Re-operations of supratentorial anaplastic astrocytomas

Summary Results of re-operations of 99 adult patients with recurrent supratentorial lobar glioblastomas (60 patients) and anaplastic astrocytomas (39 patients) have been reviewed. In all cases both surgical interventions were performed at the same institute. Age of patients with glioblastoma varied between 19 and 64 and with anaplastic astrocytoma between 21 and 68 years, with a mean value of 48 and 36 years, respectively. The median interval between the first and second operations was 47 weeks for patients with glioblastoma and 83 weeks with anaplastic astrocytoma. The mortality rate of the re-operations was 3%. Following re-operation radio-and/or chemotherapy was applied in most of the cases. Median survival time after re-operation was 18.5 weeks in patients with glioblastoma and 55 weeks with anaplastic astrocytoma. Survival curves were calculated according to Kaplan-Meier method and for statistical evaluation the generalized Wilcoxon test and multiple linear regression method were used. Histologically lower grade tumour at the first operation and longer interval between the two operations proved to influence positively and differentiation of the primary tumour negatively the survival time.     

Clinicopathological study of diffuse type brainstem gliomas: analysis of 40 autopsy cases

Diffuse type brainstem glioma is one of the most malignant types of brain tumors and the prognosis is extremely poor. The proliferative potential of these tumors is presumed to be very high, but there is little information about the cell kinetics of brainstem glioma because surgical resection is rarely performed. The histological grade, tumor spread, growth potential, and prognosis were evaluated in 40 autopsy cases of diffuse type brainstem glioma. To quantify the growth potentials of individual tumors, the proliferating cell indices of Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA) monoclonal antibodies were measured. Mean MIB-1 and PCNA proliferating cell indices were 20.4% (24 cases) and 37.0% (28 cases), respectively, in 34 glioblastomas. The median survival time was 40 weeks in 22 treated patients. The mean PCNA proliferating cell index was 10.8% in four of five anaplastic astrocytomas and the median survival time in four treated patients was 91 weeks. The MIB-1 and PCNA proliferating cell indices of one astrocytoma were 2.9% and 20.3%, respectively, and the survival time was 56 weeks. The overall median survival time was 32 weeks. There was a significant difference in PCNA proliferating cell indices between glioblastomas and anaplastic astrocytomas (p < 0.05) and there was a significant difference in survival time between glioblastomas (40 weeks) and anaplastic astrocytomas plus astrocytoma (74 weeks) among the treated patients (p < 0.05). Supratentorial extension was more frequent in glioblastomas than in anaplastic astrocytomas (p < 0.05). Our results suggest that the majority of diffuse type brainstem gliomas are glioblastoma and the proliferative potential is probably as high as that of adult supratentorial glioblastoma. Supratentorial extension and dissemination are relatively frequent in the advanced stage. Anaplastic astrocytoma or astrocytoma is rarer and less infiltrative and proliferative, and carries a slightly better prognosis than glioblastoma.     

Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme.

Although the loss of tumor suppressor genes and the activation of oncogenes have been established as two of the fundamental mechanisms of tumorigenesis in human cancer, little is known about the possible interactions between these two mechanisms. Loss of genetic material on chromosome 10 and amplification of the epidermal growth factor receptor (EGFR) gene are the most frequently reported genetic abnormalities in glioblastoma multiforme. In order to examine a possible correlation between these two genetic aberrations, the authors studied 106 gliomas (58 glioblastomas, 14 anaplastic astrocytomas, five astrocytomas, nine pilocytic astrocytomas, seven mixed gliomas, six oligodendrogliomas, two ependymomas, one subependymoma, one subependymal giant-cell astrocytoma, and three gangliogliomas) with Southern blot analysis for loss of heterozygosity on both arms of chromosome 10 and for amplification of the EGFR gene. Both the loss of genetic material on chromosome 10 and EGFR gene amplification were restricted to the glioblastomas. Of the 58 glioblastoma patients, 72% showed loss of chromosome 10 and 38% showed EGFR gene amplification. The remaining 28% had neither loss of chromosome 10 nor EGFR gene amplification. Without exception, the glioblastomas that exhibited EGFR gene amplification had also lost genetic material on chromosome 10 (p less than 0.001). This invariable association suggests a relationship between the two genetic events. Moreover, the presence of 15 cases of glioblastoma with loss of chromosome 10 but without EGFR gene amplification may further imply that the loss of a tumor suppressor gene (or genes) on chromosome 10 precedes EGFR gene amplification in glioblastoma tumorigenesis.     

