Childhood Brain Tumors Research Articles

Identification of novel therapeutic targets for histone 3 mutated children’s brain tumour, using unique tumour cell surface proteomic signatures

Abstract Aims Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome (cell membrane proteins) signature. Method We therefore analysed the cell surface proteomics of pHGG and DIPG, in order to identify novel targets for therapy. We have at first isolated the cell membrane fractions from a range of patient cells carrying different histone 3 mutations (G34R, G34V), relative to wild type histone 3. A comparative quantitative mass-spectrometry analyses of these cell surface membrane fractions is then performed. Results The results obtained to date demonstrated unique differential cell membrane expression patterns which correlated to specific mutation type. For example, increased expression of Ras-related proteins Rab-3, Rab-3D is detected only in histone H3.3-G34R mutated cell line in comparison. Conclusion Identification and analyses of these unique cell membrane proteins’ association with specific in H3.3 mutation in pHGG, will help to identify precise mutation specific therapeutic targets, benefiting the patients to receive therapy based on tumour’s molecular signature.

Review of the genomic landscape of common pediatric CNS tumors and how data sharing will continue to shape this landscape in the future.

Over the past decade we have witnessed a rapid increase in our understanding of the molecular characteristics of pediatric central nervous system (CNS) tumors. Studies that utilize genomic sequencing have revealed a heterogeneous group of genetic drivers in pediatric CNS tumors including point mutations, gene fusions, and copy number alterations. This manuscript provides an overview of somatic genomic alterations in the most common pediatric CNS tumors including low grade gliomas, high grade gliomas, medulloblastomas, and ependymomas. Additionally, we will discuss the need and opportunity for genomic and clinical data sharing through the children's brain tumor network and other international initiatives.

Communication and swallowing management in childhood brain tumour or leukaemia: A survey of health professionals and consumers

Purpose: Brain tumour and leukaemia represent the most common childhood cancers and can result in communication and swallowing difficulties. The purpose of this study was to survey health professionals and consumers regarding the management of communication and swallowing difficulties in children with brain tumour or leukaemia (CBTL). Method: In this study participants completed a survey focussing on (1) communication and swallowing assessment and intervention, (2) multidisciplinary team (MDT) practices and (3) risk factors. Quantitative data were reported using descriptive statistics. Qualitative data were analysed using NVivo12 Qualitative Data Analysis Software. Result: Twenty-four participants were included (22 health professionals; two consumers). Most participants (≥80%) agreed that comprehensive and regular communication and swallowing assessments improved outcomes. Communication and swallowing interventions were reported to improve outcomes by 96% of participants. MDT care was considered essential in improving outcomes. Speech-language pathologists were the primary health professional identified in communication management; additional multidisciplinary health professionals were highlighted in swallowing management. Risk factors were identified across three categories: cancer-related, treatment-related and child-factors. Conclusion: This study collates the expertise and experience of multidisciplinary health professionals and consumers which can be used to guide assessment and intervention for communication and swallowing in CBTL. It also provides perspectives on MDT care and consideration of patient values and risk factors.

Long-term unmet supportive care needs of teenage and young adult (TYA) childhood brain tumour survivors and their caregivers: a cross-sectional survey

