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BMJ Case Reports Feb 2019Paediatric high-grade gliomas, including glioblastoma and anaplastic astrocytoma, make up 8%-12% of paediatric central nervous system tumours and have poor prognosis,...
Paediatric high-grade gliomas, including glioblastoma and anaplastic astrocytoma, make up 8%-12% of paediatric central nervous system tumours and have poor prognosis, with 2-year survival less than 30% and overall survival less than 10%. The only known prognostic factors in this population include extent of resection and tumour histological grade. We present the case of a 9-year-old boy with disseminated anaplastic astrocytoma treated with subtotal resection, craniospinal radiation and temozolomide, with 8-year survival despite metastatic disease at presentation and subtotal resection. Next generation cancer gene panel sequencing revealed an usual pattern of 12 amplifications and four mutations not previously described.
Topics: Astrocytoma; Brain; Chemoradiotherapy; Child; Gene Amplification; High-Throughput Nucleotide Sequencing; Humans; Male; Meningeal Neoplasms; Mutation; Sequence Analysis, DNA; Survival Analysis; Temozolomide; Treatment Outcome
PubMed: 30765449
DOI: 10.1136/bcr-2018-228153 -
The Journal of Pathology Oct 2022Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase...
Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Tumor-Associated Macrophages
PubMed: 35723032
DOI: 10.1002/path.5984 -
Journal of Clinical Neuroscience :... Sep 2017This study aims to review the literature and identify key molecular markers affecting the prognosis of Gliomatosis cerebri (2) to evaluate the level of evidence and... (Review)
Review
This study aims to review the literature and identify key molecular markers affecting the prognosis of Gliomatosis cerebri (2) to evaluate the level of evidence and identify outstanding markers requiring further study. A literature search was conducted across 5 major databases using the key terms: "Molecular markers" AND "Gliomatosis cerebri" OR "diffuse astrocytoma." Critical appraisal and data presentation was performed inline with the PRISMA guidelines. Following search strategy implementation, 11 studies were included in the final review process. Our data demonstrates significant prognostic value associated with IDH1 mutation and variable evidence surrounding the role of INA expression, MGMT promoter methylation and other factors. However, there are significant limitations in the level of evidence obtained. As the genetic basis for the pathogenesis of Gliomatosis cerebri continues to widen, there is little data on markers aside from IDH1 mutation available. IDH1 mutation has been demonstrated to have significant effect on survival, particularly in patients with Gliomatosis cerebri type 2.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Humans; Neoplasms, Neuroepithelial; Prognosis
PubMed: 28539209
DOI: 10.1016/j.jocn.2017.04.043 -
Journal of Computer Assisted Tomography 1990Magnetic resonance (MR) imaging has increased sensitivity in detection of nonenhancing brain tumors and may show the extent of CNS neoplasia with greater detail than CT....
Magnetic resonance (MR) imaging has increased sensitivity in detection of nonenhancing brain tumors and may show the extent of CNS neoplasia with greater detail than CT. Magnetic resonance images of the canine brain were acquired in two dogs with diffuse leptomeningeal and cerebral low grade astrocytoma. Abnormalities were identified with MR imaging when CT and CSF analysis were noncontributory. Changes seen with MR included decreased signal on T1-weighted images and increased signal on T2-weighted images consistent with vasogenic edema. Neither MR nor CT showed post-contrast enhancement. Magnetic resonance did not show the full extent of cellular infiltration, however. This was attributed to the diffuse submacroscopic distribution and absence of corresponding edema and contrast enhancement in certain regions of brain.
