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PubMed1993

In vitro split-dose recovery of glioblastoma multiforme.

Glioblastoma multiforme is among the most clinically resistant tumors to radiation. This resistance may be due to several different factors, such as a low intrinsic radiation sensitivity, a high recovery capacity, an increased number of clonogens, and a high hypoxic fraction. Previously, we have demonstrated a very wide range of intrinsic radiation sensitivities of cells of glioblastoma multiforme cell lines in vitro after single-dose irradiation. That is, the cells of some glioblastoma multiforme cell lines were quite sensitive, while for others the sensitivity of glioblastoma multiforme was among the lower range of sensitivities reported in the literature. This finding indicates that inherent cellular radiation sensitivity is not the sole determinant of the in vivo response of glioblastoma multiforme tumors. In this report, we evaluate the role of split-dose recovery determined in vitro in relation to the poor clinical outcome of glioblastoma multiforme. Cells of seven early-passage glioblastoma multiforme cell lines and six cell lines derived from tumors of a type frequently treated successfully (two squamous cell carcinomas of head and neck, three breast cancers, and one low-grade astrocytoma cell line) were studied. The in vitro split-dose recovery has been measured using colony formation as an end point. The cells were maintained at 37 degrees C for a period of 6 h between the doses of radiation. Results are presented in terms of a recovery ratio: the ratio of the mean inactivation dose of split-dose radiation to that of single-dose radiation. The data show significantly higher recovery ratios for glioblastoma multiforme than for the other types of histology; however, glioblastoma multiforme showed a wide range of recovery ratios, varying from 1.12 to 2.02. This indicates that cells of some glioblastoma multiforme cell lines exhibit minimal split-dose recovery. No correlation was found between the recovery ratio and the intrinsic radiation sensitivity of the cell lines studied. From these data, we conclude that the recovery capacity may not be the major determinant of the clinical radiation resistance of some glioblastoma multiforme.

Cell Survival↗

PubMed1992

Clonal composition of glioblastoma multiforme.

Glioblastoma multiforme, the most common and most lethal primary central nervous system neoplasm, is noted for its phenotypic and biological heterogeneity. This heterogeneity may result from genetic alterations accumulated by a single transformed astrocyte as it evolves into a monoclonal tumor. Alternatively, it may be attributed to the presence of multiple biologically and genetically distinct astrocytic populations within a polyclonal tumor. To address the issue of clonal composition of glioblastoma multiforme the authors used two independent approaches: analysis of X-chromosome inactivation and analysis of chromosomes 10 and 17 for tumor-specific somatic deletions. The analysis included 10 tumors from nine female patients with glioblastoma multiforme (eight primary and two recurrent tumors), who were heterozygous at either of two X-chromosome genes (hypoxanthine phosphoribosyl-transferase or phosphoglycerate kinase). Nine glioblastomas multiforme demonstrated a monoclonal pattern on X-chromosome analysis; contamination with normal tissue obscured the analysis in one tumor. Somatic deletions on chromosomes 10 and/or 17 occurred in nine tumors, supporting a monoclonal composition for these tumors. These data suggest that glioblastoma multiforme is a monoclonal neoplasm, derived from the clonal expansion of a single transformed astrocyte that has, as a fundamental step in tumorigenesis, sustained a critical genetic alteration on chromosome 10 and/or 17.

Brain Neoplasms↗

PubMed1992

Cervical metastatic glioblastoma multiforme.

Glioblastoma multiforme is an anaplastic neoplasm of glial origin. In spite of the aggressive histologic features and poor prognosis, metastasis outside the cranial vault is distinctly unusual. A patient with glioblastoma multiforme metastatic to the neck is presented. We also review the topic of metastatic intracranial tumors.

Adult↗

PubMed2004

Current management of glioblastoma multiforme.