IntroductionThe supportive care needs of long-term childhood brain tumour survivors, now teenagers and young adults (TYAs), and their caregivers are largely unknown. We aimed to describe their supportive care needs and explore associations between needs and quality of life (QoL).MethodsParticipants were recruited from long-term follow-up clinics (in three NHS Trusts in England) and online. Participants included childhood brain tumour survivors, ≥ 5 years from diagnosis, currently aged 13–30, and their primary caregivers. Survivors completed the Supportive Care Needs Survey (SCNS) Short Form and caregivers the SCNS-Partners & Caregivers, alongside validated QoL questionnaires (Peds-FACT-Br and CQOLC).ResultsIn total, 112 individuals (69 survivors/43 caregivers) participated. Survivors reported on average 9.4 (± 8.5) unmet needs. Needs were greatest in the psychological domain, with anxiety (60.3%), uncertainty about the future (50.7%) and feeling down and depressed (48.5%) most commonly reported. Caregivers reported on average 12.4 (± 12.3) unmet needs. Again, the greatest number of unmet needs was observed in the psychological domain. Many caregivers also reported information needs around financial support/government benefits (42.9%) and possible survivor fertility problems (42.9%). Multivariable linear regression analysis showed that female survivors, unemployed survivors, survivors further away from diagnosis and single caregivers were more likely to report unmet needs. More unmet needs were significantly associated with poorer QoL in survivors and caregivers.ConclusionThis research provides leads to improving supportive care and long-term follow-up services. Psychological support represents the biggest gap in care. Understanding unmet needs and recognising what services are required are critical to improving quality of long-term survival.

Polycomb repressive complex 2 in the driver's seat of childhood and young adult brain tumours.

Deregulation of the epigenome underlies oncogenesis in numerous primary brain tumours in children and young adults. In this review, we describe how recurrent mutations in isocitrate dehydrogenases or histone 3 variants (oncohistones) in gliomas, expression of the oncohistone mimic enhancer of Zeste homologs inhibiting protein (EZHIP) in a subgroup of ependymoma, and epigenetic alterations in other embryonal tumours promote oncogenicity. We review the proposed mechanisms of cellular transformation, current tumorigenesis models and their link to development. We further stress the narrow developmental windows permissive to their oncogenic potential and how this may stem from converging effects deregulating polycomb repressive complex (PRC)2 function and targets. As altered chromatin states may be reversible, improved understanding of aberrant cancer epigenomes could orient the design of effective therapies.

Prevalence and risk factors of hypothalamic-pituitary dysfunction in infant and toddler childhood brain tumor survivors.

Childhood brain tumor survivors (CBTS) are at risk to develop hypothalamic-pituitary (HP) dysfunction (HPD). The risk for HPD may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. Specific studies on HPD in infant brain tumor survivors (infant-BTS, 0-1 years at diagnosis) or toddler brain tumor survivors (toddler-BTS, ≥1-3 years) have not been performed. A retrospective nationwide cohort study in CBTS was performed. Prevalence and risk factors for HPD were compared between infant-, toddler-, and older-BTS. Subgroup analysis was performed for all non-irradiated CBTS (n = 460). In total, 718 CBTS were included, with a median follow-up time of 7.9 years. Overall, despite the less frequent use of radiotherapy (RT) in infants, no differences in the prevalence of HPD were found between the three groups. RT (OR: 16.44; 95% CI: 8.93-30.27), suprasellar tumor location (OR: 44.76; 95% CI: 19.00-105.49), and younger age (OR: 1.11; 95% CI: 1.05-1.18) were associated with HP dysfunction. Infant-BTS and toddler-BTS showed more weight gain (P < 0.0001) and smaller height SDS (P = 0.001) during follow-up. In non-irradiated CBTS, infant-BTS and toddler-BTS were significantly more frequently diagnosed with TSH-, ACTH-, and ADH deficiency, compared to older-BTS. Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than older children. These results emphasize the importance of special infant and toddler brain tumor treatment protocols and the need for endocrine surveillance in children treated for a brain tumor at a young age.

