Pediatric neurosurgical medulloblastoma outcomes in La Paz, Bolivia: How a Lower Middle-Income Country (LMIC) institution in South America compares to the United States.

BACKGROUND: How pediatric medulloblastoma patients fare in Lower Middle-Income Country (LMICs) in South America is not well understood. Correspondingly, the aim of this study was to summarize the pediatric neurosurgical experience of an institution in La Paz, and compare outcomes to that of a generalized High Income Country (HIC) United States (US) experience. METHODS: A retrospective review of all pediatric neurosurgical medulloblastoma patients at the Children's Hospital of La Paz, Bolivia (Hospital del Niño "Dr. Ovidio Aliaga Uria") between 2014 and 2023 was conducted and compared to a generalized US experience abstracted from the US National Cancer Database (NCDB) and National Inpatient Sample (NIS) databases. Categorical, continuous and survival data were statistically summarized and compared. RESULTS: A total of 24 pediatric medulloblastoma patients underwent neurosurgical treatment at the Hospital del Niño. In this La Paz cohort, there were 15 (63%) males and 9 (38%) females, with a mean age of 5.6 years old at diagnosis. The majority of patients underwent subtotal resection (STR, 79%), while the remaining patients underwent biopsy only. Ten (42%) patients expired during their hospitalization, and mean length of stay overall was 39 days. Only 8 (33%) patients received adjuvant treatment after surgery. Median overall survival from diagnosis in the La Paz cohort was 1.9 months. Compared to the US databases, the La Paz cohort experienced significantly more emergency room admissions for surgery, less gross total resection, more STR, more return to operating room for ventriculoperitoneal shunting, more bacteremia, more tracheostomy procedures, more percutaneous gastrostomy placements, longer lengths of stay, less adjuvant chemotherapy, less radiation therapy, shorter follow-up, and ultimately, significantly shorter overall survival (all P < 0.050). CONCLUSIONS: Pediatric neurosurgical medulloblastoma outcomes at the Children's Hospital of La Paz, Bolivia are significantly inferior to that of a generalized US experience. Future research is required to identify institution- and country-specific initiatives to improve discrepancies between institutions in LMICs in South America compared to HICs.

Treatment response as surrogate to predict risk for disease progression in pediatric medulloblastoma with persistent MRI lesions after first-line treatment.

BACKGROUND: This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma. METHODS: Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed MRI at the end of first-line therapy were analyzed. RESULTS: Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥25% reduction, MR/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5±7.0%[MR/PR] vs. 35.9±12.8%[SD], p=0.03; pptOS: 79.7±5.9[MR/PR] vs. 55.5±13.9[SD], p=0.04). Further, R+/M+ was associated with a higher risk for progression (5-year pptPFS: 22.9±17.9%[R+,M+] vs. 72.4±12.0%[R+,M0]; p=0.03). Watch-and-wait was pursued in 58 patients, while n=26 received additional treatments (chemotherapy only, n=19; surgery only, n=2; combined, n=3; valproic acid, n=2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5±7.7% vs. 51.6±10.7% p=0.71; 5-year pptOS: 76.3±6.9% vs. 69.8±9.7%, p=0.74). For the whole cohort, five-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0±35.4%, Group-4, 52.5±10.5, Group-3 54.2±13.8%; (p=0.08). CONCLUSION: Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in case of solitary persistent medulloblastoma MRI lesion, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information needs consideration for indication of additional treatments for persisting lesions.

Case report: Therapy-related myeloid neoplasms in three pediatric cases with medulloblastoma.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents. However, therapy-related complications, such as therapy-related myeloid neoplasms (t-MNs), can arise, particularly in patients with genetic predisposition syndromes. This case report presents three pediatric cases of medulloblastoma with subsequent development of t-MNs, highlighting the potential role of genetic predisposition and the importance of surveillance for hematological abnormalities in long-term survivors. Case presentation: We describe three cases of pediatric medulloblastoma who developed t-MNs after receiving chemotherapy, including alkylating agents. Two of the patients had underlying genetic predisposition syndromes (TP53 pathologic variants). The latency period between initial diagnosis of medulloblastoma and the development of secondary cancer varied among the cases, ranging from 17 to 65 months. The three cases eventually succumbed from secondary malignancy, therapy-related complications and progression of primary disease, respectively. Conclusions: This report highlights the potential association between genetic predisposition syndromes and the development of therapy-related myeloid neoplasms in pediatric medulloblastoma survivors. It underscores the importance of surveillance for hematological abnormalities among such patients.

