Abstract RELEVANCE Medulloblastomas of the SHH account for 30% of all medulloblastomas in children and are a heterogeneous group in the histological and molecular landscape. The prognosis of the disease depends on many factors. OBJECTIVE To evaluate the factors influencing the prognosis of SHH medulloblastoma in children. MATERIAL AND METHODS The analysis of treatment results of 111 patients aged 0.5 to 17 years inclusive with a confirmed diagnosis of medulloblastoma subgroup SHH, who received treatment from 1994 to 2021, was conducted. All patients underwent tumor resection, depending on age, children under 5 years of age received polychemotherapy with or without HDCT. Patients over 5 years of age received chemoradiation therapy according to various protocols. An assessment was made of clinical (age, presence of residual tumor more than 1.5 cm3, metastasis) and molecular factors (germinal mutations TP 53, PTCH, SUFU), MYCN amplification, GLI 2. TP 53 mutations were combined in MYCN in 47.6% and GLI 2 in 38.1 %. RESULTS Prognostic factors that influenced survival: histological type of tumor, germline mutations in the TP53 gene, amplification of the NMYC gene in the tumor, mutation in the GLI 2 gene. The best 5-year survival was in patients with MBEN and DMB: OS - 87.4% and 85.7%, PFS - 87.5% and 81.8%, respectively. Patients with AMB and TP 53 mutation had a poor prognosis - OS -25%, PFS - 16.1%; similarly with TP 53 mutation: OS - 37%, PFS - 31%, as well as MYCN amplification: OS - 35.3%, PFS - 25.9%. Five-year survival in patients in the standard risk group was: OS - 90.2%, PFS 89.2%, in the low-risk group OS - 83.3%, PFS - 83.3%. CONCLUSION The prognosis was not affected by gender, age, volume of resection, presence of metastases, presence of PTCH 1, SUFU, SMO mutations. The histological variant of medulloblastoma and the presence of MYCN amplification, as well as the germline mutation TP 53 and mutation in the GLI 2 gene, had a significant impact on the prognosis.

ObjectiveThe prognosis of medulloblastoma (MB) is extremely poor. This study aimed to develop a nomogram model for predicting the recurrence of MB in children by integrating pre-treatment magnetic resonance imaging radiomics and clinical characteristics.MethodsA retrospective analysis was conducted on 95 children with MB who were pathologically diagnosed with MB and underwent radical resection surgery. On the basis of recurrence status observed within the two-year post-treatment follow-up period, patients were categorized into recurrent and non-recurrent groups. The entire cohort was subsequently randomized into a training dataset and a test dataset using a 7:3 allocation ratio. Radiomic feature extraction was carried out utilizing the Feature Explorer Pro platform, with features derived from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1-weighted imaging (T1WI_CE) sequences. The most significant features were selected using the Pearson correlation coefficient, analysis of variance (ANOVA), recursive feature elimination, and the Kruskal-Wallis test. A radiomics prediction model was developed using a support vector machine classifier. Logistic regression analysis was employed to identify the most valuable clinical characteristics, and they were used to develop a clinical model. The clinical and radiomics features were combined to develop a clinical-radiomics hybrid model, followed by establishing a nomogram. The predictive performance of each model was assessed using receiver operating characteristic curve analysis. The clinical utility of the model was evaluated via decision curve analysis (DCA) and calibration curves.ResultsTwo clinical characteristics and six radiomics features exhibiting the strongest associations with MB recurrence were selected to independently develop a hybrid model. The results showed that the hybrid model exhibited good predictive performance for MB recurrence in children. The AUC of the hybrid model reached 0.833 (95% confidence interval [CI], 0.730–0.937) in the training dataset and 0. 802 (95% CI, 0.635–0.970) in the test dataset, both of which exceeded the performance of the clinical model and the radiomics model. The calibration curve and DCA indicated that the nomogram possessed favorable clinical utility for predicting MB recurrence.ConclusionThe hybrid model, integrating pre-treatment MRI-based radiomics features and clinical characteristics, could effectively predict MB recurrence in pediatric patients.

The authors report on a 21-year-old clinically asymptomatic female patient, who was admitted with two supratentorial intradural lesions in her follow-up magnetic resonance imaging 17 years after treatment of a posterior fossa medulloblastoma. Sequential surgical removal was performed. The left parietal tumor with dural involvement was diagnosed as a transitional meningioma WHO (World Health Organization) grade 1. The right temporal lesion, which had also close relationship to the dura, was diagnosed as a spindle cell sarcoma. We therefore report a metachronous tumor development of a benign and a malignant intradural sarcomatous tumor as secondary neoplasms following childhood medulloblastoma treatment.

