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Perivascular spaces (PVS) are fluid filled compartments surrounding the small blood vessels in the brain. The impact of radiotherapy and chemotherapy on PVS remains unclear. The aim of this study is to investigate treatment effects of radiotherapy and chemotherapy at four time points (TPs) in pediatric medulloblastoma (MB) patients. We examined 778 scans from 241 MB patients at baseline (0M), after 12 weeks (about 3 months) of radiotherapy and rest (3M), after chemotherapy completion (12M), and a follow-up (FollowUp) at 18- or 21-months post-baseline. PVS was segmented by applying Frangi filter on the white matter regions on T1 weighted images acquired at 3T Siemens MRI scanner using MPRAGE. PVS volume and ratio, defined as the ratio of PVS volume to the white matter volume, were measured at the four TPs. The data was first statistically analyzed using a full model where all data were included, then a paired model, which included only patients who completed consecutive measurements under the same anesthesia and shunt conditions. Both the full model and paired model showed that PVS (including ratio and volume) increased at 3M post-radiotherapy compared to baseline. During chemotherapy, PVS decreased significantly from 3M to 12M. Subsequently, from 12M to FollowUp, PVS increased again. MRI exams under anesthesia exhibited significantly lower PVS than those without anesthesia. Patients who had undergone a shunt procedure exhibited a significantly reduced PVS compared to those who had not undergone the procedure. We concluded that craniospinal irradiation led to an elevated PVS. Conversely, chemotherapy or time post-irradiation decreased PVS. Anesthesia and shunt procedures can also influence perivascular space ratio or volume., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Central nervous system (CNS) cancers are responsible for high rates of morbidity and mortality worldwide. Malignant CNS tumors such as adult Glioblastoma (GBM) and pediatric embryonal CNS tumors such as medulloblastoma (MED) and atypical teratoid rhabdoid tumors (ATRT) present relevant therapeutic challenges due to the lack of response to classic treatment regimens with radio and chemotherapy. Recent findings on the Zika virus' (ZIKV) ability to infect and kill CNS neoplastic cells draw attention to the virus' oncolytic potential. Studies demonstrating the safety of using ZIKV for treating malignant CNS tumors, enabling the translation of this approach to clinical trials, are scarce in the literature. Here we developed a co-culture model of mature human cerebral organoids assembled with GBM, MED or ATRT tumor cells and used these assembloids to test ZIKV oncolytic effect, replication potential and preferential targeting between normal and cancer cells. Our hybrid co-culture models allowed the tracking of tumor cell growth and invasion in cerebral organoids. ZIKV replication and ensuing accumulation in the culture medium was higher in organoids co-cultured with tumor cells than in isolated control organoids without tumor cells. ZIKV infection led to a significant reduction in tumor cell proportion in organoids with GBM and MED cells, but not with ATRT. Tumoroids (3D cultures of tumor cells alone) were efficiently infected by ZIKV. Interestingly, ZIKV rapidly replicated in GBM, MED, and ATRT tumoroids reaching significantly higher viral RNA accumulation levels than co-cultures. Moreover, ZIKV infection reduced viable cells number in MED and ATRT tumoroids but not in GBM tumoroids. Altogether, our findings indicate that ZIKV has greater replication rates in aggressive CNS tumor cells than in normal human cells comprising cerebral organoids. However, such higher ZIKV replication in tumor cells does not necessarily parallels oncolytic effects, suggesting cellular intrinsic and extrinsic factors mediating tumor cell death by ZIKV.

