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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.)

Background: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown., Methods: Adult survivors of childhood medulloblastoma (n = 505; median [minimum-maximum] age, 29 [18-46] years) and sibling controls (n = 727; 32 [18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), standard-risk (CSI > 0 to <30 Gy + chemotherapy) and high-risk (CSI ≥ 30 Gy + chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, and marital/partner status. Multivariable models estimated the risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence., Results: Survivors in each treatment exposure group had a 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had a higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems, and seizures were associated with 33-34%, 25-26%, and 21-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with nonindependence., Conclusions: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Sensorineural hearing loss is typically caused by dysfunction of the inner ear or auditory nerve. In pediatric patients diagnosed with sensorineural hearing loss, work-up often includes genetic testing and imaging studies of the auditory pathway. Here, we report a case of a pediatric patient with a history of sensorineural hearing loss following cisplatin and radiation therapy for brainstem medulloblastoma, developing symptoms and signs of central hearing loss based on audiometric and MRI/diffusion tensor imaging studies. Though rare, central hearing loss should be considered among the causes of sensorineural hearing loss in children. Laryngoscope, 135:452-456, 2025., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. MB originates from neural precursor cells in distinctive regions of the rhombic lip and their maturation occurs in the cerebellum or the brain stem during embryonal development. Autophagy is also referred to as self-eating' which is a catabolic process that often triggers cellular homeostasis through the salvaging of degenerated proteins as well as organelles. Autophagy influence cell survival via aberrant proteins that could accumulate within the cell and influence potential signaling and transport mechanisms. The role of autophagy in MB aggressiveness as well as tumorigenesis is a very complex process. This review targets specifically data reporting the key roles of autophagy in the pathogenesis and therapy of MB.

Background: Primary central nervous system tumors are the second most common cancer among children in high-income countries (HICs). These tumors are also the leading cause of cancer-related deaths in children in this setting. Studies from HICs report gliomas as the most common pediatric cancer. However, there is paucity of data from low- and middle-income countries as not many publications have been made in this field., Methods: The objective was to describe the disparities in detection, treatment, and survival of children with central nervous system tumors in low-income countries (LICs) when compared with HICs, using a case series. A retrospective chart review of three children treated for medulloblastoma in Uganda was done. In addition, a review of the literature about management of pediatric central nervous system tumors in both LICs and HICs was conducted., Results: There are no quantifiable results for this case series., Conclusion: There are notable differences in the quality of care for children with pediatric central nervous system tumors in LICs when compared with HICs. In Uganda, the challenges in management of these children include few multidisciplinary specialists, long distance from the neurosurgery centers, and difficulties in making a correct pathologic diagnosis, among others., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

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).)

