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Radiologie (Heidelberg, Germany) Aug 2023Tumors of the posterior fossa account for about 50-55% of brain tumors in childhood. (Review)
Review
CLINICAL ISSUE
Tumors of the posterior fossa account for about 50-55% of brain tumors in childhood.
DIAGNOSTIC WORKUP
The most frequent tumor entities are medulloblastomas, pilocytic astrocytomas, ependymomas, diffuse midline gliomas and atypical teratoid-rhabdoid tumors. Neuroradiological differential diagnosis with magnetic resonance imaging (MRI) is of considerable importance for preoperative planning as well as planning of follow-up therapy.
PERFORMANCE
Most important findings for differential diagnosis of pediatric posterior fossa tumors are tumor location, patient age and the intratumoral apparent diffusion assessed by diffusion-weighted imaging.
ACHIEVEMENTS
Advanced MR techniques like MRI perfusion and MR spectroscopy can be helpful both in the initial differential diagnosis and in tumor surveillance, but exceptional characteristics of certain tumor entities should be kept in mind.
PRACTICAL RECOMMENDATIONS
Standard clinical MRI sequences including diffusion-weighted imaging are the main diagnostic tool in evaluating posterior fossa tumors in children. Advanced imaging methods can be helpful, but should never be interpreted separately from conventional MRI sequences.
Topics: Child; Humans; Medulloblastoma; Infratentorial Neoplasms; Brain Neoplasms; Magnetic Resonance Imaging; Cerebellar Neoplasms
PubMed: 37306749
DOI: 10.1007/s00117-023-01159-y -
Journal of Neuro-oncology Oct 2020In the last decade, a number of genomic and pharmacological studies have demonstrated the importance of epigenetic dysregulation in medulloblastoma initiation and... (Review)
Review
INTRODUCTION
In the last decade, a number of genomic and pharmacological studies have demonstrated the importance of epigenetic dysregulation in medulloblastoma initiation and progression. High throughput approaches including gene expression array, next-generation sequencing (NGS), and methylation profiling have now clearly identified at least four molecular subgroups within medulloblastoma, each with distinct clinical and prognostic characteristics. These studies have clearly shown that despite the overall paucity of mutations, clinically relevant events do occur within the cellular epigenetic machinery. Thus, this review aims to provide an overview of our current understanding of the spectrum of epi-oncogenetic perturbations in medulloblastoma.
METHODS
Comprehensive review of epigenetic profiles of different subgroups of medulloblastoma in the context of molecular features. Epigenetic regulation is mediated mainly by DNA methylation, histone modifications and microRNAs (miRNA). Importantly, epigenetic mis-events are reversible and have immense therapeutic potential.
CONCLUSION
The widespread epigenetic alterations present in these tumors has generated intense interest in their use as therapeutic targets. We provide an assessment of the progress that has been made towards the development of molecular subtypes-targeted therapies and the current status of clinical trials that have leveraged these recent advances.
Topics: Cerebellar Neoplasms; DNA Methylation; Epigenesis, Genetic; Humans; Medulloblastoma; MicroRNAs
PubMed: 32816225
DOI: 10.1007/s11060-020-03591-9 -
Oncogene Mar 2024Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection,... (Review)
Review
Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong the survival time with severe side effects and relapse. Defining the intratumoral heterogeneity, cellular origin and identifying the interaction network within tumor microenvironment are helpful for understanding the mechanisms of medulloblastoma tumorigenesis and relapse. Due to technological limitations, the mechanisms of cellular heterogeneity and tumor origin have not been fully understood. Recently, the emergence of single-cell technology has provided a powerful tool for achieving the goal of understanding the mechanisms of tumorigenesis. Several studies have demonstrated the intratumoral heterogeneity and tumor origin for each subtype of medulloblastoma utilizing the single-cell RNA-seq, which has not been uncovered before using conventional technologies. In this review, we present an overview of the current progress in understanding of cellular heterogeneity and tumor origin of medulloblastoma and discuss novel findings in the age of single-cell technologies.
Topics: Child; Humans; Medulloblastoma; Cerebellar Neoplasms; Neoplasm Recurrence, Local; Brain Neoplasms; Recurrence; Carcinogenesis; Tumor Microenvironment
PubMed: 38355808
DOI: 10.1038/s41388-024-02967-9 -
Cancer Cell Dec 2014Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the...
Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the classification of MB subgroups, historically by histopathology and currently based on genomic information. Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy.
Topics: Animals; Cerebellar Neoplasms; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Medulloblastoma; Mice; Neoplasms, Experimental
PubMed: 25490452
DOI: 10.1016/j.ccell.2014.11.015 -
Neurotherapeutics : the Journal of the... Apr 2017Recent advances in cancer genomics have revealed 4 distinct subgroups of medulloblastomas, each with unique transcription profiles, DNA alterations and clinical outcome.... (Review)
Review
Recent advances in cancer genomics have revealed 4 distinct subgroups of medulloblastomas, each with unique transcription profiles, DNA alterations and clinical outcome. Molecular classification of medulloblastomas improves predictions of clinical outcome, allowing more accurate matching of intensity of conventional treatments with chemotherapy and radiation to overall prognosis and setting the stage for the introduction of targeted therapies.
