Metabolomic profiling of childhood medulloblastoma: contributions and relevance to diagnosis and molecular subtyping.

The incidence of brain tumors among children is second only to acute lymphoblastic leukemia, but the mortality rate of brain tumors has exceeded that of leukemia, making it the most common cause of death among children. Medulloblastoma (MB) is the most common type of brain tumor among children. Malignant brain tumors have strong invasion and metastasis capabilities, can spread through cerebrospinal fluid, and have a high mortality rate. In 2010, the World Health Organization first divided MB into four molecular subtypes based on molecular markers: WNT, Sonic hedgehog (SHH), Group 3, and Group 4. MB is a highly heterogeneous tumor. Different molecular subtypes of MB have significantly different clinical, pathological, and molecular characteristics. The prognosis of MB varies significantly among patients with different subtypes of this cancer. Thus, it is needed to study new diagnostic and therapeutic strategies. Metabolomics is an advanced analytical technology that uses various spectroscopic, electrochemical, and data analysis technologies to study and analyze the body's metabolites. By detecting changes in metabolite types and quantities in different types of samples, it can sensitively discover the physiological and pathological changes in the body. It has great potential for clinical application and personalized medicine. It is promising and can help develop personalized treatment strategies based on the metabolic profiles of individuals. It can unravel the unique metabolic profiles of MB, which may revolutionize our understanding of the disease and improve patients' outcomes.

Consensus guidelines for the management of pediatric medulloblastoma in low and middle-income countries.

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.

Innovative solutions? Belzutifan therapy for hemangioblastomas in Von Hippel-Lindau disease: A systematic review and single-arm meta-analysis.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder that predisposes patients to develop multiple cysts and tumors, such as hemangioblastomas (HBs) and clear cell renal cell carcinoma (ccRCC), due to mutations in the VHL tumor suppressor gene. While treatment of HBs varies based on their characteristics and has improved patient survival, it still involves high morbidity and mortality, leading to ongoing debates and studies to refine therapy strategies. Recent developments include the emergence of Belzutifan, a novel inhibitor targeting hypoxia-inducible factor 2α (HIF-2α), which has shown promising results in ongoing trials, particularly for patients not immediately requiring surgery. METHODS: This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of Belzutifan for treating HBs associated with VHL disease. Search was conducted across Medline, Embase, Cochrane, and Web of Science databases. Statistical Analysis was performed, with proportions and 95 % confidence intervals. Statistical analyses were carried out using R Studio. RESULTS: Ten studies were selected, comprising 553 patients. The population mean age was 40 (24-65), and 50 % of the population was formed by males. In terms of proportion, 6 analyses were performed: Disease Stability of 31 % [95 %CI:14 %-47 %; I2 = 2 %]; Disease Progression of 2 %[95 %CI:0 %-9 %; I2 = 0 %]; Partial Response of 75 % [95 %CI:54 %-96 %; I2 = 58 %]. Complete response of 1 % [95 %CI:0 %-7 %; I2 = 0 %];and Side effects, anemia 81 % rate [95 % CI:54 %-100 %; I2 = 94 %], and fatigue rate of 79 % [95 % CI:54 %-100 %;I2 = 94 %]. CONCLUSION: Results indicate that Belzutifan effectively stabilizes disease, reduces tumor progression, and achieves significant therapeutic responses, although side effects like anemia and fatigue were noted.

Disease Evolution Monitored by Serial Cerebrospinal Fluid Liquid Biopsies in Two Cases of Recurrent Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in childhood. Initial treatment generally includes surgery, irradiation, and chemotherapy. Approximately 20-30% of patients will experience a recurrence, which portends a very poor prognosis. The current standard of care for evaluation for relapse includes radiographic surveillance with magnetic resonance imaging at regular intervals. The presence of circulating tumor DNA in the cerebrospinal fluid has been demonstrated to be a predictor of a higher risk of progression in a research setting for patients with medulloblastoma treated on a prospective single institution clinical trial. We have previously published and clinically validated a liquid-biopsy-based genetic assay utilizing low-pass whole genome sequencing to detect copy number alterations in circulating tumor DNA. Here, we present two teenage patients with posterior fossa medulloblastoma with recurrent disease who have been monitored with serial liquid biopsies showing tumor evolution over time, demonstrating the clinical utility of these approaches.

14q22.3 duplication including OTX2 in a girl with medulloblastoma: A case report with literature review.