Basal cell nevus syndrome (Gorlin syndrome) is a rare genetic condition characterized by multiple basal cell carcinomas, often arising before age 20. Most cases result from a mutation in the patched 1 gene-part of the sonic hedgehog pathway. Rarely, this condition is related to a suppressor of fused gene mutation, which occurs downstream from Smoothened, and is unresponsive to Smoothened inhibitors including vismodegib and sonidegib. Notably, basal cell nevus syndrome, secondary to a suppressor of fused gene mutation, is associated with a higher incidence of childhood medulloblastoma with implications for the patient and offspring. A 72-year-old man with pearly papules coalescing into plaques across the nose and cheeks presented. The lesions had appeared as a teenager, and the patient reported his sister had similar lesions. Five biopsies, reviewed by three dermatopathologists, were consistent with basal cell carcinoma. Genetic testing was negative for patched 1 and patched 2 mutations but positive for a heterozygous suppressor of fused mutation. Patients with basal cell nevus syndrome should be treated with surgical excision, counseled on sun protection, screened and monitored for complications, and treated with vismodegib (if associated with patched 1 mutation) or itraconazole (if associated with suppressor of fused mutation).

Multilevel thresholding technique with Archery Gold Rush Optimization and PCNN-based childhood medulloblastoma classification using microscopic images

Medulloblastoma is similar to other common tumors in the posterior cranial fossa of children in terms of the onset and clinical manifestations. Still, its main treatment methods, surgical methods and prognosis are quite different. Therefore, there is an urgent need for finding biomarkers for differential diagnosis. The purpose of this study was to identify new lipids and differential metabolic pathways by analyzing the significantly different lipids present in the plasma of children with medulloblastoma in comparison to those with other intracranial tumors. In this study, 35 patients with medulloblastoma and 32 matched controls were enrolled. Plasma samples and medical records were collected, and untargeted lipidomics analyses were performed using UHPLC-MS/MS. A total of 97 differential lipids in the plasma of children with medulloblastoma were identified. Seven differential lipids could be potentially useful in medulloblastoma detection and a diagnostic model was established. The metabolic pathway analysis showed that there were significant differences in patients with medulloblastoma in terms of glycerophospholipid metabolism metabolism, sphingolipid metabolism and linoleic acid metabolism pathways. The difference in plasma lipid markers between medulloblastoma and other intracranial tumors screened in this study may be useful to support and improve the differential diagnosis of medulloblastoma in children.

Objective: To explore the short-term efficacy and safety of proton radiotherapy as an adjuvant treatment for medulloblastoma in children, focusing on evaluating its impact on local tumor control rate, neurocognitive function, and pituitary-thyroid axis. Methods: Thirty children with medulloblastoma who completed surgery between May 2023 and May 2024 were included in the study. The patients were randomly assigned to two groups: the experimental group received proton radiotherapy, while the control group underwent conventional photon radiotherapy. Both groups followed a standard dose regimen: 36Gy for the whole brain and spinal cord, and 54Gy for the tumor bed. Observation indicators included the local tumor control rate, acute radiotherapy-related toxicities, and changes in pituitary-thyroid function within 6 months. Results: The local tumor control rate was better in the proton radiotherapy group compared to the control group, with no significant increase in acute toxic side effects. In neurocognitive assessments, children in the experimental group showed more stable cognitive function maintenance. Endocrine monitoring revealed that the pituitary-thyroid axis function was relatively stable in the proton group, and the risk of impairment was significantly lower than that in the photon group. Conclusion: Proton radiotherapy has significant clinical advantages as an adjuvant treatment for medulloblastoma in children. Its precise dose delivery reduces exposure to normal brain tissue, significantly reducing the risk of neurocognitive and endocrine function impairment. This therapy not only improves local tumor control but also balances the quality of life for the children, providing a more ideal treatment option. Future studies need to expand the sample size and extend follow-up time to verify long-term safety and durability of efficacy. The results of this study provide a solid clinical basis for the promotion and application of proton radiotherapy in the treatment of pediatric brain tumors.