Background: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization, and biology in pediatric survivors of a posterior fossa tumor., Methods: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic tool based on Cattell-Horn-Carroll's model for intelligence were analyzed., Results: Cognitive performance 5.14 years (mean; range = 1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had a strong impact on most subtests. pCMS was associated with psychomotor abilities (β = -0.25 to -0.16) and processing speed (β = -0.32). Postoperative hydrocephalus correlated with crystallized intelligence (β = -0.20) and short-term memory (β = -0.15), age with crystallized intelligence (β = 0.15) and psychomotor abilities (β = -0.16 and β = -0.17). Scores for fluid intelligence (β = -0.23), short-term memory (β = -0.17) and visual processing (β = -0.25) declined, and scores for selective attention improved (β = 0.29) with time after diagnosis., Conclusions: The dose of CSI was strongly associated with neurocognitive outcomes. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI dose and toxicity caused by other treatment modalities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims to give a comprehensive overview of clinical and molecular characteristics of pediatric FA MB patients., Methods: Clinical data including detailed information on the treatment and toxicities of 6 previously unreported FA MB patients were supplemented with data of 16 published cases., Results: We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n = 9), confirmed by methylation profiling in 5 patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n = 16) or FA-N (n = 3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT) ± chemotherapy (27%). Of 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI: 0.3-1.8). 1-year-progression-free-survival (PFS) was 26.3% ± 10.1% and 1-year-OS was 42.1% ± 11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3% ± 12.9%/33.3 ± 12.2% with adjuvant therapy, P = .006/P = .086)., Conclusions: MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Medulloblastoma (MB) is a primary brain malignancy. However, updated epidemiological data and long-term outcomes are lacking.The clinical and epidemiological datasets of patients with MB in the current study were obtained from the Surveillance, Epidemiology, and End Results (SEER) databases. Joinpoint regression models were used to assess the rate of changes in the incidence, prevalence, and treatment trends in patients with MB. Cox hazard and competition risk model analyses were used to assess overall survival (OS) and cancer-specific survival (CSS).The age-adjusted incidence of MB remained relatively stable at 0.15 per 100,000 individuals in 2019. The annual percentage change (APC) of females remained stable, whereas that of males increased over time. The 20-year limited-duration prevalence of patients with MB increased significantly from 0.00016 % in 1999 to 0.00203 % in 2018. Patients aged 5-19 years accounted for 46.7 % of all age groups, and the trend for the three treatments was increased. Average annual percentage change (AAPC) for the chemotherapy group was increased in patients aged 20 + years MB [AAPC = 2.66 (95 % CI 0.93-6.31)]. Multivariate analysis revealed that OS and CSS varied significantly according to age, year of diagnosis, histology, stage, surgery, and radiotherapy. Subgroup analysis showed that chemotherapy was associated with a favorable prognosis in high-risk groups.The incidence of MB remained relatively stable, and its prevalence increased significantly. This current population-based study further identified the prognostic factors in patients with MB. Moreover, the use of chemotherapy was associated with better survival in high-risk groups., 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 © 2024 Elsevier Ltd. All rights reserved.)

Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Advances in molecular biology have led to consensus classification of medulloblastoma into four broad molecular subgroups - wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively. Traditionally, children >3 years of age, with no/minimal residual tumor (<1.5 cm 2 ) and lack of metastasis were classified as average-risk disease with >80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm 2 ), and leptomeningeal metastases either alone or in combination were considered high-risk features yielding much worse 5-year survival (30-60%). This clinico-radiological risk-stratification has been refined by incorporating molecular/genetic information. Contemporary multi-modality management for non-infantile medulloblastoma entails maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. Aggressive multi-modality management achieves good survival but is associated with substantial dose-dependent treatment-related toxicity prompting conduct of subgroup-specific prospective clinical trials., Areas Covered: We conducted literature search on PubMed from 1969 till 2023 to identify putative prognostic factors and risk-stratification for medulloblastoma, including molecular subgrouping. Based on previously published data, including our own institutional experience, we discuss molecular risk-stratification focusing on WNT-pathway medulloblastoma to identify candidates suitable for treatment de-intensification to strike the optimal balance between survival and quality of survivorship., Expert Opinion: Prospective clinical trials and emerging biological information should further refine risk-stratification in WNT-pathway medulloblastoma.

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: Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects., Experimental Design: GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9., Results: GD2 was expressed in 82.68% of MB tumors. The SHH and G3-G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood-brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells., Conclusions: Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Medulloblastoma is a highly malignant, embryonal tumor, which is rare in adults, and shows distinct clinical, histopathological, molecular and treatment response features., Methods: We retrospectively investigated 44 adults (age 17-48 years) with a histological diagnosis of medulloblastoma, and in 23 immunohistochemistry was used to identify the molecular subgroups. We analyzed demographic, diagnostic, therapeutic and cognitive data, and correlated with PFS (progression-free-survival) and OS (overall survival)., Results: We observed a male prevalence and a median age of 31 years. Symptoms at onset were related to infratentorial location, while myeloradicular and/or cranial nerve involvement was rare. Histological examination showed the classic variant in 75% of patients, the desmoplastic/nodular in 23% and the anaplastic in one. As for molecular diagnosis, 17 patients were SHH and 6 non-WNT/non-SHH (5 group 4 and 1 group 3), while no WNT subgroup was found. The SHH subgroup had a prevalence of high-risk patients and leptomeningeal involvement. Patients underwent gross total or subtotal/partial resection, and craniospinal irradiation, followed in 20 cases by adjuvant chemotherapy. Median OS and PFS were 16.9 and 12 years, respectively. Metastatic disease at presentation and subtotal/partial resection were associated with worse prognosis, while the addition of chemotherapy did not yield a significant advantage over radiotherapy alone. Cognitive impairment in long-term survivors was limited and late relapses occurred in 15% of patients., Conclusions: Future studies with adequate sample size and long-term follow-up should prospectively investigate the role of surgery and adjuvant therapies across the different molecular subgroups to see whether a personalized approach is feasible.