Glioblastoma multiforme is the most common primary brain tumor in adults. Despite major research efforts and progress in neuroimaging, neurosurgery, and radiation and medical oncology, the overall survival of patients with this disease has changed little over the past 30 years. Surgery and radiation therapy remain critical components in the care of patients with glioblastoma multiforme. Treatment with chemotherapy has been hampered by the apparent resistance of these tumor cells to available agents and challenges in delivering agents to the tumor cells. The blood-brain barrier can restrict entry of some agents and the effect of antiepileptic drugs inducing hepatic P450 can significantly affect the pharmacology of a wide range of antineoplastic agents. As a result, new agents and novel approaches are required. Translational research efforts should: (1) pursue a broad research agenda until productive avenues are identified; (2) quantify the delivery of novel agents to the malignant brain tumor cells; (3) determine the maximum tolerated dose (MTD) and preliminary efficacy data on novel agents before initiating combination therapies; (4) optimize trial designs; and (5) improve psychosocial and supportive care for patients with this devastating illness.

Antineoplastic Agents↗

PubMed2006

Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme.

Glioblastoma multiforme is the most common tumor arising in the central nervous system. Patients with these tumors have limited treatment options and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment, however the use of these will require a fuller understanding of the genetic changes in these complex tumors. In this study, we identify copy number changes in a series of glioblastoma multiforme tumors and cell lines by applying high-resolution microarray comparative genomic hybridization. Molecular cytogenetic characterization of the cell lines revealed that copy number changes define translocation breakpoints. We focused on chromosome 6 and further characterized three regions of copy number change associated with translocations including a discrete deletion involving IGF2R, PARK2, PACRG and QKI and an unbalanced translocation involving POLH, GTPBP2 and PTPRZ1.

Adult↗

PubMedDate not supplied

Imaging glioblastoma multiforme.

Glioblastoma multiforme are infiltrative lesions that have a high degree of heterogeneity, both within and between different patients. Imaging is critical for all phases in the evaluation and treatment of these lesions, but has been limited in providing information that is reliable enough to stratify patients into groups with uniform behavior and to predict outcome. Although magnetic resonance imaging is the method of choice for visualizing anatomic features of the lesion, its results are ambiguous in terms of defining the functional characteristics of the lesion and distinguishing tumor from treatment induced necrosis. Recent advances in magnetic resonance have made possible the routine acquisition of physiological data such as perfusion- and diffusion-weighted images and of metabolic data such as water suppressed proton spectroscopic images. These provide quantitative measurements that are more closely related to the biological properties of the tumor and reflect changes in tumor vascularity, cellularity and proliferation that are associated with tumor progression. As the molecular properties that influence invasion and neoplastic transformation are elucidated, it is critical that noninvasive imaging techniques are available for investigating new therapies and tailoring treatment to individual patient characteristics. The data obtained from patients with glioblastoma multiforme have already demonstrated that these new magnetic resonance techniques are able to contribute to diagnosis, characterization of malignant potential, treatment planning and assessment of response to therapy.

Brain Neoplasms↗

PubMedDate not supplied

Glioblastoma multiforme.

Glioblastoma multiforme is the most common primary brain tumor of adults, as well as the most malignant. Its etiology is unknown, but the tumor is thought to arise through dedifferentiation of adult astrocytes. It occurs most frequently between the ages of 40 and 60, in men more often than in women (1.5:1). Important early symptoms include subtle personality change, headache, weakness, and intellectual impairment; specific complaints and physical findings depend on the location of the lesion. The initial diagnostic test should be a CT-scan; it will detect more than 90% of malignant astrocytomas. Surgery remains the cornerstone of treatment; patients receiving radical debulking have a median survival of 8 months compared to the 3 month survival of unoperated cases. Modern neurosurgical technique, neuroanesthesia, mannitol, and corticosteroids have reduced the surgical mortality to 3%. Most patients also receive 4500 rads of whole-brain irradiation and 1800 rads to the operative site; radiotherapy increases the median survival of operated patients by 2 to 3 months. An additional small increment in survival time and some improvement in quality of survival can be achieved by nitrosourea chemotherapy; the latter is usually given as 100 mg/m2/day x 3 days of BCNU every eight to ten weeks. Experimental treatments under study include the use of radiosensitizers, the role of immunotherapy and the application of microwave-induced hyperthermia. Two-year survival remains 10% to 20%, and there are virtually no five-year survivors. An optimal combined modality treatment plan, one in which each cellular compartment of this truly multiforme tumor is effectively addressed, remains to be designated.

