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Clinical and Translational Radiation... May 2024As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our...
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.
PubMed: 38628594
DOI: 10.1016/j.ctro.2024.100777 -
Pflugers Archiv : European Journal of... Jun 2024Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these...
Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BK 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 Ca-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 Ca signal secondarily activated the large conductance calcium-activated potassium channel (BK). 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.
Topics: Humans; Acid Sensing Ion Channels; Medulloblastoma; Cell Line, Tumor; Receptors, G-Protein-Coupled; Hydrogen-Ion Concentration; Cell Size; Cell Death; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Calcium; Cerebellar Neoplasms
PubMed: 38627262
DOI: 10.1007/s00424-024-02964-7 -
International Journal of Molecular... Mar 2024Medulloblastoma (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...
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-TGFβ-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.
Topics: Humans; Child; Medulloblastoma; Brain Neoplasms; Cerebellar Neoplasms; Histone Demethylases; Epigenesis, Genetic; Tumor Microenvironment
PubMed: 38612726
DOI: 10.3390/ijms25073917 -
Acta Neuropathologica Communications Apr 2024Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor...
Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.
Topics: Adult; Humans; Brain Neoplasms; Genes, p53; Glioblastoma; Glioma; Isocitrate Dehydrogenase; Li-Fraumeni Syndrome; Mutation
PubMed: 38605367
DOI: 10.1186/s40478-024-01762-7 -
Cancer Reports (Hoboken, N.J.) Apr 2024Medulloblastoma (MB) is a rare primitive neuroectodermal tumors originating from the cerebellum. MB is the most common malignant primary brain tumor of childhood. MB... (Review)
Review
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.
Topics: Humans; Medulloblastoma; Neural Stem Cells; Apoptosis; Cerebellar Neoplasms; DNA; Embryonic Structures; Metencephalon
PubMed: 38599791
DOI: 10.1002/cnr2.2048 -
Frontiers in Oncology 2024Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents....
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 ( 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.
PubMed: 38595820
DOI: 10.3389/fonc.2024.1364199 -
BioRxiv : the Preprint Server For... Mar 2024The biological process of RNA translation is fundamental to cellular life and has wide-ranging implications for human disease. Yet, accurately delineating the variation...
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.
PubMed: 38585907
DOI: 10.1101/2024.03.21.586110 -
BioRxiv : the Preprint Server For... Mar 2024MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening across MB cell lines,...
MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening across MB cell lines, we identified the Mediator-associated kinase CDK8 as the top dependence for MYC-driven MB. Loss of CDK8 markedly reduces MYC expression and impedes MB growth. Mechanistically, we demonstrate that CDK8 depletion suppresses ribosome biogenesis and mRNA translation. CDK8 regulates occupancy of phospho-Polymerase II at specific chromatin loci facilitating an epigenetic alteration that promotes transcriptional regulation of ribosome biogenesis. Additionally, CDK8-mediated phosphorylation of 4EBP1 plays a crucial role in initiating eIF4E-dependent translation. Targeting CDK8 effectively suppresses cancer stem and progenitor cells, characterized by increased ribosome biogenesis activity. We also report the synergistic inhibition of CDK8 and mTOR and . Overall, our findings establish a connection between transcription and translation regulation, suggesting a promising therapeutic approach targets multiple points in the protein synthesis network for MYC-driven MB.
PubMed: 38559100
DOI: 10.1101/2024.03.08.584103 -
Journal of Cancer Research and... Jan 2024Small round cell tumors (SRCTs) are a group of malignant neoplasms with minimal or no differentiation, characterized by the presence of round cells with high...
BACKGROUND
Small round cell tumors (SRCTs) are a group of malignant neoplasms with minimal or no differentiation, characterized by the presence of round cells with high nuclear-cytoplasmic ratio. Although SRCTs can occur in any part of the body, involvement of central nervous system (CNS) is uncommon.
AIM
We aimed to study the clinicopathological spectrum of cranial SRCT diagnosed in our institute over a period of four years (2016-2019).
MATERIAL AND METHODS
A retrospective review of medical records (2016-2019) with a morphological diagnosis of cranial SRCT was made. Both intra-axial and extra-axial tumors were included. A total of 60 cases were retrieved, and the clinical and histopathological features were studied. Special cytochemical staining and immunohistochemistry were performed, where needed.
RESULTS
The mean age at presentation was 18.4 years (range, 1-60 years), with a male-to-female ratio of 2.5:1. The most common site was posterior fossa of brain (n = 28, 47%), followed by dorso-lumbar spine (n = 9, 15%). The most common type of tumor was medulloblastoma (n = 29, 48.3%), followed by Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (pPNET) (n = 11, 18.3%), non-Hodgkin lymphoma (NHL) (n = 9, 15%), neuroblastoma (n = 3, 5%), and CNS embryonal tumor, NOS (n = 2, 3.3%). One case each of atypical teratoid rhabdoid tumor (ATRT), rhabdomyosarcoma, pineoblastoma, melanoma, rhabdomyosarcoma, and undifferentiated pleomorphic sarcoma was also documented.
CONCLUSIONS
SRCTs have a variable age of presentation. Their incidence in CNS is low as compared to other organ systems. On light microscopy, the histopathology of these lesions is overlapping, posing a great diagnostic dilemma for the pathologist. The use of ancillary techniques like immunohistochemistry helps in arriving at the correct diagnosis. Treatment strategy and tumor prognosis also vary along the entire spectrum of SRCT, thus making exact characterization essential for proper management.
Topics: Humans; Male; Female; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Tertiary Care Centers; Sarcoma; Rhabdomyosarcoma; Neuroectodermal Tumors, Primitive; Central Nervous System Neoplasms; Neoplasms, Germ Cell and Embryonal; Cerebellar Neoplasms
PubMed: 38554327
DOI: 10.4103/jcrt.jcrt_383_22 -
Scientific Reports Mar 2024Medulloblastoma (MB) is a malignant brain tumour that is highly common in children and has a tendency to spread to the brain and spinal cord. MB is thought to be a...
Medulloblastoma (MB) is a malignant brain tumour that is highly common in children and has a tendency to spread to the brain and spinal cord. MB is thought to be a metabolically driven brain tumour. Understanding tumour cell metabolic patterns and characteristics can provide a promising foundation for understanding MB pathogenesis and developing treatments. Here, by analysing RNA-seq data of MB samples from the Gene Expression Omnibus (GEO) database, 12 differentially expressed metabolic-related genes (DE-MRGs) were chosen for the construction of a predictive risk score model for MB. This model demonstrated outstanding accuracy in predicting the outcomes of MB patients and served as a standalone predictor. An evaluation of functional enrichment revealed that the risk score showed enrichment in pathways related to cancer promotion and the immune response. In addition, a high risk score was an independent poor prognostic factor for MB in patients with different ages, sexes, metastasis stages and subgroups (SHH and Group 4). Consistently, the metabolic enzyme ornithine decarboxylase (ODC1) was upregulated in MB patients with poor survival time. Inhibition of ODC1 in primary and metastatic MB cell lines decreased cell proliferation, migration and invasion but increased immune infiltration. This study could aid in identifying metabolic targets for MB as well as optimizing risk stratification systems and individual treatment plans for MB patients via the use of a metabolism-related gene prognostic risk score signature.
Topics: Child; Humans; Medulloblastoma; Brain Neoplasms; Cell Proliferation; Prognosis; Cerebellar Neoplasms
PubMed: 38553479
DOI: 10.1038/s41598-024-57549-2