Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptomeningeal dissemination of primary CNS tumors varies widely by histologic subtype. In certain tumors including medulloblastoma, ependymoma, germ cell tumors, and primary CNS lymphoma, seeding of the cerebrospinal fluid space is a critical factor in determining stage, prognosis and appropriate therapy. Other tumor types, such as glioma, may have radiographic evidence of leptomeningeal metastases without clear impact on prognosis or therapy.
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PMID:Leptomeningeal metastasis of primary central nervous system (CNS) neoplasms. 1621 84

The outcome for malignant glioma patients remains dismal despite treatment with surgical resection, radiation and chemotherapy. The goal of immunotherapy is to eradicate or suppress the residual infiltrative component of these tumors. Although there is clinical evidence for cell-mediated antiglioma activity, there are special considerations that need to be accounted for in the design of immunotherapeutics for CNS tumors, such as possible differences in antigen-presenting cells, trafficking of effector T-cells and immunosuppression. Previously characterized immunosuppression in glioma patients has included low peripheral blood lymphocyte counts, reduced delayed type hypersensitivity reactions to recall antigens, impaired mitogen-induced blastogenic responses by peripheral blood mononuclear cells, increased CD8+ suppressor T-cells, decreased CD4+ T-cell activity in vitro, diminished immunoglobulin synthesis by B-cells and impaired transmembrane signaling through the T-cell receptor/CD3 complex. Recent impairments that are being identified include anergy, failure of costimulation, lack of sufficient numbers of functional effector T-cells and the presence of T-suppressor cells within the tumor microenvironment. It is proposed that these inherent problems will need to be overcome in order for immunotherapies to realize their potential. Paradoxically, the efficacy of recent clinical immunotherapies for glioma patients appears equivalent to that seen in other cancer immunotherapeutic approaches. This review will provide an overview of the juxtaposition of the immune system and CNS, and will discuss the most recent and ongoing immunotherapeutic clinical trials that are demonstrating promising results.
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PMID:Immunotherapy for human glioma: innovative approaches and recent results. 1622 Oct 48

A number of reports have indicated an increasing incidence of primary brain tumors over the past few decades. The purpose of this study was to describe incidence rate trends in a population-based series of newly diagnosed primary nonmalignant and malignant brain and other CNS tumors, contributing five additional years to previously published incidence trends. Data for the years 1985 through 1999 from six collaborating state cancer registries of the Central Brain Tumor Registry of the United States were used to determine incidence trends in the broad age groups 0-19, 20-64, and >or=65 years, overall and for selected histologies. Multiplicative Poisson regression was used to express trends as average annual percent change (AAPC). Joinpoint regression was used to identify sharp changes in incidence occurring over this period. Overall, incidence increased modestly (AAPC, 1.1; 95% CI, 0.8-1.4). When brain lymphomas were excluded, this increase remained statistically significant. A sharp change in incidence of brain lymphomas from increasing to decreasing over time was identified. Specific histologies that were increasing included anaplastic astrocytomas in individuals aged >or=65 years, microscopically confirmed gliomas in both adult age groups, and microscopically confirmed glioma, not otherwise specified (NOS), in children. Increases that were not specific to any population subgroup were seen for oligodendrogliomas, ependymomas, meningiomas, and nerve sheath tumors. Decreases were noted for astrocytoma, NOS, nonmicroscopically confirmed gliomas, and pituitary tumors. Improvements in diagnosis and classification are likely reflected in the decreasing trends in unspecified glioma subgroups and the accompanying increasing trends in more specific glioma subgroups. However, increases in meningiomas and nerve sheath tumors deserve further attention.
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PMID:Temporal trends in incidence of primary brain tumors in the United States, 1985-1999. 1644 45

