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PubMed1977

Supratentorial recurrences of gliomas. Morphological studies in relation to time intervals with astrocytomas.

We report 137 recurrent supratentorial astrocytomas. The primary tumours diagnosed on the basis of a grading system with three stages were 72 astrocytomas I and 65 astrocytomas II. In the first group 14% of the recurrences were not changed, 55.5% became astrocytomas II, and 30.5% became glioblastomas. In the second group 55.4% were unchanged, and 44.6% became glioblastomas. The postoperative intervals untile reintervention or death were statistically examined. It seems that the recurrence time chielfy depends on the nature of the primary tumour. The transformation of an astrocytoma I to a glioblastoma takes longer than the transformation of an astrocytoma II into a glioblastoma. In about two thirds of all astrocytomas an increase of malignancy is to be expected. From the histological picture it is not possible in an individual case to predict the likelihood or speed of malignant change. With regard to the effect of irradiation the authors conclude that radiotherapy most probably does not produce malignancy.

Adolescent↗

PubMed1978

Computed tomography of supratentorial astrocytoma.

In a group of 40 astrocytomas the C.T. appearance was correlated with the grade of malignancy. On the plain scan the majority presented an irregular, nonhomogeneous low density lesion, better demarcatable in high than in low grade astrocytomas. Contrast enhancement was seen in 28 of the 32 high grade astrocytomas, 50% of the annular, 25% of the nodular and 25% of the mixed type. Six of the 8 low grade astrocytomas showed no contrast enhancement and 1 showed an annular type lesion. A relationship was found between the degree of contrast enhancement and the vascularity. Mass effect was observed in all but 1 patient, but more pronounced in high grade astrocytomas. At the first interpretation 98% were recognized as a lesion, 93% as a tumor and 68% as an astrocytoma. One false negative and no false postive C.T.scans were obtained. In review, high and low grade malignancies were correctly differentiated in 90%. As a screening method, the combination of EEG and echo equalled C.T.; in establishing a definite diagnosis angiography was inferior to C.T. Solely on the basis of the C.T. appearance, astrocytomas can hardly be differentiated from the other malignant brain tumors, but the grade of malignancy can be predicted reliably.

Astrocytoma↗

PubMed2025

Longitudinal profiling of IDH-mutant astrocytomas reveals acquired RAS-MAPK pathway mutations associated with inferior survival.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant astrocytomas represent the most frequent primary intraparenchymal brain tumor in young adults, which typically arise as low-grade neoplasms that often progress and transform to higher grade despite current therapeutic approaches. However, the genetic alterations underlying high-grade transformation and disease progression of IDH-mutant astrocytomas remain inadequately defined. METHODS: Genomic profiling was performed on 205 IDH-mutant astrocytomas from 172 patients from both initial treatment-naive and recurrent post-treatment tumor specimens. Molecular findings were integrated with clinical outcomes and pathologic features to define the associations of novel genetic alterations in the RAS-MAPK signaling pathway. RESULTS: Likely oncogenic alterations within the RAS-MAPK mitogenic signaling pathway were identified in 13% of IDH-mutant astrocytomas, which involved the KRAS, NRAS, BRAF, NF1, SPRED1, and LZTR1 genes. These included focal amplifications and known activating mutations in oncogenic components (e.g. KRAS, BRAF), as well as deletions and truncating mutations in negative regulatory components (e.g. NF1, SPRED1). These RAS-MAPK pathway alterations were enriched in recurrent tumors and occurred nearly always in high-grade tumors, often co-occurring with CDKN2A homozygous deletion. Patients whose IDH-mutant astrocytomas harbored these oncogenic RAS-MAPK pathway alterations had inferior survival compared to those with RAS-MAPK wild-type tumors. CONCLUSIONS: These findings highlight novel genetic perturbations in the RAS-MAPK pathway as a likely mechanism contributing to the high-grade transformation and treatment resistance of IDH-mutant astrocytomas that may be a potential therapeutic target for affected patients and used for future risk stratification.

IDH1 mutation↗

PubMed1979

Astrocytoma in children. A review of 79 cases--1960-1976.

Seventy-nine children with histologically proven astrocytomas, 32 cerebral, 30 cerebellar, 9 thalamic, 6 optic nerve, and 2 in the 4th ventricular floor were reviewed retrospectively. Seventy-one per cent of the astrocytomas were well differentiated. Unlike adult astrocytomas, there was slight female predominance in our group. Cerebral astrocytomas were more frequent beyond nine years of age. The overall five-year survival rate of cerebral astrocytomas was 95% (19/20) for well-differentiated, and 19% (2/12) for poorly-differentiated tumors. In cerebellar astrocytomas the survival rates were 75% (18/24) and 33% (2/6) respectively.