Medulloblastoma (MB) recurrence can manifest in various clinical ways and still remains a major therapeutic challenge. As reported in the international literature, high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) has low effectiveness and severe toxicity in patients with recurrent MB. Here, we analyzed the effectiveness and tolerability of HDCT with auto-HSCT in 9 pediatric and adolescent patients with MB relapses whose histological samples and magnetic resonance images had been reviewed at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from July 2013 till December 2021. The aim of the study was to evaluate the effectiveness of the HDCT with auto-HSCT approach for the treatment of MB relapses in pediatric patients. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of Russia.

Today, the contribution of hereditary tumor syndromes to the development of cancer in children is obvious, which determines the need for screening programs and selection of the most effective methods of anticancer therapy. One of the most aggressive hereditary tumor syndromes is heritable TP53-related cancer syndrome (hTP53rc, formerly known as Li–Fraumeni syndrome), characterized by a high risk, early onset and recurrent cases of malignant neoplasms in one patient. The article describes current data on hTP53rc syndrome and the features of its clinical course, and provides international recommendations for monitoring and cancer screening in pediatric patients with hTP53rc syndrome. As a clinical observation, we present an analysis of the registry of patients with relapsed and refractory forms of medulloblastoma (n = 241) with the assessment of its incidence in cases of germline mutations in the TP53 gene with the description of their medical history and the influence of this genetic event on the outcomes. The results of our study, as well as data from international literature, indicate unfavorable prognosis in tumors, including medulloblastoma, in patients with hTP53rc syndrome, however, such factors as early screening, surveillance and early and adequate therapy can help to increase their life expectancy. The study was approved by the Independent Ethics Committee and the Scientific Council of the Almazov National Medical Research Centre of Ministry of Healthcare of the Russian Federation.

MEDLIGHTNET: A LIGHTWEIGHT MULTI-COLOUR-SPACE CNN FOR CHILDHOOD MEDULLOBLASTOMA DIAGNOSIS FROM HISTOPATHOLOGICAL IMAGES

Germline loss-of-function (LOF) variants in Elongator acetyltransferase complex subunit 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ∼30% of the Sonic hedgehog (SHH) 3 subtype. The mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of premalignancy in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yields SHH-MB-like tumors with compromised p53 signaling, providing a plausible explanation for the exclusivity of ELP1-associated MBs in the SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivates p53-dependent apoptosis and extends survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics targeting MDM2 as a rational treatment option.

Primary gonadal dysfunction after oncological treatment in a cohort of childhood medulloblastoma survivors

This scoping review aims to provide a comprehensive analysis of our current understanding of the role of neurosurgery in treating recurrent medulloblastoma in children. Focusing specifically on repeat resection and biopsy, this review offers insights into the existing strengths and weaknesses of the literature and explores future directions for the treatment of recurrent medulloblastoma cases. This review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews guidelines. The Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Cochrane databases were searched for terms regarding medulloblastoma, pediatric patients, and tumor subtypes. A total of 2381 articles were retrieved from the database search along with an additional 7 studies from manual reference searching. After deduplication, 1347 articles were screened by title and abstract for inclusion and exclusion criteria. Full-text review was completed for 45 articles, and 21 were included in the final review. This review found limited evidence suggesting potential survival benefits of repeat resection in select cases, while the role of biopsy remains largely investigational. Despite significant scholarship on primary medulloblastoma, new approaches are urgently needed concerning surgical options for recurrence. More common interventions such as repeat resection are limited due to the metastatic propensity of medulloblastoma at relapse and the lack of information about the specific applications to tumor subtypes. Robust protocols and studies involving the utility of repeat biopsy at relapse for targeted therapy are lacking and further studies are required. The absence of studies evaluating the role of surgery revealed by this review highlights that to truly understand the biology of personalized approaches to recurrent medulloblastoma, it will be critical that neurosurgeons are intimately involved in these efforts.

Rethinking neurocognitive outcomes in adult survivors of childhood medulloblastoma: Progress and unmet challenges.

