UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Magnetic resonance imaging has been used increasingly in the staging and evaluation of neoplasia of the brain and leptomeninges. In the classification of gliomas, the MR accuracy rate approaches that of pathologic diagnosis. Contrast-enhanced MR imaging has improved specificity in evaluating brain tumors in children and is now the preferred modality for evaluating leptomeningeal metastases of the brain and spine. MR imaging in children has also increased the specificity of histologic diagnosis in hypothalamic hamartoma and juvenile pilocytic astrocytoma. Gadolinium enhancement is most useful in patients older than 35 years of age who have focal neurologic complaints and certain disease histories. The expense of gadolinium contrast material is the major drawback to its routine use. In patients with seizure disorder, MR imaging is more sensitive than CT for detecting abnormalities such as mesial temporal sclerosis, tumors, and vascular malformations. Gadolinium enhancement may be useful in differentiating tumors from mesial temporal sclerosis. Recent reports on the use of MR spectroscopy for evaluating brain metabolism and tumors demonstrate that differences in metabolites exist. A correlation was found in epidermoid tumors between high signal on T1-weighted images and high lipid content, and several studies have shown a positive correlation between glioma grade and glycolytic activity as determined on 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography.
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PMID:Imaging of central nervous system tumors. 202 6

In summary, many actual interactions between tumors in the CNS and the immune system have been demonstrated. The normal brain does not possess a lymphatic system and is partially hidden from the systemic immune system by the BBB, furthermore brain cells do not express MHC antigens which are necessary for the initiation of an immune response. In pathological conditions however, immunocompetent cells may find their way through transformed endothelial cells. Microglia and astrocytes may function as antigen presenting cells. Glioma cells when stimulated by cytokines such as IFN gamma can be induced to express MHC class I and class II antigens, thus making them more susceptible to an immune attack. In addition glioma cells are capable of secreting several cytokines including IL 1, IL 3 and IL 6 also involved in the generation of an immune response. Indeed, a functional analysis of lymphocytes infiltrating gliomas has revealed the accumulation at the tumor site of cytotoxic T lymphocytes as well as NK cells. However host-immune responses against gliomas seem to be weak in comparison to other cancers. Glioma cells are known to secrete TGF beta 2 and PGE 2 which may in part be responsible for this lack of immune response, thus shielding themselves from immune attack. In order to be recognized by the immune system the tumor cells must express TAA in addition to MHC antigens, and such TAA have been identified by MAbs. These MAbs can be used for "targeted" therapy when coupled to toxic agents or radionuclides. Preclinical studies have shown that, after intravenous or intracarotid injection, there is specific accumulation of the MAb in the tumor but in insufficient amounts for therapeutic use. The relatively small amount of MAb binding to the tumor in vivo can be due to several factors: not all the cells in a single tumor express a given tumor-associated antigens, the MAb may have a low affinity for the antigen, the BBB may hinder the passage of the MAb. Attempts have been made to overcome these drawbacks by opening the BBB for example. In addition MAbs can readily be used for the treatment of carcinomatous meningitis. There has been little success in the development of immunotherapy with IFN beta 1 and even less with adoptive immunotherapy using LAK cells plus IL 2. TIL as well as LAK cells can be expanded in vitro with IL2 and it is feasible to reinject these cells into the tumor site.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Immunobiology of brain tumors. 218 Apr 10

Neoplastic meningitis can result from leptomeningeal dissemination of a variety of cancers. We now report the development of animal models of human neoplastic meningitis and activity of intrathecal 4-hydroperoxycyclophosphamide (4-HC) against the human rhabdomyosarcoma cell line TE-671 and the human glioma cell line D-54 MG grown in the subarachnoid space of athymic rats. The injection of 5 x 10(5) TE-671 or D-54 MG cells resulted in leptomeningeal tumor growth from the base of the brain to the cauda equina. Daily weights and neurological examinations revealed progressive neurological deficits and weight loss, with death occurring between Days 21 and 27 for TE-671 and Days 14 and 26 for D-54 MG. 4-HC toxicity in non-tumor-bearing rats was assessed at dose levels of 2.0, 10.0, 15.0, and 20.0 mM, with clinical and histological evidence of neurotoxicity observed at the 2 highest dose levels. Intrathecal treatment with 4-HC on Day 8 following injection of TE-671 resulted in an increase in median survival of 20% (P = 0.04) at 1.0 mM 4-HC and 41% (P less than 0.001) at 2.5 mM 4-HC. Intrathecal treatment with 4-HC (2.5 mM) on Day 5 following injection of D-54 MG resulted in an increase in median survival of 23% (P = 0.009). These studies show the usefulness of the athymic rat model of human neoplastic meningitis and demonstrate the efficacy in vivo of intrathecally administered 4-HC against a human glioma and a human rhabdomyosarcoma cell line and the lack of toxicity at therapeutic levels of 4-HC in normal athymic rats.
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PMID:Activity of intrathecal 4-hydroperoxycyclophosphamide in a nude rat model of human neoplastic meningitis. 230 44