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.

Objective: Brain tumors are a global problem, leading to higher cancer-related morbidity and mortality rates in children. Despite the progressive though slow advances in neuro-oncology care, research, and diagnostics in sub-Saharan Africa (SSA), the epidemiological landscape of pediatric brain tumors (PBTs) remains underestimated. This study aimed to systematically analyze the distribution of PBT types in SSA., Methods: Ovid Medline, Global Index Medicus, African Journals Online, Google Scholar, and faculty of medicine libraries were searched for literature on PBTs in SSA published before October 29, 2022. A proportional meta-analysis was performed., Results: Forty-nine studies, involving 2360 children, met the inclusion criteria for review; only 20 (40.82%) were included in the quantitative analysis. South Africa and Nigeria were the countries with the most abundant data. Glioma not otherwise specified (NOS) was the common PBT in the 4 SSA regions combined. However, medulloblastoma was more commonly reported in Southern SSA (p = 0.01) than in other regions. The prevalence and the overall pooled proportion of the 3 common PBTs was estimated at 46.27% and 0.41 (95% CI 0.32-0.50, 95% prediction interval [PI] 0.11-0.79), 25.34% and 0.18 (95% CI 0.14-0.21, 95% PI 0.06-0.40), and 12.67% and 0.12 (95% CI 0.09-0.15, 95% PI 0.04-0.29) for glioma NOS, medulloblastoma, and craniopharyngioma, respectively. Sample size moderated the estimated proportion of glioma NOS (p = 0.02). The highest proportion of craniopharyngiomas was in Western SSA, and medulloblastoma and glioma NOS in Central SSA., Conclusions: These findings provide insight into the trends of PBT types and the proportion of the top 3 most common tumors across SSA. Although statistical conclusions are difficult due to the inconsistency in the data, the study identifies critical areas for policy development and collaborations that can facilitate improved outcomes in PBTs in SSA. More accurate epidemiological studies of these tumors are needed to better understand the burden of the disease and the geographic variation in their distribution, and to raise awareness in their subsequent management.

Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong the survival time with severe side effects and relapse. Defining the intratumoral heterogeneity, cellular origin and identifying the interaction network within tumor microenvironment are helpful for understanding the mechanisms of medulloblastoma tumorigenesis and relapse. Due to technological limitations, the mechanisms of cellular heterogeneity and tumor origin have not been fully understood. Recently, the emergence of single-cell technology has provided a powerful tool for achieving the goal of understanding the mechanisms of tumorigenesis. Several studies have demonstrated the intratumoral heterogeneity and tumor origin for each subtype of medulloblastoma utilizing the single-cell RNA-seq, which has not been uncovered before using conventional technologies. In this review, we present an overview of the current progress in understanding of cellular heterogeneity and tumor origin of medulloblastoma and discuss novel findings in the age of single-cell technologies., (© 2024. The Author(s).)

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.

Somatic versus Germline-A Case Series of Three Children with ATM- mutated Medulloblastoma.

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.)