This work aimed to demonstrate the therapeutic effects of tumor microenvironment-responsive nanotherapeutic drugs targeting PSD95/Discs-large/ZO-1 domain (PDZ)-binding-kinase (PBK) in medulloblastoma Daoy and ONS-76 cells. The objective was to provide critical theoretical and practical foundations for the clinical adoption of tumor microenvironment-responsive nanotherapeutic drugs targeting PBK. The rabies virus glycoprotein (RVG) was utilized as a specific targeting molecule to form a tumor microenvironment-responsive nanocomplex, HPAA/RVG/PBK-siRNA, which incorporated glutathione (GSH) as a microenvironment stimulus factor within a hyperbranched polymer polyamide amine (HPAA). This nanocomplex also carried PBK-small interfering RNA (siRNA) for targeted PBK therapy. Characterization of HPAA, maleimide-polyethylene glycol-N-succinyl ester (MAL-PEG-NHS), HPAA-PEG, RVG, HPAA-RVG, and HPAA/RVG/PBK-siRNA was conducted using nuclear magnetic resonance spectroscopy, high-performance liquid chromatography (HPLC), dynamic light scattering, and transmission electron microscopy (TEM). Flow cytometry was employed to assess endocytosis and cell transfection of HPAA-RVG and HPAA/RVG/PBK-siRNA in Daoy and ONS-76 cells. The two cell lines were treated with HPAA/RVG/PBK-siRNA (HPAA/siRNA group), methoxy-PEG polyethylenimine (PEI-25k)/PBK-siRNA (PEI group), HPAA/RVG nanocarriers without PBK-siRNA (HPAA/RVG group), Dharmacon™ non-targeting siRNA (shNTC group), PBK-siRNA (Control group 1), AChR inhibitor (Control group 2), and GSH inhibitor (Control group 3), and compared with the control group (medium without any substances). Western blot analysis validated PBK expression levels (ELs) in various cell groups. Additionally, cell viability and proliferation were evaluated using methyl tetrazolium (MTT) assays and 5-Bromo-2'-deoxyuridine (BrdU) incorporation assays. The results revealed proton absorption peaks for HPAA at 2.78 ppm, 3.21 ppm, and 3.49 ppm, while RVG and HPAA-RVG exhibited characteristic absorption peaks at 23.653 min and 23.584 min, respectively, with peak areas of 4,856.6 and 6,927.3 for RVG. The nanoparticle sizes were 50-100 nm for HPAA-RVG and 100 nm for HPAA/RVG/PBK-siRNA, displaying spherical morphology and uniform size distribution. The average potential of HPAA-PEG was lower than that of HPAA ( P <0.05), and HPAA-RVG showed dramatically lower potential than HPAA ( P <0.001). At 8 hours, Daoy cells displayed higher endocytosis rates versus ONS-76 cells ( P <0.05). The transfection rates of HPAA-RVG in both ONS-76 and Daoy cells were higher than those of HPAA, with Daoy cells showing higher transfection rates than HPAA ( P <0.05). Under HPAA-RVG treatment, AChR levels in ONS-76 cells were significantly lower than those in Daoy cells ( P < 0.05). Compared to the control group, the PBK protein expression levels, cell survival rates, and the number of cells in the proliferative phase were significantly reduced in Control group 1, the PEI group, and the HPAA/siRNA group in both ONS-76 and Daoy cells, with the ONS-76 cells in the HPAA/siRNA group showing the lowest values among these groups ( P < 0.05). In summary, the findings indicated that the tumor microenvironment-responsive nanocomposite HPAA/RVG/PBK-siRNA selectively inhibited PBK expression in Daoy medulloblastoma cells, showcasing potential applicability in medulloblastoma therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Purpose: The Korean Society of Pediatric Neuro-Oncology (KSPNO) conducted treatment strategies for children with medulloblastoma (MB) by using alkylating agents for maintenance chemotherapy or tandem high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) according to the risk stratification. The purpose of the study was to assess treatment outcomes and complications based on risk-adapted treatment and HDC., Materials and Methods: Fifty-nine patients diagnosed with MB were enrolled in this study. Patients in the standard-risk (SR) group received radiotherapy (RT) after surgery and chemotherapy using the KSPNO M051 regimen. Patients in the high-risk (HR) group received two and four chemotherapy cycles according to the KSPNO S081 protocol before and after reduced RT for age following surgery and two cycles of tandem HDC with ASCR consolidation treatment., Results: In the SR group, 24 patients showed 5-year event-free survival (EFS) and overall survival (OS) estimates of 86.7% (95% confidence interval [CI], 73.6 to 100) and 95.8% (95% CI, 88.2 to 100), respectively. In the HR group, more infectious complications and mortality occurred during the second HDC than during the first. In the HR group, the 5-year EFS and OS estimates were 65.5% (95% CI, 51.4 to 83.4) and 72.3% (95% CI, 58.4 to 89.6), respectively., Conclusion: High intensity of alkylating agents for SR resulted in similar outcomes but with a high incidence of hematologic toxicity. Tandem HDC with ASCR for HR induced favorable EFS and OS estimates compared to those reported previously. However, infectious complications and treatment-related mortalities suggest that a reduced chemotherapy dose is necessary, especially for the second HDC.

The posterior fossa is a limited compartment therefore lesions compressing its structures can result in devastating outcomes. It can cause significant neurological deficit due to mass effect on critical structures and hydrocephalus. Due to the nature of the infratentorial region, urgent surgical intervention is often the first-line option. Surgical neuro-oncologists guide patients and caregivers through the course of this disease and to inform them about the various options for management and long-term outcome optimisation. There is currently conflicting data; however, institutional experiences can guide us towards achieving improvements in surgical outcomes and quality of life. Advances in molecular classifications coupled with highdose radiation treatment improve our capacity for improving overall survival in these patients. Common childhood tumours are ependymomas, medulloblastomas, and juvenile pilocytic astrocytomas, while adults often present with metastases, and less commonly, cerebellar haemangioblastomas and gliomas. This paper outlines management strategies with consideration for multidisciplinary care and resourcelimited settings.

The management of medulloblastoma, a pediatric brain tumor, has evolved significantly with the advent of genomic subgrouping, yet morbidity and mortality remain high in LMICs like Pakistan due to inadequate multidisciplinary care infrastructure. This paper aims to establish evidence-based guidelines tailored to the constraints of such countries. An expert panel comprising neuro-oncologists, neurosurgeons, radiologists, radiation oncologists, neuropathologists, and pediatricians collaborated to develop these guidelines, considering the specific challenges of pediatric brain tumor care in Pakistan. The recommendations cover various aspects of medulloblastoma treatment, including pre-surgical workup, neurosurgery, neuropathology, chemotherapy, radiation therapy, and supportive care. They offer both minimum required and additional optional protocols for more advanced centers, ensuring comprehensive patient management with attention to complications and complexities encountered in Pakistan. The paper's consensus guidelines strive for uniformity in healthcare delivery and address significant gaps in diagnosis, treatment, and follow-up of pediatric medulloblastoma patients.