Topics: Cerebellar Neoplasms; Genomics; Hedgehog Proteins; Humans; Medulloblastoma; Mutation; Precision Medicine; Signal Transduction; Wnt Signaling Pathway
PubMed: 28386677
DOI: 10.1007/s13311-017-0526-y -
Biochemical Pharmacology Sep 2023Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged... (Review)
Review
Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged as key factors in the development, progression, and response to therapy in various types of cancer. Cancer cells exhibit remarkable adaptability by modulating glucose, lipids, amino acids, and nucleotide metabolism to survive in nutrient- and oxygen-deprived environments. Although medulloblastoma has been extensively studied from a genomic perspective, leading to the identification of four subgroups and their respective subcategories, the investigation of its metabolic phenotype has remained relatively understudied. This review focus on the available literature, aiming to summarize the current knowledge about the main metabolic pathways that are deregulated in medulloblastoma tumors, while emphasizing the controversial aspects and the progress that is yet to be made. Furthermore, we underscored the insights gained so far regarding the impact of metabolism on the development of drug resistance in medulloblastoma and the therapeutic strategies employed to target specific metabolic pathways.
Topics: Humans; Medulloblastoma; Cerebellar Neoplasms; Hunger; Brain Neoplasms; Metabolic Networks and Pathways
PubMed: 37481140
DOI: 10.1016/j.bcp.2023.115697 -
Biochemical Pharmacology Aug 2017Sonic hedgehog (Shh) signaling plays a key role in regulation of normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts... (Review)
Review
Sonic hedgehog (Shh) signaling plays a key role in regulation of normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts to finely tune Shh signaling, providing tight control of normal developmental processes. Hyperactivation of Shh signaling often leads to many human malignancies, including basal cell carcinoma and medulloblastoma (MB). However, how tumor cells sustain the aberrant activation of Shh signaling is still not completely understood. We recently revealed that during MB formation, tumor cells express Nestin, a type VI intermediate filament protein, which maintains uncontrolled Shh signaling by abolishing negative feedback by Gli3. Therefore, Nestin expression is a necessary step for MB formation. These findings highlight the novel function of Nestin in regulating Shh signaling, as well as the important role of a disrupted negative feedback mechanism in MB tumorigenesis. Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies.
Topics: Animals; Antineoplastic Agents; Cerebellar Neoplasms; Disease Progression; Feedback, Physiological; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Medulloblastoma; Models, Biological; Molecular Targeted Therapy; Neoplasm Proteins; Nerve Tissue Proteins; Nestin; Signal Transduction; Tumor Burden; Zinc Finger Protein Gli3
PubMed: 28389227
DOI: 10.1016/j.bcp.2017.04.003 -
Neuro-oncology May 2023Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among...
BACKGROUND
Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma.
METHODS
SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo.
RESULTS
High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells.
CONCLUSIONS
High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.
Topics: Humans; Medulloblastoma; Cisplatin; Up-Regulation; Irinotecan; Cerebellar Neoplasms; Epigenesis, Genetic; Hedgehog Proteins; Nuclear Proteins
PubMed: 36273330
DOI: 10.1093/neuonc/noac243 -
Journal of the National Comprehensive... Aug 2023Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is... (Review)
Review
Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.
Topics: Child; Infant; Humans; Adolescent; Child, Preschool; Medulloblastoma; Cerebellar Neoplasms; Hedgehog Proteins; Neoplasm Recurrence, Local; Recurrence
PubMed: 37643637
DOI: 10.6004/jnccn.2023.7024 -
Cancer Science Aug 2021Medulloblastoma is the most common malignant cerebellar tumor in children. Recent technological advances in multilayered 'omics data analysis have revealed 4 molecular... (Review)
Review
Medulloblastoma is the most common malignant cerebellar tumor in children. Recent technological advances in multilayered 'omics data analysis have revealed 4 molecular subgroups of medulloblastoma (Wingless/int, Sonic hedgehog, Group3, and Group4). (Epi)genomic and transcriptomic profiling on human primary medulloblastomas has shown distinct oncogenic drivers and cellular origin(s) across the subgroups. Despite tremendous efforts to identify the molecular signals driving tumorigenesis, few of the identified targets were druggable; therefore, a further understanding of the etiology of tumors is required to establish effective molecular-targeted therapies. Chromatin regulators are frequently mutated in medulloblastoma, prompting us to investigate epigenetic changes and the accompanying activation of oncogenic signaling during tumorigenesis. For this purpose, we have used germline and non-germline genetically engineered mice to model human medulloblastoma and to conduct useful, molecularly targeted, preclinical studies. This review discusses the biological implications of chromatin regulator mutations during medulloblastoma pathogenesis, based on recent in vivo animal studies.
Topics: Animals; Biomarkers, Tumor; Cerebellar Neoplasms; Chromatin; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Engineering; Humans; Medulloblastoma; Mice; Mutation
PubMed: 34050694
DOI: 10.1111/cas.14990