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PubMed1985

Familial glioblastoma multiforme without neurofibromatosis.

Glioblastoma multiforme is a rapidly growing anaplastic primary tumor of the central nervous system. It is frequently associated with neurofibromatosis or other hamartomatous syndromes, and in such kindreds may be found in several generations. We describe a highly inbred family in which glioblastoma multiforme presents in males only as an isolated central nervous system neoplasm on the right side, without evidence of other underlying genetic disease. It is speculated that in this family the tumor develops as the consequence of an autosomal recessive or an X-linked recessive mutation. In addition, the gene for cystic fibrosis segregates in this family and an undefined autosomal recessive malformation syndrome was detected.

Cystic Fibrosis↗

PubMed1993

Long-term survival in patients with glioblastoma multiforme.

Few patients with glioblastoma multiforme survive more than 5 years. To identify the factors associated with long-term survival, patients with primary supratentorial glioblastoma multiforme diagnosed between 1969 and 1985 were identified from our computer data base. Twenty-two (5%) of the 449 patients identified survived at least 5 years after surgical diagnosis. There were 12 female and 10 male patients, with a mean age of 39.2 years (range, 15 to 63 yr). Twenty patients had a subtotal resection, and 2 had a gross total resection. The median duration of survival was 9.4 years. As of August 1, 1992, 10 patients were alive 5.2 to 13.6 years after diagnosis, and 1 patient was lost to follow-up after 9.4 years. Ten patients died from their tumors; 2 patients with stable tumors died, 1 from a ruptured intracranial aneurysm and 1 from erythromycin-induced hepatitis. Unusual sequelae were noted in irradiated areas in several cases. One patient had a scalp sarcoma and a basal cell carcinoma, and three patients had strokes; each of these events occurred more than 5 years after diagnosis. We conclude that among patients with glioblastoma multiforme, long-term survival is most likely for those who have a long disease-free interval after the initial diagnosis and receive multimodal therapy, including aggressive tumor removal. Other factors associated with long-term survival were younger age and high Karnofsky scores.

Adolescent↗

PubMed1988

[Fine structure of glioblastoma multiforme with "adenoid formation"].

Glioblastoma multiforme with "adenoid formation" (Kepes) in the temporal lobe of a 70 year old man was presented. In addition to the classical features of glioblastoma multiforme, the tumor presented a pattern of anastomosing trabeculae of polygonal cells, mimicking epithelial tubules, in a myxoid stroma. On electron microscopic examination, the tumor cells were devoid of well-developed cytoplasmic processes. The cytoplasm of some tumor cells contained glycogen particles and lipid vacuoles in addition to usual organelles. The cell surface was partly covered by basal lamina associated with half desmosomes and had occasional filopodia-like cytoplasmic projections. A few tumor cells contained a dense intracytoplasmic accumulation of glial filaments. Intercellular junctional complexes were poorly developed. There was no evidence of differentiation of tumor cells toward ependymal cells or epithelial cells. These electron microscopic findings suggest that this tumor is predominantly composed of immature astrocytes. In spite of a superficial resemblance to adenocarcinoma on light microscopy, the tumor cells are devoid of the differentiating features of epithelial neoplasms, and their ultrastructure is essentially similar to that of glioblastoma multiforme.

Astrocytes↗

PubMed1987

Proliferative potential of vascular components in human glioblastoma multiforme.