Adult↗

PubMed2005

PIK3CA mutations in glioblastoma multiforme.

Glioblastoma multiforme WHO grade IV is the most common and malignant variant of astrocytic tumors. Loss of heterozygosity of chromosome 10 and mutations in the tumor suppressor gene PTEN on 10q are molecular hallmarks of glioblastomas. Recently, mutations were identified in PIK3CA, encoding a protein that antagonizes the function of PTEN protein in the PI3K/Akt pathway. To address the question whether an exclusive mutation pattern can be observed in PIK3CA and PTEN, we determined the frequency of mutations in both genes. All coding exons were examined by single strand confirmation polymorphism and direct sequencing. Additionally, we analyzed chromosome 10 for loss of heterozygosity and evaluated the mutational status of TP53. In 70 glioblastomas, 5 (7%) PIK3CA mutations and 10 (14%) PTEN mutations were found. All mutations in PIK3CA located to exons 1, 9 and 20, thereby supporting the concept of mutational hot spot regions. In all but one glioblastoma, mutations were seen either in PIK3CA or in PTEN. In conclusion, the frequency of PIK3CA mutations in glioblastomas appears to be much lower than initially reported.

Base Sequence↗

PubMed2006

Impact of novel PTEN mutations in Turkish patients with glioblastoma multiforme.

Glioblastoma multiforme (GBM) represents the most common and aggressive type of primary neoplasms of the central nervous system. The PTEN (phosphatase, tensin homologue, deleted on chromosome TEN; MIM # 601728) tumor suppressor gene has an essential biological role in the formation of glioblastomas. It is known that there are variations in genetic alterations in tumors that develop in patients with different ethnic backgrounds and because there is no study evaluating PTEN mutation in Turkish patients with GBM, we aimed to realize the present study. We investigated 62 GBM tumors for mutations of the PTEN gene using single strand conformational polymorphism (SSCP) method followed by DNA sequencing. As a result of our investigation, PTEN mutations were detected in 15 of 62 tumors (24.19%). Nine different sequence variants were identified: one novel promoter site mutation (5'UTR -9C-->T), one novel intronic mutation (IVS2-2delA), four novel point mutations (61A-->G, 105T-->G, 248C-->G, and 364C-->G), two novel frameshift mutations (213delC) and 378delGATA) and one previously reported global exonic transition type mutation (129G-->A). Since the majority of PTEN mutations identified in the present study are novel, we believe that these alterations may be specific to Turkish population. Furthermore, though no significant correlation was found between PTEN mutations and histopathological properties of GBM tumors, our findings indicate that localizations of mutations in PTEN gene may have an effect on clinical aggressiveness of GBM tumors.

Adult↗

PubMed1987

Primary cerebellar glioblastoma multiforme.

Glioblastoma multiforme in adults arising in the cerebellum is a rare tumor, well documented in only 13 cases in the literature. We report a fourteenth case, an 80-year-old female, and reassess the clinical and CT aspects of this tumor based on review of the world's literature. The median age of patients is 53 years with a median survival of three months, which is less than adult cerebral hemisphere malignant gliomas.

Aged↗

PubMed1992

In vitro intrinsic radiation sensitivity of glioblastoma multiforme.