Serum IgM level as an index of malignancy in brain tumours

Summary Serum IgG, IgA, and IgM levels have been measured in patients with brain tumours. Only in astrocytomas have significant differences been found with respect to the other brain tumours. The specific elevation of IgM levels in astrocytoma grade III (X=313+36, n=4) and astrocytoma grade IV (X=671+ 146, n=4) in comparison with astrocytoma grade II (X=180, n=2) shows clear correlation with the malignancy of astrocytomas.     

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

Summary On the basis of a three stage grading system we report 23 stage one recurrent oligodendrogliomas (O 1), and 29 stage two recurrent oligodendrogliomas (O 2). In the O 1 group after the first interval 15 became O 2 and 2 became glioblastomas. Twenty tumours of the O 2 group after the first interval were not changed, three became oligodendroglioma-astrocytomas stage 2, and six became glioblastomas. The time relation for the recurrent phase in the primary O 1 group is calculated as 42 months, and in the primary O 2 group as 22 months, but this is without significance. For the development of malignancy, especially for the change to glioblastoma, a prominent participation by transformed local astrocytes seems to be essential. Postoperative irradiation most probably does not favour malignant change. A prolongation of the expectation of life by radiotherapy is not noticed.     

Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas

Thirty-one patients operated upon for supratentorial glioblastomas or anaplastic astrocytomas were studied to evaluate the effect of the extent of surgical resection on the length and quality of survival. The median age was 50 years and the median preoperative Karnofsky rate was 80. Twenty-one patients (68%) had glioblastoma multiforme, and 10 patients (32%) had anaplastic astrocytoma. Early postoperative enhanced computed tomography was used to determine the extent of tumor resection. Gross total tumor resection was accomplished in 19 patients (61%), and subtotal resection was performed in 12 patients (39%). The two groups were comparable regarding age, sex, pathological condition, preoperative Karnofsky rating, tumor location, postoperative radiation therapy, and postoperative chemotherapy (P greater than 0.05). The gross total resection group lived longer than the subtotal resection group by life table analysis (P less than 0.001; median survival of 90 and 43 weeks, respectively). Postoperatively, the mean functional ability measured by the Karnofsky rating was significantly increased in the gross total resection group (P = 0.006), but not in the subtotal resection group (P greater than 0.05). The difference in degree of change between preoperative and postoperative Karnofsky rating in the two groups was statistically significant (P = 0.002). The gross total resection group spent significantly more time after the operation in an independent status (Karnofsky rating greater than or equal to 80) compared to the subtotal resection group (P = 0.007; median time of 185 and 12.5 weeks, respectively). Gross total resection of supratentorial glioblastomas and anaplastic astrocytomas is feasible and is directly associated with longer and better survival when compared to subtotal resection.     

Quantitative analysis of glutathione in human brain tumors.

Reduced glutathione (gamma-glutamylcysteinylglycine, GSH) plays an important role in the protection of cells against damage from free radicals and other electrophils and also influences cellular radiosensitivity, cellular response to hyperthermia, and cytotoxicity to some kinds of chemotherapeutic agents. The concentrations of GSH in 40 primary and metastatic brain tumors were quantitatively analyzed, and GSH was localized in these tumors by a novel o-phthalaldehyde histofluorescence method. The level of GSH was 195.2 +/- 57.1 micrograms/gm (mean +/- standard deviation) in glioblastomas multiforme, 444.1 +/- 105.1 micrograms/gm in normal brain tissues, and 614.4 +/- 237.4 micrograms/gm in meningiomas. The differences in GSH levels between glioblastomas and normal brain tissues and between glioblastomas and meningiomas were statistically significant (p less than 0.01). The mean GSH level in astrocytoma grades II and III was 321.9 +/- 11.8 micrograms/gm. The difference in the GSH level between glioblastomas and astrocytomas was statistically significant (p less than 0.05). Radiosensitive tumors, such as multiple myeloma, germinoma, and small-cell carcinoma, showed low GSH levels. These data suggest the possibility that the GSH may be a predictor for the efficacy of radiation therapy. The cytochemical study showed GSH localized in the cytoplasm; although it stained well in meningioma tissue, GSH was not well stained in sections of multiple myeloma. The endothelial proliferation did not stain well in glioblastoma, which seems to imply that this area is vulnerable to attack by free radicals from irradiation and/or chemotherapy.     