Purpose of Review: Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma., Recent Findings: The classic four subgroups have been reclassified and further subdivided based on new molecular findings. Research is revealing the cell origins of the different subtypes of medulloblastoma. There has been continued personalization of management based on molecular parameters. While many advances have been made in the knowledge base of this most common malignant pediatric brain tumor, there has not yet been translation into more effective therapies to prolong survival in all subgroups with the possible exception of children with group 3 disease. Quality of life remains a major challenge for long-term survivors., (© 2023. The Author(s).)

Objective: Medulloblastoma is the most common malignant intracranial tumor affecting the pediatric population. Despite advancements in multimodal treatment over the past 2 decades yielding a 5-year survival rate > 75%, children who survive often have substantial neurological and cognitive sequelae. The authors aimed to identify risk factors and develop a clinically friendly online calculator for prognostic estimation in pediatric patients with medulloblastoma., Methods: Pediatric patients with a histopathologically confirmed medulloblastoma were extracted from the Surveillance, Epidemiology, and End Results database (2000-2018) and split into training and validation cohorts in an 80:20 ratio. The Cox proportional hazards model was used to identify the univariate and multivariate survival predictors. Subsequently, a calculator with those factors was developed to predict 2-, 5-, and 10-year overall survival as well as median survival months for pediatric patients with medulloblastoma. The performance of the calculator was determined by discrimination and calibration., Results: One thousand seven hundred fifty-nine pediatric patients with medulloblastoma met the prespecified inclusion criteria. Age, sex, race, ethnicity, median household income, county attribute, laterality, anatomical location, tumor grade, tumor size, surgery status, radiotherapy, and chemotherapy were variables included in the calculator (https://spine.shinyapps.io/Peds&#95;medullo/). The concordance index was 0.769 in the training cohort and 0.755 in the validation cohort, denoting clinically useful predictive accuracy. Good agreement between the predicted and observed outcomes was demonstrated by the calibration plots., Conclusions: An easy-to-use prognostic calculator for a large cohort of pediatric patients with medulloblastoma was established. Future efforts should focus on improving granularity of population-based registries and externally validating the proposed calculator.

Objectives: To retrospectively compare the overall and event-free survival rates of patients with standard and high risk medulloblastoma who received postoperative radiotherapy (RT) followed by maintenance chemotherapy., Methods: The study included 48 patients with medulloblastoma who were treated and followed-up between 2005 and 2021. Patients were classified according to the Chang classification because no molecular analysis was done. Immediately after surgery all patients received postoperative RT followed by eight cycles of chemotherapy (SIOP/UKCCSG PNET-3 protocol); if thrombocytopenia developed, carboplatin was replaced by cisplatin to avoid treatment delay. The clinical characteristics, risk categories and treatment outcomes of all patients were analyzed., Results: The mean age of the 48 patients (26 males, 22 females) at diagnosis was 7.27±4.21 y. The median start time of RT after surgery was 37 (range 19-80) d. The median follow-up was 56 (3-216) mo. The 5-year event-free survival was 61.2±10% in the high-risk group and 82.5±11.5% in the standard-risk group. The 5-year overall survival was 73.2±7.1%; it was 61.2±10% and 92.9±6.9% for high- and standard-risk patients, respectively (p = 0.026)., Conclusions: The outcomes of patients who were started on the modified SIOP/UKCCSG PNET-3 chemotherapy protocol, in which RT was begun as soon as possible after surgery, were comparable to those of current treatment protocols. Although a definitive conclusion is difficult, given the limited number of patients in the present study, authors suggest that their treatment protocol is a viable option for centers with limited facilities (such as an inability to perform molecular analysis)., (© 2023. The Author(s).)