Abstract In the 20 years since the completion of the Human Genome Project, cancer biology remains rooted in the belief that the human genome encodes ∼20,000 protein-coding genes. This assumption has been fundamentally challenged by the discovery of microproteins, which are encoded across the genome by thousands of non-canonical open reading frames (ORF). Whether these microproteins reflect a previously untapped source of cancer genes may therefore have a profound impact on our understanding of cancer biology. To address this question, we have interrogated the prevalence and impact of non-canonical ORF translation across multiple cancer types. Using ribosome profiling, ORF cDNA libraries, expression profiling and CRISPR/Cas9 screens, we find that thousands of non-canonical ORFs are translated in cancer cells; nearly half (46%) of tested non-canonical ORFs may make a detectable microprotein; nearly 30% induced gene expression changes in cancer cell lines; and 10% induced a cancer cell viability defect when knocked-out. High-resolution CRISPR saturation mutagenesis identified a subset of non-canonical ORFs with exquisite genetic selectivity in about one-third of cases, providing high-confidence genetic evidence for a causal role of the non-canonical ORF in cancer cell viability. To position specific candidates in the context of cancer biology, we have characterized two cancer-associated microproteins encoded by non-canonical ORFs. In breast cancer, we described G029442 - renamed glycine-rich extracellular protein-1 (GREP1) - as a secreted protein that is a preferential genetic dependency in this disease through its regulation of the oncogenic cytokine, GDF15. Moreover, GREP1 expression is prognostic for poor patient outcomes. In childhood medulloblastoma, we found that MYC-driven medulloblastoma cells preferentially upregulated an upstream open reading frame in the ASNSD1 5’ untranslated region, termed ASNSD1-uORF. ASNSD1 uORF was a top genetic vulnerability in multiple models of medulloblastoma and it functions as a component of the prefoldin-like complex, which post-translationally regulates nascent proteins. Together, ASNSD1-uORF and the prefoldin-like complex impacted cancer cell cycle through the proteomic regulation of proteins involved in mitosis and chromosome spindle complexes. In summary, our work supports a generalizable principle that ncORFs commonly encode biologically-active microproteins in diverse malignancies. Ongoing investigation of ncORFs therefore represents a new frontier in cancer research with the potential to define the next generation of therapeutic target genes. Citation Format: John R. Prensner. Mapping the functional microproteome in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY04-01.

BackgroundSonic hedgehog (SHH) medulloblastoma is the most common molecular group of infant and early childhood medulloblastoma (iMB) and has no standard of care at relapse. This work aimed to evaluate the post-relapse survival (PRS) and explore prognostic factors of patients with nodular desmoplastic (ND) and/or SHH iMB.MethodsThis international retrospective study included 147 subjects diagnosed with relapsed ND/SHH iMB between 1995 and 2017, <6 years old at original diagnosis, and treated without initial craniospinal irradiation (CSI). Univariable and multivariable Cox models with propensity score analyses were used to assess PRS for those in the curative intent cohort.ResultsThe 3-year PRS was 61.6% (95% confidence interval [CI], 52.2–69.6). The median age at relapse was 3.4 years (interquartile range [IQR], 2.6–4.1). Those with local relapse (40.8%) more often received salvage treatment with surgery (P < .001), low-dose CSI (≤24 Gy; P < .001), or focal radiotherapy (P = .008). Patients not receiving CSI (40.5%) more often received salvage marrow-ablative chemotherapy (HDC + AuHCR [P < .001]). On multivariable analysis, CSI was associated with improved survival (hazard ratio [HR] 0.33 [95% CI, 0.13–0.86], P = .04). Salvage HDC + AuHCR, while clinically important, did not reach statistical significance (HR 0.24 [95% CI, 0.0054–1.025], P = .065).ConclusionsSurvival of patients with relapsed SHH iMB is not satisfactory and relies on treatments associated with toxicities including CSI and/or HDC + AuHCR. Cure at initial diagnosis to avoid relapse is crucial. For patients with localized relapse undergoing resection, alternative salvage regimens that avoid high-dose CSI (>24 Gy) can be considered.

