of pediatric glial lesions. OPGs are believed to be the most prevalent intracranial tumor in patients with neurofibromatosis type 1 (NF-1) and can occur in 15–20% of NF-1 cases. The aim of this study is to evaluate the clinical features and treatment response in patients diagnosed with optic glioma and NF-1.
 Methods: All cases diagnosed with OPG and received treatment in the Pediatric Oncology Department, between January 2015 to January 2021 were retrospectively evaluated. Inclusion criteria include children and adolescents with OPG aged between 0 and 18 years. The medical records (gender, age, tumor entity, tumor location) of patients, as well as their treatment history and magnetic resonance imaging (MRI) scans, were examined. The diagnosis of OPG was made clinically and radiologically by the tumor board. The recommendations of the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group were used in the diagnosis and evaluation of treatment response. Patients received intravenous chemotherapy with SIOP LGG 2004 (vincristine- carboplatin) with or without bevacizumab (10 mg/kg, started every 2 weeks), therapy or vinblastine (3 mg/m2, weekly). 
 Results: This study included 27 cases during the study period from January 2015 to January 2021. In this study there were 14 male (51.8 %) and 13 female (48.1 %) patients. The median age was 4.8 (range: 0.5–14.9) years. Biopsy was performed in three patients and the diagnosis was low-grade glioma (pilocytic astrocytoma) for all of them. Chemotherapy was administered to 22 cases in total. Twelve patients received vincristine-carboplatine, 5 patients received vincristine-carboplatin with bevacizumab and 5 patients received vinorelbine. Radiological response was evaluated in all 22 patients at 3 months MRI. No patient had a radiological complete respons, 11 patients (50%) had partial response, 2 patients (9%) presented with a progressive disease, showing an increase in measurements of 35% and 9 patients(40.9%) had stable disease at the 3-month evaluation.
 Conclusions: Systemic and visual problems play a significant role in the selection of treatment for pediatric patients with optic gliomas. An essential treatment option for improving symptoms and reducing tumor size is systemic chemotherapy. A crucial therapy option for enhancing vision is bevacizumab for the patients with NF-associated OPG.

Childhood, adolescent, and adult primary brain and central nervous system tumor statistics for practicing healthcare providers in neuro-oncology, CBTRUS 2015-2019.

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention (CDC) and National Cancer Institute (NCI), is the largest aggregation of histopathology-specific population-based data for primary brain and other central nervous system (CNS) in the US. CBTRUS publishes an annual statistical report which provides critical reference data for the broad neuro-oncology community. Here, we summarize the key findings from the 2022 CBTRUS annual statistical report for healthcare providers. Incidence data were obtained from the CDC's National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology, and End Results Program for 52 central cancer registries (CCRs). Survival data were obtained from 42 NPCR CCRs. All rates are per 100 000 and age-adjusted using the 2000 US standard population. Overall median survival was estimated using Kaplan-Meier models. Survival data for selected molecularly defined histopathologies are from the National Cancer Database. Mortality data are from the National Vital Statistics System. The average annual age-adjusted incidence rate of all primary brain and other CNS tumors was 24.25/100 000. Incidence was higher in females and non-Hispanics. The most commonly occurring malignant and predominately non-malignant tumors was glioblastoma (14% of all primary brain tumors) and meningioma (39% of all primary brain tumors), respectively. Mortality rates and overall median survival varied by age, sex, and histopathology. This summary describes the most up-to-date population-based incidence, mortality, and survival, of primary brain and other CNS tumors in the US and aims to serve as a concise resource for neuro-oncology providers.

Pesticide exposure and risk of Central Nervous System tumors in children: a systematic review with meta-analysis.

Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.

Treatments associated with all-cause mortality among children with primary brain and central nervous system tumors: a retrospective cohort study from the SEER database.