Adolescent↗

PubMed2026

Targeting SUV4-20H2-mediated H4K20 methylation restrains growth and migration in pediatric high-grade astrocytomas.

Pediatric astrocytomas are characterized by increased molecular and clinical heterogeneity with epigenetic alterations contributing to aggressiveness and therapy resistance. The repressive histone mark H4K20 trimethylation (H4K20me3) and the methyltransferase SUV4-20H2 (KMT5C) are critical regulators of chromatin integrity and genome stability, with limited investigation in pediatric astrocytomas. KMT5C mRNA levels were evaluated in a publicly available pediatric gliomas database using bioinformatic analysis. Investigation of SUV4-20H2 and H4K20me3 expression was performed in a cohort of 43 pediatric astrocytoma tissues by immunohistochemistry. Their functional role and mechanism of action was investigated in pediatric glioma cell lines by using the substrate-competitive inhibitor of SUV4-20, A-196. Cell viability, apoptosis and migration were assessed using XTT, cleaved PARP, and wound healing assays, respectively. Effects of treatment on H4K20 methylation, DNA damage, mitotic stress [Polo-like kinase (PLK1) expression], and invasion markers (N-cadherin, β-catenin expression) were examined by western immunoblotting. KMT5C mRNA was significantly enriched in pediatric high-grade astrocytomas compared to low-grade tumors. A significant elevation of SUV4-20H2 and H4K20me3 expression was detected in astrocytoma tissues indicating epigenetic dysregulation contributing to malignancy. Treatment with A-196 reduced cell proliferation of pediatric glioma cell lines and induced apoptosis in a dose-dependent manner. It further impaired cell migration, accompanied by reduced N-cadherin and β-catenin expression. Mechanistically, inhibition of SUV4-20 depleted H4K20me3, inducing chromatin destabilization, replication-associated DNA damage and was associated with increased PLK1 expression, consistent with activation of a mitotic stress response. Our findings indicate that SUV4-20H2-mediated H4K20 activity in pediatric high-grade astrocytomas maintains their growth and migratory potential by regulating chromatin integrity and may serve as potential therapeutic target.

H4K20me2/3↗

PubMed1978

Malignant transformation in benign cerebellar astrocytoma. Case report.

The authors give follow-up information on Case 59 of Cushing's 1931 series of cerebellar astrocytomas. The patient died with a malignant cerebellar astrocytoma 48 years after partial removal of a previously benign astrocytoma at the same site. Including the present one, there have been only five reported cases in which this has occurred. Ordinarily, juvenile pilocytic astrocytomas are of extremely genign character, and it is well established that even with incomplete resections patients have survived for years without progression of the tumor. Not all of the cases so reported can be wholly accepted as respresenting malignant transformation of the tumor, but may instead be instances of recurrence of an inherently benign glioma since the presence of features such as endothelial hyperplasia or nuclear atypicality in a juvenile pilocytic astrocytoma does not warrant is being classified as malignant. Features truly suggestive of malignancy are hypercellularity, frequent mitoses, necrosis, and, in some instances, a diffusely infiltrative growth pattern; all of these features were found in the present case.

Astrocytoma↗

PubMed1978

Supratentorial recurrences of gliomas. Results of reoperations on astrocytomas and oligodendrogliomas.

On the basis of our previous investigation regarding histological transformation of recurrent astrocytomas and oligodendrogliomas we report the clinical results of reoperations. The present observations deal with 121 cases: grade 1 astrocytomas (45), oligodendrogliomas (12), grade 2 astrocytomas (47), and oligodendrogliomas (17), respectively. In all these a second reoperation was performed in 14 cases. Operative mortality was relatively high, but without significant difference in the two groups of maligancy: 24.5% and 29.6%. Survival times in both groups showed striking individual differences. We achieved post-reoperation survivals exceeding one year in 18 and 14 cases, respectively. The results of second reoperations were generally poor. We find no remarkable differences in survival time following reoperations in primary grade 1 and grade 2 tumours. Similarly, malignant change proved to be not decisive for survival times. On the contrary, most of our patients with unchanged grade 1 astrocytomas, reoperated on after a longer interval, achieved a short second survival only. Prolongation of life expectancy by radiotherapy is doubtful. Irradiation seems to be necessary with malignantly transformed tumours if the patient did not have any treatment before reoperation.

Adolescent↗

PubMed1976

Topographical anatomy of human cerebral and cerebellar astrocytomas in vitro.