Medulloblastoma (MB) represents the predominant intracranial neoplasm observed in pediatric populations, characterized by a five-year survival rate ranging from 60% to 80%. Anticipating the prognostic outcome of medulloblastoma in children prior to surgical intervention holds paramount significance for informing treatment modalities effectively. Radiomics has emerged as a pervasive tool in both prognostic anticipation and therapeutic management across diverse tumor spectra. This study aims to develop a radiomics-based prediction model for the prognosis of children with MB and to validate the contribution of radiomic features in predicting the prognosis of MB when combined with clinical features. Patients diagnosed with medulloblastoma at our hospital from December 2012 to March 2022 were randomly divided into a training cohort (n = 40) and a test cohort (n = 41). Regions of interest (ROIs) were manually drawn on T1-weighted images (T1WI) along the boundary of the tumor, and radiomic features were extracted. Radiomic features related to survival prognosis were selected and used to construct a radiomics model. The patients were classified into two different risk stratifications according to the Risk-score calculated from the radiomics model. The log-rank test was used to test the difference in survival between the two stratifications to verify the classification value of the radiomics model. Clinical features related to the prognosis were used to construct a clinical model or clinical-radiomics model together with the radiomic features. Then, the clinical model, radiomics model, and clinical-radiomics model were compared to validate the improvement of radiomics in predicting the prognosis of medulloblastoma. The performance of the three models was evaluated with the C-index and the time-dependent AUC. Overall survival (OS) was defined as the time from receiving the operation to death or last follow-up. A total of 81 children were included in this study. A total of five prognostic radiomic features were selected. The radiomics model could discriminate different risk hierarchies with good performance power in the training and testing datasets (training set p= 0.0009; test set p = 0.0286). Six clinical features associated with prognosis (duration of disease, risk hierarchy, dissemination, radiology, chemotherapy, and last postoperative white blood cell (WBC) level in CSF) were selected. The radiomic-clinical molecular features had better predictive value for OS (C-index = 0.860; Brier score: 0.087) than the radiomic features (C-index = 0.762; Brier score: 0.073) or clinical molecular characteristics (C-index = 0.806; Brier score: 0.092). Radiomic features based on T1-weighted imaging have predictive value for pediatric medulloblastoma. Radiomics has incremental value in predicting the prognosis of MB, and clinical-radiomics models have a better predictive effect than clinical models.

To this day, there is no Class I (A) evidence base that could serve as a guideline for the treatment of tumor-associated hydrocephalus in children. Tumors of the posterior cranial fossa (PCF), due to their special interaction with the cerebrospinal fluid pathways, are most often accompanied by the development of hydrocephalus. It is debatable which treatment tactics should be applied correctly: whether to install an external ventricular drainage or a ventriculoperitoneal shunt, whether to perform an endoscopic triventriculostomy, or postpone the procedure of cerebrospinal fluid removal until resection of the tumor. This does not exclude the progression of post-resection hydrocephalus, which occurs in 37 % of cases in the pediatric population.

ObjectivePostoperative tracheostomy is a significant complication following medulloblastoma (MB) resection. This study aimed to develop a predictive model for postoperative tracheostomy requirement in children undergoing MB surgical resection. This model was derived as a side product of a larger research project analyzing surgical outcomes in pediatric MB patients.ResultsForty-five patients (26%) required tracheostomy postoperatively. Using multivariable logistic regression, five models were developed, and the final model was selected based on performance and simplicity. The simplified version included two predictors: preoperative brainstem invasion and postoperative brainstem contusion, each contributing equally to the score. The model demonstrated an AUC of 0.845. Predicted risks of requiring a tracheostomy were 5.8%, 57.7%, and 75% for scores of 0, 1, and 2, respectively. This tool provides clinicians with a quantitative approach to assess tracheostomy risk, improving decision-making and patient management.

Medulloblastoma (MB) in children is associated with distinct molecular subgroups, reflecting substantial biological heterogeneity. The presence of isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations in paediatric MB has been rarely reported and not routinely investigated. Our study included 23 samples from paediatric patients diagnosed with MB. Hotspot alterations at codons IDH1 R132 and IDH2 R172 were examined using Sanger sequencing following polymerase chain reaction (PCR). The mean age of the patients was 10 years (SD: 4.25), comprising 17 males and 6 females. All cases exhibited classical histological features of MB. β-Catenin expression was observed in four cases (17.4 %), while 19 cases (82.6 %) showed no expression. No statistically significant differences in progression-free survival (PFS) were found between MBs with positive or negative β-catenin expression (P = 0.6). Radiotherapy alone was administered to four patients (17.4 %), while 19 patients (82.6 %) received combined radiotherapy and chemotherapy. The median PFS was 383 days (1 year and 18 days). IDH1 R132 or IDH2 R172 hotspot mutations were not detected in any of the samples. The absence of IDH1 or IDH2 mutations in paediatric MB may be attributed to differences in mutational profiles and cellular origins in childhood MB, despite its histomolecular similarities with adult MB.