Pediatric-Like Brain Tumors in Adults.

Pediatric brain tumors are different to those found in adults in pathological type, anatomical site, molecular signature, and probable tumor drivers. Although these tumors usually occur in childhood, they also rarely present in adult patients, either as a de novo diagnosis or as a delayed recurrence of a pediatric tumor in the setting of a patient that has transitioned into adult services.Due to the rarity of pediatric-like tumors in adults, the literature on these tumor types in adults is often limited to small case series, and treatment decisions are often based on the management plans taken from pediatric studies. However, the biology of these tumors is often different from the same tumors found in children. Likewise, adult patients are often unable to tolerate the side effects of the aggressive treatments used in children-for which there is little or no evidence of efficacy in adults. In this chapter, we review the literature and summarize the clinical, pathological, molecular profile, and response to treatment for the following pediatric tumor types-medulloblastoma, ependymoma, craniopharyngioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, germ cell tumors, choroid plexus tumors, midline glioma, and pleomorphic xanthoastrocytoma-with emphasis on the differences to the adult population.

Late-onset lymphopenia during radiation is associated with an increased risk of tumor recurrence in newly diagnosed pediatric medulloblastoma.

BACKGROUND: Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy-naïve. PROCEDURE: We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2-21 years) treated between 1997 and 2013 with craniospinal RT. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. RESULTS: Eighty-three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty-four of 79 (30%) patients developed disease recurrence at an average 27.0 months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log-rank p = .016; Cox p = .03) and Week 5 (log-rank p = .024; Cox p = .032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p = .04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0-3) or absolute lymphocyte count (ALC) below the median at any time during RT. CONCLUSIONS: Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.

Secondary cerebro-cerebellar and intracerebellar dysfunction in cerebellar mutism syndrome.

BACKGROUND: Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebrocerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebrocerebellar dysfunction may be related to chronic, rather than transient, symptomatology. METHODS: We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury. RESULTS: CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere. CONCLUSIONS: The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal grey and other critical midbrain targets.

Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules.

Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFß-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial-mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.

The pivotal role of irradiation-induced apoptosis in the pathogenesis and therapy of medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is a rare primitive neuroectodermal tumors originating from the cerebellum. MB is the most common malignant primary brain tumor of childhood. 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. Also, apoptosis is a programmed cell death associated with numerous physiological as well as pathological regulations. RECENT FINDINGS: Irradiation (IR)-induce apoptosis triggers cell death, with or without intervening mitosis within a few hours of IR and these share different morphologic alteration such as, loss of normal nuclear structure as well as degradation of DNA. Moreover, MB is strikingly sensitive to DNA-damaging therapies and the role of apoptosis a key treatment modality. Furthermore, in MB, the apoptotic pathways are made up of several triggers, modulators, as well as effectors. Notably, IR-induced apoptotic mechanisms in MB therapy are very complex and they either induce radiosensitivity or inhibit radioresistance leading to potential effective treatment strategies for MB. CONCLUSION: This review explicitly explores the pivotal roles of IR-induced apoptosis in the pathogenesis and therapy of MB.

Helical tomotherapy craniospinal irradiation in primary brain tumours: Toxicities and outcomes in a peadiatric and adult population.

Objective: As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period. Methods and materials: Our study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed. Results: Among the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1-52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18-36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %). Conclusion: CSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.

Deep learning to decode sites of RNA translation in normal and cancerous tissues.

The biological process of RNA translation is fundamental to cellular life and has wide-ranging implications for human disease. Yet, accurately delineating the variation in RNA translation represents a significant challenge. Here, we develop RiboTIE, a transformer model-based approach to map global RNA translation. We find that RiboTIE offers unparalleled precision and sensitivity for ribosome profiling data. Application of RiboTIE to normal brain and medulloblastoma cancer samples enables high-resolution insights into disease regulation of RNA translation.

Are the Radiological and Molecular Features of Pediatric Medulloblastomas Valuable Prognostic Indicators? A 10-year Retrospective Review in the Middle East.

