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Polish Journal of Pathology : Official... 2019In this study we assessed whether gliomas could be subdivided into different molecular subtypes by immunohistochemistry (IHC) reminiscent of those first described by...
In this study we assessed whether gliomas could be subdivided into different molecular subtypes by immunohistochemistry (IHC) reminiscent of those first described by Verhaak et al. in 2010 (classical, proneural, mesenchymal and neural). We also evaluated the prognostic significance of single molecular factors and searched for significant correlations between markers. In this study, we included 146 patients with glioblastomas (GBMs) and 26 with diffuse astrocytomas (DAs). The glioma samples were tested for PDGFRA, IDH1 R132H, CD44, p53, Ki-67, p21 and p27 expression. We found that gliomas could be subdivided into molecular subtypes by IHC. Fifty per cent of GBMs were of the proneural subtype, 18.5% of mesenchymal subtype and 31.5% were not otherwise classified. However, most of the DAs (92.3%) belonged to the proneural subtype. No prognostic role was found for the molecular subtypes, but predictive roles were noted. Both proneural and mesenchymal molecular subtypes showed a benefit from the addition of chemotherapy and radiotherapy; however, the mesenchymal subtype showed a greater response. Interestingly, the mesenchymal subtype did not receive any benefit from the addition of radiotherapy compared with palliative management and surgery alone. Regarding single molecular markers, only IDH1 R132H was found to have a prognostic role for GBMs. There was a trend towards better survival in tumours with lower PDGFRA expression (p = 0.066). In DAs, PDGFRA and Ki-67 expression had prognostic roles. The following statistically significant correlations were found in GBMs: Ki-67/p53, Ki-67/p27 and p53/PDGFRA; in DAs: p53/PDGFRA, CD44/PDGFRA, and p21/PDGFRA.
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Glioma; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Mutation; Prognosis
PubMed: 32146793
DOI: 10.5114/pjp.2019.93126 -
The Oncologist 2004Pediatric high-grade gliomas represent a heterogeneous group of tumors that accounts for 15%-20% of all pediatric central nervous system tumors. These neoplasms... (Review)
Review
Pediatric high-grade gliomas represent a heterogeneous group of tumors that accounts for 15%-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons, in which case the tumors are usually called diffuse brainstem gliomas. The diagnosis of supratentorial neoplasms is dependent on their histologic appearance. The maximum possible surgical resection is always attempted since the degree of surgical resection is the main prognostic factor for these patients. Older children (>3 years) with supratentorial neoplasms undergo a multimodality treatment comprised of surgical resection, radiation therapy, and chemotherapy. The addition of chemotherapy seems to improve the survival of a subset of these children, particularly those with glioblastoma multiforme. However, 2-year survival rates remain poor for children with supratentorial neoplasms, ranging from 10%-30%. The diagnosis of a diffuse brainstem glioma is based upon typical imaging, dispensing with the need for surgery in the majority of cases. Radiation therapy is the mainstay of treatment for children with diffuse brainstem gliomas. The role of chemotherapy for these children is not clear, and it is, in general, employed in the context of an investigational study. Less than 10% of children with diffuse brainstem gliomas survive 2 years. Because the outcome for patients with either type of tumor is poor when standard multimodality therapy is used, these children are ideal candidates for innovative treatment approaches.
Topics: Astrocytoma; Brain Neoplasms; Brain Stem Neoplasms; Child; Disease Progression; Glioma; Humans; Neoplasm Recurrence, Local; Prognosis; Treatment Outcome
PubMed: 15047924
DOI: 10.1634/theoncologist.9-2-197 -
Pathology Jun 2023Homozygous deletion (HD) of the CDKN2A/B locus has emerged as an unfavourable prognostic marker in diffuse gliomas, both IDH-mutant and IDH-wild-type. Testing for...