Background: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients., Methods: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated., Results: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH&#95;3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively)., Conclusions: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Non-WNT/non-SHH medulloblastoma (MB) is one of the subtypes with the highest genetic heterogeneity in MB, and its current treatment strategies have unsatisfactory results and significant side effects. As a member of the centromere protein (CENP) family, centromeric protein E (CENPE) is a microtubule plus-end-directed kinetochore protein. Heterozygous mutations in CENPE can leads to primary microcephaly syndrome. It has been reported that CENPE is upregulated in MB, but its role in MB development is still unknown., Methods: We downloaded the relevant RNA seq data and matched clinical information from the GEO database. Bioinformatics analysis includes differential gene expression analysis, Kaplan-Meier survival analysis, nomogram analysis, ROC curve analysis, immune cell infiltration analysis, and gene function enrichment analysis. Moreover, the effects of CENPE expression on cell proliferation, cell cycle, and p53 signaling pathway of non-WNT/non-SHH MB were validated using CENPE specific siRNA in vitro experiments., Results: Compared with normal tissues, CENPE was highly expressed in MB tissues and served as an independent prognostic factor for survival in non-WNT/non-SHH MB patients. The nomogram analysis and ROC curve further confirmed these findings. At the same time, immune cell infiltration analysis showed that CENPE may participate in the immune response and tumor microenvironment (TME) of non-WNT/non-SHH MB. In addition, gene enrichment analysis showed that CENPE was closely related to the cell cycle and p53 pathway in non-WNT/non-SHH MB. In vitro experimental validation showed that knockdown of CENPE inhibited cell proliferation by activating the p53 signaling pathway and blocking the cell cycle., Conclusion: The expression of CENPE in non-WNT/non-SHH MB was positively correlated with poor prognosis. CENPE may affect tumor progression by regulating cell cycle, p53 pathway, and immune infiltration. Hence, CENPE is highly likely a novel biomarker and potential therapeutic target for non-WNT/non-SHH MB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fang, Zhang, Lin, Sun, Wen, Sheng and Lin.)

Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the four distinct molecular subgroups, Group 3 and 4 have the poorest patient outcomes due to the aggressive nature of the tumor and propensity to metastasize and recur post therapy. The toxicity of the SOC and lack of response in specific subtypes to the SOC underscores the urgent need for developing and translating novel treatment options including immunotherapies. To identify differentially enriched surface proteins that could be evaluated for potential future immunotherapeutic interventions, we leveraged N-glycocapture surfaceome profiling on Group 3 MB cells from primary tumor, through therapy, to recurrence using our established therapy-adapted patient derived xenograft model. Integrin 𝛼5 (ITGA5) was one of the most differentially enriched targets found at recurrence when compared to engraftment and untreated timepoints. In addition to being enriched at recurrence, shRNA-mediated knockdown and small molecule inhibition of ITGA5 have resulted in marked decrease in proliferation and self-renewal in vitro and demonstrated a survival advantage in vivo. Together, our data highlights the value of dynamic profiling of cells as they evolve through therapy and the identification of ITGA5 as a promising therapeutic target for recurrent Group 3 MB., (© 2023. The Author(s).)

Introduction: Medulloblastoma is the most common and lethal pediatric malignant brain tumor. It comprises four main molecular subgroups: WNT-activated, SHH-activated, Group 3, and Group 4. Medulloblastoma treatment is surgical resection, craniospinal radiation, and chemotherapy. However, many patients do not respond to therapy, and most suffer severe side effects. Cancer immunotherapy targeting immune checkpoints (IC) (PD-1, PD-L1, and CTLA4) has been getting disappointing outcomes in brain tumors. Nevertheless, other less explored immune checkpoints may be promising candidates for medulloblastoma therapy., Objectives: In the present study, we aimed to characterize the expression profile of 19 immune checkpoints in medulloblastoma., Methods: We analyzed 88 formalin-fixed paraffin-embedded medulloblastomas previously classified for each molecular subgroup and three non-tumoral brain tissue. mRNA levels of 19 immune checkpoint-related genes were quantified using the nCounter (PanCancer Immune Profiling Panel) assay. Further in silico analysis was performed in two larger public microarray datasets, one of which enabled comparisons between tumoral and non-tumoral tissues. Immunohistochemistry of PD-L1 was performed in a subset of cases. Microsatellite instability was also molecularly analyzed., Results: We observed an absence of expression of the canonic ICs, namely PDCD1 (PD-1), CD274 (PD-L1), and CTLA4 , as well as CD80, CD86, BTLA, IDO1, CD48, TNFSF14, CD160, CEACAM1 , and CD244. PD-L1 protein expression was also practically absent. We found higher mRNA levels of CD24, CD47 , CD276 (B7-H3), and PVR , and lower mRNA levels of HAVCR2 , LAG3 , and TIGIT genes, with significant differences across the four molecular subgroups. Compared to the non-tumor tissues, the expression levels of CD276 in all subgroups and CD24 in SHH, Group 3, and Group 4 subgroups are significantly higher. The in silico analysis confirmed the expression profile found in the Brazilian cohort, including the lower/absent expression of the canonic ICs. Moreover, it confirmed the overexpression of CD24 and CD276 in medulloblastomas compared with the non-tumor tissue. Additionally, CD276 and CD24 high levels were associated with worse survival., Conclusion: These results highlight the low or absence of mRNA levels of the canonic targetable ICs in medulloblastomas. Importantly, the analysis revealed overexpression of CD24 and CD276 , which can constitute prognostic biomarkers and attractive immunotherapy targets for medulloblastomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marques, Moreno, da Silva, Leal, de Paula, Santana, Teixeira, Saggioro, Neder, Junior, Mançano and Reis.)