Evidence on treatment modalities and survival in childhood primary brain and central nervous system (CNS) tumors remains contradictory, with previous studies often lacking sufficient patient cohort sizes to assess the differences in histological subtypes. This cohort study based on a large population investigated the effects of various treatments on the mortality of patients with different histological types of primary brain and CNS tumors from the Surveillance, Epidemiology, and End Results (SEER) database. Data of demography, primary tumor site, histology, tumor grade and treatments from all pediatric patients with primary brain and CNS tumors were extracted in this retrospective cohort. The outcomes were overall, 1-, 5-, and 10-year all-cause mortality. Multivariate Cox proportional hazards models were to explore the associations of treatment with overall, 1-, 5-, and 10-year all-cause mortality, with hazard ratios (HRs) and 95% confidence intervals (CIs). Totally 10,994 children were included, with the mean age at diagnosis of 7.3 years, and the median follow-up time of 5.0 years. Of which, 2,003 (18.2%) were diffuse astrocytoma, 3,188 (29.0%) were embryonal tumors, and 3,691 (33.5%) were malignant glioma. Then 4,333 (39.41%) children died during the follow-up. For diffuse astrocytomas and malignant gliomas, patients who received all other treatments were associated with overall, 1-, 5- and 10-year all-cause mortality compared to those only received resection. Embryonal tumors patients receiving resection with radiation only and those receiving resection with both chemotherapy and radiation were associated with lower odds of overall, 1-, 5- and 10-year all-cause mortality compared to patients who only received resection. For ependymal tumors, no surgery/only biopsy with chemotherapy, resection with chemotherapy only, resection with both chemotherapy and radiation, and other treatments had increased risks of overall all-cause mortality compared with resection. The risk of 1-year all-cause mortality increased in ependymal tumors with treatment involving resection and radiation. However, resection with both chemotherapy and radiation was not significantly associated with the 1- nor 5-year all-cause mortality. Resection may be recommended for children with diffuse astrocytoma, ependymal tumors, and malignant glioma, while resection with radiotherapy or chemoradiation may be recommended for children with embryonal tumors.

Neurocutaneous Syndromes, Perinatal Factors, and the Risk of Childhood Cancer in Sweden

Neurocutaneous syndromes are associated with cancer predisposition and sometimes associated with perinatal factors. A better understanding of the association between neurocutaneous syndromes, perinatal factors, and childhood cancer is key for earlier cancer detection. To evaluate the association of neurocutaneous syndromes and perinatal factors with childhood cancer risk in a cohort of Swedish children. In this nationwide cohort study, all children and adolescents up to age 20 years, from 1973 to 2015, were identified through the Swedish National Medical Birth Register (MBR), provided they had information on both biological parents. Analyses were conducted from April 2021 through May 2023. Diagnoses of neurocutaneous syndromes were obtained from the MBR, National Patient Register, and Cause of Death register. Perinatal factors (birth weight, gestational age, birth weight by gestational age, 5-minute Apgar score, and head circumference) were obtained from the MBR. Childhood cancer risk (<20 years at diagnosis; identified from the National Cancer Register), including leukemia, lymphoma, and central nervous system (CNS) tumors. Among 4 173 108 included children (2 143 133 [51.4%] male, median [IQR] follow-up 20 [9.7-20] years), 1783 had neurofibromatosis type 1 (NF1), 444 tuberous sclerosis, 63 von Hippel-Lindau disease, and 39 ataxia-telangiectasia. An increased cancer risk was observed among children with any neurocutaneous syndrome (HR, 34.9; 95% CI, 30.8-39.6) and was particularly pronounced for CNS tumors (HR, 111.7; 95% CI, 96.8-128.8), except among children with ataxia-telangiectasia, where the increased risk was associated with lymphomas (HR, 233.1; 95% CI, 75.0-724.1). Leukemia risk was increased only among children with NF1 (HR, 4.1; 95% CI, 1.7-9.8). Several perinatal factors, including high birth weight, being born large for gestational age, preterm birth, low 5-minute Apgar score, and large head circumference had lesser associations with childhood cancer. Adjusting for neurocutaneous syndromes did not affect these associations. In this nationwide cohort study, neurocutaneous syndromes were associated with an increased risk of childhood cancer, especially CNS tumors. Several perinatal factors had lesser associations with childhood cancer, independently of the presence of neurocutaneous syndromes. Other biological mechanisms likely underlie the association between perinatal factors and childhood cancer.

Circulating tumor DNA sequencing of pediatric solid and brain tumor patients: An institutional feasibility study

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time “liquid biopsy” for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.