This study further characterizes the morphological and in vitro properties of human neoplastic cells derived from one Grade IV cerebral astrocytoma and one Grade III cerebellar astrocytoma. Light microscopic observations performed weekly over a four month period revealed two morphologically indistinguishable cell populations in each of the tumor cultures. Scanning electron microscopy demonstrated the presence of microvilli, blegs, and ruffles on the cell surfaces of both tumors; however, these topographical features were more prominent in the cultures derived from the Grade III cerebellar astrocytoma. Scanning electron microscopy may provide a useful tool for the further morphologic classification of human astrocytomas.

Adult↗

PubMed1978

Chemotherapy in recurrent noncystic low-grade astrocytomas of the cerebrum in children.

Six children with grade II astrocytomas were treated with combination chemotherapy consisting of 1,3 bis(2-chloroethyl) 1-nitrosourea (BCNU). Vincristine (VCR), intrathecal Methotrexate (i.t. MTX), and Dexamethasone. Of the children, 3 showed a partial remission, and 1 other showed clinical improvement. Our data suggest that chemotherapy is effective in low-grade astrocytomas, and there is now a need for larger trials in low-grade astrocytomas to document the role of chemotherapy accurately in these tumors. It is suggested that trials of chemotherapy as adjuvant to surgery and radiotherapy should be initiated.

Antineoplastic Agents↗

PubMed1978

Computed tomography in astrocytomas. A statistical analysis of the parameters of malignancy and the positive contrast-enhanced CT scan.

Four histopathological indices of malignancy--cellularity, pleomorphism, vascularity, and necrosis--were correlated with the positive-contrast CT scan in 84 patients with pathologically proved astrocytoma. Vascularity and necrosis correlated best with the scan in supratentorial tumors, while vascularity and cellularity correlated significantly with the scan in cerebellar astrocytomas. These findings indicate that the degree of malignancy of a supratentorial astrocytoma can be inferred from the contrast-enhanced scan, but that this is not generally possible with posterior fossa tumors.

Adolescent↗

PubMed1977

Chemotherapeutic trials on human malignant astrocytomas in organ culture.

A technique of organ culture based on a three-dimensional porous matrix was employed for chemotherapeutic trials on human malignant astrocytomas. The method allows neoplasms to retain the morphological identity and the histological characteristics they possess in vivo. Success in culture was greatest with high-grade astrocytomas, the majority of which showed definite infiltration of the matrix. Low-grade tumors, if viable, did not display active penetration. Drug trials on eight malignant astrocytomas included BCNU, methyl CCNU, VP 16-213, and Solu-Medrol. Cyanide and luciferase were used as experimental metabolic toxins. Evidence of cytotoxicity was assesed qualitatively by histological changes on microscopic preparations of treated and control cultures. Microfluorometric determinations of reduced nicotinamide adenine dinucleotide (NADH) were applied to these trials in an effort to detect a quantitative biochemical index of drug effects. A variable rise in although correlation with microscopic changes was inconsistent. Because of its potential merits, organ culture may be a valuable tool for further work on pharmacological management of malignant gliomas.

Antineoplastic Agents↗

PubMed1979

Cytotoxic antibody responses in astrocytoma patients. An improved allogeneic assay.

Early diagnosis of brain tumors may be facilitated by a microcytotoxicity assay which the authors have used to detect a humoral immune response against an allogeneic glioblastoma cell line. Sixty-seven of 82 serum samples (82%) from astrocytoma patients elicited significant cytotoxicity, while only six of 65 samples (9%) from normal blood-bank donors demonstrated a similar response. Positive results were more frequently obtained in lower-grade astrocytomas. Meningiomas, acoustic schwannomas, pituitary adenomas, and metastatic tumors were positive in variable numbers of cases. A small series of serum samples were platelet-absorbed to insure that cytotoxicity was not merely due to histocompatibility antigens, and seven of eight samples, when retested on the target cell line, remained significantly positive. The assays were performed under strictly monitored conditions that afforded optimum reliability and minimal experimental variability. As the specificity of this test increases, it may lead to early detection of astrocytomas.

Antibodies, Neoplasm↗

PubMed1976

Regulation of glycogen metabolism in astrocytoma and neuroblastoma cells in culture.

