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Brain Pathology (Zurich, Switzerland) Jul 2003The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss... (Review)
Review
The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss clinical, histological and molecular features that can be used in such treatment customization, focusing on how histopathological grading can impact both patient care and research on the molecular basis of CNS embryonal tumors. Medulloblastomas span a histological spectrum ending in overtly malignant large cell/anaplastic lesions characterized by increased nuclear size, marked cytological anaplasia, and increased mitotic and apoptotic rates. These "high-grade" lesions make up approximately one quarter of medulloblastomas, and recur and metastasize more frequently than tumors lacking anaplasia. We believe anaplastic change represents a type of malignant progression common to many medulloblastoma subtypes and to other CNS embryonal lesions as well. Correlation of these histological changes with the accumulation of genetic events suggests a model for the histological and molecular progression of medulloblastoma.
Topics: Anaplasia; Carcinoma, Large Cell; Cerebellar Neoplasms; Disease Progression; Gene Expression Profiling; Humans; Medulloblastoma; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal
PubMed: 12946027
DOI: 10.1111/j.1750-3639.2003.tb00037.x -
Cancer Science May 2016Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination... (Review)
Review
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long-term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients.
Topics: Animals; Cell Separation; Drug Resistance, Neoplasm; Humans; Medulloblastoma; Meningeal Neoplasms; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Signal Transduction
PubMed: 27171351
DOI: 10.1111/cas.12925 -
Journal of B.U.ON. : Official Journal... 2018The aim of this study was to present the management and treatment of children with medulloblastoma in Serbia, a middle-income country (MIC).
PURPOSE
The aim of this study was to present the management and treatment of children with medulloblastoma in Serbia, a middle-income country (MIC).
METHODS
The data of 87 children diagnosed with medulloblastoma and treated at the Institute for Oncology and Radiology of Serbia from 2000 to 2013 were analyzed.
RESULTS
The children's median age was 8.3 years (range 2.5-17.3). Eighty-two (94.2%) were 3 years or older. Sixtytwo (71.3%) patients had stage M0 medulloblastoma, 12 (13.8%) had stage M1 and 13 (14.9%) had stage M2 or M3. As of October 2015, 51 (58.6%) patients were alive and 31 (35.6%) had died. Five patients (5.7%) were lost to followup. Twenty-six patients relapsed. The median follow-up time was 58 months (range 4-187). Mean overall survival (OS) was 76.4% at 3 years, 66.2% at 5 years and 59.2% at 10 years. Mean disease-free survival (DFS) was 75.8% at 3 years, 62.8% at 5 years and 56.6% at 10 years. Mean OS of stage M0 patients was 86.4% at 3 years, 74% at 5 years and 63.1% at 10 years. The OS of stage M1, M2 and M3 patients combined was 48.9% at 3 years, 44.0% at 5 years and 37.7% at 10 years.
CONCLUSION
In Serbia, a MIC, it is possible to achieve good treatment results in children with medulloblastoma using international treatment guidelines and recommendations, available resources and an experienced team of professionals dedicated to pediatric neurooncology.
Topics: Adolescent; Cerebellar Neoplasms; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Male; Medulloblastoma; Neoplasm Staging; Prognosis; Serbia; Survival Analysis; Treatment Outcome
PubMed: 30358225
DOI: No ID Found -
Wiley Interdisciplinary Reviews.... Jul 2019Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor... (Review)
Review
Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Signaling Pathways > Cell Fate Signaling.
Topics: Animals; Brain Neoplasms; Epigenesis, Genetic; Glioma; Humans; Medulloblastoma; Neural Stem Cells; Oligodendrocyte Precursor Cells
PubMed: 30945456
DOI: 10.1002/wdev.342 -
La Clinica Terapeutica 2022Histograms can be determined throughout tumors, relying partly on existing tumor microstructure knowledge and the sampling effect from area of interest analyses. We...
PURPOSE
Histograms can be determined throughout tumors, relying partly on existing tumor microstructure knowledge and the sampling effect from area of interest analyses. We aimed to investigate the impact of ADC histogram parameters in discriminating medulloblastoma, ependymoma, and pilocytic astrocytoma.