Cardiorespiratory fitness and health-related quality of life in survivors of childhood central nervous system tumours

PurposeWe assessed cardiorespiratory fitness and health-related quality of life (HRQoL) in survivors of childhood central nervous system (CNS) tumours.MethodsParticipants were recruited from the National Children’s Cancer Service in Children’s Health Ireland at Crumlin. Inclusion criteria included diagnosis of a primary CNS tumour, aged between 6 and 17 years, between 3 months and 5 years post completion of oncology treatment, independently mobile, and deemed clinically appropriate to participate by treating oncologist. Cardiorespiratory fitness was assessed using the six-minute walk test. HRQoL was assessed with the PedsQL Generic Core Scales, Version 4.0.ResultsThirty-four participants (n = 16 male) were recruited, with a mean age of 12.21 ± 3.31 years and a mean time since completion of oncology treatment of 2.19 ± 1.29 years. Mean six-minute walk distance (6MWD) achieved was 489.56 ± 61.48 m, equating to the 8th percentile overall. 6MWD was significantly reduced when compared to predicted population norms (p < 0.001). PedsQL parent proxy-report and child-report scores were significantly lower when compared to healthy paediatric norms (p < 0.001 – p = 0.011). A significant positive correlation was found between 6MWD and both parent proxy-report (r = 0.55, p < 0.001) and child-report (r = 0.48, p = 0.005) PedsQL total scores.ConclusionSurvivors of childhood CNS tumours present with impaired cardiorespiratory fitness and HRQoL. Higher levels of cardiorespiratory fitness are associated with higher levels of HRQoL.Implications for Cancer SurvivorsRoutine screening of cardiorespiratory fitness and HRQoL in survivors of childhood CNS tumours may be beneficial. Healthcare providers should encourage and provide education on the potential benefits of physical activity to improve overall quality of life.

IMG-01. LONGITUDINAL FMRI OF VISUAL, AUDITORY AND MOTOR FUNCTION IN PEDIATRIC CRANIOPHARYNGIOMA AFTER TREATMENT WITH PROTON RADIOTHERAPY

Abstract INTRODUCTION Craniopharyngioma accounts for approximately 4% of childhood central nervous system tumors and has a 5-year overall survival rate exceeding 90%. Survivors of childhood craniopharyngioma may experience neurologic sequalae, including visual and fine motor deficits, and subclinical hearing loss associated with tumor and treatment. Contemporary treatment includes radical surgery or more limited surgery and proton radiotherapy (PRT). Here we report on a longitudinal fMRI study probing visual, auditory, and motor function in pediatric craniopharyngioma patients. METHOD: The study (NCT01419067) was IRB approved and informed consent was obtained for each patient. Functional MR images were acquired at 4 time points: after surgery and before PRT (TP1), and 18-months (TP2), 36-months (TP3), and 60-months (TP4) after PRT. Data from a sensory survey fMRI task (visual: flashing checkerboard; auditory: dissonant ascending/descending pure tones; and sensory/motor: button pushing when stimuli were on) for 67 patients were analyzed at the 4 time points. The median age was 11.7 years (range 8.3-20.2 years) and the female/male ratio was 37/30. RESULTS Significant brain activation was seen in visual cortices, auditory cortices, and supplementary motor area (SMA) and motor cortices for all 4 time points. Over the time, visual and motor cortices showed minimum changes in activation; however, there was a small increase in SMA. For the auditory cortices, the activation volume in Heschl’s gyri increased bilaterally, and the lateralization index decreased (TP1: 70%; TP2: 46%; TP3: 39%; and TP4: 26%) due to larger increases in the right Heschl’s gyrus. CONCLUSION Increasing activation in Heschl’s gyri, especially on the right side, after PRT suggests decreasing efficiency in distinguishing tones in these patients. These findings may be associated with late effects involving the specific gyri or neuropathways affected by surgery or irradiation.