Topics: Animals; Astrocytoma; Brain Neoplasms; Cerebral Cortex; Dog Diseases; Dogs; Magnetic Resonance Imaging; Male; Meninges
PubMed: 2370354
DOI: 10.1097/00004728-199007000-00010 -
Methods in Molecular Biology (Clifton,... 2007Astrocytoma is graded as pilocytic (WHO grade I), diffuse (WHO grade II), anaplastic (WHO grade III), and glioblastoma multiforme (WHO grade IV). The progression from... (Review)
Review
Astrocytoma is graded as pilocytic (WHO grade I), diffuse (WHO grade II), anaplastic (WHO grade III), and glioblastoma multiforme (WHO grade IV). The progression from low- to high-grade astrocytoma is associated with distinct molecular changes that vary with patient age, yet the prognosis of high-grade tumors in children and adults is equally dismal. Whether specific gene expression changes are consistently associated with all high-grade astrocytomas, independent of patient age, is not known. To address this question, we reanalyzed the microarray datasets comprising astrocytomas from children and adults, respectively. We identified nine genes consistently dysregulated in high-grade tumors, using four novel tests for identifying differentially expressed genes. Four genes encoding ribosomal proteins (RPS2, RPS8, RPS18, RPL37A) were upregulated, and five genes (APOD, SORL1, SPOCK2, PRSS11, ID3) were downregulated in high-grade by all tests. Expression results were validated using a third astrocytoma dataset. APOD, the most differentially expressed gene, has been shown to inhibit tumor cell and vascular smooth muscle cell proliferation. This suggests that dysregulation of APOD may be critical for malignant astrocytoma formation, and thus a possible novel universal target for therapeutic intervention. Further investigation is needed to evaluate the role of APOD, as well as the other genes identified, in malignant astrocytoma development.
Topics: Adult; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Child; Chromosomes, Human; Cluster Analysis; Data Interpretation, Statistical; Disease Progression; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Models, Genetic; Neoplasm Recurrence, Local; Oligonucleotide Array Sequence Analysis; Reproducibility of Results
PubMed: 17634619
DOI: 10.1007/978-1-59745-390-5_13 -
Oncotarget Mar 2014Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from...
Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Exome; High-Throughput Nucleotide Sequencing; Humans; Mutation; Prognosis
PubMed: 24140581
DOI: 10.18632/oncotarget.1505 -
Acta Neuropathologica Oct 2020Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary...
Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary infratentorial IDH-mutant astrocytic tumors with respect to clinical and molecular parameters. We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss and MGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinctiveness of infratentorial IDH-mutant astrocytomas. Clinical outcome of patients with infratentorial IDH-mutant astrocytomas is significantly better than that of patients with diffuse midline gliomas, H3K27M-mutant (p < 0.005) and significantly worse than that of patients with supratentorial IDH-mutant astrocytomas (p = 0.028). The presented data highlight the very existence and distinctiveness of infratentorial IDH-mutant astrocytomas that have important implications for diagnostics and prognostication. They imply that molecular testing is critical for detection of these tumors, since many of these tumors cannot be identified by immunohistochemistry applied for the mutated IDH1-R132H protein or loss of ATRX.
Topics: Adolescent; Adult; Aged; Astrocytoma; Child; Child, Preschool; Female; Humans; Infant; Infratentorial Neoplasms; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Young Adult
PubMed: 32776277
DOI: 10.1007/s00401-020-02194-y -
Advances in Anatomic Pathology Nov 2017As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its... (Review)
Review
As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its simple definition of presence of vascular proliferation and/or necrosis in a diffuse astrocytoma, the wide variety of cytohistomorphologic appearances overlap with many other neoplastic or non-neoplastic lesions. Here, after a brief review of glioblastoma is provided, the differential diagnostic possibilities with an emphasis on mimics and pitfalls are discussed. To provide an approach applicable to diagnostic practice, these discussions are grouped arbitrarily according to general malignant appearance such as pleomorphic xanthoastrocytoma and ganglioglioma, especially their anaplastic versions, and cellular features such as small cell and epithelioid glioblastoma. Some non-neoplastic lesions that can potentially be mistaken for glioblastoma under certain circumstances are also briefly mentioned. Additional studies, including immunohistochemistry and molecular markers, are included where applicable. Otherwise, exhaustive review of these individual entities, including their epidemiology and molecular biology, is outside the scope of this discussion.