METHODS
This study received approval from the Institutional Ethics Review Committee of Children's Hospital 02. Processes were conducted according to relevant laws and regulations, and requirements for written informed consent were fulfilled. The study involved 24 patients at Children's Hospital 02 from February-December 2019. Group 1 included 12 children with medulloblastoma, group 2 included 5 with ependymoma, and group 3 included 7 with pilocytic astrocytoma. All patients underwent MRI followed by surgery or biopsy to obtain histopathological confirmations.
RESULTS
Our analysis indicated that AUC, sensitivity, and specificity were 96.7%, 91.7%, and 100%, respectively when ADCkurtosis (cut-off point = 2.34) was taken to differentiate between medulloblasto-mas and ependymomas. To distinguish between medulloblastomas and pilocytic astrocytomas, the cut-off points of ADCmean, ADCmedian, ADCmax, ADCmin, rADCmean, rADCmax, and rADCmin of 0.985, 0.910, 1.305, 0.710, 1.349, 1.738, and 1.251, were taken respectively with AUC, sensitivity, and specificity elicited at 100%. To discriminate between ependymomas and pilocytic astrocytomas, the cut-off points of ADCmean, ADCmedian, ADCmax, ADCmin, rADCmean, rADC-median, rADCmax and rADCmin were 1.010, 0.930, 1.270, 0.735, 1.346, 1.324, 1.676, and 1.273, respectively, with AUC, sensitivity, and specificity at 100%.
CONCLUSION
ADC histograms can facilitate differentiation among juvenile medulloblastoma, ependymoma, and pilocytic astrocytoma, providing reliable, objective evidence of tumor differentiation.
Topics: Astrocytoma; Cerebellar Neoplasms; Child; Diffusion Magnetic Resonance Imaging; Ependymoma; Humans; Medulloblastoma; Retrospective Studies
PubMed: 35857056
DOI: 10.7417/CT.2022.2448 -
Neuro-oncology Mar 2022Group 3 medulloblastoma (MB) is often accompanied by MYC amplification. PLK1 is an oncogenic kinase that controls cell cycle and proliferation and has been preclinically...
BACKGROUND
Group 3 medulloblastoma (MB) is often accompanied by MYC amplification. PLK1 is an oncogenic kinase that controls cell cycle and proliferation and has been preclinically validated as a cancer therapeutic target. Onvansertib (PCM-075) is a novel, orally available PLK1 inhibitor, which shows tumor growth inhibition in various types of cancer. We aim to explore the effect of onvansertib on MYC-driven medulloblastoma as a monotherapy or in combination with radiation.
METHODS
Crisper-Cas9 screen was used to discover essential genes for MB tumor growth. Microarray and immunohistochemistry on pediatric patient samples were performed to examine the expression of PLK1. The effect of onvansertib in vitro was measure by cell viability, colony-forming assays, extreme limiting dilution assay, and RNA-Seq. ALDH activity, cell-cycle distribution, and apoptosis were analyzed by flow cytometry. DNA damage was assessed by immunofluorescence staining. Medulloblastoma xenografts were generated to explore the monotherapy or radio-sensitizing effect.
RESULTS
PLK1 is overexpressed in Group 3 MB. The IC50 concentrations of onvansertib in Group 3 MB cell lines were in a low nanomolar range. Onvansertib reduced colony formation, cell proliferation, stem cell renewal and induced G2/M arrest in vitro. Moreover, onvansertib in combination with radiation increased DNA damage and apoptosis compared with radiation treatment alone. The combination radiotherapy resulted in marked tumor regression in xenografts.
CONCLUSIONS
These findings demonstrate the efficacy of a novel PLK1 inhibitor onvansertib in vitro and in xenografts of Group 3 MB, which suggests onvansertib is an effective strategy as monotherapy or in combination with radiotherapy in MB.