A Case of Infant-type Hemispheric Glioma with NTRK1 fusion (P9-13.003)

<h3>Objective:</h3> Not applicable <h3>Background:</h3> The incidence of childhood central nervous system tumors in infants is about 6 per 100,000 children with glioma having the highest incidence at 1.38 per 100,000. A study by Wu et al. showed recurrent fusion of the <i>NTRK</i> gene in 10% of non-brainstem high grade glioma in very young children suggesting an oncogenic effect of the <i>NTRK</i> fusion genes. Here we present a rare case of a full-term neonate who was noted to have widely splayed sutures and a bulging fontanelle at birth who was found to have infant-type hemispheric glioma with <i>NTRK1</i> fusion. <h3>Design/Methods:</h3> Not applicable <h3>Results:</h3> A full-term infant with normal prenatal course, including a 20-week anatomy scan, was born with widely splayed sutures, bulging anterior fontanelle and head circumference &gt;99^th percentile (40 cm). Head ultrasound showed severe hydrocephalus and a large intracranial mixed echogenicity lesion in the left cerebral hemisphere with hemorrhage. He had sustained leftward gaze, and video EEG revealed seizures. MRI demonstrated a large 6×7cm lesion, hydrocephalus with subfalcine herniation and mass effect on the brainstem (figure, A–B). He underwent biopsy and ventriculoperitoneal shunt placement. MRI 2 weeks later showed tumor enlargement, obstructive hydrocephalus and severe brainstem compression (figure, C–D). Pathology was consistent with infant-type hemispheric glioma with <i>NTRK1</i> fusion. Due to the dismal prognosis, the family prioritized palliative care. <h3>Conclusions:</h3> Infant-type hemispheric glioma, previously termed glioblastoma (GBM), is a rare, rapidly-growing congenital tumor, and prenatal imaging is often normal. Mixed-age hemorrhages and diffusion restriction is suggestive of the diagnosis. The neurotrophic tyrosine receptor kinase (NTRK) genes <i>NTRK1, NTRK2</i>, and <i>NTRK3</i> are involved in infant-type hemispheric gliomas and are typically high grade in histology. A recent study by Torre et al. showed most <i>NTRK-</i>fused gliomas were hemispheric and had a higher prevalence in non-brainstem high grade gliomas in patients younger than 3 years old. <b>Disclosure:</b> Dr. Garcia has nothing to disclose. Dr. Bell has nothing to disclose. Dr. Nelson has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Segal has nothing to disclose.

Genetic predisposition and evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors.

The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking. In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives. Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected. Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

Relationship between parental exposure to radiofrequency electromagnetic fields and primarily hematopoietic neoplasms (lymphoma, leukemia) and tumors in the central nervous system in children: a systematic review.

Low-frequency electromagnetic fields have grown exponentially in recent years due to technological development and modernization. The World Health Organization (WHO)/International Agency for Research on Cancer (IARC) has classified radiofrequency electromagnetic fields (RF-EMFs) as possibly carcinogenic to humans (Group 2B), and recent studies have investigated the association between exposure to electromagnetic fields in parents and possible health effects in children, especially the development of tumours of the central nervous system (CNS). The objective of this systematic review was to collate all evidence on the relationship between parental occupational exposure to electromagnetic fields and the development of CNS cancer in children and to evaluate this association. This review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, and Web of Science were searched from January 1990 to April 2021. The search was conducted using the following search string: "occupational" AND "child" AND "electromagnetic" AND "cancer". Seventeen articles met our inclusion criteria: 13 case-control studies, two cohort studies, and 2 meta-analyses. Most of the studies showed several methodological weaknesses that limited their results. Due to a lack of consistency regarding the outcome as well as the heterogeneity in the reviewed studies, the body of evidence for the effects of parental exposure to electromagnetic fields is not clear. Methodological heterogeneity in the way that studies were conducted could be responsible for the lack of consistency in the findings. Overall, the body of evidence allows no conclusion on the relationship between parental exposure to electromagnetic fields and the occurrence of CNS tumours in children.

Neuroimaging to diagnose central nervous system tumours in children.