Intra-operative characterization of gliomas by near-infrared spectroscopy: possible association with prognosis

Summary ?Background. Growth and expansion of gliomas are highly dependent on vascular neogenesis. An association of microvascular density and tumour energy metabolism is assumed in most human gliomas. The purpose of this investigation was to characterize a series of gliomas by intra-operative near-infrared spectroscopy (NIRS), and to elucidate the relationship between microvascular blood volume (BV), oxygen saturation (SaO₂), histology and patient survival. Method. The study included 13 patients with gliomas, in whom complete tumour resection according to postoperative magnetic resonance imaging criteria was achieved. Intra-operatively, one low grade astrocytoma, five anaplastic astrocytomas and seven glioblastomas with the ipsilateral cortex were investigated by NIRS revealing capillary BV (total haemoglobin) and SaO₂. Intratumoural BV (tBV) and SaO₂ (tSaO₂) were additionally used in relation to histology and survival. Findings. The mean tBV of the astrocytomas was 4.96 mg/ml compared to 18.40 mg/ml in the glioblastoma group. Mean tSaO₂ was 36% in the astrocytoma group and 52% in the glioblastomas, respectively. Both tBV and tSaO₂ were significantly higher (p<0.01) in the glioblastoma group. Median survival time was shortest for patients with glioblastoma (12.5 months), with tBV >10/mg/ml (10 months), and tSaO₂ >50% (10 months). Longest median survival times were observed in the astrocytoma group (32.5 months), in patients with Tbv <10/mg/ml (30 months), and tSaO₂ <50% (27.5 months). The differences were highly significant (p<0.01). Interpretation. Intra-operative characterization of gliomas by NIRS is feasible. High tBV represents extensive angiogenetic activity of the tumour, whereas high tSaO₂ may be result of non-oxidative glucose metabolism with less oxygen extraction from the capillary bed of the tumour. However, the extent of tBV and tSaO₂ are both of possible prognostic value thus resulting in additional information about the tumour. Published online June 11, 2003     

Glioblastomes : oncogenèse et bases biologiques

Background and purpose

Glioblastomas are the most malignant gliomas of the central nervous system. Currently, numerous studies are attempting to decipher their genetic and epigenetic modifications, to identify the cells at the origin of gliomagenesis, and to better understand the molecular bases responsible for invasion and angiogenesis processes.

Methods

This article reviews recent data on the cellular and molecular biology of gliomas delineated by several teams including ours. We and others have underlined the role played by cancer stem cells in gliomagenesis; the Cancer Genome Atlas Network has described most glioblastoma genetic alterations.

Results

According to many studies, glioblastomas derive from malignant transformation of stem cells and/or glial precursor cells. Moreover, the topographic microenvironment is important regarding invasion and angiogenesis processes. Finally, it is now well established, thanks to IDH1 mutation identification, that primary and secondary glioblastomas are two different clinical and genetic entities. Interestingly, IDH1 mutation seems to be a very early genomic modification in astrocytoma, oligodendroglioma, and secondary glioblastoma tumorigenic processes.

Conclusions

Regarding all these data, we suggest a hypothetical model of glioma initiation, growth, and progression. Moreover, the histomolecular glioma classification has been substantially revised and new therapeutic targets have been identified.     

Proto-oncogene analyses in brain tumors

The present study determined which oncogenes (N-myc, c-myc, v-sis, or v-fos) were amplified and which messenger ribonucleic acids (mRNA's) accumulated in 10 primary human brain tumors of neuroectodermal origin. The tumors included four glioblastomas multiforme, one mixed glioma (astrocytoma grade I and ependymoma), one astrocytoma grade II, one cystic cerebellar astrocytoma, one ependymoma, one ganglioglioma, and one medulloblastoma. The relative amounts of polyadenylated (poly(A)+) RNA's homologous to these genes and their copy number were determined using the RNA and deoxyribonucleic acid blot hybridization techniques. The N-myc and v-sis probes hybridized strongly to the poly(A)+ RNA from the same recurrent glioblastoma with gene amplifications (N-myc 80 copies; v-sis three to four copies). The c-myc probe hybridized strongly to the recurrent medulloblastoma without gene amplification. The amplification or abundant accumulation of mRNA's homologous to their oncogenes may be involved in tumorigenesis or the aggressiveness of these malignant brain tumors of neuroectodermal origin and may be good molecular indicators of an extremely malignant state in these tumors.     