Malignant central nervous system (CNS) tumors, such as glioblastoma multiforme, invade the brain and disrupt normal tissue architecture, making complete surgical removal virtually impossible. Here, we have developed and optimized a purification strategy to isolate and identify natural inhibitors of glioma cell invasion in a three-dimensional collagen type I matrix. Inter alpha-trypsin inhibitor heavy chain 2 (ITI H2) was identified from the most inhibitory fractions and its presence was confirmed both as a single protein and in a bikunin-bound form. Stable overexpression in U251 glioma cells validated ITI H2's strong inhibition of human glioma cell invasion together with significant inhibition of cell proliferation and promotion of cell-cell adhesion. Analysis of primary human brain tumors showed significantly higher levels of ITI H2 in normal brain and low-grade tumors compared with high-grade gliomas, indicating an inverse correlation with malignancy. The phosphatidylinositol 3-kinase/Akt signaling cascade seemed to be one of the pathways involved in the effect of ITI H2 on U251 cells. These findings suggest that reduction of ITI H2 expression correlates with brain tumor progression and that targeting factors responsible for its loss or restoring the ITI supply exogenously may serve as potential therapeutic strategies for a variety of CNS tumors.
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PMID:Isolation of a natural inhibitor of human malignant glial cell invasion: inter alpha-trypsin inhibitor heavy chain 2. 1645 2

Human gliomas are the most common primary central nervous system neoplasm, and they are a complex, heterogeneous, and difficult disease to treat. In the past two decades, advances in molecular biology have revolutionized our understanding of the mechanism by which these neoplasms are initiated and progress. While surgery, radiation therapy, and chemotherapy have roles to play in the treatment of patients with gliomas; these therapies are self-limited because of the intrinsic resistance of glioma cells to therapy, and the diffusely infiltrating nature of the lesions. It is now known that malignant gliomas arise from a number of well-characterized genetic alterations and activations of oncogenes and inactivation of tumor suppressor genes. These genetic alterations disrupt critical cell cycle, growth factor activation, apoptotic, cell motility, and invasion pathways that lead to phenotypic changes and neoplastic transformation. Research in each of these fields has uncovered potential therapeutic targets that look promising for disease control. Gliomas can now be modeled with fidelity and reproducibility using several transgenic and knockout strategies. Transgenic mouse models are facilitating the testing of various therapeutic strategies in vivo. Finally, the recognition of the putative brain tumor stem cell, the tumor initiating cell in brain cancer, provides an enticing target through which we could eliminate the source of the brain tumor with increased efficacy and less toxicity to normal tissues. In this review, we provide an up-to-date discussion of the many of key technologies and tools that are being used in molecular biology to advance our understanding of the biological behavior of human malignant gliomas.
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PMID:Molecular biology of human gliomas. 1670 Jun 15

VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents-the sulfonylhydrazines-that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.
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PMID:Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice. 1752 34

Pediatric CNS tumors are the most common solid tumor of childhood and are the leading cause of cancer-related death in this age group. Improving prognosis is not the only challenge facing physicians managing these young patients as it is vital to consider the quality of survival. Current management strategies rely on surgery, radiotherapy and conventional cytotoxic chemotherapy, and although ongoing clinical trials continue to refine these treatments, newer approaches are required. This article will discuss current treatment standards for the most common pediatric CNS tumors: astrocytomas (low- and high-grade glioma), ependymoma and primitive neuroectodermal tumors (medulloblastoma), as well as future biological-based novel therapies.
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PMID:Pediatric CNS tumors: current treatment and future directions. 1767 98

