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PubMed1990

Hexose monophosphate shunt measurement in cultured cells with [1-13C]glucose: correction for endogenous carbon sources using [6-13C] glucose.

Hexose monophosphate shunt (HMPS) activity can be measured with 1H nuclear magnetic resonance spectroscopy or gas chromatography--mass spectrometry by monitoring the differential production of [3-13C]lactate and [3-12C]lactate from the degradation of [1-13C]-glucose. Errors in measurement of HMPS activity can arise from unlabeled lactate precursors, by recycling of HMPS products, and by incomplete fractional enrichment of labeled glucose. A method utilizing cultured cells incubated with [1-13C]glucose in parallel with incubations using [6-13C]glucose to correct for all these problems is presented. In cultured rat C6 glioma and 9L gliosarcoma cells, failure to apply this correction results in an approximately twofold overestimation of HMPS activity.

Animals↗
PubMed1993

Intracellular distribution of various boron compounds for use in boron neutron capture therapy.

The neutron capture reaction in boron (10B(n, alpha)7Li) generates two short-range particles with high linear energy transfer. The effect of neutron capture therapy depends on the selective localization of 10B atoms in target cells. The determination of the distribution of boron compounds in cancer cells at the subcellular level is required for the understanding of the effect of this treatment. The monomeric sulfhydryl borane (BSH) compound has been used clinically in Japan and preclinically in the U.S.A. Recently, new compounds have been developed: a dimeric sulfhydryl borane (BSSB), a boronophenylalanine (BPA), and two porphyrin complexes (BOPP and VCDP). This study demonstrates that the porphyrin complexes (BOPP and VCDP) are more cytotoxic than the other three compounds to the rat 9L gliosarcoma cell line. Using atomic absorption spectrophotometry to determine boron content for cellular uptake studies of these agents, we found that of the five compounds tested BOPP (25 microM) exposure resulted in the greatest boron uptake averaging 305 ng B/10(6) cells. BSSB (500 microM) was second averaging 93 ng B/10(6) cells, BSH (500 microM) third averaging 62 ng B/10(6) cells, VCDP (25 microM) fourth averaging 58 ng B/10(6) cells, and BPA (500 microM) fifth averaging 7.4 ng B/10(6) cells. Data on the distribution of boron in the nuclei, mitochondria, lysosomes, microsomes, and cytosomes of 9L cells are also presented.

Animals↗
PubMed1995

Adenovirus-mediated gene therapy for experimental spinal cord tumors: tumoricidal efficacy and functional outcome.

We evaluated the efficacy of adenoviral-mediated gene therapy of experimental spinal cord tumors and the functional outcome after this treatment. Spinal cord tumors were generated in the thoracic region of the spinal cord in Fischer 344 rats by stereotaxic intramedullary injection of 1 x 10(4) 9L gliosarcoma cells. Seven days after tumor cell injection, a replication-defective adenoviral vector carrying the herpes simplex virus thymidine kinase gene (ADV-tk) or a control adenoviral vector carrying the beta-galactosidase gene (ADV-beta gal) was injected into the tumors. Beginning 12 h later the animals were treated with the antiviral drug ganciclovir (GCV; 50 mg/kg) or saline twice a day for 6 days. The neurological performance of the animals was assessed during and following treatment. Eighteen days after tumor cell injection, all of the control animals had paraplegia and large tumors. In contrast, no tumors were detected in animals treated with ADV-tk and GCV. In long-term studies, two of the 5 animals treated with ADV-tk and GCV remained tumor-free and remained neurologically intact at 6 months whereas all animals in the control groups became paraplegic within 18 days.

Animals↗
PubMed1985

Cellular regulation of poly(ADP) ribosylation of proteins. I. Comparison of hepatocytes, cultured cells and liver nuclei and the influence of varying concentrations of NAD.