The regulation of glycogen metabolism in C-6 astrocytoma and C-1300 neuroblastoma cells in culture has been investigated. Two modes of control of glycogen metabolism appear to be operative. The regulation of intracellular glycogen concentrations and the predominant forms of glycogen phosphorylase and glycogen synthase vary with (a) the available energy supply, and (b) altered intracellular concentration of cyclic adenosine 3':5'-monophosphate (cyclic AMP). Both cell lines respond to glucose in the medium; when glucose levels are high, glycogen is synthesized, glycogen phosphorylase a decreases, and glycogen synthase a increases. When glucose in the medium decreases to a critical level, the phosphorylase a increases and glycogen concentrations in the cells decrease in aprallel with the medium glucose. The critical glucose concentration is 2.5 mM for the astrocytoma cells and 4 mM for the neuroblastoma cells. Insulin promotes the conversion of phosphorylase to the b form and synthase to the a form in both cell lines. All of these changes occur without alteration in the intracellular cyclic AMP concentrations. When cyclic AMP concentrations are increased in either cell line, phosphorylase a is increased, synthase a is decreased, and glycogen concentrations decrease. Isobutyl methylxanthine is effective in promoting glycogenolysis in both cell lines. Norepinephrine is effective with the astrocytoma cells, and prostaglandin E1 is effective with the neuroblastoma cells.

Astrocytoma↗

PubMed2026

DNA copy number patterns reveal prognostic markers and elucidate mechanisms of evolution in IDH-mutant astrocytoma.

BACKGROUND: Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. METHODS: A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. RESULTS: The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P < .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P < .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P < .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. CONCLUSIONS: Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

Humans↗

PubMed1979

Late-onset malignant astrocytoma in a case of multiple sclerosis. Clinical, neuropathological, virological, and tissue culture studies.

An unusual case of concurrent MS and anaplastic astrocytoma is presented. MS was diagnosed in a female patient at the age of 22 years. A left side thalamotomy was performed for relief of severe intention tremor at age 28 and at age 32 she received immunosuppressive therapy for 1 year. At the age of 36 after a severe exacerbation of her symptoms a left side fronto-temporal tumor was diagnosed and a subtotal neurosurgical extirpation was performed. Histopathologically, the tumor was an anaplastic astrocytoma, which was further substantiated by electron microscopy and establishment of a permanent cell line in vitro. The cultured tumor cells were negative for measles virus by immunofluorescence. The relationship between the reactive astrocytes in MS plaques and astrocytic neoplasia is discussed.

Adult↗

PubMed1978

The course of intracranial pressure and volume-pressure relationships following extirpation of meningiomas and astrocytomas.

Thirty-five patients with meningiomas were compared with 37 patients with astrocytomas with respect to the postoperative course of their ICP and elastance. In the case of the meningioma patients, the ICP increased on average over a longer period and achieved higher values than in the astrocytoma patients. In the first group, the elastance attained values that were three times as high as in the second group. There was no fixed relationship between pressure and elastance in the two groups of patients.

Astrocytoma↗

PubMed1979

Glial fibrillary acidic protein (GFAP): purification from human fibrillary astrocytoma, development and validation of a radioimmunoassay for GFAP-like immunoactivity.

The extraction and purification of glial fibrillary acidic protein (GFAP) from human fibrillary cerebellar astrocytoma is described. Using an immunoperoxidase method, antisera raised to the protein showed specific staining of astrocytes in normal spinal cord and in tumours of astrocytic origin. A double antibody radioimmunoassay for GFAP in tissue extract was developed, the detection limit of the assay being 360 pg. Extracts of tissues other than brain or spinal cord did not cross-react significantly in the assay, neither did purified preparations of myelin basic and S-100 proteins. Levels of GFAP in normal CNS tissue were higest in spinal cord (1370 microgram/g wet weight) but a level of 3050 microgram/g wet weight was detected in a fibrillary astrocytoma.

Astrocytes↗

PubMed1979

Lactic dehydrogenase in ethylnitrosourea-induced rat gliomas. Total lactic dehydrogenase activity and isozymes in autochthonous gliomas and cloned transplantable astrocytomas.

Total lactic dehydrogenase (LDH) levels and LDH isozyme patterns were measured in homogenates of 12 autochthonous ethylnitrosourea-induced rat gliomas and 5 cloned rat astrocytoma cell lines maintained in culture and transplanted to brain or flank sites in syngeneic hosts. The total LDH values in the autochthonous gliomas did not differ appreciably from normal brain controls, but the proportions of the cathodal isozymes, LDH4 and LDH5, were increased to a degree similar to that reported by others in spontaneous human malignant astrocytic gliomas. The cloned astrocytoma lines, both in vitro and in transplants at intracerebral or subcutaneous sites, commonly demonstrated elevated total LDH values and, without exception, showed a preponderance of isozymes, LDH4 and LDH5, that was distinctly more marked than in autochthonous tumors. Especially in cultured and transplanted rat gliomas, these findings suggest that astrocytic tumor cells maintain energy supplies by utilizing anaerobic glycolysis in relatively hypoxic environments. These data further underscore the need to develop laboratory brain tumor models for use in therapy trials that not only retain the convenience and predictability of transplantable gliomas but also approximate closely the metabolic properties of human spontaneous gliomas.

Animals↗