BACKGROUND: Medulloblastomas are the most common malignant brain tumors in the pediatric population. Based on the idea that tumors with identical radio-genomic features should behave similarly, the four molecular subtypes are now widely accepted as a guide for the management and prognosis. The radiological features of medulloblastomas can predict the molecular subtype; thus, anticipating the subsequent disease progression. However, this has not been evaluated comprehensively. PURPOSE: We aim to thoroughly study the association between the molecular subtypes and radiological features of medulloblastomas. Moreover, we aim to investigate the efficacy of this correlation with the use of progression-free survival (PFS) and five-year survival rates. METHODS: A retrospective analysis was conducted for all histopathological confirmed medulloblastomas in pediatric patients (<16 years old) that were operated on in Kuwait over the past ten years (n=44). The radiological, histological, and molecular characteristics were justifiably evaluated and analyzed in our sample. RESULTS: The overall progression-free survival after one year was noticed among 27 cases (≈44%) and the non-specific five-year survival was seen in 31 cases (≈70%) after a five-year follow-up. SHH and WNT had the best outcomes, while group 3 showed the worst outcomes. CONCLUSION: Our findings did not support the association between most of the typical MRI characteristics and survival rate. We further established that SHH and WNT biological types have a better prognosis. There was no association observed between the radiographic features, specifically the location, and the molecular subtype.

Comparing the effects of irradiation with protons or photons on neonatal mouse brain: Apoptosis, oncogenesis and hippocampal alterations.

BACKGROUND AND PURPOSE: Medulloblastoma (MB) is a common primary brain cancer in children. Proton therapy in pediatric MB is intensively studied and widely adopted. Compared to photon, proton radiations offer potential for reduced toxicity due to the characteristic Bragg Peak at the end of their path in tissue. The aim of this study was to compare the effects of irradiation with the same dose of protons or photons in Patched1 heterozygous knockout mice, a murine model predisposed to cancer and non-cancer radiogenic pathologies, including MB and lens opacity. MATERIALS AND METHODS: TOP-IMPLART is a pulsed linear proton accelerator for proton therapy applications. We compared the long-term health effects of 3 Gy of protons or photons in neonatal mice exposed at postnatal day 2, during a peculiarly susceptible developmental phase of the cerebellum, lens, and hippocampus, to genotoxic stress. RESULTS: Experimental testing of the 5 mm Spread-Out Bragg Peak (SOBP) proton beam, through evaluation of apoptotic response, confirmed that both cerebellum and hippocampus were within the SOBP irradiation field. While no differences in MB induction were observed after irradiation with protons or photons, lens opacity examination confirmed sparing of the lens after proton exposure. Marked differences in expression of neurogenesis-related genes and in neuroinflammation, but not in hippocampal neurogenesis, were observed after irradiation of wild-type mice with both radiation types. CONCLUSION: In-vivo experiments with radiosensitive mouse models improve our mechanistic understanding of the dependence of brain damage on radiation quality, thus having important implications in translational research.

Radiomic- and dosiomic-based clustering development for radio-induced neurotoxicity in pediatric medulloblastoma.

BACKGROUND: Texture analysis extracts many quantitative image features, offering a valuable, cost-effective, and non-invasive approach for individual medicine. Furthermore, multimodal machine learning could have a large impact for precision medicine, as texture biomarkers can underlie tissue microstructure. This study aims to investigate imaging-based biomarkers of radio-induced neurotoxicity in pediatric patients with metastatic medulloblastoma, using radiomic and dosiomic analysis. METHODS: This single-center study retrospectively enrolled children diagnosed with metastatic medulloblastoma (MB) and treated with hyperfractionated craniospinal irradiation (CSI). Histological confirmation of medulloblastoma and baseline follow-up magnetic resonance imaging (MRI) were mandatory. Treatment involved helical tomotherapy (HT) delivering a dose of 39 Gray (Gy) to brain and spinal axis and a posterior fossa boost up to 60 Gy. Clinical outcomes, such as local and distant brain control and neurotoxicity, were recorded. Radiomic and dosiomic features were extracted from tumor regions on T1, T2, FLAIR (fluid-attenuated inversion recovery) MRI-maps, and radiotherapy dose distribution. Different machine learning feature selection and reduction approaches were performed for supervised and unsupervised clustering. RESULTS: Forty-eight metastatic medulloblastoma patients (29 males and 19 females) with a mean age of 12 ± 6 years were enrolled. For each patient, 332 features were extracted. Greater level of abstraction of input data by combining selection of most performing features and dimensionality reduction returns the best performance. The resulting one-component radiomic signature yielded an accuracy of 0.73 with sensitivity, specificity, and precision of 0.83, 0.64, and 0.68, respectively. CONCLUSIONS: Machine learning radiomic-dosiomic approach effectively stratified pediatric medulloblastoma patients who experienced radio-induced neurotoxicity. Strategy needs further validation in external dataset for its potential clinical use in ab initio management paradigms of medulloblastoma.