The in vitro rates (vinit) of poly(ADP-ribose) polymerase of permeabilized rat hepatocytes and of nuclei, isolated from hepatocytes, did not differ significantly. Incubation beyond 3 min resulted in diminished poly(ADP) ribosylation in hepatocytes compared with nuclei, coinciding with high rates of plasma membrane-associated NAD-glycohydrolase. Cultured cells (Drosophila Kc cells, gliosarcoma 9L, human fibroblasts and mouse spleen lymphocytes) exhibit variations of NAD-glycohydrolase and poly(ADP-ribose) polymerase activities and the assessment of poly(ADP-ribose) polymerase activity in permeabilized cells requires simultaneous assay of NAD-glycohydrolase. In rat liver nuclei during 10 min incubation with 500 microM NAD, 40% of NAD is consumed, 10% ADP-ribose is bound to proteins, and 20% ADP-ribose, 5% AMP and 2.7% adenosine are liberated. As determined by solvent partitioning (Jackowski, G & Kun, E, J biol chem 258 (1983) 12587) [1], the phenol-soluble protein-ADP-ribose fraction represents largely mono(ADP)-ribose protein adducts, whereas the H2O-soluble phase contains poly(ADP)-ribosylated proteins. The quantity of ADP-ribose protein adducts, the chain length of oligomers and the nature of apparent acceptor proteins in liver nuclei vary significantly with the concentration of NAD as substrate. At 500 microM NAD concentration the quantity of ADP-ribose containing adducts was in the nmol per mg DNA range, the polymers are long chains and the acceptor proteins predominantly non-histone proteins. At 0.1 microM NAD as substrate pmol quantities of monomeric ADP-ribose adducts per mg DNA were formed and the main acceptors were sharply discernable on the basis of molecular mass as histones, high mobility non-histone proteins, two protein groups of a mass of 66 and 44 kD respectively, and the poly(ADP-ribose) polymerase enzyme protein of 119 kD mass. Whereas products in the presence of 0.1 microM NAD may indicate acceptors of highest reactivity, protein adducts formed in the presence of 500 microM NAD resemble a pattern found in vivo.

ADP Ribose Transferases↗
PubMed1993

Distribution of intrathecally administered ACNU in mongrel dogs: pharmacokinetics and quantitative autoradiographic study.

The pharmacokinetics of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the cerebrospinal fluid (CSF), were determined in dogs after ventriculolumbar perfusion (VLP, n = 6), and bolus injection into the ventricle (VB, n = 2), cisterna magna (MB, n = 5), and lumbar cistern (LB, n = 3), by high-performance liquid chromatography. The VLP method introduced effective amounts of ACNU into the lumbar cistern for cell kill in vitro. That is, the areas under the time concentration curve (AUC) of ACNU in the lumbar CSF for those receiving a 1.5 mg perfusion of ACNU were 481, 791, and 520 micrograms.min/ml and those receiving a 5 mg perfusion were 1,081, 2,048, and 1,215 micrograms.min/ml, respectively. These values were superior to 3-log cell kill condition of 9L gliosarcoma and 1.5-log cell kill of HU-126 human glioma cell line. Among the groups to which 5 mg of ACNU was administered, the VLP method attained significantly higher AUC values in the lumbar CSF than MB method. Quantitative autoradiography using an imaging plate system was performed in the VLP group (n = 2), VB group (n = 1), MB group (n = 2), and LB group (n = 2) using a 10 microCi/kg [ethylene-14C] ACNU dose which is thought to be related to the alkylating activity of ACNU. The VLP method attained a stable and abundant distribution of ACNU in the neural axis from the ventricular cavity to the lumbar cistern, but the cerebral convexity surface was devoid of a significant level of ACNU. When the MB method was used, the pharmacokinetic data varied in the cisterna magna and lumbar region, and again no significant level of ACNU was detected in the ventricular cavity. With the LB method, although a rich distribution was detected in the spinal cord, the concentration decreased abruptly at the upper cervical level. The VB method was unsatisfactory for obtaining an effective amount of ACNU in the lumbar region. The research and testing to date indicate that the VLP method is the procedure of choice in the treatment of meningeal dissemination.

Animals↗
PubMed1989

A cytogenetic study of 53 human gliomas.