Sixteen patients with glioblastoma multiforme received a 1-h intravenous infusion of 5-bromo-deoxyuridine (BrdU), 150-200 mg/m2 at the start of surgery, to label S-phase cells in tumor tissue. Labeled cells of vascular components and of tumor parenchyma were detected in excised tumor specimens by indirect immunoperoxidase staining using anti-BrdU monoclonal antibodies followed by periodic acid-Schiff staining. The BrdU labeling index (LI, defined as the percentage of labeled cells in relation to the total number of cells scored) was calculated separately for vascular components and tumor parenchyma in each specimen. The BrdU LI of vascular components of glioblastoma multiforme was remarkably higher than that of normal brain (1.1%-8.7% vs. less than 0.05%). The mean BrdU LIs of vascular components and tumor cells in eight primary glioblastomas were 4.5 +/- 0.8% (mean +/- SE) and 9.9 +/- 1.1%, respectively, while the corresponding BrdU LIs in eight recurrent tumors were 2.7 +/- 0.5% and 9.3 +/- 0.7%. The differences in the BrdU LIs of primary and recurrent tumors were not statistically significant, but the BrdU LI of vascular components was consistently much lower than that of tumor cells. BrdU labeling of vascular components was inconsistent and occurred mostly in glomerular-shaped vessels, but only about 20% of them contained labeled cells. These results suggest that unusual vascular proliferation, such as the formation of glomerular-shaped vessels and endothelial or adventitial proliferation, in glioblastoma multiforme may have been programmed to slow down or even to cease at a certain stage, and is not likely to be the result of neoplastic transformation.

Adolescent↗

PubMed2005

Lack of survival benefit after stereotactic radiosurgery boost for glioblastoma multiforme: randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of radiation therapy oncology group 93-05 protocol: in regard to Souhami et al. (Int J Radiat Oncol Biol Phys 2004;60:853-860).

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Antineoplastic Agents, Alkylating↗

PubMed1999

Evidence of focal genetic microheterogeneity in glioblastoma multiforme by area-specific CGH on microdissected tumor cells.

The term "multiforme" in glioblastoma multiforme (GBM) indicates the highly variable histomorphology that cannot be addressed by studies on homogenized tissue probes. In order to relate genetic findings with histomorphologically distinct areas we used microdissection to procure defined cell populations from microscopic tissue sections under direct visualization. Formalin-fixed and paraffin-embedded tissue sections of 10 GBM were evaluated for intratumoral genetic heterogeneity by microdissection of multiple areas of 20-50 tumor cells and DOP-PCR of DNA isolated from the dissected cell groups, followed by comparative genomic hybridization (CGH). Microdissected cells from histomorphologically normal extratumoral blood vessels from the same slides served as controls. The individual tumors showed variable combinations of primary chromosomal gains and losses common to all studied areas of a given case along with secondary, area-specific additional aberrations. CGH displayed a wider variety of chromosomal aberrations than metaphase cytogenetics of cell cultures from the same tumors. The most frequent aberrations observed were previously unperceived gains on chromosomes 4q (8/10) and 5q (5/10). Other nonrandom aberrations were gains on 12q (6/10), 13q (6/10), and 7 (5/10), and losses of 22 (5/10). Amplifications on 7p were intratumorally heterogeneous and only found in single areas of 2 tumors. In contrast to normal extratumoral vessels, vascular proliferates in most cases demonstrated chromosomal aberrations (CGH) which were partially different from the aberrations observed in the tumor itself. The described method gives evidence of considerable intratumoral genetic heterogeneity in GBM and provides a sensitive tool for the detection of quantitative chromosomal changes that are present only regionally within a given tumor.

Adult↗

PubMed2003

p53, mdm2, EGFR, and msh2 expression in paired initial and recurrent glioblastoma multiforme.