Roles and interactions of tumor microenvironment components in medulloblastoma with implications for novel therapeutics.

Medulloblastomas, the most common malignant pediatric brain tumors, can be classified into the wingless, sonic hedgehog (SHH), group 3, and group 4 subgroups. Among them, the SHH subgroup with the TP53 mutation and group 3 generally present with the worst patient outcomes due to their high rates of recurrence and metastasis. A novel and effective treatment for refractory medulloblastomas is urgently needed. To date, the tumor microenvironment (TME) has been shown to influence tumor growth, recurrence, and metastasis through immunosuppression, angiogenesis, and chronic inflammation. Treatments targeting TME components have emerged as promising approaches to the treatment of solid tumors. In this review, we summarize progress in research on medulloblastoma microenvironment components and their interactions. We also discuss challenges and future research directions for TME-targeting medulloblastoma therapy.

A Prognostic Methylation-Driven Two-Gene Signature in Medulloblastoma.

Medulloblastoma (MB) is one of the most common pediatric brain tumors and it is estimated that one-third of patients will not achieve long-term survival. Conventional prognostic parameters have limited and unreliable correlations with MB outcome, presenting a major challenge for patients' clinical improvement. Acknowledging this issue, our aim was to build a gene signature and evaluate its potential as a new prognostic model for patients with the disease. In this study, we used six datasets totaling 1679 samples including RNA gene expression and DNA methylation data from primary MB as well as control samples from healthy cerebellum. We identified methylation-driven genes (MDGs) in MB, genes whose expression is correlated with their methylation. We employed LASSO regression, incorporating the MDGs as a parameter to develop the prognostic model. Through this approach, we derived a two-gene signature (GS-2) of candidate prognostic biomarkers for MB (CEMIP and NCBP3). Using a risk score model, we confirmed the GS-2 impact on overall survival (OS) with Kaplan-Meier analysis. We evaluated its robustness and accuracy with receiver operating characteristic curves predicting OS at 1, 3, and 5 years in multiple independent datasets. The GS-2 showed highly significant results as an independent prognostic biomarker compared to traditional MB markers. The methylation-regulated GS-2 risk score model can effectively classify patients with MB into high and low-risk, reinforcing the importance of this epigenetic modification in the disease. Such genes stand out as promising prognostic biomarkers with potential application for MB treatment.

PUMC-MB1 is a novel group 3 medulloblastoma preclinical model, sensitive to PI3K/mTOR dual inhibitor.

PURPOSE: Medulloblastoma (MB), a common and heterogeneous posterior fossa tumor in pediatric patients, presents diverse prognostic outcomes. To advance our understanding of MB's intricate biology, the development of novel patient tumor-derived culture MB models with necessary data is still an essential requirement. METHODS: We continuously passaged PUMC-MB1 in vitro in order to establish a continuous cell line. We examined the in vitro growth using Cell Counting Kit-8 (CCK-8) and in vivo growth with subcutaneous and intracranial xenograft models. The xenografts were investigated histopathologically with Hematoxylin and Eosin (HE) staining and immunohistochemistry (IHC). Concurrently, we explored its molecular features using Whole Genome Sequencing (WGS), targeted sequencing, and RNA sequecing. Guided by bioinformatics analysis, we validated PUMC-MB1's drug sensitivity in vitro and in vivo. RESULTS: PUMC-MB1, derived from a high-risk MB patient, displayed a population doubling time (PDT) of 48.18 h and achieved 100% tumor growth in SCID mice within 20 days. HE and Immunohistochemical examination of the original tumor and xenografts confirmed the classification of PUMC-MB1 as a classic MB. Genomic analysis via WGS revealed concurrent MYC and OTX2 amplifications. The RNA-seq data classified it within the Group 3 MB subgroup, while according to the WHO classification, it fell under the Non-WNT/Non-SHH MB. Comparative analysis with D283 and D341med identified 4065 differentially expressed genes, with notable enrichment in the PI3K-AKT pathway. Cisplatin, 4-hydroperoxy cyclophosphamide/cyclophosphamide, vincristine, and dactolisib (a selective PI3K/mTOR dual inhibitor) significantly inhibited PUMC-MB1 proliferation in vitro and in vivo. CONCLUSIONS: PUMC-MB1, a novel Group 3 (Non-WNT/Non-SHH) MB cell line, is comprehensively characterized for its growth, pathology, and molecular characteristics. Notably, dactolisib demonstrated potent anti-proliferative effects with minimal toxicity, promising a potential therapeutic avenue. PUMC-MB1 could serve as a valuable tool for unraveling MB mechanisms and innovative treatment strategies.