Aims: To assess the clinical, pathological and molecular characteristics (Sonic hedgehog and group 3/4 molecular subtypes expression) and treatment modalities for infantile medulloblastoma in correlation with outcomes. Materials & methods: A retrospective study of 86 medulloblastoma patients (≤3 years) was conducted. M0 patients <2.5 years received four cycles of chemotherapy followed by focal radiotherapy (FRT) and chemotherapy. Between 2007 and 2015, Metastatic patients <2.5 years received craniospinal irradiation (CSI) after the end of chemotherapy. After 2015, metastatic patients <2.5 years received CSI postinduction. Results: The hazard ratio for death was significantly higher in the FRT (HR = 2.8) group compared with the CSI group (hazard ratio = 1). Metastatic disease significantly affected the overall survival of the Sonic hedgehog group and the overall survival and event-free survival of group 3/4. Conclusion: Metastatic disease had a significant impact on outcomes. FRT is not effective in treating infantile medulloblastoma.

Medulloblastoma (MB) is the most common malignant central nervous system tumor of childhood, comprising a heterogenous group of tumors each with distinct biology, clinical behavior, and prognosis. Long-term survival remains unacceptable, and those who do survive face high late mortality risk, new chronic treatment-related medical conditions, neurocognitive impairments, and poor health-related quality of life. Up-front treatment strategies now integrate molecular subgrouping with standard clinico-radiological factors to more actually risk stratify newly-diagnosed patients. To what extent this new stratification will lead to improvements in treatment outcome will be determined in the coming years. In parallel, discovery and appreciation for medulloblastoma's inter- and intra-tumoral heterogeneity continues growing. Clinical trials treating relapsed disease now encompass precision medicine, epigenetic modification, and immune therapy approaches. The Pacific Pediatric Neuro-Oncology (PNOC) Medulloblastoma Working Group is committed to developing clinical trials based on these evolving therapeutic strategies and supports translational efforts by PNOC researchers and the multi-stakeholder medulloblastoma community at large., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Medulloblastoma is the commonest embryonal brain tumor in children. It has shown improved outcomes with combined modality treatment. We aimed to study patient characteristics and survival outcomes of patients with this disease across two tertiary care centers in India., Methods: We analyzed data of patients with histological diagnosis of medulloblastoma treated from January 2010 to January 2016. Patient characteristics and follow-up data were retrieved from hospital records. Descriptive statistics were used to describe clinical and pathological characteristics. Overall survival (OS) was calculated from date of diagnosis to death due to any cause. Relapse-free survival (RFS) was calculated from date of diagnosis to occurrence of relapse or death., Result: Out of 26 patients treated, 24 were children and 2 were adults. Median age was 10 years (range = 0.8-22 years). Twenty (76.9%) patients were male. Fifteen (57.7%) patients were stratified as high-risk (HR), rest 11 (42.3%) were categorized as average risk (AR). Histopathology showed classical variety in majority of patients except for 4 (15%) cases, 3 with desmoplastic and 1 with anaplastic subtype. Median follow-up was 49.7 months (range= 4.2-102.5 months). Overall, eight (30.8%) patients relapsed and six (23%) deaths occurred. Five (33.3%) patients in HR category and 3 (27.3%) patients in AR group showed relapse. Median RFS and OS were not yet reached. Five-year RFS was 69.2% whereas five-year OS was 76.9%., Conclusion: This study highlighted patient characteristics and treatment outcomes in Indian patients. With adherence to standard treatment, high remission rates and improvement in mortality rates were achieved.

Critical discoveries over the past two decades have transformed our understanding of medulloblastoma from a single entity into a clinically and biologically heterogeneous disease composed of at least four molecularly distinct subgroups with prognostically and therapeutically relevant genomic signatures. Contemporary clinical trials also have provided valuable insight guiding appropriate treatment strategies. Despite therapeutic and biological advances, medulloblastoma patients across the age spectrum experience tumor- and treatment-related morbidity and mortality. Using an updated risk stratification approach integrating both clinical and molecular features, ongoing research seeks to (1) cautiously reduce therapy and mitigate toxicity in low-average risk patients, and (2) thoughtfully intensify treatment with incorporation of novel, biologically guided agents for patients with high-risk disease. Herein, we review important historical and contemporary studies, discuss management updates, and summarize current knowledge of the biological landscape across unique pediatric, infant, young adult, and relapsed medulloblastoma populations., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Background: Medulloblastoma is a malignant brain tumor that is common in children but very uncommon in adults, especially those older than 40 years, accounting for less than 1% of all primary brain tumors in adults. Although surgery and radiotherapy play an important role treatment of adult medulloblastoma, the use of chemotherapy is controversial. This is the first instance of adult medulloblastoma at the Ocean Road Cancer Institute in Tanzania., Case Description: We report the case of a 51-year-old female of African ethnicity who was diagnosed with high-risk hemispheric posterior cranial fossa medulloblastoma of classic type with World Health Organization central nervous system grade 4 and Chang stage M0. Immunohistochemistry, reticulin stain, and molecular subtyping could not be done because they were not available. She was treated by subtotal posterior cranial fossa tumor resection followed by adjuvant concurrent chemo-craniospinal radiation and adjuvant chemotherapy., Conclusion: Even in adults over 50 years old, medulloblastoma should be included in the differential diagnosis of posterior fossa tumor. Adult medulloblastoma is a very rare and very heterogeneous tumor, but it has a good prognosis. Immunohistochemistry and molecular subclustering are difficult to implement in low-income countries such as Tanzania owing to cost. Treatment of adult medulloblastoma is highly heterogeneous among (and even within) facilities. There is no evidence that the extent of resection enhances survival. While craniospinal radiation therapy improves survival, there is controversy about the role of chemotherapy in managing adult MB., (© 2022. The Author(s).)