Postoperative radiotherapy of hemispheric glioma in the adult. A propos of 134 cases]

We are dealing here with a series of 134 hemispheric gliomas of the adult subject submitted to irradiation after surgical exeresis. The 2 years survival rate reaches 51 p. 100 for stage I and II astrocytomas (15/29) and 3,3 p. 100 for glioblastomas (30/91), the I year survival rate for the latter ones reaching 33 p. 100. The analytic study of medical literature lets appear that if roentgentherapy remains controverted in the case of stage I and II astrocytomas, it is recognized as useful, by all the authors, in the glioblastomas. Modalities and technique of the irradiation are object of an analytic study. Authors are favourable to post-operative irradiation stage I and II astrocytomas exhibiting pejorative features (focalized 6.000 to 6.500 rads) and to systematic post-operative irradiation in the glioblastomas over extended fields, either spreaded on irradiation (6.000 rads) or concentrated irradiation (two series of 1.800 rads). This latter technique has provided identical results as the spreaded on irradiation and represents a less heavy procedure. Mention is made of roentgentherapy in the supratentorial ependymomas (3 cases) and in the oligodendrogliomas (6 cases), followed by an analytic study of the complications consecutive to roentgentherapy of the encephalic tumors.     

Expression of platelet-derived growth factors, transforming growth factors, and the ros gene in a variety of primary human brain tumors

Ribonucleic acid was isolated from a wide spectrum of central nervous system tumors to examine the expression of platelet-derived growth factors (PDGF) A and B, tumor growth factors (TGF-beta) 1 and 2, and ros messenger ribonucleic acid. Eight glioblastoma cell lines were examined as well as cell cultures from 22 tumor explants. The explants included 6 glioblastomas, 4 anaplastic astrocytomas, 5 astrocytomas, 3 ependymal tumors, 2 meningiomas, 1 medulloblastoma. and 1 ganglioglioma. For comparison, 2 nontumor glial cell cultures were included. The PDGF B-chain was expressed in 5 of 8 glioblastoma cell lines, 2 of 6 glioblastomas, and in 3 of 4 anaplastic astrocytoma explants. There was no PDGF B expression in 4 astrocytomas, 3 ependymomas of varying malignancy, in the remainder of the tumors, or in the nontumor glial cells. The PDGF A-chain was expressed in all of the tumors, with the exception of the malignant ependymoma and in both nontumor glial cell cultures. TGF-beta 1 was expressed in all of the tumors and in nontumor glial cells. The expression of TGF-beta 2 was expressed in many of the benign and malignant tumors and also in both nontumor glial cell cultures. The ros messenger ribonucleic acid was expressed in 1 of 5 glioblastoma cell lines and in 2 of 6 glioblastoma cell explants, but in none of the other tumors or in the nontumor glial cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative analysis of glutathione and glutathione S-transferase in human brain tumors, C6 rat glioma cells and drug resistant C6 cells]

Glutathione (GSH) and Glutathione S-transferase (GST) plays an important role in the protection of cells against damage from free radicals and also influences cytotoxicity to some kinds of chemotherapeutic agents. GST comprises a group of abundant and widely distributed catalytic and binding proteins that facilitate the conjugation of GSH with the electrophilic center of a large spectrum of hydrophilic molecules. Multiple GST isozymes in mammalian tissues arise from dimeric combination of a number of distinct subunits grouped into three major classes: alpha (alpha), mu (mu), and pi (p). We report the total GST, GST-p activity and GSH content of human brain tumors, C6 rat glioma cells and drug resistant C6 cells. The values of total GST activity in 42 normal brain and brain tumors were quantitatively analyzed. Total GST activity was 92.6 +/- 25.1 units (mean +/- standard deviation) in 8 samples of normal brain tissues, 126 +/- 58.8 units in five grade II or III astrocytomas (154 +/- 63.3 units in grade II astrocytomas, 84.4 +/- 2.7 units in 2 grade III astrocytoma), 66.2 +/- 29.3 in 5 glioblastoma cases, 94.7 +/- 47.7 units in 3 metastatic tumors, 302 +/- 114 unit in 8 meningiomas and 213 +/- 90.4 units in 3 neurinomas. Differences of GST activity between glioblastomas and meningiomas, grade II or III astrocytomas and meningioma, in normal brain tissues and meningioma were statistically significant (p < 0.01). The difference between normal brain tissues and benign tumors (meningiomas and neurinomas), gliomas and benign tumors were also statistically significant (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cellular targets of exogenous tumour necrosis factor-alpha (TNFα) in human gliomas

Summary To identify the cellular targets of TNF in human gliomas, a total of 30 surgical specimens (12 glioblastomas, 4 anaplastic astrocytomas, 3 astrocytomas, 7 brains adjacent to tumour (BAT), 4 histologically normal-appearing brains) were examined by in vitro binding technique using biotinylated TNFa. The TNF-binding sites (TNF-BS) were recognized in the tumour cells in 8 of the 12 glioblastomas. 3 of the 4 anaplastic astrocytomas and in all the 3 astrocytomas. The TNF-BS were also recognized in the vascular endothelial cells in all these cases. The presence of TNF-BS in blood vessels ranged from 7.7 to 74.4% of the background vessels. This wide range of variation in the presence of TNF-BS within the tumour cells and tumour blood vessels may be relevant to the variable response of individual tumours to TNF therapy. Since the tissue of normal brain, which lacks TNF-BS, might hardly be affected by this cytokine, administration of TNFa may be considered as an adjuvant therapy in selected groups of patients.     

