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CNS Oncology Jul 2016Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification... (Review)
Review
Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification schemes will include molecular alterations. AA can be separated into subgroups, which share similar molecular profiles, age at diagnosis and median survival, based on 1p/19q co-deletion status and IDH mutation status. AA with co-deletion of chromosomes 1p and 19q and IDH mutation have the best prognosis. AA with IDH mutation and no 1p/19q co-deletion have intermediate prognosis and AA with wild-type IDH have the worst prognosis and share many molecular alterations with glioblastoma. Treatment of noncodeleted AA based on preliminary results from the CATNON clinical trial consists of maximal safe resection followed by radiotherapy with post-radiotherapy temozolomide (TMZ) chemotherapy. The role of concurrent TMZ and whether IDH1 subgroups benefit from TMZ is currently being evaluated in the recently completed randomized, prospective Phase III clinical trial, CATNON.
Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Humans; Isocitrate Dehydrogenase; Mutation
PubMed: 27230974
DOI: 10.2217/cns-2016-0002 -
Acta Neuropathologica Aug 2018Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular...
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Histones; Humans; Infant; Isocitrate Dehydrogenase; Kaplan-Meier Estimate; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Retrospective Studies; Signal Transduction; Tumor Suppressor Proteins; X-linked Nuclear Protein; Young Adult
PubMed: 29564591
DOI: 10.1007/s00401-018-1837-8 -
Acta Neuropathologica Jul 2018According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade...
According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII), and WHO grade IV glioblastoma, IDH-mutant (GBM). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII and AAIII have lost their significance. In contrast, GBM still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
Topics: Adolescent; Adult; Aged; Algorithms; Astrocytoma; Brain Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Expression Regulation, Neoplastic; Humans; Isocitrate Dehydrogenase; Ki-67 Antigen; Male; Middle Aged; Models, Biological; Mutation; Neoplasm Grading; Neoplasm Proteins; World Health Organization; Young Adult
PubMed: 29687258
DOI: 10.1007/s00401-018-1849-4 -
Acta Neuropathologica Nov 2018EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-), and TERT promoter mutation (pTERTmut) are alterations...
Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma.
EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-), and TERT promoter mutation (pTERTmut) are alterations frequently observed in adult IDH-wild-type (IDHwt) glioblastoma (GBM). In the absence of endothelial proliferation and/or necrosis, these alterations currently are considered to serve as a surrogate for upgrading IDHwt diffuse or anaplastic astrocytoma to GBM. Here, we set out to determine the distribution of EGFRamp, 7+/10-, and pTERTmut by analyzing high-resolution copy-number profiles and next-generation sequencing data of primary brain tumors. In addition, we addressed the question whether combinations of partial gains on chromosome 7 and partial losses on chromosome 10 exhibited a diagnostic and prognostic value similar to that of complete 7+/10-. Several such combinations proved relevant and were combined as the 7/10 signature. Our results demonstrate that EGFRamp and the 7/10 signature are closely associated with IDHwt GBM. In contrast, pTERTmut is less specific for IDHwt GBM. We conclude that, in the absence of endothelial proliferation and/or necrosis, the detection of EGFRamp is a very strong surrogate marker for the diagnosis of GBM in IDHwt diffuse astrocytic tumors. The 7/10 signature is also a strong surrogate marker. However, care should be taken to exclude pleomorphic xanthoastrocytoma. pTERTmut is less restricted to this entity and needs companion analysis by other molecular markers to serve as a surrogate for diagnosing IDHwt GBM. A combination of any two of EGFRamp, the 7/10 signature and pTERTmut, is highly specific for IDHwt GBM and the combination of all three alterations is frequent and exclusively seen in IDHwt GBM.
Topics: Adult; Aged; Astrocytoma; Brain; Brain Neoplasms; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 7; Cohort Studies; ErbB Receptors; Female; Glioblastoma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation
PubMed: 30187121
DOI: 10.1007/s00401-018-1905-0 -
The Lancet. Oncology Jul 2012Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma.
METHODS
Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m(2) temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6-7 weeks in 30 fractions of 1·8-2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241.