Background: Medulloblastoma is the most common malignant primary pediatric brain tumor. Over the years, an increase in published research has been observed on this topic. However, there is a lack of analysis on the characteristics and trends and the socioeconomic indicators associated with medulloblastoma research productivity and impact., Methods: The Scopus database was used to search all articles from inception to 2020. Bibliometric information was obtained from Scopus, and bibliometrics diagrams were created using VOSviewer software. Statistical analysis was performed using the GraphPad Prism software version 7., Results: A total of 4058 research articles on medulloblastoma research worldwide were included in this study. There has been an increase in published articles, with a steep increase observed in the last decade. The country with the most publications is the USA, with St. Jude Children's Research Hospital as the most productive institution in medulloblastoma research. The articles mainly focused on molecular biology, diagnosis, treatment, prognostic factors for medulloblastoma, and research on other pediatric tumors. The number of collaborations with other countries showed the strongest positive correlation with scientific productivity., Conclusion: This analysis showed the trend and characteristics of published articles. The results of this study emphasized the need to increase funding for research, support for researchers and physicians, and promote more collaborations with countries and institutions engaged in medulloblastoma research., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: BACKGROUND: With the improvement of technology and the advancement of medical treatment in recent decades, more and more pediatric medulloblastoma survivors reintegrate to the community. This study aimed to examine the experiences of pediatric medulloblastoma survivors. METHODS: A qualitative research was conducted. Twenty Chinese pediatric medulloblastoma survivors were interviewed. Interviews were recorded and transcribed. Colaizzi's analysis method was used to analyze data. RESULTS: There were 4 themes in this study: physical health issues, community reintegration challenges, overcoming psychological pressure, and multiple unmet needs. CONCLUSION: Pediatric medulloblastoma survivors face challenges in the physical, psychological, and social aspects of their health, along with multiple unmet healthcare needs. Nurses should comprehensively assess the survivor's needs from admission, plan for discharge, and provide regular follow-up care after discharge. Furthermore, nurses should collaborate with caregivers, clinicians, and schoolteachers to develop programs aimed at enhancing the quality of life for survivors. It is also important to explore the survival experiences of individuals in different regions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

Medulloblastoma (MB) is one of the most common malignant childhood brain tumors (WHO grade IV). Its high degree of malignancy leads to an unsatisfactory prognosis, requiring more precise and personalized treatment in the near future. Multi-omics and artificial intelligence have been playing a significant role in precise medical research, but their implementation needs a large amount of clinical information and biomaterials. For these reasons, it is urgent for current MB researchers to establish a large sample-size database of MB that contains complete clinical data and sufficient biomaterials such as blood, cerebrospinal fluid (CSF), cancer tissue, and urine. Unfortunately, there are few biobanks of pediatric central nervous system (CNS) tumors throughout the world for limited specimens, scarce funds, different standards collecting methods and et cl. Even though, China falls behind western countries in this area. The present research set up a standard workflow to construct the Beijing Children's Hospital Medulloblastoma (BCH-MB) biobank. Clinical data from children with MB and for collecting and storing biomaterials, along with regular follow-up has been collected and recorded in this database. In the future, the BCH-MB biobank could make it possible to validate the promising biomarkers already identified, discover unrevealed MB biomarkers, develop novel therapies, and establish personalized prognostic models for children with MB upon the support of its sufficient data and biomaterials, laying the foundation for individualized therapies of children with MB., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Medulloblastomas are embryonal tumors predominantly affecting children. Recognition of molecularly defined subgroups has advanced management. Factors influencing the management and prognosis of adult patients with medulloblastoma remains poorly understood., Methods: We examined the management, prognostic factors, and, when possible, molecular subgroup differences (subset) in adult patients (aged 18 years or older) with medulloblastoma from our center (specialty Neuro-Oncology clinic within a large academic practice) diagnosed between 1992 and 2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (with log-rank test) were performed for univariate survival analysis with Cox regression used for multivariate analyses., Results: We included 76 adult patients with medulloblastoma (62% male), with a median age of 32 years at diagnosis (range: 18-66) and median follow-up of 7.7 years (range: 0.6-27). A subset of 58 patients had molecular subgroup characterization-37 SHH-activated, 12 non-WNT/non-SHH, and 9 WNT-activated. Approximately 67% underwent gross total resection, 75% received chemotherapy at diagnosis, and 97% received craniospinal irradiation with boost. The median overall survival (OS) for the whole cohort was 14.8 years. The 2-, 5-, and 10-year OS rates were 93% (95% CI 88-99), 86% (78-94), and 64% (53-78), respectively. Survival was longer for younger patients (aged 30 years or older: 9.9 years; younger than 30 years: estimated >15.4 years; log-rank p < 0.001). There was no survival difference by molecular subgroup or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses., Discussion: We report one of the largest retrospective cohorts in adult patients with medulloblastoma with molecular subtyping. Survival and molecular subgroup frequencies were similar to prior reports. Survival was better for adult patients younger than 30 years at diagnosis and was not significantly different by molecular subgroup or management characteristics (extent of resection, RT characteristics, or chemotherapy timing or regimen)., (© 2023 American Academy of Neurology.)

Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.

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).)

Survivors of childhood central nervous system (CNS) tumors experience early-onset aging-related phenotypes. DNA methylation (DNAm) age is an emerging epigenetic biomarker of physiologic age and may be predictive of chronic health conditions in long-term survivors. This report describes the course of epigenetic age acceleration using post-diagnosis blood samples (median: 3.9 years post-diagnosis; range: 0.04-15.96) from 83 survivors of pediatric CNS tumors. Epigenetic age acceleration was detected in 72% of patients, with an average difference between chronologic and DNAm age of 2.58 years (95% CI: 1.75-3.41, p  < 0.001). Time from diagnosis to sample collection correlated with the magnitude of epigenetic age acceleration.

Medulloblastoma (MB) is a malignant brain tumor that mainly affects children. It is rarely found in adults. Among the four groups of MB defined today according to molecular characteristics, group 3 is the least favorable with an overall survival rate of 50 %. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not sufficiently adapted to the different characteristics of the four MB groups. However, the use of new cellular and animal models has opened new doors to interesting therapeutic avenues. In this review, we detail recent advances in MB research, with a focus on the genes and pathways that drive tumorigenesis, with particular emphasis on the animal models that have been developed to study tumor biology, as well as advances in new targeted therapies., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Brain tumors are the most common solid tumors in children and a leading cause of cancer-related mortality in children worldwide. Data on the epidemiology and management of pediatric brain tumors in Uganda are limited. We aimed to assess the clinicopathological profile and management of pediatric brain tumors at the national oncology center in Uganda since the inception of weekly multidisciplinary meetings. Records of children younger than19 years diagnosed with primary brain tumors at Uganda Cancer Institute between 2017 and 2021 were retrospectively reviewed. Patient and tumor characteristics were collected with multidisciplinary team management treatment plans for analysis. There were 35 patients evaluated, most of whom were males (57.1%). Craniopharyngioma (n = 9, 25.7%) was the most common brain tumor, followed by astrocytoma (n = 5, 14.2%) and medulloblastoma (n = 4, 11.4%). Management included surgical resection in 28.5% of patients, chemotherapy (28.6%), radiotherapy (17.1%) and palliative care (20.0%). Over the last five years, there were increasing trends in the number of cases discussed in the multidisciplinary team and the number for whom the multidisciplinary management decisions were implemented. The majority (n = 18, 51.4%) of the children with brain tumors were alive and active in care, 34.2% abandoned treatment/lost to follow-up, and 8.6% died. The relative distribution of pediatric brain tumors types in Uganda Cancer Institute differs slightly from international reports, and there has been a notable increase in the number of cases over the years. Implementing multidisciplinary management decisions benefited patients and decreased abandonment and patient loss to follow-up.