EPIDEMIOLOGICAL PATTERNS OF PAEDIATRIC BRAIN TUMORS IN COIMBATORE

Background: Tumors of the nervous system are the second most common childhood tumors after leukemia,constituting approximately 35% of all childhood malignancies and remain the leading cause of cancer related deaths in children. In India,in the absence of a comprehensive population based national cancer registry,we depend on local hospital based registries for assessing the incidence of pediatric brain tumor.Hence,more and more institutional data are required to assess the actual disease load in India. Objective: The main objective of the present study is to assess the epidemiological patterns of brain tumors in children presenting in CMCH. Materials and Methods: Data regarding age,gender,topography and histopathology of 22 pediatric patients (0-18years)with brain tumors operated inCMCH over a period of 5 years(January 2015 to December 2019)was collected retrospectively and analysed. The results obtained were compared with available Indiandata and western literature. Results: Of 22 cases, males(63.6%) outnumbered females. In the present study, the most common anatomical site for brain tumors was cerebellum(45.5%) followed by cerebral hemispheres(36.2%), ventricles(13.6%) and sellar region(4.5%). The present study showed that Infratentorial tumors were more common (54.5%) as compared to Supratentorial tumors (45.5%).Thepresent study revealed that astrocytoma(36.4%) is the most common brain tumor in childhood. other common tumors include medulloblastoma(27.2%), followed by ependymoma(13.6%), oligodendroglioma(9%),pineal gland tumor(4.5%),craniopharyngioma(4.5%) and meningeal tumor(4.5%). Conclusion: From the present series, we conclude that, the frequencies of major histologic types of brain tumors found in the study do not differ substantially from that found in other developed and developing countries. Medulloblastomas and astrocytomas, which form the major histologic types in pediatric patients need special attention.

Late effects care for childhood brain Tumor Survivors: A Quality-Improvement Initiative

Childhood and adolescent brain tumor survivors are at risk for long-term consequences of therapy. We reviewed adherence to long-term follow-up (LTFU) guidelines, assessed provider perspectives, and studied the needs, experience and quality of life (QOL) of pediatric malignant brain tumor survivors in the McMaster Children’s Hospital Neuro-Oncology clinic. LTFU areas for improvement were evaluated using an anonymous health provider needs assessment questionnaire. The Cancer Care Experience Questionnaire (CCEQ), Cancer Worry Scale (CWS), Self-Management Skills Scale (SMSS), and PedsQL measured parents/patients’ needs and QOL. Individual care plans were based on the Children’s Oncology Group (COG) LTFU guidelines. Based on 17 responses, staff perceived areas for improvement included: increased multi-disciplinary participation, improved patient education and increased surveillance for therapy-related late effects. Thirty-two families participated, most felt they received high-quality care. Mean cancer worry scores were low (71.8 (± 28.4)). Survivors reported limited self-management skills (58.5 (±18.2)), requiring support with medical needs and activities of daily living. Overall median QOL scores were ‘good’ (parental report 72.3 (±17.7), survivor 68.2 (±16.6)). Utilizing survivorship guidelines and assessments from patients, caregivers and health providers, we implemented improvements in our provision of neuro-oncology survivorship care. Lessons learned may assist other LTFU programs.

Exploring Evidence of Fatigue in Survivors of Pediatric Brain Tumors

Background: As the number of survivors of childhood brain tumor increase, fatigue is increasingly recognized as a long-term correlate of survivorship. Objective: To systematically evaluate the evidence for fatigue in pediatric brain tumor survivors. Method: A systematic search using EMBASE, Medline, and PsycINFO identified 20 papers meeting the inclusion criteria. Result: Nineteen of the 20 studies reviewed showed conclusive evidence of fatigue in survivors of pediatric brain tumor. This review found that the construct of fatigue was poorly defined throughout, with early onset fatigue associated with the physical effects of treatment and later emergent fatigue associated with long-term cognitive impairment not distinguished. Conclusion: Poor construct validity reduces the generalizability of the data and its utility in developing effective interventions. Current research does not provide a sound basis for developing effective management and rehabilitation plans and fails to support children who have survived brain tumor. Implications for Practice: The nebulous definition and imprecise measurement of posttumor fatigue leaves survivors without a clear diagnosis of impairment, and, in the case of some regions, access to treatment. Further research built on a well-defined construct offers the potential to improve the quality of life of pediatric brain tumor survivors. What is Foundational: Despite the significant impact of “fatigue” on cancer survivorship, much of the research available is based upon a poorly defined construct. This paper is the first to question the utility of this all-encompassing construct and to call for further research that identifies the fatigue experience in different subgroups of brain tumor survivors.