A retrospective observational study on the treatment outcomes of 26 patients with spinal cord astrocytoma including two cases of malignant transformation

Purpose

To determine the biologic behavior and prognostic factors of spinal cord astrocytoma, we reviewed surgical and clinical outcomes. Due to the rarity of spinal cord astrocytoma, there is a lack of research regarding this type of tumor and malignant transformation.

Methods

We retrospectively reviewed the data from all patients on whom we performed spinal cord tumor removal between 1983 and 2014. Twenty-six patients were pathologically confirmed to have spinal cord astrocytoma or glioblastoma. Surgical extent and disease progression were confirmed by the surgeon based on operative findings, postoperative MRI, and outpatient department (OPD) follow-up.

Results

Pain or neurological deficit was the chief complaint for all patients. With MRI studies, there is a tendency for high-grade astrocytomas to show as enhanced and heterogeneous images. Two of the low-grade astrocytomas showed malignant transformation over the course of 4 and 11 months, respectively. The overall survival (OS) for low-grade astrocytoma was 28–480 months (mean 156.38 months); the OS for high-grade astrocytoma was 1–36 months (mean 12.00 months).

Conclusions

Two of 12 low-grade cases showed malignant transformations at 4 and 11 months, respectively, based on pathological confirmation. With spinal cord astrocytomas, enhanced MRI results appeared similar to those of a malignant lesion. We suggest close observation and image correlation of low-grade astrocytomas, even when pathologically confirmed as low-grade. In this review, we found that histologic grade is the most important prognostic factor, although it is not always concordant with biologic behaviors.

     

Brachytherapy of recurrent malignant brain tumors with removable high-activity iodine-125 sources

Thirty-seven patients harboring recurrent malignant primary or metastatic brain tumors were treated by 40 implantations of high-activity iodine-125 (125I) sources. All patients had been treated with irradiation and most had been treated with chemotherapeutic agents, primarily nitrosoureas. Implantations were performed using computerized tomography (CT)-directed stereotaxy; 125I sources were held in one or more afterloaded catheters that were removed after the desired dose (minimum tumor dose of 3000 to 12,000 rads) had been delivered. Patients were followed with sequential neurological examinations and CT scans. Results of 34 implantation procedures were evaluable: 18 produced documented tumor regression (response) for 4 to 13+ months; five, performed in deteriorating patients, resulted in disease stability for 4 to 12 months. The overall response rate was 68%. In 11 patients, implantation did not halt clinical deterioration. At exploratory craniotomy 5 to 12 months after implantation, focal radiation necrosis was documented in two patients whose tumor had responded initially and then progressed, and in three patients whose disease had progressed initially (four glioblastomas, one anaplastic astrocytoma); histologically identifiable tumor was documented in two of these patients. All improved after resection of the focal necrotic mass and are still alive 10, 15, 19, 24, and 25 months after the initial implantation procedure; only one patient has evidence of tumor regrowth. The median follow-up period after implantation for the malignant glioma (anaplastic astrocytoma and glioblastoma multiforme) group is 9 months, with 48% of patients still surviving. While direct comparison with the results of chemotherapy is difficult, results obtained in this patient group with interstitial brachytherapy are probably superior to results obtained with chemotherapy.     

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.     

Pilomyxoid astrocytoma of the fourth ventricle in an adult

Pilomyxoid astrocytomas have been identified as a variant of pilocytic astrocytoma. They are listed as a novel clinico-pathological entity in the 2007 World Health Organisation (WHO) classification of tumours of the central nervous system. This tumour corresponds to a WHO grade II neoplasm whereas pilocytic astrocytoma corresponds to WHO grade I. We have encountered an infratentorial tumour with pilomyxoid features in an adult. A 25 year old man presented with tinnitus and hyperacusis. Brain MRI revealed a mass occupying the fourth ventricle. We performed partial resection, but no adjuvant therapy was given. The staining index for the anti-Ki-67 monoclonal antibody MIB-1 was less than 1% in this patient. Pilomyxoid astrocytomas are not limited to the hypothalamic/chiasmatic region in children. Additional knowledge and recognition of this entity is necessary to improve treatment of pilomyxoid astrocytoma.