Orthodenticle homeobox 2 (OTX2) is a known oncogenic driver of medulloblastoma. Germline duplication of 14q22.3 including OTX2 is a rare condition reported in patients with combined pituitary hormone deficiency, oculo-auriculo-vertebral spectrum, and hemifacial microsomia. There has been one previously published case of a patient carrying a 14q22.3 duplication that included OTX2 with hemifacial microsomia who also developed medulloblastoma. Here, we present a case of a 6-year-old girl with a history of delayed development who was diagnosed with medulloblastoma. Genetic evaluations revealed that she inherited a germline duplication of 14q22.3, which included OTX2. This genetic alteration was passed down from her mother, who also had a history of delayed development. Results from other genetic testing, including exome sequencing, fragile X syndrome, and mtDNA testing, were negative/normal. This is the second report of a 14q22.3 duplication that included OTX2 in a patient with medulloblastoma. Further studies are necessary to establish a clear association.

Development and validation of a nomogram and risk stratification system to predict overall survival after surgical repair for pediatric patients with medulloblastoma based on easily accessible variables.

OBJECTIVE: This study aimed to develop and validate a nomogram and risk stratification system for the overall survival of pediatric patients with medulloblastoma after surgical repair. PATIENTS AND METHODS: In this multicenter, retrospective study, consecutive patients who underwent surgery for medulloblastoma at Shanghai Children's Medical Center and the First Affiliated Hospital of Fujian Medical University from 2010 to 2022 formed the training and external validation datasets, respectively. Univariable and multivariable Cox regression analyses were performed to identify variables associated with mortality in the training dataset. A nomogram prediction model was developed based on independent variables in the multivariable Cox regression analysis to predict the 1-, 3-, and 5-year overall survival. The area under receiver operating characteristic curve (AUC) and calibration curve were used to evaluate the discrimination and calibration of the nomogram. A risk stratification system based on the median risk score was also established to divide patients into two risk groups. RESULTS: In the training dataset, Cox regression analyses identified tumor size, brainstem involvement and chemotherapy as independent predictors for overall survival. The AUC of the nomogram was 0.75 at 1 year, 0. 75 at 3 years, 0.77 at 5 years in the training dataset, 0.74 at 1 year, 0.70 at 3 years, and 0.70 at 5 years in the validation dataset. The calibration curve for the probability of 1-, 3-, and 5-year survival showed good agreement between the nomogram prediction and actual observation in the training and validation datasets. The risk stratification system could perfectly classify patients into two risk groups, and the overall survival in the two groups had a good division. CONCLUSIONS: This low-cost, convenient, and noninvasive nomogram can be translated into clinical practice as a tool for risk stratification and individualized prognosis prediction for children with medulloblastoma.

Cribriform-morular Thyroid Carcinoma Arising in a Medulloblastoma Survivor: Two Metachronous Tumors Shared with the Activation of the Wnt Signaling Pathway.

Wnt signaling pathway activation is involved in the pathogenesis of a series of malignant tumors and is characterized by the nuclear accumulation of ß-catenin protein. The occurrence of two or more Wnt pathway-associated tumors in a single individual is uncommon and generally attributed to inherited cancer syndrome, especially familial adenomatous polyposis (FAP). Herein, we presented a rare case of a child who suffered from the occurrence of Wnt-activated medulloblastoma and cribriform-morular thyroid carcinoma (CMTC) within a 9-year interval. She had no history of FAP and harbored an unexpected somatic mutation of the APC gene in the CMTC tumor. The potential agents involved in the pathogenesis of the two molecular-linked tumors other than FAP were discussed in this report.

Metabolite profiles of medulloblastoma for rapid and non-invasive detection of molecular disease groups.

BACKGROUND: The malignant childhood brain tumour, medulloblastoma, is classified clinically into molecular groups which guide therapy. DNA-methylation profiling is the current classification 'gold-standard', typically delivered 3-4 weeks post-surgery. Pre-surgery non-invasive diagnostics thus offer significant potential to improve early diagnosis and clinical management. Here, we determine tumour metabolite profiles of the four medulloblastoma groups, assess their diagnostic utility using tumour tissue and potential for non-invasive diagnosis using in vivo magnetic resonance spectroscopy (MRS). METHODS: Metabolite profiles were acquired by high-resolution magic-angle spinning NMR spectroscopy (MAS) from 86 medulloblastomas (from 59 male and 27 female patients), previously classified by DNA-methylation array (WNT (n = 9), SHH (n = 22), Group3 (n = 21), Group4 (n = 34)); RNA-seq data was available for sixty. Unsupervised class-discovery was performed and a support vector machine (SVM) constructed to assess diagnostic performance. The SVM classifier was adapted to use only metabolites (n = 10) routinely quantified from in vivo MRS data, and re-tested. Glutamate was assessed as a predictor of overall survival. FINDINGS: Group-specific metabolite profiles were identified; tumours clustered with good concordance to their reference molecular group (93%). GABA was only detected in WNT, taurine was low in SHH and lipids were high in Group3. The tissue-based metabolite SVM classifier had a cross-validated accuracy of 89% (100% for WNT) and, adapted to use metabolites routinely quantified in vivo, gave a combined classification accuracy of 90% for SHH, Group3 and Group4. Glutamate predicted survival after incorporating known risk-factors (HR = 3.39, 95% CI 1.4-8.1, p = 0.025). INTERPRETATION: Tissue metabolite profiles characterise medulloblastoma molecular groups. Their combination with machine learning can aid rapid diagnosis from tissue and potentially in vivo. Specific metabolites provide important information; GABA identifying WNT and glutamate conferring poor prognosis. FUNDING: Children with Cancer UK, Cancer Research UK, Children's Cancer North and a Newcastle University PhD studentship.