FINDINGS
Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3-10·2) in the temozolomide group versus 9·6 months (8·2-10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84-1·42, p(non-inferiority)=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2-4·1] vs 4·7 [4·2-5·2]; HR 1·15, 95% CI 0·92-1·43, p(non-inferiority)=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0-10·0]; HR 0·62, 95% CI 0·42-0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5-11·7] vs 4·6 [4·2-5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0-3·5] vs 4·6 months [3·7-6·3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight).
INTERPRETATION
Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.
FUNDING
Merck Sharp & Dohme.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Dacarbazine; Disease-Free Survival; Female; Humans; Isocitrate Dehydrogenase; Male; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 22578793
DOI: 10.1016/S1470-2045(12)70164-X -
AJNR. American Journal of Neuroradiology Sep 2010Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the...
Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the mechanism of action as well as the clinical role for this chemotherapeutic drug.
Topics: Administration, Oral; Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; Dacarbazine; Drug Costs; Glioblastoma; Humans; Temozolomide
PubMed: 20538821
DOI: 10.3174/ajnr.A2170 -
Child's Nervous System : ChNS :... Nov 2016The purpose of this review is to document the various types of astrocytoma that occur in the fetus and neonate, their locations, initial findings, pathology, and... (Review)
Review
INTRODUCTION
The purpose of this review is to document the various types of astrocytoma that occur in the fetus and neonate, their locations, initial findings, pathology, and outcome. Data are presented that show which patients are likely to survive or benefit from treatment compared with those who are unlikely to respond.
MATERIALS AND METHODS
One hundred one fetal and neonatal tumors were collected from the literature for study.
RESULTS
Macrocephaly and an intracranial mass were the most common initial findings. Overall, hydrocephalus and intracranial hemorrhage were next. Glioblastoma (GBM) was the most common neoplasm followed in order by subependymal giant cell astrocytoma (SEGA), low-grade astrocytoma, anaplastic astrocytoma, and desmoplastic infantile astrocytoma (DIA). Tumors were detected most often toward the end of the third trimester of pregnancy.
CONCLUSION
A number of patients were considered inoperable since their tumor occupied much of the intracranial cavity involving large areas of the brain. High-grade astrocytomas were more common than low-grade ones in this review. Fetuses and neonates with astrocytoma have a mixed prognosis ranging from as low as 20 % (GBM) to a high of 90 %. The overall survival was 47/101 or 46 %.
Topics: Astrocytoma; Brain Neoplasms; Female; Fetus; Humans; Infant, Newborn; Pregnancy
PubMed: 27568373
DOI: 10.1007/s00381-016-3215-y -
Archives of Pathology & Laboratory... Mar 2007Glioblastoma (GBM), the most common primary intracranial malignancy, is a morphologically diverse neoplasm with dismal prognosis despite multimodality therapy. Only 3... (Review)
Review
CONTEXT
Glioblastoma (GBM), the most common primary intracranial malignancy, is a morphologically diverse neoplasm with dismal prognosis despite multimodality therapy. Only 3 distinct morphologic variants of GBM are currently recognized by the current World Health Organization classification scheme, including GBM, giant cell GBM, and gliosarcoma. Additional variants, some of which have significant morphologic overlap with tumors that have more favorable prognosis and treatment response rates, particularly anaplastic oligodendroglioma, have been described since its publication in 2000 and may be included in the next classification.
OBJECTIVE
To summarize the morphologic and molecular genetic diversity of both well-established and novel GBM variants and outline our approach to these heterogeneous neoplasms and their distinction from other diffuse, high-grade gliomas.
DATA SOURCES
Published literature and our own experience in an active academic diagnostic surgical neuropathology practice were reviewed.
CONCLUSIONS
Precise subclassification of GBM is required for accurate prognostication and appropriate treatment planning.
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Gliosarcoma; Humans; Oligodendroglioma
PubMed: 17516742
DOI: 10.5858/2007-131-397-G -
Cancer Reports (Hoboken, N.J.) Oct 2023A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying... (Review)
Review
BACKGROUND
A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying astrocytoma formation has not yet been revealed, although various factors have been investigated. Therefore, our objective was to unravel and summarize our current understanding of molecular genetics and associated signaling pathways with some possible therapeutic strategies for astrocytoma.