The presence of necrosis within a diffuse glioma is a powerful predictor of poor prognosis, yet little is known of its origins. Intravascular thrombosis is a frequent finding in glioblastoma [GBM; World Health Organization (WHO) grade IV] specimens and could potentially be involved in astrocytoma progression to GBM or represent a surrogate marker of GBM histology. We investigated whether intravascular thrombosis was more frequent or prominent in GBM than other central nervous system (CNS) malignancies and considered its prognostic significance in anaplastic astrocytoma (AA; WHO grade III), which lacks necrosis. Histologic sections were examined for thrombosis, necrosis and microvascular hyperplasia from each of 297 CNS tumors, including 103 GBMs, 46 AAs, 20 diffuse astrocytoma (DAs; WHO grade II), eight anaplastic oligodendrogliomas (AOs; WHO grade III), 20 oligodendrogliomas (ODs; WHO grade II), 49 metastatic carcinomas (METs), 31 primary central nervous system lymphomas (PCNSLs) and 20 medulloblastomas (MBs). Among newly diagnosed tumors, thrombosis was present in 92% of GBM resections, significantly greater than other types of CNS malignancies. Of tumors with thrombosis, GBMs had a higher frequency of affected vessels than AAs, DAs, AOs, ODs and MBs, but had a frequency similar to METs and PCNSLs. The sensitivity of thrombosis for the diagnosis of GBM in this set of tumors was 92% and the specificity was 91%. Intravascular thrombosis was uncommon in AAs and was only noted in stereotactic biopsies. This subset of patients had shorter survivals than those AAs without thrombosis. Thus, intravascular thrombosis is more frequent in GBM than other CNS malignancies. When present in AAs, it appears to indicate aggressive clinical behavior.
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PMID:Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma. 1809 51

Various radiation-induced tumors, including meningioma, glioma, and sarcoma, have been reported; however, metachronous intracranial double tumors induced by radiation therapy are extremely rare. A 1-year-old boy had undergone tumor removal and craniospinal radiation therapy (30 Gy) for cerebellar medulloblastoma. At 24 years old, parasagittal meningioma developed in the left parietal region and was totally removed. Six years later, an infiltrative tumor was newly found in the right fronto-temporal white matter. The patient underwent stereotactic biopsy, and the tumor was found to be an anaplastic astrocytoma. Chromosomal analysis by fluorescence in situ hybridization (FISH) revealed loss of heterozygosity (LOH) of 1p. As the patient had previously had craniospinal irradiation, no additional radiation therapy was delivered. He underwent chemotherapy with temozolomide and the disease is now stable. Since both secondary tumors were located within the area of previous radiation and the patient did not have any genetic disease predisposing him to tumors, radiation therapy was considered to be responsible for their tumorigenesis. To our knowledge, this case is the fourth case of radiation-induced double CNS tumors arising after radiotherapy to be described in the literature. Whenever radiation is administered to children or young adults, careful serial screening studies are needed.
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PMID:Two metachronous tumors induced by radiation therapy: case report and review of the literature. 1837 66

Medulloblastoma spreads by leptomeningeal dissemination rather than by infiltration that characterizes other CNS tumors, eg, gliomas. This study represents an initial attempt to identify both the molecules that mediate medulloblastoma adhesion to leptomeninges and the pathways that are key to survival and proliferation of tumor following adhesion. As a first step in molecule identification, we produced adhesion of D283 medulloblastoma cells to the extracellular matrix (ECM) of H4 glioma cells in vitro. Within this context, D283 cells preferentially expressed the alpha9 and beta1 integrin subunits; antibody and disintegrin blockade of alpha9 and beta1 binding eliminated the adhesion. The H4 ECM was enriched in tenascin, a binding partner for the alpha9beta1 integrin heterodimer. Purified tenascin-C supported D283 cell adhesion. The adhesion was blocked by antibodies to alpha9 and beta1 integrin. In vivo data were similar; immunohistochemistry of primary human medulloblastomas with leptomeningeal extension demonstrated increased expression of alpha9 and beta1 integrins as well as tenascin at the interface of brain and leptomeningeal tumor. These data suggest that tumor-cell expressions of alpha9 and beta1 integrins in combination with extracellular tenascin are necessary for medulloblastoma adhesion to the leptomeninges. As a first step in the identification of pathways that mediate survival and proliferation of tumor following adhesion, we demonstrated that adhesion to H4 ECM was associated with survival and proliferation of D283 cells as well as activation of the MAPK pathway in a growth factor deficient environment. Antibody blockade of alpha9 and beta1 integrin binding that eliminated adhesion also eliminated the in vitro survival benefit. These data suggest that adhesion of medulloblastoma to the meninges is necessary for the survival and proliferation of these tumor cells at the secondary site.
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PMID:Integrins mediate adhesion of medulloblastoma cells to tenascin and activate pathways associated with survival and proliferation. 1879 52


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