Identification and validation of miRNA-target genes network in pediatric brain tumors.

Alterations in miRNA levels have been observed in various types of cancer, impacting numerous cellular processes and increasing their potential usefulness in combination therapies also in brain tumors. Recent advances in understanding the genetics and epigenetics of brain tumours point to new aberrations and associations, making it essential to continually update knowledge and classification. Here we conducted molecular analysis of 123 samples of childhood brain tumors (pilocytic astrocytoma, medulloblastoma, ependymoma), focusing on identification of genes that could potentially be regulated by crucial representatives of OncomiR-1: miR-17-5p and miR-20a-5p. On the basis of microarray gene expression analysis and qRTPCR profiling, we selected six (WEE1, CCND1, VEGFA, PTPRO, TP53INP1, BCL2L11) the most promising target genes for further experiments. The WEE1, CCND1, PTPRO, TP53INP1 genes showed increased expression levels in all tested entities with the lowest increase in the pilocytic astrocytoma compared to the ependymoma and medulloblastoma. The obtained results indicate a correlation between gene expression and the WHO grade and subtype. Furthermore, our analysis showed that the integration between genomic and epigenetic pathways should now point the way to further molecular research.

Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level.

Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically heterogenous. The application of omics technologies-mainly studying nucleic acids-has significantly improved MB classification and stratification, but treatment options are still unsatisfactory. The proteome and their N-glycans hold the potential to discover clinically relevant phenotypes and targetable pathways. We compile a harmonized proteome dataset of 167 MBs and integrate findings with DNA methylome, transcriptome and N-glycome data. We show six proteome MB subtypes, that can be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pG3myc), and synapses/immunological processes (pSHHs, pG3 and pG4). Multiomic analysis reveals different conservation levels of proteome features across MB subtypes at the DNA methylome level. Aggressive pGroup3myc MBs and favorable pWNT MBs are most similar in cluster hierarchies concerning overall proteome patterns but show different protein abundances of the vincristine resistance-associated multiprotein complex TriC/CCT and of N-glycan turnover-associated factors. The N-glycome reflects proteome subtypes and complex-bisecting N-glycans characterize pGroup3myc tumors. Our results shed light on targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.

Medulloblastoma subgrouping at first sight.

Recent incorporation of the four primary medulloblastoma subgroups into the WHO Classification of Central Nervous System Tumors necessitates globally accessible methods to discern subgroups. In this issue of Cancer Cell, Wang et al. develop a rapid and reliable machine learning workflow for pre-operative subgroup determination using routine magnetic resonance imaging.

Survival-Related Genes on Chromosomes 6 and 17 in Medulloblastoma.

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival-related genes (SRGs) using a gene expression dataset and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1) on chromosome 6, which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4ß, the MB subtype, with 93% deletion of 17p and 98% copy gain of 17q. GO enrichment analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provided a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosomes 6 and 17, warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB.

The Role of the RNA Helicase DDX3X in Medulloblastoma Progression.

Medulloblastoma is the most common pediatric brain cancer, with about five cases per million in the pediatric population. Current treatment strategies have a 5-year survival rate of 70% or more but frequently lead to long-term neurocognitive defects, and recurrence is relatively high. Genomic sequencing of medulloblastoma patients has shown that DDX3X, which encodes an RNA helicase involved in the process of translation initiation, is among the most commonly mutated genes in medulloblastoma. The identified mutations are 42 single-point amino acid substitutions and are mostly not complete loss-of-function mutations. The pathological mechanism of DDX3X mutations in the causation of medulloblastoma is poorly understood, but several studies have examined their role in promoting cancer progression. This review first discusses the known roles of DDX3X and its yeast ortholog Ded1 in translation initiation, cellular stress responses, viral replication, innate immunity, inflammatory programmed cell death, Wnt signaling, and brain development. It then examines our current understanding of the oncogenic mechanism of the DDX3X mutations in medulloblastoma, including the effect of these DDX3X mutations on growth, biochemical functions, translation, and stress responses. Further research on DDX3X's mechanism and targets is required to therapeutically target DDX3X and/or its downstream effects in medulloblastoma progression.