Somatic Versus Germline: A Case Series of Three Children With ATM-Mutated Medulloblastoma.

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

Long-term Outcomes of Protocol-Based Treatment for Newly Diagnosed Medulloblastoma.

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.

Characterising the Long-Term Language Impairments of Children Following Cerebellar Tumour Surgery by Extracting Psycholinguistic Properties from Spontaneous Language.

Following cerebellar tumour surgery, children may suffer impairments of spontaneous language. Yet, the language processing deficits underlying these impairments are poorly understood. This study is the first to try to identify these deficits for four levels of language processing in cerebellar tumour survivors. The spontaneous language of twelve patients who underwent cerebellar tumour surgery (age range 3-24 years) was compared against his or her controls using individual case statistics. A distinction was made between patients who experienced postoperative cerebellar mutism syndrome (pCMS) and those who did not. Time since surgery ranged between 11 months and 12;3 years. In order to identify the impaired language processing levels at each processing level (i.e., lexical, semantic, phonological and/or morphosyntactic) nouns and verbs produced in the spontaneous language samples were rated for psycholinguistic variables (e.g., concreteness). Standard spontaneous language measures (e.g., type-token ratio) were calculated as well. First, inter-individual heterogeneity was observed in the spontaneous language outcomes in both groups. Nine out of twelve patients showed language processing deficits three of whom were diagnosed with pCMS. Results implied impairments across all levels of language processing. In the pCMS-group, the impairments observed were predominantly morphosyntactic and semantic, but the variability in nature of the spontaneous language impairments was larger in the non-pCMS-group. Patients treated with cerebellar tumour surgery may show long-term spontaneous language impairments irrespective of a previous pCMS diagnosis. Individualised and comprehensive postoperative language assessments seem necessary, given the inter-individual heterogeneity in the language outcomes.

Mitochondrial subtype MB-G3 contains potential novel biomarkers and therapeutic targets associated with prognosis of medulloblastoma.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. There are four groups, each with different causal mutations, affected pathways and prognosis. Here, we investigated the role of mitochondria in medulloblastoma and whether there are differences between the different groups. METHODS: We compared the gene expression levels in the four different medulloblastoma groups (MB-WNT, MB-SHH, MB-G3 and MB-G4), with the focus on genes associated with mitochondria. We used several tools including Salmon, Tximeta, DESeq2, BiomaRt, STRING, Ggplot2, EnhancedVolcano, Venny 2.1 and Metscape. RESULTS: A total of 668 genes were differentially expressed and the most abundant genes were associated with cell division pathway followed by modulation of chemical synaptic transmission. We also identified several genes (ABAT, SOX9, ALDH5A, FOXM1, ABL1, NHLH1, NEUROD1 and NEUROD2) known to play vital role in medulloblastoma. Comparative expression analysis revealed OXPHOS complex-associated proteins of mitochondria. The most significantly expressed genes in the MB-SHH and MB-G4 groups were AHCYL1 and SFXN5 while PAICS was significantly upregulated in MB-WNT group. Notably, MB-G3 contained the most downregulated genes from the OXPHOS complexes, except COX6B2 which was strongly upregulated. CONCLUSIONS: We show the importance of mitochondria and compare their role in the four different medulloblastoma groups.

[Medulloblastoma].