Background: Medulloblastoma 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., Aim: In 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., Methods: Fifty-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., Results: We 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., Conclusion: Hypermutation 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., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Medulloblastoma is an aggressive brain tumor that occurs predominantly in children. Despite intensive therapy, many patients die of the disease, and novel therapies are desperately needed. Although immunotherapy has shown promise in many cancers, the low mutational burden, limited infiltration of immune effector cells, and immune-suppressive microenvironment of medulloblastoma have led to the assumption that it is unlikely to respond to immunotherapy. However, emerging evidence is challenging this view. Here we review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medulloblastoma patients and their families., (© 2022 Eisemann and Wechsler-Reya; Published by Cold Spring Harbor Laboratory Press.)

Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc -driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1 -deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1 -deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1 + macrophages, and we show that CD45 high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abbas, George, Ancliffe, Howlett, Jones, Kuchibhotla, Wechsler-Reya, Gottardo and Endersby.)

Purpose: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles or other molecular parameters of high risk for group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an IHC marker as a clinically tractable method for improved medulloblastoma risk stratification., Experimental Design: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three group 3/4 medulloblastoma clinical cohorts ( n = 387) treated with conventional therapies., Results: TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was a predictive indicator of poor response to chemotherapy [HR, 12.66; 95% CI, 3.53-45.40; P < 0.0001], suggesting important implication for therapeutic choices., Conclusions: This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques., (©2021 American Association for Cancer Research.)

Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. Here we develop a proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that aberrant splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors., (© 2021. The Author(s).)

The onset of malignant solid tumors in infants is insidious and difficult to diagnose on time. The purpose of our study is to provide a theoretical basis for clinical diagnosis by retrospective analysis of the data in the past 14 years. Here, we retrospectively collected the clinical data of infants aged 0-12 months with malignant solid tumors in Beijing Tongren Hospital Affiliated to Capital Medical University from May 2005 to May 2019. The epidemiology, clinical characteristics, treatments and prognosis were statistically analyzed. A total of 496 infants (294 males and 202 females) with malignant solid tumors were analyzed. The main period of onset was 1-11 months. The most common tumor was retinoblastoma (RB, 51.8%), followed by hepatoblastoma (HB, 26.6%), neuroblastoma (NB, 10.5%), rhabdomyosarcoma (RMS, 3.4%), malignant renal tumors (3.2%), infantile fibrosarcoma (IFS, 1.6%), malignant teratoma (1.2%), Ewing's sarcoma (ES, 0.8%), medulloblastoma (MB, 0.4%) and inflammatory myofibroblastic tumor (IMT, 0.4%). The median follow-up time was 32 months (range 2-162 months). The 1-year, 3-year, and 5-year overall survival of all patients were 97.3%, 89.2%, and 81.1%, respectively, and event-free survival was 94.7%, 84.8%, and 75.8%, respectively. In conclusion, as a special group, malignant solid tumors in infants are complex, heterogeneous, and relatively rare. The prognosis of RB, HB, NB, RMS, malignant renal tumors, IFS, malignant teratoma, ES, MB, and IMT, were excellent duo to timely diagnosis and rational treatment.

Purpose: Medulloblastoma is composed of four clinically and prognostically distinct molecular subgroups (WNT, SHH, group 3, and group 4). However, the clinical implications of these subgroups in the context of the unique challenges of low- to middle-income countries are rarely reported., Methods: We assembled an institutional cohort of children (3-18 years) diagnosed with medulloblastoma and treated in Jordan between 2003 and 2016. Tumors were subgrouped by NanoString and correlated with clinical and radiologic characteristics., Results: Eighty-eight patients were identified (63% male); median age was 6.9 years (interquartile range 4.8-9.2) and median symptom duration was 6 weeks (interquartile range 4-11). Radiotherapy was implemented as standard-risk in 41 patients (47%) and high-risk in 47 patients (53%). Subgrouping revealed 17 WNT (19%), 22 SHH (25%), 21 group 3 (24%), and 28 group 4 tumors (32%). Median time between craniotomy and radiotherapy was 45 days (17-155); 44% of them > 49 days. Median duration of radiotherapy was 44 days (36-74). Seventy-two patients (82%) received chemotherapy afterward. With a median follow-up of 4.6 years (0.2-14.9), 5-year progression-free survival (PFS) and overall survival were 73.5% and 69.4%, respectively, with no statistically significant survival difference between standard-risk and high-risk patients. Metastasis was significant for overall survival ( P = .011). Patients with SHH and group 4 tumors had very good PFS (83.4% and 87.0%, respectively) and those with group 3 tumors had dismal outcomes (PFS 44.9%), whereas WNT tumors had less-than expected PFS (70.5%). PFS was statistically significant in patients with nonmetastatic tumors receiving radiotherapy ≤ 49 days ( P = .011), particularly group 3 tumors., Conclusion: Patients with SHH and group 4 medulloblastoma had excellent survival comparable with high-income countries. Compliance with treatment protocols and avoiding radiotherapy delays are important in achieving adequate survival in low- to middle-income country settings. Subgroup-driven treatment protocols should be considered in countries with limited resources., Competing Interests: Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers Squibb Vijay RamaswamyHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca CanadaNo other potential conflicts of interest were reported.