Childhood head trauma and the risk of childhood brain tumours: A case-control study in Ontario, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population-based and hospital-based case-control study of children 0 to 15 years with newly diagnosed CBTs from 1997 to 2003 recruited across Ontario through paediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, or head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research.

Sleep disturbances in craniopharyngioma: a challenging diagnosis

Craniopharyngiomas are rare solid or mixed solid and cystic tumors that arise from Rathke’s pouch remnants along the pituitary-hypothalamic axis, from the sella turcica to the brain third ventricle. Both the tumor and its treatment can lead to significant neurological and endocrinological complications. Due to the essential role of the hypothalamus in the complex neurophysiologic process of sleep, tumors involving the hypothalamic area may be responsible for disturbances in sleep–wake regulation with alterations in the circadian rhythm, sleep fragmentation, and increased daytime sleepiness. We report two cases of patients with craniopharyngioma, who came to our attention due to the occurrence of episodes characterized by psychomotor slowing and afinalistic limb movements, temporal and spatial disorientation, psychomotor agitation, and oneiric stupor like episodes. A comprehensive clinical data collection and a targeted diagnostic work-up led to a diagnosis of severe sleep disorder characterized by hypersomnia, altered sleep–wake rhythm, and sleep-related breathing disorder. In addition, the polysomnography revealed peculiar alterations in the sleep structure. The diagnostic work-up lead to an accurate differential diagnosis between epileptic seizures and episodes expressions of sleep disturbances. These clinical features can be challenging to diagnose and can lead to misdiagnosis and inappropriate treatment. Diagnosis of sleep disorders is crucial, considering the impact of sleep on general health, cognition, and neuropsychological functioning. These findings support the need to incorporate a comprehensive sleep evaluation in childhood brain tumor involving the suprasellar/hypothalamic region.

OS10.6.A Supportive care needs of TYA childhood brain tumour survivors and their caregivers: a mixed methods study

Abstract BACKGROUND Childhood brain tumour survivors and their family caregivers can experience many late effects of treatment including social, cognitive and physical issues. Yet, the supportive care needs of survivors, now teenagers and young adults (TYAs), and their caregivers population are largely unknown. We aimed to gain an in-depth understanding of this populations’ supportive care needs. MATERIAL AND METHODS This study used a convergent mixed methods design including quantitative (survey) and qualitative data (in-depth semi-structured interviews). Participants were recruited from long-term follow-up clinics (in three NHS Trusts in England) and online. Participants included childhood brain tumour survivors, at least five years from diagnosis, currently aged 13–30 and their primary caregivers. The results from quantitative and qualitative data were integrated using a Joint Display Table. RESULTS 136 eligible survivors and caregivers (78 survivors/58 caregivers) were approached to take part in the survey. In total, 112 participants (69 survivors/43 caregivers) completed the survey. A further 22 participants took part in face-to-face semi-structured interviews (11 survivors/11 caregivers). The integrated findings indicate that both survivors and caregivers have unmet needs many years after diagnosis. TYA survivors specifically had high unmet needs in relation to their psychological health, social lives (including romantic relationships), employment, and independence. Caregivers experienced even more unmet needs - including regarding their own psychological well-being and survivors’ financial issues. Survivors further from diagnosis, unemployed survivors and single caregivers were more likely to report unmet needs. Barriers preventing survivors and caregivers accessing supportive services were highlighted, including (but not exclusive to) families not being aware of support available, location of services, and accessibility to information/support. CONCLUSION This research provides leads to improving supportive care and long-term follow-up services. Understanding unmet needs and recognising what services are required is critical to improving survivor and caregiver quality of long-term survival.