In the 5th edition of the WHO classification, medulloblastomas, which are representative pediatric brain tumors, are categorized into four groups: WNT, SHH-TP53 wild, SHH-TP53 mutant, and non-WNT/non-SHH, based on their molecular background. While the histopathological findings still hold importance in predicting prognosis, the histopathological classification is no longer utilized in this edition. SHH medulloblastomas are further subdivided into two groups based on the presence or absence of TP53 mutation, as their clinical characteristics and prognosis differ. Group 3 and Group 4 medulloblastomas, recognized as distinct molecular groups in clinical practice, are combined into a single group called "non-WNT/non-SHH", because they lack specific molecular pathway activation. Furthermore, based on methylation profiling, dividing SHH medulloblastoma into four subgroups and non-WNT/non-SHH medulloblastoma into eight subgroups was proposed. Understanding the unique clinical characteristics and prognosis associated with each group is crucial. However, it is important to acknowledge that our current understanding of prognosis is based on treatment approaches guided by clinical risk factors such as postoperative residual tumor volume and the presence of metastatic disease. This molecular-based classification holds promise in guiding the development of optimal treatment strategies for patients with medulloblastoma.

Deriving a continuum score for group 3 and 4 medulloblastoma tumor samples analyzed via RNA-sequencing or DNA methylation microarray.

Here, we present a protocol for deriving a continuum score for group 3 and 4 medulloblastoma tumor samples analyzed via RNA-sequencing or DNA methylation microarray. We describe steps for utilizing NMF-defined group 3/group 4 metagenes to calculate a continuum score between 0 and 1 that can be projected onto new sample data analyzed via RNA-sequencing. We then detail procedures for reverse engineering a continuum score for samples analyzed via DNA methylation microarray using a random forest classifier.

Immunohistochemical Surrogates for Molecular Stratification in Medulloblastoma.

BACKGROUND: The WHO classification of central nervous system neoplasms (2016) recognized 4 histologic variants and genetically defined molecular subgroups within medulloblastoma (MB). Further, in the 2021 classification, new subtypes have been provisionally added within the existing subgroups reflecting the biological diversity. YAP1, GAB1, and ß-catenin were conventionally accepted as surrogate markers to identify these genetic subgroups. OBJECTIVES: We aimed to stratify MB into molecular subgroups using 3 immunohistochemical markers. TP53 mutation was also assessed in Wingless (WNT), and Sonic Hedgehog (SHH) subgroups. Demographic profiles, imaging details, and survival outcomes were compared within these molecular subgroups. PATIENTS AND METHODS: Our cohort included 164 MB cases diagnosed over the last 10 years. The histologic variants were identified on histology, and tumors were molecularly stratified using YAP1, GAB1, and ß-catenin. Further, TP53 mutation was assessed using immunohistochemical in WNT and SHH subgroups. The clinical details and survival outcomes were retrieved from the records, and the mentioned correlates were evaluated statistically. RESULTS: The age ranged from 1 to 52 years with M:F ratio of 2:1. Group 3/group 4 constituted the majority (48.4%), followed by SHH (45.9%) and WNT subgroups (5.7%). Desmoplastic/nodular and MB with extensive nodularity had the best survival, whereas large cell/anaplastic had the worst. The follow-up period ranged from 1 to 129 months. The best outcome was observed for the WNT subgroup, followed by the SHH subgroup; group 3/group 4 had the worst. Among the SHH subgroup, TP53 mutant tumors had a significantly poorer outcome compared with SHH-TP53 wildtype. CONCLUSIONS: Molecular stratification significantly contributes to prognostication, and a panel of 3 antibodies is helpful in stratifying MB into its subgroups in centers where access to advanced molecular testing is limited. Our study reinforces the efficacy of incorporating this cost-effective, minimal panel into routine practice for stratification. Further, we propose a 3-risk stratification grouping, incorporating morphology and molecular markers.

Management and Long-term Outcomes of Adults With Medulloblastoma: A Single-Center Experience.

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).

[Pediatric posterior fossa tumors]. / Infratentorielle Hirntumoren bei Kindern.

CLINICAL ISSUE: Tumors of the posterior fossa account for about 50-55% of brain tumors in childhood. DIAGNOSTIC WORKUP: The most frequent tumor entities are medulloblastomas, pilocytic astrocytomas, ependymomas, diffuse midline gliomas and atypical teratoid-rhabdoid tumors. Neuroradiological differential diagnosis with magnetic resonance imaging (MRI) is of considerable importance for preoperative planning as well as planning of follow-up therapy. PERFORMANCE: Most important findings for differential diagnosis of pediatric posterior fossa tumors are tumor location, patient age and the intratumoral apparent diffusion assessed by diffusion-weighted imaging. ACHIEVEMENTS: Advanced MR techniques like MRI perfusion and MR spectroscopy can be helpful both in the initial differential diagnosis and in tumor surveillance, but exceptional characteristics of certain tumor entities should be kept in mind. PRACTICAL RECOMMENDATIONS: Standard clinical MRI sequences including diffusion-weighted imaging are the main diagnostic tool in evaluating posterior fossa tumors in children. Advanced imaging methods can be helpful, but should never be interpreted separately from conventional MRI sequences.