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006-2012 and 2013-2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006-2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

Medulloblastoma is a rare tumour in postpubertal patients and adults that is potentially curable. Several subgroups have been defined that are associated with clinical features, have different prognoses, and in some cases offer personalized treatment options. In adults, the sonic hedgehog (SHH) subtype is the most common subtype, followed by the wingless (WNT) and group 4 subtypes. Multimodal therapies allow 5-year overall survival rates of up to 70%. However, in adults, therapeutic evidence from prospective randomized trials is largely lacking. Therefore, regardless of individual risk, most patients are currently treated uniformly with craniospinal chemoradiation with a boost to the tumour bed, followed by maintenance chemotherapy, usually with alkylating agents. In Europe, the so-called Packer regimen, together with cisplatin-etoposide regimens, is the most commonly used chemotherapy option. Targeted treatment approaches have not yet been implemented, although tumour biology is well understood and offers personalized approaches, especially for the SHH subgroup. At relapse, rapid resistance occurs frequently, necessitating repositioning of these agents in an earlier treatment phase. Due to the good to intermediate prognosis, patients with medulloblastoma require structured long-term clinical follow-up including MRI of the brain, monitoring of side effects, and psychosocial and fertility counselling. Recently, clinical trials have been initiated with the aim of de-escalating treatment to reduce toxicity and adding targeted therapies to increase efficacy, with the main goal of therapy to cure the tumour while maintaining the physical and psychosocial integrity of affected patients. This article summarizes our opinion on the diagnosis and treatment of medulloblastoma in adults., Competing Interests: Disclosure EF has received honoraria for lectures, consultation or advisory board participation from the following for-profit company: Karyopharm Therapeutics. CS has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: AbbVie, Bristol-Myers Squibb, HRA Pharma, Medac, Roche. FS has received honoraria (speaker) lectures, consultation or advisory board participation from the following for-profit companies: AbbVie, Bayer, Illumina. PH has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Antisense Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Medac, Merck Sharp & Dome, Nanotherm, Novartis, Novocure, Roche. The following for-profit companies have supported clinical trials and contracted research conducted by PH with payments made to his institution: Antisense Pharma. KWP has declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5-19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5., Methods: All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy)., Results: Fifty-one patients (median age, 8 y; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated., Conclusions: This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient's age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects that influence the central nervous system's function and cause neurocognitive deficits. Therefore, they substantially lower the quality of life, which is especially severe in a developing organism. Thus, there is a need for new therapies that are less toxic and even more effective. Recently, knowledge about the epigenetic mechanisms that are responsible for medulloblastoma development has increased. Epigenetics is a phenomenon that influences gene expression but can be easily modified by external factors. The best known epigenetic mechanisms are histone modifications, DNA methylation, or noncoding RNAs actions. Epigenetic mechanisms comprehensively explain the complex phenomena of carcinogenesis. At the same time, they seem to be a potential key to treating medulloblastoma with fewer complications than past therapies. This review presents the currently known epigenetic mechanisms that are involved in medulloblastoma pathogenesis and the potential therapies that use epigenetic traits to cure medulloblastoma while maintaining a good quality of life and ensuring a higher median overall survival rate.

Introduction: Radiation induced gliomas often occurs after radiation therapy for other brain tumors. Medulloblastoma often occurs in children and its associated radiation-induced glioblastoma multiforme's (GBM) after radiotherapy often has a long latency period. Our case is very unique because the medulloblastoma was detected at an advance age and the latency period of radiation-induced GBM was relatively shorter., Patients Concerns: A 64-year-old male was first admitted at our hospital in March 2018 with dizziness, vomiting, and blurred vision., Diagnosis: Magnetic resonance imaging of brain revealed a lesion with local mixed density and mass enhancement in left cerebellar region. Histopathology established medulloblastoma (World Health Organization) grade 4 and a classic histological subtype after surgery., Intervention: Surgical resection followed by radiation therapy were the initial therapeutic modalities., Outcomes: In April 2019, the patient was readmitted with dizziness and blurred vision. Magnetic resonance imaging showed the left cerebellar hemisphere bulky enhancement lesion. Again, a multimodal therapy comprising surgical resection, radiation therapy as well as chemotherapy was adapted after histopathology established GBM., Lesion: Radiotherapy for medulloblastoma patients at advance ages is a critical predisposing factor for the development of radiation-induced GBM in a very short period of time. We suggest that, radiotherapy as adjuvant therapy for medulloblastoma patients at advance ages should be chosen with extreme caution., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Treatment of MB is based on histopathological and molecular stratification, and includes surgical intervention, often with craniospinal irradiation and adjuvant chemotherapy. Unfortunately, however, this treatment leads to a high morbidity rate, and it does not cure all patients either, with around 30% succumbing to their disease. With improved cancer genomics and better molecular characterization, MB has been classified into four major subgroups, wingless-activated, sonic hedgehog-activated, Group 3, and Group 4, with each group consisting of additional subtypes. Recently disclosed genetic drivers of MB may in the future help improve treatment, and in this way reduce therapy-related toxicity. In this review, we describe the heterogeneity of the MB subgroups, and potential new options for targeted therapy.

Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To study the clinical features of children with recurrent medulloblastoma (MB) and treatment regimens., Methods: A retrospective analysis was performed on 101 children with recurrent MB who were admitted to the hospital from August 1, 2011 to July 31, 2017. The children were followed up to July 31, 2020. The Kaplan-Meier method was used for survival analysis. The Cox regression model was used for multivariate regression analysis., Results: Of the 101 children, 95 underwent remission induction therapy, among whom 51 had response, resulting in a response rate of 54%. The median overall survival (OS) time after recurrence was 13 months, and the 1-, 3-, and 5-year OS rates were 50.5%±5.0%, 19.8%±4.0%, and 10%±3.3% respectively. There was no significant difference in the 5-year OS rate between the children with different ages (< 3 years or 3-18 years), sexes, pathological types, or Change stages, between the children with or without radiotherapy before recurrence or re-irradiation after recurrence, and between the children with different times to recurrence (< 12 months or ≥ 12 months after surgery) ( P > 0.05). There were significant differences in the 5-year OS rate between the children with or without reoperation after recurrence and between the children with different recurrence sites ( P < 0.05). The children with reoperation after recurrence had a significantly longer survival time than those without reoperation ( P =0.007), and the risk of death in children undergoing reoperation after recurrence was 0.389 times (95% confidence interval:0.196-0.774) that in children who did not undergo such reoperation., Conclusions: As for the recurrence of MB, although remission induction therapy again can achieve remission, such children still have a short survival time. Only reoperation can significantly prolong survival time, and therefore, early reoperation can be considered to improve the outcome of children with recurrent MB.

Approximately 30% of medulloblastoma (MB) patients exhibit metastasis at initial diagnosis, which often leads to a poor prognosis. Here, by using univariate Cox regression analysis, two machine learning methods (Lasso-penalized Cox regression and random survival forest-variable hunting (RSF-VH)), and multivariate Cox regression analysis, we established two metastasis-related prognostic models, including the 47-mRNA-based model based on the Lasso method and the 21-mRNA-based model based on the RSF-VH method. In terms of the results of the receiver operating characteristic (ROC) curve analyses, we selected the 47-mRNA metastasis-associated model with the higher area under the curve (AUC). The 47-mRNA-based prognostic model could classify MB patients into two subgroups with different prognoses. The ROC analyses also suggested that the 47-mRNA metastasis-associated model may have a better predictive ability than MB subgroup. Multivariable Cox regression analysis demonstrated that the 47-mRNA-based model was independent of other clinical characteristics. In addition, a nomogram comprising the 47-mRNA-based model was built. The results of ROC analyses suggested that the nomogram had good discrimination ability. Our 47-mRNA metastasis-related prognostic model and nomogram might be an efficient and valuable tool for overall survival (OS) prediction and provide information for individualized treatment decisions in patients with MB.

Medulloblastoma is the most common malignant brain tumour in children and is a major cause of mortality and morbidity, particularly in low- and middle-income countries. It has been risk-stratified on the basis of clinical (age, metastasis and extent of resection) and histological subtypes (classic, desmoplastic and anaplastic). However, recently medulloblastoma has been sub-grouped by using a variety of different genomic approaches, such as gene expression profiling, micro-ribonucleic acid profiling and methylation array into 4 groups, namely Wingless, Sonic hedgehog, Group 3 and Group 4. This new sub-grouping has important therapeutic and prognostic implications. After acute leukaemia, brain tumour is the second most common malignancy in the paediatric age group. The improvement in outcome of acute lymphoblastic leukaemia in low- and middle-income countries reflects the relative simplicity of diagnostic procedures and management. Unlike leukaemia, the management of brain tumours requires a complex multidisciplinary approach, including neuro-radiologists, neurosurgeons with a paediatric expertise, neuropathologists, radiation oncologists and neuro-oncologists. In addition, the equipment required for the diagnosis (magnetic resonance imaging scan, histological, molecular and genetic techniques) and the management (operating room, radiation facilities) is a limiting factor in countries with limited resources. In Pakistan, there are very few centres able to treat children with brain tumours. The current literature review was planned to provide an update on the management of this tumour.

To investigate the prognoses associated with different locations of medulloblastoma (MB) in terms of survival through a case-control study and evaluate the prognostic factors for MB.The Surveillance, Epidemiology, and End Results database was used to identify MB patients diagnosed from 1975 to 2016. Each brainstem MB (bMB) patient was matched to a cerebellum MB (cMB) patient by propensity score matching based on age, sex, tumor size, extent of metastasis, extent of surgical resection, radiotherapy status and chemotherapy status. Univariate and multivariate analyses were performed to assess the effect of prognostic factors on overall survival. Ethical approval was not necessary as this study is based on a public database.A total of 172 bMB patients and 1417 cMB patients were included in the study. A total of 144 pairs of patients were matched to constitute the matched cohort. Within the matched cohort, the median survival times were 213 months and 96 months for cMB and bMB, respectively. Within the unmatched cohort, the median survival times were 111 months and 97 months for cMB and bMB, respectively. Brainstem location detrimentally affected the survival time of MB patients in both the matched cohort (hazard ratios =8.14, 95% confidence interval =5.98-11.08) and the unmatched cohort (hazard ratios =1.44, 95% confidence interval =1.20-1.74). Age <5 years and receipt of radiotherapy were favorable prognostic factors, whereas gross total resection, brainstem location and receipt of chemotherapy were unfavorable prognostic factors. Radiotherapy alone was associated with superior outcomes concerning adjuvant chemotherapy or radiotherapy.This study uncovers a survival advantage for cMB patients versus bMB patients. Additionally, prognostic factors include age, extent of surgical resection, and receipt of radiotherapy or chemotherapy. Radiotherapy after surgery and rational use of chemotherapy drugs are crucial for treatment of MB patients. Further studies of these prognostic factors are required to improve the survival time.