Headache, vomiting, lethargy, and seizures are common symptoms in healthy children with benign viral illnesses, but they are also signs that could represent a central nervous system (CNS) tumour. Primary care providers and guardians are hesitant to expose children to radiation associated with computed tomography scans or take on risks associated with the sedation frequently needed for magnetic resonance imaging. When should primary care providers order radiologic head imaging for children with common symptoms to identify those with a CNS tumour? Central nervous system tumours have no pathognomonic features, which often results in delays in diagnosis. Owing to the high prevalence of infratentorial tumours, children commonly present with symptoms of increased intracranial pressure, making a detailed history and a comprehensive physical examination, including ophthalmoscopy for papilledema, especially important. Magnetic resonance imaging is the criterion standard test but it may take time to access, and young children may need sedation. Hence, computed tomography may be a preferable first option.The HeadSmart initiative in the United Kingdom provides guidance to obtain brain imaging within 4 weeks of onset of persistent symptoms that are associated with CNS tumours. We advocate applying the same criteria in Canada in order to reduce delay in diagnosis of CNS tumours in children.

The Greatest Healthcare Disparity: Addressing Inequities in the Treatment of Childhood Central Nervous System Tumors in Low- and Middle-Income Countries.

The antithesis between childhood cancer survival rates in low- and middle-income countries (LMIC) and high-income countries (HIC) represents one of healthcare's most significant disparities. In HICs, the 5-year survival rate for children with cancer, including most brain tumors, exceeds 80%. Unfortunately, children in LMICs experience far worse outcomes with 5-year survival rates as low as 20%. To address inequities in the treatment of childhood cancer and disease burden globally, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer. Within this initiative, pediatric low-grade glioma (LGG) represents a unique opportunity for the neurosurgical community to directly contribute to a paradigm shift in the survival outcomes of children in LMICs, as many of these tumors can be managed with surgical resection alone. In this chapter, we discuss the burden of pediatric LGG and outline actions the neurosurgical community might consider to improve survival for children with LGG in LMICs.

An international multicenter survey reveals health care providers' knowledge gap in childhood central nervous system tumors.

Childhood central nervous system (CNS) tumors have longer delays in diagnosis than do other pediatric malignancies because health care providers (HCPs) lack awareness about clinical presentation of these tumors. To evaluate the knowledge gap among HCPs, we conducted a global cross-sectional survey. The survey consisted of a set of CNS tumor knowledge questions focused on symptoms, signs, and imaging indications. The survey was disseminated to HCPs via email (November 2018-March 2020). Participants had to complete a pre-test survey, attend an education seminar on CNS tumors, and complete a post-test survey. The knowledge gap was evaluated using pre-test and post-test scores. We received 889 pre-test and 392 post-test responses. Most respondents were from Asia (73.1% of pre-test responses; 87.5% of post-test responses). The median pre-test score was 40.0% (range: 13.1-92.9%). A high percentage of correct answers were given in post-test responses (median score: 77.1%, range: 14.9-98.2%). In the pre-test, 18.7% of participants accurately responded that Cushing's triad was a less common symptom, and 15.0% recognized that children aged > 10years are at risk of late diagnosis. Surprisingly, 21.9% falsely reported that patients with malignancy experienced the longest pre-diagnostic symptom interval, and 54.5% of respondents wrongly selected medulloblastoma as the most common CNS tumor. Overall, pediatricians demonstrated a greater knowledge gap on both surveys than did other specialties. Conclusion: Pre- and post-test surveys revealed significant knowledge gaps in childhood CNS tumors among HCPs. Thus, raising professional awareness on clinical presentations of CNS tumors through educational strategies is important to address this knowledge deficit. What is Known: •Diagnostic delay in childhood central nervous system (CNS) tumors continues to be a significant problem that negatively impacts the quality of life and treatment sequelae. • Lack of medical education on CNS tumors is a contributing factor to this problem. What is New: •Most health care providers do not realize that low-grade tumors are the most common neoplasm in children. • Health care providers fail to recognize that teenagers and adolescents are a vulnerable age group for diagnostic delays, with the longest pre-diagnostic symptom interval.