P06.03 Child, parent, and clinician selection of patient-reported outcome measures to use in pediatric neuro-oncology outpatient follow-up clinics

Abstract BACKGROUND Survivors of childhood brain tumours are at risk of poor health-related quality of life (HRQoL). Appropriate and relevant measures can be used to monitor HRQoL so that timely interventions may be made for issues thus identified. We had previously selected patient-reported outcome measures (PROMs) with good psychometric properties that had emerged as well-suited for this use in two systematic reviews. The aim of the present study was to ascertain the views of families regarding the suitability of the selected measures for use in paediatric neuro-oncology follow-up clinics. These views were then used to inform the choice of PROMs for use on the KLIK PROM portal, a website designed to gather HRQoL information from families. MATERIAL AND METHODS As part of the PROMOTE study, we used a multi-centre, multi-informant, cross-sectional, qualitative methods research design. Using ‘think aloud’ audio-recorded interviews, children aged 8–17 years diagnosed within the previous five years with a brain tumour, off treatment and receiving outpatient care, and their parents, were shown a total of nine PROMs and asked to express their views on which they preferred. Detailed notes were made of all audio-recordings by two independent researchers. The final choice of PROMs to be included on the KLIK PROM portal was agreed through discussion of the PROMs selected by families with an expert panel of clinicians, researchers, and parent representatives. RESULTS 16 children and 17 parents participated and of these 2 children and 2 parents did not express a preference. The Pediatric Quality of Life Inventory (PedsQL) Core module was the most popular among the children and parents with 7/14 (50%) of children selecting it as either their 1st or 2nd choice citing that they liked the questions and felt them to be most relevant to them, and 8/15 (53%) of parents citing that it was easy, quick and simple, the wording was easy, and they liked the questions about emotional, social, and school functioning. The least popular questionnaires, with no participants selecting them as first choices, were the Kidscreen-10 and the Health Utilities Index. The latter 2 were selected only as 2nd or lower choices by 1 child and 3 parents respectively. CONCLUSION The PROMs that were finally selected for the KLIK PROM portal were the parent- and child-report PedsQL-Core measures of HRQoL due to their good psychometric properties, family and clinician preference and perceived relevance to follow-up care, and for clinical utility on the KLIK PROM portal.

Recent Advances in ALK2 Inhibitors.

Activin receptor-like kinase-2 (ALK2) is a type I bone morphogenetic protein (BMP) receptor which has a role in biological processes that control the development of bone, heart, brain, and other tissue. Gain of function mutations in ALK2 have been identified in fibrodysplasia ossificans progressiva (FOP) and the childhood brain tumor, diffuse intrinsic pontine glioma (DIPG), which has given focus to the development of ALK2 inhibitors as targeted treatments. This review covers the structural features of ALK2 inhibitors which contribute to their ALK2 potency and selectivity, and the pharmacokinetic or in vivo efficacy data available to demonstrate their suitability for treating a peripheral or CNS disease.

Rare cases of medulloblastoma with hypermutation.

BackgroundMedulloblastoma is the most common malignant brain tumor of childhood and is considered a tumor with low mutational burden (~1 Mut/Mb). Therefore, though the medulloblastoma genomes have been extensively characterized in literature, reports on potential hypermutations and underlying mutagenic processes in medulloblastomas are limited.AimIn this report, we studied the landscape of mutational burden in primary and recurrent medulloblastoma. Furthermore, we wanted to understand the differences in underlying mutagenic mechanisms in medulloblastoma with low and high mutational burdens.MethodsFifty‐three primary and recurrent medulloblastoma genomic sequence were downloaded from the European Genome Archive as BAM files. Thirty‐three cases were obtained from formalin‐fixed paraffin‐embedded tissues from pathology diagnostic archives of Spectrum Health and Cooperative Human Tissue Network. Somatic mutations were called using Mutect2, following best practices guidelines for Genome Analysis Toolkit V4. Mutational signatures were analyzed using deconstructSigs.ResultsWe identified nine medulloblastoma cases with high mutational burden (>5 Mut/Mb). Of them, five cases met the criteria of hypermutation (>10Mut/Mb), two of the five tumors had canonical mutations in the POLE proof‐reading domain, where a large proportion of mutations in these tumor genomes contributed to signature 10. The hypermutated cases also demonstrated mutational signatures 14, 15, and 21, indicating the role of mis match repair deficiency in their mutagenesis. Of the four known molecular subgroups in medulloblastoma–SHH, WNT, Group 3, and Group 4—both the POLE‐mutated cases belonged to the SHH subgroup. This report identifies rare cases of hypermutation in medulloblastoma driven by defects in DNA repair mechanisms.ConclusionHypermutation in medulloblastoma can impact therapeutic decisions, especially at recurrence in otherwise fatal high risk SHH‐medulloblastomas. A defect in DNA repair leading to SHH ‐medulloblastoma is yet another important mechanism that should be further investigated in the genesis of these tumors. Therefore, this report provides important scientific and clinical rationale for future research looking for incidence of hypermutation in large cohorts of medulloblastoma patients.

Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma

Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.

Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.

Sonic hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors commonly cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that Nestin Cre-driven conditional knock-out (CKO) of a Shh pathway repressor-Rab23 in the mouse brain of both genders caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly, Rab23-depleted GCPs exhibited upregulated basal level of Shh pathway activities despite showing an abnormal ciliogenesis of primary cilia. In line with the compromised ciliation, Rab23-depleted GCPs were desensitized against Hh pathway activity stimulations by Shh ligand and Smoothened (Smo) agonist-SAG, and exhibited attenuated stimulation of Smo-localization on the primary cilium in response to SAG. These results implicate multidimensional actions of Rab23 on Hh signaling cascade. Rab23 represses the basal level of Shh signaling, while facilitating primary cilium-dependent extrinsic Shh signaling activation. Collectively, our findings unravel instrumental roles of Rab23 in GCP proliferation and ciliogenesis. Furthermore, Rab23's potentiation of Shh signaling pathway through the primary cilium and Smo suggests a potential new therapeutic strategy for Smo/primary cilium-driven medulloblastoma.SIGNIFICANCE STATEMENT Primary cilium and Sonic hedgehog (Shh) signaling are known to regulate granule cell precursor (GCP) proliferation. Aberrant overactivation of Shh signaling pathway ectopically increases GCP proliferation and causes malignant childhood tumor called medulloblastoma. However, the genetic and molecular regulatory cascade of GCP tumorigenesis remains incompletely understood. Our finding uncovers Rab23 as a novel regulator of hedgehog (Hh) signaling pathway activity and cell proliferation in GCP. Intriguingly, we demonstrated that Rab23 confers dual functions in regulating Shh signaling; it potentiates primary cilium and Shh/Smoothened (Smo)-dependent signaling activation, while antagonizes basal level Hh activity. Our data present a previously underappreciated aspect of Rab23 in mediating extrinsic Shh signaling upstream of Smo. This study sheds new light on the mechanistic insights underpinning Shh signaling-mediated GCP proliferation and tumorigenesis.

Reimagining pilocytic astrocytomas in the context of pediatric low-grade gliomas.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pLGGs and an incomplete understanding of their molecular and cellular pathogenesis. While large-scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA), in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.

Medulloblastoma: A Common Pediatric Tumor: Experience of a Tertiary Care Cancer Center of Bangladesh.