Few reports on clinical factors, treatment, and survival in children and adolescents with Central nervous system tumors in low-income and middle-income countries in Latin America exist. We retrospectively reviewed such data in all cases of patients younger than 18 years with brain tumors diagnosed in a single tertiary care center in Peru from 2007 through 2017. Variables were analyzed for association with overall survival and event-free survival by using the Kaplan-Meier method and the Cox hazards ratio regression. Seventy-five patients' data were analyzed (40 boys, 35 girls; mean age=7.7 y). The main clinical symptoms were headache, vomiting, difficulty walking, and visual disturbances. The most frequent clinical signs were hydrocephalus, cerebellar signs, visual abnormalities, and focal motor signs. The median time to diagnosis was 12 weeks. Tumor resection was performed in 68 patients, and 37 patients received postoperative radiotherapy. The most frequent histologic subtypes were low-grade gliomas and medulloblastomas. Overall survival rates at 1 and 5 years of disease were 78% (CI 95%, 0.67 to 0.86) and 74% (CI 95%, 0.62 to 0.82), respectively, and the 5-year event-free survival rate was 62% (CI 95%, 0.47 to 0.73). Although diagnosis occurred late in our cohort, the survival rate was higher than that in other Latin American countries., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Intraventricular compartmental radioimmunotherapy (cRIT) with 131-I-omburtamab is a potential therapy for recurrent primary brain tumors that can seed the thecal space. These patients often previously received external beam radiotherapy (EBRT) to a portion or full craniospinal axis (CSI) as part of upfront therapy. Little is known regarding outcomes after re-irradiation as part of multimodality therapy including cRIT. This study evaluates predictors of response, patterns of failure, and radiologic events after cRIT., Methods: Patients with recurrent medulloblastoma or ependymoma who received 131-I-omburtamab on a prospective clinical trial were included. Extent of disease at cRIT initiation (no evidence of disease [NED] vs measurable disease [MD]) was assessed as associated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis., Results: All 27 patients (20 medulloblastoma, 7 ependymoma) had EBRT preceding cRIT: most (22, 81%) included CSI (median dose 2340 cGy, boost to 5400 cGy). Twelve (44%) also received EBRT at relapse as bridging to cRIT. There were no cases of radionecrosis. At cRIT initiation, 11 (55%) medulloblastoma and 3 (43%) ependymoma patients were NED, associated with improved PFS (p = 0.002) and OS (p = 0.048) in medulloblastoma. Most relapses were multifocal. With medium follow-up of 3.0 years (95% confidence interval, 1.8-7.4), 6 patients remain alive with NED., Conclusion: For patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis., (© 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.

Background: Embryonal tumors are highly malignant cancers of the central nervous system, with a relatively high incidence in infants and young children. Even with intensive multimodal treatment, the prognosis of many types is guarded, and treatment-related toxicity is significant. Recent advances in molecular diagnostics allowed the discovery of novel entities and inter-tumor subgroups, with opportunities for improved risk-stratification and treatment approaches., Summary: Medulloblastomas separate into four distinct subgroups with distinct clinicopathologic characteristics, and data from recent clinical trials for newly diagnosed medulloblastoma support subgroup-specific treatment approaches. Atypical teratoid rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and pineoblastoma, as well as other rare embryonal tumors, can be distinguished from histologically similar tumors by virtue of characteristic molecular findings, with DNA methylation analysis providing a strong adjunct in indeterminate cases. Methylation analysis can also allow further subgrouping of ATRT and pineoblastoma. Despite the dire need to improve outcomes for patients with these tumors, their rarity and lack of actionable targets lead to a paucity of clinical trials and novel therapeutics., Key Messages: (1) Embryonal tumors can be accurately diagnosed with pediatric-specific sequencing techniques. (2) Medulloblastoma risk stratification and treatment decisions should take into account molecular subgroups. (3) There is a dire need for a novel collaborative clinical trial design to improve outcomes is rare pediatric embryonal tumors., (© 2023 S. Karger AG, Basel.)

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.)