BACKGROUND: The clinical course of glioblastoma multiforme is characterised by invasive growth and regular recurrence. Many genetic alteration have been identified in the genesis of the disease. However, information about immunohistochemical expression in recurrent lesions is sparse. OBJECTIVES: To determine (1) whether the p53/mdm2/EGFR/msh2 expression pattern differs in initial v recurrent glioblastoma multiforme; (2) whether a possible change in expression correlates with prognostic variables (progression-free survival time, total survival time); and (3) whether chemotherapy in addition to surgery and radiotherapy influences the p53/mdm2/EGFR/msh2 expression profile. METHODS: 27 patients were studied. They met the following criteria: histologically confirmed diagnosis of glioblastoma multiforme (WHO IV); total tumour resection at initial craniotomy; at least one re-craniotomy for glioblastoma multiforme recurrence; age 21 years or older. All underwent radiotherapy of at least 54 Gy, and 17 received additional chemotherapy. Immunohistochemical staining of initial tumours and recurrences was done with the following monoclonal antibodies: anti-p53 (DO-1), anti-mdm2 (IF-2), anti-EGFR (H11), and anti-msh2 (AB-1). RESULTS: In comparison with the initial tumour, recurrent lesions were characterised by reduced expression of p53 (p < 0.0001) and msh2 (p = 0.0012), while the numbers of mdm2 (p = 0.02), EGFR (p < 0.0001), and msh2 positive specimens (p < 0.0001) were reduced. Chemotherapy was associated with reduced msh2 expression (p < 0.0001). Immunohistochemical variables were not associated with patient survival. CONCLUSIONS: There are significant differences in the p53/mdm2/EGFR/msh2 expression patterns in initial v recurrent glioblastoma multiforme. There may be interactions between chemotherapy and changes in the msh2 expression.

Adult↗

PubMed1998

Spinal drop metastases in recurrent glioblastoma multiforme.

Multifocal dissemination of glioblastomas is very rare but is increasing as patients live longer. Between April 1994 and December 1997 one hundred and fifty one patients with a histologically proven glioblastoma multiforme were operated on in the Neurosurgical Department of the University of Kiel, Germany. Recurrent tumours of these patients were removed in 36 patients. Two patients developed multifocal spread of glioblastoma multiforme including spinal drop metastases. Both patients died 10 and 7 months after the primary operation. On histological examination both tumours showed wide perivascular tumour-cell cuffings in the surrounding brain tissue, so that this perivascular growth might be another explanation for the dissemination in these glioblastomas.

Brain↗

PubMed2004

Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multiforme cells.

BACKGROUND: Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. METHOD: Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). FINDINGS: At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death > or =75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. CONCLUSION: Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM.

Adult↗

PubMed2003

O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme.

PURPOSE: In glioblastoma multiforme (GBM), the cytotoxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolamide is dependent on O(6) alkylation, which correlates inversely with expression of the DNA repair enzyme O(6)-methyl-guanine-DNA methyltransferase (MGMT). Thus, MGMT assessment can be useful in predicting response in GBM, but the scarcity of neoplastic cells limits the practicality of MGMT assessment in these tumors. Although GBM grows within the skull, we investigated the concordance of methylation in glioma tissue, and paired serum DNA and the potential correlation with response and time to progression. EXPERIMENTAL DESIGN: Using MSP assay, we assessed the methylation of MGMT, p16, DAPK, and RASSF1A in tumor and serum DNA from 28 GBM patients treated with BCNU or with temozolamide plus cisplatin. RESULTS: The concordance between methylation in tumor and serum was highly significant. Overall, response plus stable disease was noted in 10 of 11 (90.9%) patients with MGMT methylation and in 5 of 14 (35.7%) patients without (P = 0.01). In the 16 patients treated with temozolamide plus cisplatin, no significant correlation between MGMT methylation status and response was observed, whereas in BCNU-treated patients, a significant difference was observed in favor of those with methylated MGMT. Time to progression was 29.9 weeks in 12 patients with MGMT methylation and 15.7 weeks in 10 patients without (P = 0.006). No correlation was observed between response or time to progression and p16, DAPK, or RASSF1A methylation. CONCLUSIONS: Methylated MGMT, p16, DAPK, and RASSF1A were found in serum DNA of GBM patients, with a good correlation between serum and primary tumor tissue. Serum MGMT methylation predicted response and time to progression in BCNU-treated GBM patients. The methylation-specific PCR assay in serum DNA could be a good predictive tool for selecting GBM patients to be treated with BCNU or alternatively with the combination of temozolamide plus cisplatin.