This paper reviews the diagnostic role of monoclonal antibody immunohistochemistry in a series of 189 brain tumour biopsies and 22 cases of neoplastic meningitis. The diagnostic monoclonal antibody panel, which includes markers for glial, neural, epithelial and lymphoid differentiation antigens, was used to test a wide variety of cerebral and spinal tumours by indirect immunofluorescence and immunoperoxidase techniques on unfixed frozen sections. Gliomas, meningiomas, schwannomas, medulloblastomas, choroid plexus tumours, cerebral lymphomas and metastatic carcinomas could all be reliably differentiated by means of their characteristic antigenics profiles, as defined by their patterns of reactivity with the antibody panel. Confident diagnosis was possible even in very poorly differentiated tumours and in biopsies distorted by surgical squeeze artefact, where paucity of morphological clues made diagnosis by conventional histological methods difficult or impossible. It was estimated that use of the antibody panel was responsible for, or made a significant contribution towards the final diagnosis in approximately 20% of cases. The monoclonal reagents were also found to be of great value in the detection and characterisation of neoplastic cells in CSF specimens from patients with malignant meningitis. Malignant cells were detected in 73% of cases and characterised in 16% of cases by routine cytological techniques. Employing monoclonal immunocytology however, these figures were improved to 95% and 95% respectively. Our findings suggest that patients with neoplastic meningitis can be spared prolonged investigation and inappropriate management by the early detection and characterisation of malignant cells in CSF using panels of monoclonal antibodies.
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PMID:The role of monoclonal antibodies in brain tumour diagnosis and cerebrospinal fluid (CSF) cytology. 403 74

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomyosarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations. Comparison of a single dose of 1 mM melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.
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PMID:Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats. 806 69

To evaluate the possible intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis, its antitumor activity and neurotoxicity in vivo were assessed. FdUrd at doses in the range 5-100 microg/animal was effective against meningeal carcinomatosis using Walker 256 carcinoma cells in rats and MM46 mammary cancer cells in mice and against meningeal gliomatosis using 203 glioma cells in mice. After four intrathecal injections, FdUrd at these doses also showed minimal neurotoxicity in the C57BL/6 mouse brain. To estimate the mechanism of FdUrd efficacy, thymidine phosphorylase (TPase) and thymidine kinase (TK), key enzymes in the metabolism of FdUrd, were measured in rat, mouse and normal human brain tissue, and in human brain tumor tissues and cerebrospinal fluid (CSF) from patients with malignant brain tumors including meningeal carcinomatosis. TPase levels were lower in brain and malignant brain tumors than in other organs and their tumors. Moreover, the activity of TPase in the gray matter of human brain, which faces the cerebrospinal fluid across the cortical surface and into which malignant cells invade in meningeal carcinomatosis, was lower than that in the white matter. TK was undetectable, and TPase was detected (at very low concentrations) in only 4 of 56 patients with brain tumors or meningeal carcinomatosis. These findings indicate that brain tissue and CSF are favorable sites for FdUrd chemotherapy because the rate of conversion of FdUrd to 5-FU would be minimal. In conclusion, FdUrd is potentially useful for intrathecal treatment of neoplastic meningitis from primary brain tumors and systemic cancer.
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PMID:Intrathecal 5-fluoro-2'-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study. 992 56

The incidence of neoplastic meningitis is on the rise. Neoplastic meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of neoplastic meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a neoplastic meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing neoplastic meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.
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PMID:Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1. 1049 44

The current study was designed to evaluate the toxicity and activity of Spartaject Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 micromol of intrathecal Spartaject Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 micromol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 micromol x 1, 6.2 micromol x 4 and 4.1 micromol x 4, respectively, against D-456 MG. A single dose of 8.1 micromol of intrathecal Spartaject Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 micromol x 1), 52.3% (2.0 micromol x 4), and 23% (8.1 micromol x 4) (p < 0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose-response relationships of alkylating agents, provide rationale for further evaluation of this agent.
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PMID:Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats. 1072 Feb 3

Temozolomide is a novel, oral, second-generation alkylating agent. Preclinical and phase I/II studies have demonstrated its efficacy against newly diagnosed high-grade glioma and anaplastic astrocytoma. Its antineoplastic effect is accompanied by quality of life benefits in patients with these debilitating tumors. Neoplastic meningitis, a refractory disorder, develops in approximately 3% to 8% of patients with systemic cancers. Traditional approaches to leptomeningeal metastases, such as radiation and intrathecal chemotherapy, have limited success and a high degree of toxicity. Temozolomide offers a number of potential therapeutic advantages in this disorder, including activity against a wide spectrum of human cancers that produce neoplastic meningitis and penetration of the blood-brain barrier. Patients treated with temozolomide benefit from both its systemic and intracranial activity. Recently, intrathecal temozolomide has been shown to increase median survival in athymic rats bearing subarachnoid human malignant glioma xenografts. Its efficacy, convenient dosing, and predictable safety profile make it an ideal agent for future study of these difficult-to-treat central nervous system malignancies.
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PMID:Temozolomide in early stages of newly diagnosed malignant glioma and neoplastic meningitis. 1086 48

Among methylating agents of clinical interest, temozolomide is a novel antitumor compound that has raised particular interest due to its acceptable safety profile and activity against tumors poorly responsive to conventional chemotherapy, such as malignant glioma and metastatic melanoma. Moreover, the drug has recently shown promising antitumor activity in a patient affected by primary brain lymphoma and is currently under phase II clinical trials for leptomeningeal metastases from leukemia and lymphoma or for brain metastases from lung and breast cancers. The antitumor activity of TMZ, that generates different types of methyl adducts (70% N7-methylguanine, 10% N3-methyladenine and 9% O6-methylguanine), has been mainly attributed to the formation of O6-methylguanine adducts. Indeed, tumor cell susceptibility to TMZ is strongly affected by the functional status of DNA repair systems, involved either in the removal of methyl adducts from O6G or in the apoptotic signaling triggered by O6-methylG:T mispairs. This review will focus on the different pharmacological strategies aimed at overcoming tumor resistance to TMZ such as new formulations of the drug or dosing schedules, and combined treatments with other chemotherapeutic agents, modulators of DNA repair systems, or gene therapy. The potential use of N3-methyladenine selective agents in the case of tumors tolerant to O6-methylguanine will be also discussed.
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PMID:Pharmacological strategies to increase the antitumor activity of methylating agents. 1205 67

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