Topics: Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cerebellar Neoplasms; Child; G2 Phase Cell Cycle Checkpoints; Humans; Medulloblastoma; Piperazines; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pyrazoles; Quinazolines
PubMed: 34477871
DOI: 10.1093/neuonc/noab207 -
Neuro-oncology Jan 2014Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Patients with MB who are classified as having high-risk disease or those with recurrent... (Review)
Review
Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Patients with MB who are classified as having high-risk disease or those with recurrent disease respond poorly to current therapies and have an increased risk of MB-related mortality. Preclinical studies and molecular profiling of MB tumors have revealed upregulation or activation of several key signaling pathways such as the sonic hedgehog and WNT pathways. Although the exact mechanisms underlying MB tumorigenesis remain poorly understood, inhibiting these key pathways with molecularly targeted therapies represents an important approach to improving MB outcomes. Several molecularly targeted therapies are already under clinical investigation in MB patients. We discuss current preclinical and clinical data, as well as data from clinical trials of targeted therapies that are either ongoing or in development for MB.
Topics: Animals; Antineoplastic Agents; Cerebellar Neoplasms; Humans; Medulloblastoma; Molecular Targeted Therapy; Neoplasm Proteins; Signal Transduction
PubMed: 24305711
DOI: 10.1093/neuonc/not147 -
Cell Feb 2018While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth...
While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.
Topics: Allografts; Animals; Cell Line, Tumor; Chemokine CCL2; Chromosomes, Human, Pair 10; Female; Humans; Male; Medulloblastoma; Meningeal Neoplasms; Mice, SCID; Neoplastic Cells, Circulating; Parabiosis
PubMed: 29474906
DOI: 10.1016/j.cell.2018.01.038 -
Expert Review of Neurotherapeutics Jul 2012Recent efforts at stratifying medulloblastomas based on their molecular features have revolutionized our understanding of this morbidity. Collective efforts by multiple... (Review)
Review
Recent efforts at stratifying medulloblastomas based on their molecular features have revolutionized our understanding of this morbidity. Collective efforts by multiple independent groups have subdivided medulloblastoma from a single disease into four distinct molecular subgroups characterized by disparate transcriptional signatures, mutational spectra, copy number profiles and, most importantly, clinical features. We present a summary of recent studies that have contributed to our understanding of the core medulloblastoma subgroups, focusing largely on clinically relevant discoveries that have already, and will continue to, shape research.
Topics: Cerebellar Neoplasms; Humans; Medulloblastoma
PubMed: 22853794
DOI: 10.1586/ern.12.66 -
Brain Pathology (Zurich, Switzerland) Jan 2011Embryonal brain tumors are a heterogeneous group of neoplasms united by the presence of poorly differentiated stem-like cells. Molecular details are increasingly being... (Review)
Review
Embryonal brain tumors are a heterogeneous group of neoplasms united by the presence of poorly differentiated stem-like cells. Molecular details are increasingly being used to separate them into biologically and clinically meaningful groups. For medulloblastoma, integrated mRNA expression profiling and DNA analysis by a number of research groups defines 4-6 distinctive molecular variants. A subset with prominent Wnt activity is associated with good clinical outcomes and classic histology. Medulloblastomas showing a Hedgehog gene expression signature are frequently of the desmoplastic/nodular subtype. Interestingly, Hedgehog activity is found in tumors arising either in infants or older teenagers and adults. The association of clinically aggressive medulloblastoma with MYC expression, large cell/anaplastic change and high levels of photoreceptor differentiation transcripts has also been noted in several studies. Immunohistochemical analysis of just one or two genes per molecular medulloblastoma variant may be sufficient for accurate classification, and this would be of great practical utility if validated. Advances have also been made in the classification of central nervous system (CNS) Primitive Neuroectodermal Tumors (PNET), as several groups have identified an amplicon at chromosome 19q13.41-42, which appears to define a unique PNET subtype associated with prominent true rosettes, young age and very poor outcomes.
Topics: Brain Neoplasms; Carcinoma, Embryonal; Humans; Medulloblastoma; Neuroectodermal Tumors, Primitive; Pathology, Molecular
PubMed: 21129063
DOI: 10.1111/j.1750-3639.2010.00455.x