Background: Medulloblastoma is a common malignancy in the paediatric population, accounting for 25% of all childhood brain tumors. The increasing magnitude of childhood cancer has become a threatening problem in developing countries like Bangladesh. But we have not enough data regarding the diseases of the children of Bangladesh. There is no literature available to shed light on Clinico-pathological types, diagnostic facilities and treatment patterns of this childhood cancer in our population. So this study is an opportunity to have experience about pediatric medulloblastoma of Bangladesh.&#x0D; Methods: The study conducted from January 2014 to December 2018 at National Institute of Cancer Research and Hospital (NICRH). Data are collected from admitted children aged under 18 years in the department of Pa ediatric Hematology and Oncology (PHO) and confirmed by histopathology and/or immunohistochemistry after collection of tissues from pathological lab. The data were obtained from statistical analysis by PSPP software&#x0D; Results: During 2014 to 2018 total diagnosed cases of childhood meduloblastoma were 57 but data were analyzed from only 52 patients. Male female ratio was 1.9:1. Median age of our patients was 6.12 years. Most common clinical features at preoperative assessment were vomiting, headache, fever, convulsion, eye/vision involvement. Hydrocephalus was Present in 48 (92%) cases. Radiologically distal metastasis were found in 2 (3.85%) cases. Tumor resection was performed in all patients and total removal in 56.80% (N-25), gross total removal 25% (N-11), and partial removal 18.20% (N-8) and in 8 cases resection type were not elicited. Pathological grading were recorded in 52 patients , where all were Grade-IV (100 %).Within 22 months of follow up time absconded patients were 44.4%, partially treated cases are 9.6% with high death rate (23%). Regular treated cases with good outcome were 23%.&#x0D; Conclusions: Medulloblastoma is a challenging condition for neurosurgeon, radiotherapist and oncologists of Bangladesh. We have to reduce the abandon cases; review the risk stratification by using molecular profile and enhance the support service to improve the survival rate. RT- radiotherapy, CT-Chemotherapy, UB-Urinary Bladder. All patients underwent preoperative Computed tomography (CT) or Magnetic resonance imaging (MRI) of head (Fig.1) But 90.4% (N-47) MRI/CT reports were able to given a proposed diagnosis like medulloblastoma or ependymoma, 5.7% (N-3) diagnosed as space occupying lesion (SOL) and 2 (3.9%) case didn’t make any remarks regarding the brain lesion (Table-3).Tumors arise from midline (Vermis) were 71.15% (N-37 ) and from hemisphere were 28.85% (N-15).&#x0D; Bang. J Neurosurgery 2021; 10(2): 154-162

Functional Connectivity Networks and Their Recruitment During Working Memory Tasks in Adult Survivors of Childhood Brain Tumors.

Background: Assessments of functional connectivity of default mode network (DMN) and positive task-related networks (TRNs) using independent component analysis (ICA) may help describe long-term effects of childhood brain tumors and adjuvant treatments. Methods: Aiming to identify potential neuronal markers that may aid in prognosis and inform interventions to optimize outcomes, this study used ICA to evaluate the presence of functional connectivity networks and their recruitment during a letter n-back task in 23 adult survivors of childhood posterior fossa tumors (9 low grade, 14 high grade) at least 5 years past diagnosis compared with 40 age- and sex-matched healthy peers. Results: DMN components generally demonstrated increasing disengagement as task difficulty increased, and relationships between effective DMN disengagement and improved performance were observed in healthy controls (HCs). Low-grade brain tumor survivors (LGS) demonstrated unique patterns in DMN recruitment that suggested increased involvement of the medial prefrontal cortex in LGS during tasks. TRN components generally demonstrated increasing engagement, which was related to improved task performance in HCs for one executive control network (ECN) component. High-grade brain tumor survivors (HGS) demonstrated distinct challenges recruiting an ECN component at more difficult task levels and showed a relationship between recruitment of another ECN component and task performance, indicating a potential compensatory mechanism for some HGS. Conclusions: Findings suggest the importance of cognitive intervention in both survivor groups and the necessity to track LGS despite their cognitive abilities often resembling those of their healthy peers. Impact statement Distinct functional connectivity patterns were identified between both adult survivor of childhood brain tumor groups and peers during attention and working memory tasks, reflecting different damage and recovery from treatment. Survivors of low-grade tumors demonstrated unique patterns of recruitment of default mode network components in the context of similar cognitive abilities, whereas survivors of high-grade tumors demonstrated poorer cognitive abilities and may be utilizing compensatory executive control network components in the face of challenging tasks. Long-term clinical follow-up and cognitive remediation is warranted for both groups, including low grade cerebellar tumor patients who have traditionally not been monitored as closely.