Background: Medulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MB SHH , MB WNT , MB Group 3 , and MB Group 4 , representing the second most common type of pediatric brain cancer after high-grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MB SHH caused by germline mutations in only six genes. However, the spectrum of germline mutations in MB SHH remains incomplete., Methods: Comprehensive Next-Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer., Results: Here, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MB SHH , but reached remission with current treatment protocols., Conclusions: We propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/β-catenin signaling.

Background: Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies., Methods: Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature., Results: Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance., Conclusions: This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The lack of success of standard therapies for medulloblastoma has highlighted the need to plan a new therapeutic approach. The purpose of this article is to provide an overview of the novel treatment strategies based on the molecular characterization and risk categories of the medulloblastoma, also focusing on up-to-date relevant clinical trials and the challenges in translating tailored approaches into clinical practice., Methods: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites about molecular classification of medulloblastomas, ongoing clinical trials and new treatment strategies. Only articles in the English language and published in the last five years were selected. The research was refined based on the best match and relevance., Results: A total 58 articles and 51 clinical trials were analyzed. Trials were of phase I, II, and I/II in 55%, 33% and 12% of the cases, respectively. Target and adoptive immunotherapies were the treatment strategies for newly diagnosed and recurrent medulloblastoma in 71% and 29% of the cases, respectively., Conclusion: Efforts are focused on the fine-tuning of target therapies and immunotherapies, including agents directed to specific pathways, engineered T-cells and oncoviruses. The blood-brain barrier, chemoresistance, the tumor microenvironment and cancer stem cells are the main translational challenges to be overcome in order to optimize medulloblastoma treatment, reduce the long-term morbidity and increase the overall survival.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor arising in the cerebellum or the 4 th ventricle. Cerebellopontine angle (CPA) MBs are extremely rare tumors, with few cases previously described. In this study, we sought to describe the clinical characteristics, molecular features and outcomes of CPA MB. We retrospectively reviewed a total of 968 patients who had a histopathological diagnosis of MB at the Beijing Neurosurgical Institute between 2002 and 2016. The demographic characteristics, clinical manifestations and radiological features were retrospectively analyzed. Molecular subgroup was evaluated by the expression profiling array or immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier analysis. In this study, 15 patients (12 adults and 3 children) with a mean age at diagnosis of 25.1 years (range 4-45 years) were included. CPA MBs represented 1.5% of the total cases of MB (15/968). Two molecular subgroups were identified in CPA MBs: 5 WNT-MBs (33%) and 10 SHH-MBs (67%). CPA WNT-MBs had the extracerebellar growth with the involvement of brainstem (P = 0.002), whereas CPA SHH-MBs predominantly located within the cerebellar hemispheres (P = 0.004). The 5-year OS and PFS rates for CPA MB were 80.0% ± 10.3% and 66.7% ± 12.2%, respectively. Pediatric patients with CPA MBs had worse outcomes than adult patients (OS: P = 0.019, PFS: P = 0.078). In conclusion, CPA MB is extremely rare and consists of two subgroups. Adult patients with CPA MB had a good prognosis. Maximum safe surgical resection combined with adjuvant radiotherapy and chemotherapy can be an effective treatment strategy for this rare tumor.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

Background: Central nervous system tumors remain the leading cause of cancer-related mortality amongst children with solid tumors, with medulloblastoma (MB) representing the most common pediatric brain malignancy. Despite best current therapies, patients with recurrent MB experience have an alarmingly high mortality rate and often have limited therapeutic options beyond inadequate chemotherapy or experimental clinical trials. Therefore, a systematic review of the literature regarding treatment strategies employed in recurrent pediatric MB will evaluate previous salvage therapies in order to guide future clinical trials. The aim of this systematic review will be to investigate the efficacy and safety of salvage therapies for the management of children with progressive, treatment-refractory, or recurrent MB., Methods: We will conduct literature searches (from 1995 onwards) in MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Cochrane Central Register of Controlled Trials. Studies examining the survival and toxicity of therapies administered to treatment-refractory pediatric MB patients will be included. Two reviewers will independently assess the search results based on predefined selection criteria, complete data abstraction, and quality assessment. The primary outcomes of this review will be overall and progression-free survival. Secondary outcomes will include safety and toxicity of each therapy administered. The study methodological quality (or bias) will be appraised using an appropriate tool. Due to the nature of the research question and published literature, we expect large inter-study heterogeneity and therefore will use random effects regression analysis to extract the combined effect. In additional analyses, we will investigate the role of re-irradiation and mono- vs. poly-therapy in recurrent disease, and whether molecular subgrouping of MB influences salvage therapy., Discussion: This systematic review will provide an overview of the current literature regarding salvage therapies for relapsed MB patients. Investigation of clinically tested therapies for children with recurrent MB has significant implications for clinical practice. By reviewing the efficacy and toxicity of MB salvage therapies, this study will identify effective therapeutic strategies administered to recurrent MB patients and can inform future clinical trials aimed to improve patient survivorship and quality of life., Systematic Review Registration: PROSPERO CRD42020167421.