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression.

SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

Neurosurgical short-term outcomes for pediatric medulloblastoma patients and molecular correlations: a 10-year single-center observation cohort study.

This study examined the risk factors for short-term outcomes, focusing particularly on the associations among molecular subgroups. The analysis focused on the data of pediatric patients with medulloblastoma between 2013 and 2023, as well as operative complications, length of stay from surgery to adjuvant treatment, 30-day unplanned reoperation, unplanned readmission, and mortality. 148 patients were included. Patients with the SHH TP53-wildtype exhibited a lower incidence of complications (45.2% vs. 66.0%, odds ratio [OR] 0.358, 95% confidence interval [CI] 0.160 - 0.802). Female sex (0.437, 0.207 - 0.919) was identified as an independent protective factor for complications, and brainstem involvement (1.900, 1.297 - 2.784) was identified as a risk factor. Surgical time was associated with an increased risk of complications (1.004, 1.001 - 1.008), duration of hospitalization (1.006, 1.003 - 1.010), and reoperation (1.003, 1.001 - 1.006). Age was found to be a predictor of improved outcomes, as each additional year was associated with a 14.1% decrease in the likelihood of experiencing a prolonged length of stay (0.859, 0.772 - 0.956). Patients without metastasis exhibited a reduced risk of reoperation (0.322, 0.133 - 0.784) and readmission (0.208, 0.074 - 0.581). There is a significant degree of variability in the occurrence of operative complications in pediatric patients with medulloblastoma. SHH TP53-wildtype medulloblastoma is commonly correlated with a decreased incidence of complications. The short-term outcomes of patients are influenced by various unmodifiable endogenous factors. These findings could enhance the knowledge of onconeurosurgeons and alleviate the challenges associated with patient/parent education through personalized risk communication. However, the importance of a dedicated center with expertise surgical team and experienced neurosurgeon in improving neurosurgical outcomes appears self-evident.

Clinically unfavorable transcriptome subtypes of non-WNT/non-SHH medulloblastomas are associated with a predominance in proliferating and progenitor-like cell subpopulations.

The non-WNT/non-SHH (Grp3/Grp4) medulloblastomas (MBs) include eight second-generation subgroups (SGS; I-VIII) each with distinct molecular and clinical characteristics. Recently, we also identified two prognostically relevant transcriptome subtypes within each SGS MB, which are associated with unique gene expression signatures and signaling pathways. These prognostic subsets may be in connection to the intra-tumoral cell landscape that underlies SGS MB clinical-molecular diversity. Here, we performed a deconvolution analysis of the Grp3/Grp4 MB bulk RNA profiles using the previously identified single-cell RNA-seq reference dataset and focusing on variability in the cellular composition of SGS MB. RNA deconvolution analysis of the Grp3/Grp4 MB disclosed the subgroup-specific neoplastic cell subpopulations. Neuronally differentiated axodendritic GP3-C1 and glutamatergic GP4-C1 subpopulations were distributed within Grp3- and Grp4-associated SGS MB, respectively. Progenitor GP3-B2 subpopulation was prominent in aggressive SGS II MB, whereas photoreceptor/visual perception GP3/4-C2 cell content was typical for SGS III/IV MB. The current study also revealed significant variability in the proportions of cell subpopulations between clinically relevant SGS MB transcriptome subtypes, where unfavorable cohorts were enriched with cell cycle and progenitor-like cell subpopulations and, vice versa, favorable subtypes were composed of neuronally differentiated cell fractions predominantly. A higher than median proportion of proliferating and progenitor cell subpopulations conferred the shortest survival of the Grp3 and Grp 4 MB, and similar survival associations were identified for all SGS MB except SGS IV MB. In summary, the recently identified clinically relevant Grp3/Grp4 MB transcriptome subtypes are composed of different cell populations. Future studies should aim to validate the prognostic and therapeutic role of the identified Grp3/Grp4 MB inter-tumoral cellular heterogeneity. The application of the single-cell techniques on each SGS MB separately could help to clarify the clinical significance of subgroup-specific variability in tumor cell content and its relation with prognostic transcriptome signatures identified before.