Medulloblastoma is the primary malignant embryonic tumor of the cerebellum and the most common malignant tumor of childhood, accounting up to 25% of all CNS tumors in children, but is extremely rare in adults. Despite the fact that medulloblastomas are one of the most malignant human tumors, it is worthy to note that a great breakthrough has been achieved in our understanding of oncogenesis and the development of real methods of treatment. The main objective of surgical treatment is a maximum resection of tumor with minimal impairment of neurological functions, in order to reduce the volume, remove tumor tissue, get the biopsy, and restore the cerebrospinal fluid flow. The progress of surgical techniques (using a microscope, ultrasound suction), anesthesiology, and intensive care has significantly decreased surgical mortality and increased radicality of tumor removal. Postoperative mortality is less than one percent in most studies, while neurological complications have been reported between 5-10%. Radiotherapy is the main method of treatment in patients older than 3 years, which dramatically improved the recurrence-free survival. Nevertheless, the radiation therapy without systemic chemotherapy leads to a high risk of systemic metastases. After the role of chemotherapy was statistically proven, investigations of the optimal combination of different chemotherapy regimens continued around the world. Currently, 80% of patients can already be cured, however, the quality of life of patients in the long-term period remains quite low, which depends on many factors including endocrinological, cognitive, neurological, and otoneurologic aspects. Thus, the main strategic goal of the development of neuro-oncology is to reduce the doses of radiation therapy to the CNS and the main task of international research is to optimize existing protocols and develop fundamentally new ones based on molecular genetic research in order to improve the quality of life., (© 2023. Springer Nature Switzerland AG.)

Background: Medulloblastomas (MB) are the most common malignant brain tumors in the pediatric age. In 2021, WHO categorized medulloblastomas into two groups: molecularly defined and histologically defined medulloblastomas. Molecularly defined medulloblastomas are divided into WNTactivated medulloblastoma, SHH-activated and TP53-wildtype medulloblastoma, SHH-activated, and TP53-mutant and non-WNT/non-SHH medulloblastoma, which include Group 3 (MYC) and Group 4 (CDK6 and MYCN). In this paper, we will focus on molecularly defined medulloblastomas., Objective: This paper aims to review the literature in order to describe the molecular structure of the medulloblastoma groups and to emphasize the importance of genetic predictors in medulloblastoma that can be used in clinical practice, either as a prognostic tool or as a therapeutic target in the future., Results: Each molecular subtype of medulloblastoma presents a different prognosis, and the molecular subtype with the best prognosis is medulloblastoma-activated WNT. It has even been observed that a reduction in the intensity of the combined treatment does not modify the prognosis of the patients, resulting in even fewer adverse effects due to the treatment. On the other hand, it was observed that the subtypes with the worst prognosis are medulloblastomas with activated MYC and medulloblastomas with activated SHH and mutated TP53, due to their high capacity to metastasize or to their radio-resistance. However, a new target therapy has emerged that could help improve the prognosis in these patients., Conclusion: The deeper knowledge of the molecular pathways involved in the appearance and progression of medulloblastomas will allow us to offer a prognosis at the time of diagnosis and more specific treatments through the development of the targeted therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and accounts for approximately 20% of all pediatric CNS tumors. Current multimodal treatment is associated with a 70%-90% 5-year survival rate; however, the prognosis for patients with tumor dissemination and recurrent MB remains poor. The majority of survivors exhibit long-term neurocognitive complications; thus, more effective and less toxic treatments are critically needed. Tumor treating fields (TTFields) are low-intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. Side effects from TTField therapy are minimal, making it an ideal candidate for MB treatment., Methods: To determine if TTFields can be an effective treatment for MB, the authors conducted an in vitro study treating multiple MB cell lines. Three MB molecular subgroups (SHH [sonic hedgehog], group 3, and group 4) were treated for 24, 48, and 72 hours at 100, 200, 300, and 400 kHz. Combinatorial studies were conducted with the small-molecule casein kinase 2 inhibitor CX-4945., Results: TTFields reduced MB cell growth with an optimal frequency of 300 kHz, and the most efficacious treatment time was 72 hours. Treatment with TTFields dysregulated actin polymerization and corresponded with a reduction in cell motility and invasion. TTFields also induced DNA damage (γH2AX, 53BP1) that correlated with an increase in apoptotic cells. The authors discovered that CX-4945 works synergistically with TTFields to reduce MB growth. In addition, combining CX-4945 and TTFields increased the cellular actin dysregulation, which correlated with a decrease in MB migration., Conclusions: The findings of this study demonstrate that TTFields may be a novel and less toxic method to treat patients with MB.