Multifunctional Fluoropolymer-Engineered Magnetic Nanoparticles to Facilitate Blood-Brain Barrier Penetration and Effective Gene Silencing in 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.

Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells.

Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these harsh conditions. In that regard, acid-sensitive membrane receptors constitute a particularly interesting target, since they can affect cellular functions through ion flow and second messenger cascades. Our knowledge of these processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. In this study, using RT-qPCR, whole-cell patch clamp, and Ca2+-imaging, we uncovered several ion channels and a G protein-coupled receptor, which were regulated directly or indirectly by low extracellular pH in DAOY and UW228 medulloblastoma cells. Acidification directly activated acid-sensing ion channel 1a (ASIC1a), the proton-activated Cl- channel (PAC, ASOR, or TMEM206), and the proton-activated G protein-coupled receptor OGR1. The resulting Ca2+ signal secondarily activated the large conductance calcium-activated potassium channel (BKCa). Our analyses uncover a complex relationship of these transmembrane proteins in DAOY cells that resulted in cell volume changes and induced cell death under strongly acidic conditions. Collectively, our results suggest that these ion channels in concert with OGR1 may shape the growth and evolution of medulloblastoma cells in their acidic microenvironment.

Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.

OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSION: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.

Multiparametric MRI-Based Interpretable Radiomics Machine Learning Model Differentiates Medulloblastoma and Ependymoma in Children: A Two-Center Study.

RATIONALE AND OBJECTIVES: Medulloblastoma (MB) and Ependymoma (EM) in children, share similarities in age group, tumor location, and clinical presentation. Distinguishing between them through clinical diagnosis is challenging. This study aims to explore the effectiveness of using radiomics and machine learning on multiparametric magnetic resonance imaging (MRI) to differentiate between MB and EM and validate its diagnostic ability with an external set. MATERIALS AND METHODS: Axial T2 weighted image (T2WI) and contrast-enhanced T1weighted image (CE-T1WI) MRI sequences of 135 patients from two centers were collected as train/test sets. Volume of interest (VOI) was manually delineated by an experienced neuroradiologist, supervised by a senior. Feature selection analysis and the least absolute shrinkage and selection operator (LASSO) algorithm identified valuable features, and Shapley additive explanations (SHAP) evaluated their significance. Five machine-learning classifiers-extreme gradient boosting (XGBoost), Bernoulli naive Bayes (Bernoulli NB), Logistic Regression (LR), support vector machine (SVM), linear support vector machine (Linear SVC) classifiers were built based on T2WI (T2 model), CE-T1WI (T1 model), and T1 + T2WI (T1 + T2 model). A human expert diagnosis was developed and corrected by senior radiologists. External validation was performed at Sun Yat-Sen University Cancer Center. RESULTS: 31 valuable features were extracted from T2WI and CE-T1WI. XGBoost demonstrated the highest performance with an area under the curve (AUC) of 0.92 on the test set and maintained an AUC of 0.80 during external validation. For the T1 model, XGBoost achieved the highest AUC of 0.85 on the test set and the highest accuracy of 0.71 on the external validation set. In the T2 model, XGBoost achieved the highest AUC of 0.86 on the test set and the highest accuracy of 0.82 on the external validation set. The human expert diagnosis had an AUC of 0.66 on the test set and 0.69 on the external validation set. The integrated T1 + T2 model achieved an AUC of 0.92 on the test set, 0.80 on the external validation set, achieved the best performance. Overall, XGBoost consistently outperformed in different classification models. CONCLUSION: The combination of radiomics and machine learning on multiparametric MRI effectively distinguishes between MB and EM in childhood, surpassing human expert diagnosis in training and testing sets.