Homozygous deletion (HD) of the CDKN2A/B locus has emerged as an unfavourable prognostic marker in diffuse gliomas, both IDH-mutant and IDH-wild-type. Testing for CDKN2A/B deletions can be performed by a variety of approaches, including copy number variation (CNV) analysis based on gene array analysis, next generation sequencing (NGS) or fluorescence in situ hybridisation (FISH), but questions remain regarding the accuracy of testing modalities. In this study, we assessed: (1) the utility of S-methyl-5'-thioadenosine phosphorylase (MTAP) and cellular tumour suppressor protein pl61NK4a (p16) immunostainings as surrogate markers for CDKN2A/B HD in gliomas, and (2) the prognostic value of MTAP, across different histological tumour grades and IDH mutation status. One hundred consecutive cases of diffuse and circumscribed gliomas (Cohort 1) were collected, in order to correlate MTAP and p16 expression with the CDKN2A/B status in the CNV plot of each tumour. IDH1 R132H, ATRX and MTAP immunohistochemistry was performed on next generation tissue microarrays (ngTMAs) of 251 diffuse gliomas (Cohort 2) for implementing survival analysis. Complete loss of MTAP and p16 by immunohistochemistry was 100% and 90% sensitive as well as 97% and 89% specific for CDKN2A/B HD, respectively, as identified on CNV plot. Only two cases (2/100) with MTAP and p16 loss of expression did not demonstrate CDKN2A/B HD in CNV plot; however, FISH analysis confirmed the HD for CDKN2A/B. Moreover, MTAP deficiency was associated with shortened survival in IDH-mutant astrocytomas (n=75; median survival 61 vs 137 months; p<0.0001), IDH-mutant oligodendrogliomas (n=59; median survival 41 vs 147 months; p<0.0001) and IDH-wild-type gliomas (n=117; median survival 13 vs 16 months; p=0.011). In conclusion, MTAP immunostaining is an important complement for diagnostic work-up of gliomas, because of its excellent correlation with CDKN2A/B status, robustness, rapid turnaround time and low costs, and provides significant prognostic value in IDH-mutant astrocytomas and oligodendrogliomas, while p16 should be used cautiously.
Topics: Humans; Cyclin-Dependent Kinase Inhibitor p16; Oligodendroglioma; Homozygote; DNA Copy Number Variations; Sequence Deletion; Gene Deletion; Glioma; Biomarkers; Phosphorylases; Astrocytoma; Brain Neoplasms; Isocitrate Dehydrogenase; Mutation
PubMed: 37032198
DOI: 10.1016/j.pathol.2023.01.005 -
Acta Neuropathologica Communications Nov 2023As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount...
As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.
Topics: Humans; Brain Neoplasms; Retrospective Studies; Glioma; Astrocytoma; Mutation; Temozolomide; Genomics; Isocitrate Dehydrogenase
PubMed: 37932833
DOI: 10.1186/s40478-023-01669-9 -
Cancer Reports (Hoboken, N.J.) Mar 2022Pilocytic astrocytoma is the most common brain tumour type in childhood located in the posterior fossa, and treated mainly with surgery. These tumours have low...
BACKGROUND
Pilocytic astrocytoma is the most common brain tumour type in childhood located in the posterior fossa, and treated mainly with surgery. These tumours have low mortality, but knowledge concerning its long-term outcome is sparse.
AIM
The aim of this study was to investigate whether children treated for pilocytic astrocytoma in the posterior fossa had late complications affecting cognition, language and learning.
METHODS
This descriptive single-centre study includes eight children and 12 adults treated as children for pilocytic astrocytoma in the posterior fossa, with a mean follow-up time of 12.4 (range 5-19) years. Well-established tests of intelligence, executive, language and academic function were used.
RESULTS
Intelligence tests showed average results compared with norms. Five patients scored <-1 SD (70-84) and 3 low average (85-92) on full scale IQ. The patients scored average on subtests regarding executive function, except for significantly lower results in inhibition/switching (p = .004). In Rey complex figure test half of the patients scored below -1 SD. Language tests were normal except for significantly lower results in naming ability (p = .049) and in inference (p = .046). In academic tests, results were average, except for significantly lower results in reading speed (p = .024). Patients with learning difficulties performed worse in the tests.
CONCLUSIONS
The patients' functional outcome was favourable but, a not-negligible part of the patients displayed neurocognitive difficulties as revealed by extensive neuro-cognitive and academic testing. Thus, it is important to identify those in need of more thorough cognitive and pedagogic follow-up programmes, including school interventions.
Topics: Astrocytoma; Brain Neoplasms; Child; Cognition; Cognition Disorders; Humans; Language; Young Adult
PubMed: 34231973
DOI: 10.1002/cnr2.1494 -
Asian Pacific Journal of Cancer... Sep 2022This study evaluated the differences between IDH1-R132H and CD133 expression in different categories of astrocytoma.
OBJECTIVE
This study evaluated the differences between IDH1-R132H and CD133 expression in different categories of astrocytoma.
MATERIAL AND METHODS
This study used a cross-sectional design. Sixty-seven paraffin embedded block of Diffuse Astrocytoma (DA), Anaplastic Astrocytoma (AA) and Glioblastoma (GB) were assessed using using the monoclonal antibody IDH1-R132H and Rabbit polyclonal antibody CD133.
RESULTS
It was found that there was a significant relationship between the expression of IDH1-R132H and CD133 in DA, AA and GB (p<0.001). Astrocytoma with IDH-mutant molecular status will express more markers of cancer stem cell CD133 than IDH-wildtype.