Glioblastoma multiforme is one of the most resistant of human tumors to radiation whether used alone or in combination with surgery and/or chemotherapy. This resistance may be caused by one or more of several different factors. These include inherent cellular radiation sensitivity, an efficient repair of radiation damage, an increased number of clonogens per unit of volume, a high hypoxic fraction, high [GSH] concentration, and rapid proliferation between fractions. In the present study, we evaluate the intrinsic radiation sensitivity (surviving fraction at 2 Gy or mean inactivation dose) of malignant human glioma cells in vitro. The in vitro radiation sensitivity of 21 malignant glioma cell lines (early and long term passages) has been measured using colony formation as the end-point of cell viability. The survival curve parameters (SF2 measured and calculated, alpha, beta, D0, n and MID) have been determined for single dose irradiations of exponential phase cells (18-24 hr after plating) under aerobic conditions and growing on plastic. The mean SF2 of the 21 cell lines is 0.51 +/- 0.14 (with a range of 0.19 to 0.76). This value may be compared to the mean SF2 of 0.43-0.47 for SCC, 0.43 for melanoma, and 0.52 for glioblastoma as reported from other authors when using colony formation of cells in exponential phase on plastic. Although glioblastoma is almost invariably fatal, our data demonstrate a very wide range of intrinsic radiosensitivities. These broadly overlap the radiation sensitivities of cell lines from tumors that are often treated successfully. We conclude that standard in vitro measurements of cellular radiation sensitivity (SF2) do not yield values that track in a simple manner with local control probability at the clinical level and that, for at least some of the tumors, other parameters and/or physiological factors are more important.

Cell Survival↗

PubMed2006

Chromosome transfer experiments link regions on chromosome 7 to radiation resistance in human glioblastoma multiforme.

Glioblastoma multiforme (GM) is the most lethal form of brain tumor, with a median survival of approximately 1 year. Treatment options are limited. Radiation therapy is a common form of treatment, but many tumors are resistant. In earlier studies, we found that gain of chromosome 7 is associated with radiation resistance in human primary GM. In this study, we extend that result to a model system in which we transferred chromosome 7 to recipient cells and confirmed radiation resistance as a function of chromosome 7 gain. We identified three candidate regions on chromosome 7 that conferred radiation resistance in our model system.

Brain Neoplasms↗

PubMedDate not supplied

Association of chromosome 7, chromosome 10 and EGFR gene amplification in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is characterized by intratumoral heterogeneity in both histomorphological and genetic changes, displaying a wide variety of numerical chromosome aberrations, the most common of which are trisomy 7 and monosomy 10. The amplification of the epidermal growth factor receptor (EGFR) gene is the most frequently reported genetic abnormality. The associations between these parameters and their implication in the tumoral progression are poorly understood. We performed simultaneous fluorescence in situ hybridization (FISH) with centromeric DNA probes for chromosomes 7 and 10 in smear preparations, and EGFR gene amplification by PCR from 25 cases of GBM. Trisomy/ polysomy for chromosome 7 was present in 76% of cases and monosomy 10 in 68%. Both alterations were associated in 56% of cases. The EGFR gene was amplified in 52% of tumors; in 44% associated with trisomy/ polysomy 7, and in 36% with monosomy 10. The three parameters were associated together in 28% of cases. Kaplan-Meier survival rate analysis demonstrated lower survival rates in patients with monosomy 10, trisomy 7, and monosomy associated with trisomy 7. The other combinations were not different in frequency in relation to survival. In the present study, trisomy/polysomy 7 and monosomy 10 have been found to be frequently associated. The combination of both anomalies is probably important in the tumorigenesis of glioblastoma. Moreover, this association is apparently independent of EGFR gene amplification, which could be a later event in this process.

Adult↗

PubMed1986

Spiromustine and intracarotid artery cisplatin in the treatment of glioblastoma multiforme.

Glioblastoma multiforme is a highly malignant and rapid-growing primary brain tumor. It constitutes one-fourth of all intracranial tumors and about half of all gliomas. Survival rate following conventional treatment is only 12 to 18 months. At the National Institutes of Health, two promising therapies are currently undergoing clinical trials. Spirohydantoin mustard (spiromustine) is a combination of a nitrogen mustard and a derivative of phenytoin, an anticonvulsant drug that rapidly penetrates the blood-brain barrier and localizes in brain tumors. Intracarotid administration of cis-diamminedichloroplatinum (cisplatin) increases drug delivery to the tumor and, through hemodialysis, systemic exposure is reduced. Nursing management of patients receiving these two agents requires precise planning and implementation of an individualized plan of care to ensure a successful chemotherapeutic regimen.