[Clinicopathological characteristics of the CD8+ T lymphocytes infiltration and its mechanism in distinct molecular subtype of medulloblastoma].

OBJECTIVE: To investigate the characteristics of the CD8+ T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8+ T cells infiltration and prognosis, to study the function of C-X-C motif chemokine ligand 11 (CXCL11) and its receptor in CD8+ T cells infiltration into tumors and to explore the potential mechanism, and to provide the necessary clinicopathological basis for exploring the immunotherapy of MB. METHODS: In the study, 48 clinical MB samples (12 cases in each of 4 subtypes) were selected from the multiple medical center from 2012 to 2019. The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString PanCancer IO360TM Panel (NanoString Technologies). Immunohistochemistry (IHC) staining of formalin-fixed, paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8+ T cells in the MB four subtypes. Through bioinformatics analysis, the relationship between CD8+T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated. The expression of CXCR3 receptor on the surface of CD8+T cells in MB was verified by double immunofluorescence staining, and the underlying molecular mechanism of CD8+T cells infiltration into the tumor was explored. RESULTS: The characteristic index of CD8+T cells in the WNT subtype of MB was relatively high, suggesting that the number of CD8+T cells in the WNT subtype was significantly higher than that in the other three subtypes, which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus (GEO) database analysis by using R2 online data analysis platform. And the increase of CD8+T cells infiltration was positively correlated with the patient survival. The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes. Immunofluorescence staining showed the presence of CXCL11 receptor, CXCR3, on the surface of CD8+T cells, suggesting that the CD8+T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3. CONCLUSION: The CD8+T cells infiltrate more in the WNT subtype MB than other subtypes. The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system, and the patients with more infiltration of CD8+T cells in tumor have better prognosis. This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8+T cells infiltration in MB, and give a new potential therapeutic target for the future immunotherapy of MB.

Using diffusion MRI to understand white matter damage and the link between brain microstructure and cognitive deficits in paediatric medulloblastoma patients.

PURPOSE: Survivors of medulloblastoma face a range of challenges after treatment, involving behavioural, cognitive, language and motor skills. Post-treatment outcomes are associated with structural changes within the brain resulting from both the tumour and the treatment. Diffusion magnetic resonance imaging (MRI) has been used to investigate the microstructure of the brain. In this review, we aim to summarise the literature on diffusion MRI in patients treated for medulloblastoma and discuss future directions on how diffusion imaging can be used to improve patient quality. METHOD: This review summarises the current literature on medulloblastoma in children, focusing on the impact of both the tumour and its treatment on brain microstructure. We review studies where diffusion MRI has been correlated with either treatment characteristics or cognitive outcomes. We discuss the role diffusion MRI has taken in understanding the relationship between microstructural damage and cognitive and behavioural deficits. RESULTS: We identified 35 studies that analysed diffusion MRI changes in patients treated for medulloblastoma. The majority of these studies found significant group differences in measures of brain microstructure between patients and controls, and some of these studies showed associations between microstructure and neurocognitive outcomes, which could be influenced by patient characteristics (e.g. age), treatment, radiation dose and treatment type. CONCLUSIONS: In future, studies would benefit from being able to separate microstructural white matter damage caused by the tumour, tumour-related complications and treatment. Additionally, advanced diffusion modelling methods can be explored to understand and describe microstructural changes to white matter.

Advancing presurgical non-invasive molecular subgroup prediction in medulloblastoma using artificial intelligence and MRI signatures.

Global investigation of medulloblastoma has been hindered by the widespread inaccessibility of molecular subgroup testing and paucity of data. To bridge this gap, we established an international molecularly characterized database encompassing 934 medulloblastoma patients from thirteen centers across China and the United States. We demonstrate how image-based machine learning strategies have the potential to create an alternative pathway for non-invasive, presurgical, and low-cost molecular subgroup prediction in the clinical management of medulloblastoma. Our robust validation strategies-including cross-validation, external validation, and consecutive validation-demonstrate the model's efficacy as a generalizable molecular diagnosis classifier. The detailed analysis of MRI characteristics replenishes the understanding of medulloblastoma through a nuanced radiographic lens. Additionally, comparisons between East Asia and North America subsets highlight critical management implications. We made this comprehensive dataset, which includes MRI signatures, clinicopathological features, treatment variables, and survival data, publicly available to advance global medulloblastoma research.

REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma.

The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)-a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein - a component of an E3 ligase complex that ubiquitinates HIF1α. Human SHH-medulloblastoma tumors with higher REST expression exhibit nuclear localization of HIF1α, in contrast to its cytoplasmic localization in low-REST tumors. In vitro, REST knockdown promotes an increase in VHL levels and a decrease in cytoplasmic HIF1α protein levels, and autophagy flux. In contrast, REST elevation causes a decline in VHL levels, as well as its interaction with HIF1α, resulting in a reduction in HIF1α ubiquitination and an increase in autophagy flux. These data suggest that REST elevation promotes autophagy in SHH medulloblastoma cells by modulating HIF1α ubiquitination and stability in a VHL-dependent manner. Thus, our study is one of the first to connect VHL to REST-dependent control of autophagy in a subset of medulloblastomas.

Deep learning models for predicting the survival of patients with medulloblastoma based on a surveillance, epidemiology, and end results analysis.

Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in medulloblastoma patients. We analyzed data from 2,322 medulloblastoma patients using the SEER database and randomly divided the dataset into training and testing datasets in a 7:3 ratio. We chose three models to build, one based on neural networks (DeepSurv), one based on ensemble learning that Random Survival Forest (RSF), and a typical Cox Proportional-hazards (CoxPH) model. The DeepSurv model outperformed the RSF and classic CoxPH models with C-indexes of 0.751 and 0.763 for the training and test datasets. Additionally, the DeepSurv model showed better accuracy in predicting 1-, 3-, and 5-year survival rates (AUC: 0.767-0.793). Therefore, our prediction model based on deep learning algorithms can more accurately predict the survival rate and survival period of medulloblastoma compared to other models.

Mechanistic insights into medulloblastoma relapse.

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.

Secondary cancer risk assessment in healthy organs following craniospinal irradiation.

INTRODUCTION: Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI. MATERIALS AND METHODS: Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs. RESULTS: The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels. CONCLUSIONS: From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.

Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.

Epidemiological trends and factors associated with survival in patients with medulloblastoma: A 45-year population-based retrospective study.

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.

Risk-stratification for treatment de-intensification in WNT-pathway medulloblastoma: finding the optimal balance between survival and quality of survivorship.

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 cm2) and lack of metastasis were classified as average-risk disease with >80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm2), 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.

Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results Overall, 82 participants with medulloblastoma (mean age, 11.0 years ± 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years ± 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, χ2 = 12.4, P < .001) and right (coefficient = -0.15, χ2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion The severity of CMS-associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dorigatti Soldatelli and Ertl-Wagner in this issue.

Singular Value Decomposition-Based Penalized Multinomial Regression for Classifying Imbalanced Medulloblastoma Subgroups Using Methylation Data.

Medulloblastoma (MB) is a molecularly heterogeneous brain malignancy with large differences in clinical presentation. According to genomic studies, there are at least four distinct molecular subgroups of MB: sonic hedgehog (SHH), wingless/INT (WNT), Group 3, and Group 4. The treatment and outcomes depend on appropriate classification. It is difficult for the classification algorithms to identify these subgroups from an imbalanced MB genomic data set, where the distribution of samples among the MB subgroups may not be equal. To overcome this problem, we used singular value decomposition (SVD) and group lasso techniques to find DNA methylation probe features that maximize the separation between the different imbalanced MB subgroups. We used multinomial regression as a classification method to classify the four different molecular subgroups of MB using the reduced DNA methylation data. Coordinate descent is used to solve our loss function associated with the group lasso, which promotes sparsity. By using SVD, we were able to reduce the 321,174 probe features to just 200 features. Less than 40 features were successfully selected after applying the group lasso, which we then used as predictors for our classification models. Our proposed method achieved an average overall accuracy of 99% based on fivefold cross-validation technique. Our approach produces improved classification performance compared with the state-of-the-art methods for classifying MB molecular subgroups.