Adult↗

PubMedDate not supplied

[Glioblastoma multiforme... with multifocal presentation].

Glioblastoma multiforme is the most common malignant primary brain tumor in adults (+/- 40% of the Central Nervous System primary tumors). Representing only 2% of all oncologic processes, they are associated with a great deterioration of cerebral functions and a poor prognosis, facts that contribute to their great individual and social impact. The authors report a case of glioblastoma multiforme, with multifocal lesions "ab initio" and show the difficulty to make a correct diagnosis, even with the most modern imagiologic techniques. They also make a brief review of the literature.

Brain Neoplasms↗

PubMedDate not supplied

Differential cyclooxygenase-2 enzyme expression in radiosensitive versus radioresistant glioblastoma multiforme cell lines.

BACKGROUND: Glioblastoma multiforme (GBM) is a high-grade primary brain tumor that is refractory to current forms of treatment. In cell studies, the growth rate of GBM cells correlates with the level of Cyclooxygenase-2 (COX-2) enzyme expression. COX-2 has been implicated in carcinogenesis of systemic cancers. Recently, COX-2 inhibition has been shown to increase the radiosensitivity of various tumors. We wished to assess whether the expression of COX-2 is greater in radioresistant versus radiosensitive forms of GBM. MATERIALS AND METHODS: The radiosensitive (A172) and radioresistant (T98G) Glioblastoma multiforme cell lines were assayed for COX-2 expression using standard immunofluorescence histochemistry. Fluorescence readings were recorded per field. Western blot analysis was performed on both A172 and T98G GBM cell lines. The radioresistant cells were exposed to incremental doses of radiation in the presence and absence of a COX-2-selective inhibitor. Radioresistant cells were then exposed to incremental doses of COX-2-selective inhibitor at a constant dose of radiation. RESULTS: The radioresistant cell line T98G had an approximate 1. 7-fold greater expression of COX-2 than did the radiosensitive cell line A172, as per immunofluorescence histochemistry. Western blot analysis confirmed this finding. Statistical analysis (Bonferroni/Dunn) showed the results to be significant (p<0.0001). The wells containing radioresistant cells exposed to incremental doses of radiation and COX-2 inhibitors appeared to have higher cell kill when compared to radiation alone. Furthermore, increasing the COX-2 inhibitor concentration yielded higher cell kill. CONCLUSION: The results presented here show that the radioresistant GBM cell line, T98G, has a greater expression of COX-2 than does the radiosensitive GBM cell line, A172. These results suggest that: (i) COX-2 expression may serve as a marker for assessing radioresistance in GBM, (ii) COX-2 inhibition may lower the required doses of postoperative radiation, (iii) COX-2 inhibitors may have a role in radiosensitizing otherwise radioresistant forms of GBM.

Blotting, Western↗

PubMed2004

Long-term survival and complete response of a patient with recurrent diffuse intrinsic brain stem glioblastoma multiforme.

Recurrent diffuse intrinsic brain stem glioblastoma multiforme carries an extremely poor prognosis and a median survival of less than 7 months. In this article, the authors report good results in a 40-year-old man diagnosed with glioblastoma multiforme who received antineoplastons. The patient's brain tumor was diagnosed in May 1999, and he subsequently underwent subtotal tumor resection and standard radiation therapy. Magnetic resonance imaging and positron emission tomography scans documented his tumor recurrence. Approximately 2 months after completion of radiation therapy, he was admitted for administration of intravenous antineoplastons A10 and AS2-1 through a subclavian venous catheter by intermittent bolus injections 6 times per day using a portable pump. Administration of antineoplastons A10 and AS2-1 was over 655 consecutive days with the exception of a few short interruptions. The maximum dosage of A10 was 8.15 g/kg/d and AS2-1 0.35 g/kg/d. Antineoplastons A10 and AS2-1 administration was very well tolerated with only mild reversible side effects. Follow-up magnetic resonance imaging and positron emission tomography scans revealed decrease and eventually disappearance of the tumor. A complete response was documented after approximately 1 year of antineoplastons A10 and AS2-1 administration. More than 4 years later, off antineoplastons A10 and AS2-1, the patient is tumor free, able to carry on normal activities, and works full-time, and his Karnofsky Performance Status increased from 50 to 100. Extensive phase II trials with antineoplastons A10 and AS2-1 in patients with glioblastoma multiforme are nearing completion. These trials may provide more data regarding the efficacy of antineoplastons A10 and AS2-1 in the treatment of glioblastoma multiforme in untreated patients compared to the results in those patients with tumor recurrence after radiation therapy.