Topics: Biomarkers, Tumor; Biopsy; Brain Neoplasms; Diagnosis, Differential; Diagnostic Errors; Glioblastoma; Humans; Immunohistochemistry; Molecular Diagnostic Techniques; Predictive Value of Tests
PubMed: 28885262
DOI: 10.1097/PAP.0000000000000170 -
Brain Tumor Pathology Jul 2012To investigate whether grade II oligodendroglioma was transformed to glioblastoma or not, histopathological evaluation of recurrent oligodendrogliomal tumors (OG) and...
To investigate whether grade II oligodendroglioma was transformed to glioblastoma or not, histopathological evaluation of recurrent oligodendrogliomal tumors (OG) and diffuse astrocytomas (DA) was performed. The OG group was composed of ten patients with OG, including seven oligodendrogliomas and three oligoastrocytomas. The DA group was composed of ten patients with DA, including eight fibrillary astrocytomas and two gemistocytic astrocytomas. The histopathological parameters of glioblastoma including nuclear atypia, multinucleated giant cells, glomeruloid tufts (GT) as a marker of microvascular proliferation, necrosis, and the Ki-67 staining index were investigated. Evaluation of these parameters was scored as follows: 0, none; 1, sporadic; 2, partial; 3, extensive. There were no cases of transformation to glioblastoma in the OG group. There were five cases of transformation to secondary glioblastoma in the DA group. In recurrent tumors, scores of GT and necrosis in the OG group were significantly lower than those in the DA group (p < 0.005). Nuclear atypia and high proliferative activity (Ki-67 index) were identified in recurrent tumors of the OG group. Our study suggested that the extent of GT and necrosis in recurrent OG was less than that in recurrent DA, and transformation to glioblastoma from oligodendroglial tumor was exceptional.
Topics: Adolescent; Adult; Astrocytoma; Brain Neoplasms; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Oligodendroglioma
PubMed: 22648019
DOI: 10.1007/s10014-012-0104-2 -
Bratislavske Lekarske Listy 2021Due inter alia to wide-spread cell lines cross-contamination it is not clear, which kind of normal or tumoral tissue give rise to permanent cell lines.
OBJECTIVES
Due inter alia to wide-spread cell lines cross-contamination it is not clear, which kind of normal or tumoral tissue give rise to permanent cell lines.
BACKROUND
Few permanent cell lines have been established from low-grade astrocytomas. However, recently some of these have been identified as being cross-contaminated with other cell lines.
METHODS
Morphology, cell growth and GFAP immunophenotype of low-grade astrocytomas were examined on 9 pilocytic and 15 fibrillary (diffuse) tissue cultures.
RESULTS
GFAP-positive process-bearing cells were present in all the cultures, mainly during the first days in vitro (DIV). In pilocytic cultures, cells with hairy (piloid) processes were present. GFAP-positive cells completely disappeared by passages 3 to 5 and all the cultures contained only GFAP-negative "glia-like" cells, which underwent cellular senescence within passages 8 to 15.
CONCLUSION
Key differences in the morphology and GFAP expression between the neoplastic astrocytes and normal "glia-like" cells allow the observation of perceptibly more rapid growth of normal cells in astrocytoma cultures. We caution that cultures prepared from macroscopically tumoral brain tissue may contain rapidly proliferating normal cells. Based on this and our previous studies in relation to the high percentage of cross-contaminated cell lines, we conclude that cells in low-grade astrocytoma cultures lack the capacity for spontaneous immortalization (Fig. 14, Ref. 15). Text in PDF www.elis.sk Keywords: pilocytic astrocytoma, fibrillary astrocytoma, "glia-like" cells, glioma cell lines, GFAP.
Topics: Astrocytoma; Brain Neoplasms; Cell Line; Cell Proliferation; Glial Fibrillary Acidic Protein; Glioma; Humans; Neuroglia
PubMed: 34002608
DOI: 10.4149/10.4149/BLL_2021_061