Brain and Brainstem Necrosis after Re-Irradiation for Recurrent Childhood Central Nervous System (CNS) Tumors: A Report from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Task Force

<h3>Purpose/Objective(s)</h3> Re-irradiation is increasingly used in children, adolescents and young adults (AYA) with recurrent CNS tumors. The PENTEC re-irradiation task force reports the results on the risk of symptomatic necrosis following cranial re-irradiation, and its dependence on cumulative dose. <h3>Materials/Methods</h3> A systematic literature search for peer-reviewed articles 1975 to 2021 identified 1183 studies on re-irradiation and 92 studies on re-irradiation for recurrent CNS tumors. Studies on predominantly adult populations and re-irradiation for secondary neoplasms were excluded (n=49). Data from the remaining 43 studies were captured. 17 studies (n=449), reporting brain and brainstem necrosis were used for analysis. While all studies mentioned techniques and range of doses used for re-irradiation, they lacked details on significant dose-volume metrics (e.g., percentage of re-irradiation treatment volume overlapping with primary radiotherapy, mean and maximum cumulative equivalent dose in 2Gy fractions, with alpha-beta ratio=2 (EQD2/2) to organs at risk) necessary for a dose-response modelling. We, therefore, estimated the incidence of necrosis with an exact 95% confidence interval (CI) and provided a qualitative description of the data. <h3>Results</h3> Treated cancers included ependymoma (n=279;7 studies), medulloblastoma (n=98; 6 studies), any CNS tumors (n=62: 3 studies) and supratentorial high-grade gliomas (n=10: 1 study). The median interval between initial and re-irradiation was 2.3 years (range 1.2-4.75). The median cumulative EQD2/2 prescription dose was 103.8 Gy (range 79.7-141.3). Among 449 children/AYA treated with re-irradiation, 22 (4.9%, 95% CI 3.1-7.3%) developed brain necrosis and 14 (3.1%, 95% CI 1.7-5.2%) brainstem necrosis. The median cumulative prescription EQD2/2 was 111.4 Gy (range 79.7-141.3) for development of any necrosis, 107.7 Gy (range 79.7-141.3) for brain necrosis and 112.1 Gy (range 100.2-117) for brainstem necrosis. In 6 studies (n=176) of conventionally fractionated (≤2 Gy per fractions) re-irradiation, 7 patients developed brain necrosis (3.9%) and 4 brainstem necrosis (1.7). In the 5 studies (n=160) of hypofractionated (4-24 Gy per fraction) re-irradiation, 9 patients developed brain necrosis (5.6%) and 10 brainstem necrosis (6.9%). Though there were more necroses in the hypofractionated group, it was not statistically significant (Fisher's exact test 2-tailed p value=0.4664). The remaining six studies (n=113) used a range of fraction size (1.8-24 Gy). No studies reported cumulative dosing for individual organs at risk. <h3>Conclusion</h3> Existing literature suggests that in children and AYA with recurrent brain tumors, re-irradiation results in less than 5-7% incidence of brain/brainstem necrosis with conventional prescription doses after a median follow-up of 2.3 years. A uniform approach for reporting dosimetric endpoints is recommended to derive a robust predictive model of late toxicities following re-irradiation.

Childhood Obesity: A Potential Key Factor in the Development of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a malignant primary tumor type of the central nervous system (CNS). This type of brain tumor is rare and is responsible for 12–15% of all brain tumors. The typical survival rate of GBM is only 12 to 14 months. GBM has a poor and unsatisfactory prognosis despite advances in research and therapeutic interventions via neurosurgery, radiation, and chemotherapy. The molecular heterogeneity, aggressive nature, and occurrence of drug-resistant cancer stem cells in GB restricts the therapeutic efficacy. Interestingly, the CNS tumors in children are the second most usual and persistent type of solid tumor. Since numerous research studies has shown the association between obesity and cancer, childhood obesity is one of the potential reasons behind the development of CNS tumors, including GBM. Obesity in children has almost reached epidemic rates in both developed and developing countries, harming children’s physical and mental health. Obese children are more likely to face obesity as adults and develop non-communicable diseases such as diabetes and cardiovascular disease as compared to adults with normal weight. However, the actual origin and cause of obesity are difficult to be pointed out, as it is assumed to be a disorder with numerous causes such as environmental factors, lifestyle, and cultural background. In this narrative review article, we discuss the various molecular and genetic drivers of obesity that can be targeted as potential contributing factors to fight the development of GBM in children.