Adult↗

PubMed1975

Multicentric and isolated multifocal glioblastoma multiforme simulating metastatic disease.

Single case reports of multicentric glioblastoma multiforme and multifocal glioblastoma multiforme tumours are presented. Multicentric glioblastoma multiforme tumours are those which have no macroscopic or microscopic connection. Multifocal gliomatous tumours, on the other hand, are those with either gross or microsopic continuity or evidence of cerebral spinal fluid spread and/or local metastases. The cerebral scintigram findings, cerebral angiogram studies and pathological description of these entities are presented. These lesions may be mistaken for metastases. In patients with multiple cerebral lesions multiple primary malignancies of brain should be considered when there is no clinical or radiographical evidence for extracranial primary neoplasms.

Aged↗

PubMed2005

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines.

Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K(+) channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K(+) channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K(+) channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies.

Adult↗

PubMed1992

Comparative treatment planning: proton vs. x-ray beams against glioblastoma multiforme.

The survival of patients with glioblastoma multiforme is extremely poor, the 5-year survival rate being almost zero. The cause of failure is almost exclusively local progression of tumor, the remainder is due to complications of treatment. Although this tumor is clearly radiation resistant, there is evidence of a dose response relationship. Using a thin slice CT scan of the entire head of a patient with glioblastoma multiforme, 3-dimensional radiation treatment plans were developed for treatment to a dose of 90 cobalt-Gray-equivalent (CGE). Dose distributions using protons were compared to those using x-rays. The results showed advantages for the proton beam technique. Namely the proton plan irradiated less non-target brain than the x-ray plan; this was especially so in the decrease of coverage of deep-seated structures. The volume of non-target brain that received more than 70 CGE was 175 ml for the x-ray plan and 94 ml for the proton plan. This study indicates that for a subpopulation of patients with glioblastoma multiforme, at least 90 CGE could be delivered with proton beam techniques to the target with only small volumes of normal brain structures receiving more than 70 CGE.

Brain Neoplasms↗

PubMed1989

Multiple bone metastases in a patient with glioblastoma multiforme.

Extracranial bone metastases from glioblastoma multiforme are rarely reported in the medical literature. The authors describe a case of glioblastoma multiforme with distant osseous metastases that were detected by a Tc-99m MDP image. The metastases were osteolytic and expansile on plain radiographs.

Adult↗

PubMed2003

Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme.

Despite advances in the molecular pathogenesis of glioblastoma multiforme, no reliable prognostic markers have been identified. We analysed telomerase activity and telomere lengths in glioblastoma multiformes from 77 patients. 19 patients (25%) had tumours with the alternative-lengthening-of-telomere (ALT) phenotype. Median survival for patients with this phenotype was 542 days (95% CI 114-970) compared with 247 days (224-270) for glioblastoma multiformes with normal telomeres (p=0.0003). Cox's regression analysis showed that this association is independent of age. In patients with non-ALT tumours, telomerase activity did not affect survival (median 287 [199-375] vs 236 [230-242] days, p=0.275). We conclude that ALT is a prognostic indicator for patients with glioblastoma multiforme.

Adult↗