CONCLUSION
The IDH1-R132H and CD133 can provide predictive value on treatment success, disease prognosis, recurrence and can be considered as target combination therapy with chemotherapy.
Topics: Animals; Antibodies, Monoclonal; Astrocytoma; Biomarkers; Brain Neoplasms; Cross-Sectional Studies; Glioblastoma; Isocitrate Dehydrogenase; Mutation; Neoplastic Stem Cells; Rabbits
PubMed: 36172668
DOI: 10.31557/APJCP.2022.23.9.3051 -
Acta Neuropathologica Communications Jun 2021Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations...
Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.
Topics: Adolescent; Adult; Aged; Astrocytoma; Child; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Retrospective Studies; Spinal Cord Neoplasms; Young Adult
PubMed: 34193285
DOI: 10.1186/s40478-021-01222-6 -
Arquivos de Neuro-psiquiatria Dec 2023Long-term epilepsy-associated tumors (LEATs) include a series of neoplasms that commonly occur in children, adolescents, or young adults, have an astrocytic or...
Long-term epilepsy-associated tumors (LEATs) include a series of neoplasms that commonly occur in children, adolescents, or young adults, have an astrocytic or glioneuronal lineage, are histologically benign (WHO grade1) with a neocortical localization predominantly situated in the temporal lobes. Clinically, chronic refractory epilepsy is usually the unique symptom. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNT) are the most common representative entities besides pilocytic astrocytomas (PA) and angiocentric gliomas (AG). Recent molecular studies have defined new clinicopathological entities, which are recognized by the WHO 2021 classification of brain tumors. Some of them such as diffuse astrocytoma or altered, polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and multilocular and vacuolating neuronal tumor (MVNT) are currently considered LEATs. The relationship between LEATs and epilepsy is still a matter of debate, and there is a general agreement about the beneficial effects of an early neurosurgical intervention on the clinical outcome.
Topics: Adolescent; Young Adult; Humans; Child; Epilepsy; Glioma; Brain Neoplasms; Ganglioglioma; Astrocytoma; Neoplasms, Neuroepithelial
PubMed: 38157880
DOI: 10.1055/s-0043-1777730 -
The American Journal of Pathology May 2007Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary... (Review)
Review
Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.
Topics: Brain Neoplasms; Chromosomes, Human, Pair 10; Glioblastoma; Humans; Loss of Heterozygosity; Mutation; PTEN Phosphohydrolase; Tumor Suppressor Protein p53
PubMed: 17456751
DOI: 10.2353/ajpath.2007.070011 -
Oncotarget Apr 2017Astrocytoma, a common and highly malignant type of brain tumor, is associated with poor overall survival despite advances in surgical treatment, radiotherapy, and...
BACKGROUND
Astrocytoma, a common and highly malignant type of brain tumor, is associated with poor overall survival despite advances in surgical treatment, radiotherapy, and chemotherapy. The nuclear transcription factor Fli-1 has been shown to increase cellular proliferation and tumorigenesis in many types of cancer; however, previous reports have not described a correlation between clinical outcomes and Fli-1 in astrocytoma patients. The present study aimed to elucidate the clinical role of Fli-1 in astrocytoma.
RESULTS
High-level of Fli-1 protein expression was significantly association with World Health Organization (WHO) high grade and poor prognosis. A multivariate analysis revealed that the WHO grade and Fli-1 protein expression were independent factor of prognostic factors of patients with astrocytoma. In addition, Fli-1 silencing inhibited proliferation, migration, and invasion and led to the downregulation of Ki-67, VEGF, and cyclin D1 expression in the astrocytoma cells.
MATERIALS AND METHODS
Fli-1 protein expression in astrocytoma tissue samples were detected via immunohistochemistry, and potential correlations between clinical parameters and Fli-1 expression were assessed in patients with astrocytoma. Additionally, proliferation, invasion, and migration assays of astrocytoma cell lines were conducted to evaluate the effects of short interfering RNA (siRNA) on these processes; in addition, these cells were subjected to western blotting to detect the expression levels of Fli-1, Ki-67, VEGF, and Cyclin D1.
CONCLUSION
Fli-1 shows promise as a potential prognostic biomarker and therapeutic molecular target for astrocytoma patients.
Topics: Astrocytoma; Cell Culture Techniques; Cell Line, Tumor; Female; Humans; Male; Microfilament Proteins; Prognosis; Receptors, Cytoplasmic and Nuclear; Survival Analysis; Trans-Activators; Transfection
PubMed: 28418872
DOI: 10.18632/oncotarget.16303