RECENT FINDINGS
In general, four different forms of astrocytoma have been identified in individuals, including circumscribed, diffuse, anaplastic, and multiforme glioblastoma, according to a recent literature review. All types of astrocytoma have a direct connection with some oncogenic signaling cascade. Common signaling is MAPK cascade, including Ras-Raf-ERK, up-regulated with activating EGFR/AKT/PTEN/mTOR and PDGFR. Recent breakthrough studies found that BRAF mutations, including KIAA1549: BRAF and BRAF V600E are responsible for astrocytoma progression. Additionally, cancer progression is influenced by mutations in some tumor suppressor genes, such as the Tp53/ATRX and MGMT mutant. As synthetic medications must cross the blood-brain barrier (BBB), modulating signal systems such as miRNA is the primary option for treating patients with astrocytoma. However, available surgery, radiation therapy, and experimental therapies such as adjuvant therapy, anti-angiogenic therapy, and EGFR-targeting antibody drug are the usual treatment for most types of astrocytoma. Similar to conventional anticancer medications, some phytochemicals slow tumor growth by simultaneously controlling several cellular proteins, including those involved in cell cycle regulation, apoptosis, metastatic spread, tyrosine kinase, growth factor receptor, and antioxidant-related proteins.
CONCLUSION
In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.
Topics: Humans; Proto-Oncogene Proteins B-raf; Brain Neoplasms; Astrocytoma; Glioblastoma; ErbB Receptors
PubMed: 37675821
DOI: 10.1002/cnr2.1889 -
The Neuroradiology Journal Oct 2021To characterise peritumoral zones in glioblastoma and anaplastic astrocytoma evaluating T2 values using T2 mapping sequences.
PURPOSE
To characterise peritumoral zones in glioblastoma and anaplastic astrocytoma evaluating T2 values using T2 mapping sequences.
MATERIALS AND METHODS
In this study, 41 patients with histopathologically confirmed World Health Organization high grade gliomas and preoperative magnetic resonance imaging examinations were retrospectively identified and enrolled. High grade gliomas were differentiated: (a) by grade, glioblastoma versus anaplastic astrocytoma; and (b) by isocitrate dehydrogenase mutational state, mutated versus wildtype. T2 map relaxation times were assessed from the tumour centre to peritumoral zones by means of a region of interest and calculated pixelwise by using a fit model.
RESULTS
Significant differences between T2 values evaluated from the tumour centre to the peritumoral zone were found between glioblastoma and anaplastic astrocytoma, showing a higher decrease in signal intensity (T2 value) from tumour centre to periphery for glioblastoma (0.0049 - fit-model: glioblastoma -25.02± 19.89 (-54-10); anaplastic astrocytoma -5.57±22.94 (-51-47)). Similar results were found when the cohort was subdivided by their isocitrate dehydrogenase profile, showing an increased drawdown from tumour centre to periphery for wildtype in comparison to mutated isocitrate dehydrogenase ( = 0.0430 - fit model: isocitrate dehydrogenase wildtype -10.35±16.20 (-51) - 0; isocitrate dehydrogenase mutated 12.14±21.24 (-15-47)). A strong statistical proof for both subgroup analyses ( = 0.9987 - glioblastoma 0.93±0.08; anaplastic astrocytoma 0.94±0.15) was found.
CONCLUSION
Peritumoral T2 mapping relaxation time tissue behaviour of glioblastoma differs from anaplastic astrocytoma. Significant differences in T2 values, using T2 mapping relaxation time, were found between glioblastoma and anaplastic astrocytoma, capturing the tumour centre to the peritumoral zone. A similar curve progression from tumour centre to peritumoral zone was found for isocitrate dehydrogenase wildtype high grade gliomas in comparison to isocitrate dehydrogenase mutated high grade gliomas. This finding is in accordance with the biologically more aggressive behaviour of isocitrate dehydrogenase wildtype in comparison to isocitrate dehydrogenase mutated high grade gliomas. These results emphasize the potential of mapping techniques to reflect the tissue composition of high grade gliomas.
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Humans; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Mutation; Retrospective Studies
PubMed: 33573473
DOI: 10.1177/1971400921989325