Brain Neoplasms↗

PubMed2006

Long term responses with cetuximab therapy in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is responsible for most of the deaths associated with primary brain tumors. Standard treatment includes maximal surgical resection followed by chemotherapy and concomitant radiotherapy. Most patients, however, recur shortly after treatment. Second line treatment has little efficacy and the majority of patients die soon from the disease. Recent advances in molecular biology have implicated the epidermal growth factor receptor (EGFR) signaling pathways in the progression and resistance to standard therapies for GBM. This has prompted the evaluation of EGFR tyrosine- kinase inhibitors with encouraging results. Cetuximab is a monoclonal antibody targeted against the extra cellular domain of the EGFR with activity against different tumor types, either alone or in combination with chemotherapy and/or radiation therapy. Here we describe three patients with recurrent, heavily pretreated, EGFR expressing GBM who responded to treatment with single agent cetuximab.

Adult↗

PubMed2006

Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme.

Glioblastomas multiforme (GBMs) are highly vascular brain tumors characterized by abnormal vessel structures in vivo. This finding supports the theory that glioma-associated endothelial cells (ECs) have intrinsically different properties from ECs in normal human brain. Therefore, identification of the functional and phenotypic characteristics of tumor-associated ECs is essential for designing a rational antiangiogenic therapy. The GBM-associated ECs have a large, flat, and veil-like appearance, in contrast to normal ones, which are small and plump. Although the tumor ECs have the typical markers, they proliferate more slowly than these cell types in normal brain. The GBM-associated ECs are resistant to cytotoxic drugs, and they undergo less apoptosis than control cells. Also, GBM-associated ECs migrate faster than controls and constitutively produce high levels of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor. An understanding of these unique characteristics of glioma-associated ECs is important for the development of novel antiangiogenic agents that specifically target tumor-associated ECs in gliomas.

Angiogenesis Inhibitors↗

PubMed2004

Isolation of cancer stem cells from adult glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is comprised of a heterogeneous population of cells. It is unclear which cells within the tumor mass are responsible for tumor initiation and maintenance. In this study, we report that brain tumor stem cells can be identified from adult GBMs. These tumor stem cells form neurospheres, possess the capacity for self-renewal, express genes associated with neural stem cells (NSCs), generate daughter cells of different phenotypes from one mother cell, and differentiate into the phenotypically diverse populations of cells similar to those present in the initial GBM. Having a distinguishing feature from normal NSCs, these tumor stem cells can reform spheres even after the induction of differentiation. Furthermore, only these tumor stem cells were able to form tumors and generate both neurons and glial cells after in vivo implantation into nude mice. The identification of tumor stem cells within adult GBM may represent a major step forward in understanding the origin and maintenance of GBM and lead to the identification and testing of new therapeutic targets.

Adult↗

PubMed2000

Molecular and cytogenetic analysis of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common primary tumor occurring in the central nervous system of adults. Although progress has been made in clinical management of this tumor, little is known about the molecular defects underlying the initiation and progression of GBM. To address these issues, we have characterized five cases of GBM using cytogenetics, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and direct sequencing. All of these tumors were observed to have clonal chromosome aberrations. Complicated chromosome translocations including der(18)t(2;4;12;18), der(X)t(X;10)(q27.1;p12.1) and der(10)t(10;15)(p11.23;q11.2), and der(1) (:1p31-->1q44::7q11. 3-->7qter) were seen in three tumors. Loss of the CDKN2 gene was noted in four tumors. A gain of copy number of the Cathepsin L gene was seen in two tumors. Amplification of the CDK4, MDM2, and GLI/CHOP genes was noted in two tumors, and amplification of the PDGFR gene was detected in one tumor. Mutation of exon 5 of the TP53 gene was found in three tumors. No mutation of the BCL10 gene was detected in five cases of GBM analyzed, although deletion of chromosome 1p was seen in two tumors. These results provide information for further investigation of GBM.

Adult↗