Cytogenetic studies were performed on human glioma samples obtained by stereotactic biopsy, stereotactic craniotomy, or routine craniotomy. Using in situ culture and robotic harvesting techniques, we obtained suitable metaphases in 50 (94%) of 53 tumors, including 28 diffuse astrocytomas, four juvenile pilocytic astrocytomas, two gliosarcomas, three other miscellaneous astrocytomas, eight oligodendrogliomas, four mixed oligodendroglioma-astrocytomas, and four ependymomas. Cytogenetic studies were performed only on primary cultures; the mean culture time was 9.6 days (range 1-31 days). One or more chromosomally abnormal clones were observed in 35 (66%) tumors. Eleven (21%) other specimens had random nonclonal chromosome abnormalities. In four (8%) specimens, no chromosome abnormalities were noted. The results of this study suggest that grade 3 and 4 tumors are more likely to contain an abnormal clone than tumors of grade 1 or 2 (p less than 0.01). The most common numeric chromosome abnormalities were -6, +7, -10, -13, -14, -15, -18, and -Y. The most common structural abnormalities involved 1p, 6q, 7q, 8p, 9p, 11p, 11q, 13q, and 19q. Four tumors had two or more independent clones and ten contained subclones demonstrating karyotype evolution. With in situ culture and robotic harvesting techniques, cytogenetic studies can be successful on nearly all human gliomas, including those derived from small stereotactic biopsies.

Adolescent↗
PubMed1995

Chromosome 7 in glioblastoma tissue. Parenchymal vs. endothelial cells.

Strong endothelial proliferation is a prominent feature of glioblastomas and sometimes these proliferated areas transform into a malignant component of glioblastoma, resulting in gliosarcomas. It has not been established whether the proliferated endothelial areas are cytogenetically abnormal. To clarify this question, the most common cytogenetic aberration, gain of chromosome 7, was chosen and in situ hybridization was performed on paraffin-embedded tissue sections of three glioblastomas. The purpose was to compare the parenchymal tumor cells and the endothelial cells. The results showed trisomy 7 in only a small amount of endothelial cells (5-8%), whereas 23-38% of parenchymal tumor cells displayed trisomy 7.

Cell Division↗
PubMed1988

Effect of Fluosol-DA on the response of intracranial 9L tumors to X rays and BCNU.

Treatment with a perfluorochemical emulsion combined with breathing a 95% or 100% oxygen atmosphere has been shown to be an effective adjuvant to radiation therapy in several animal tumor systems. Similarly, the addition of treatment with a perfluorochemical emulsion combined with breathing a high oxygen atmosphere has been shown to improve the response of several animal tumor systems to treatment with BCNU. We now report results of the use of the perfluorochemical emulsion, Fluosol-DA, and carbogen breathing with single dose radiation treatment, BCNU and combined drug and radiation treatment in intracranially implanted 9L gliosarcoma. The median enhancement in life span produced by Fluosol-DA and carbogen breathing in addition to radiation was 2 days at 10 Gy and 6 days at 20 Gy compared to radiation treatment alone. In the group receiving 20 Gy with Fluosol-DA and carbogen breathing, 2 of 20 lived 120 days. Treatment with a single intraperitoneal injection of BCNU (10 mg/kg) on day 7 post tumor cell implantation produced an increase in life span of 2 days compared to untreated control animals. The combination of drug treatment with Fluosol-DA and carbogen breathing produced an increase in life span of 26 days, which was significantly different from BCNU treatment with air breathing (p less than 0.001). Finally, when BCNU and Fluosol-DA and carbogen were combined with radiation treatment (20 Gy), an increase in life span of nearly 85 days compared to untreated controls was produced, with 47% (9 or 19) surviving 120 days. These results suggest that this combination might be effective in the treatment of malignant brain tumors.

Administration, Inhalation↗
PubMed1990

Intra-cerebral ventricular infusion of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer in the treatment of a rat glioma.

The efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when administered by continuous infusion into the cerebral spinal fluid (CSF) of the lateral cerebral ventricle was evaluated in a 9L gliosarcoma rat brain tumor model. Stereotactic implantation of a 5 x 10(4) tumor cell suspension into the left caudate nucleus was carried out in four groups of 10 rats each. Control animals had a median survival of 16.9 days (range 16-21 days). IUDR, 8.4 mg over 7 days administered by continuous infusion into the left lateral ventricle produced a slight survival advantage (median survival 21.5 days, range 12-56). Irradiation of the entire brain, 8 Gy on days 4, 6 and 7 after tumor cell implantation also produced a slight improvement in survival (median 19.5 days, range 17-34). The combination of radiation and IUDR infusion into the CSF produced a marked survival advantage (median 30.5, range 22-54) compared to the control and single modality treatment groups. This is the first demonstration of the effectiveness of IUDR as a radiosensitizer when administered into the lateral cerebral ventricle in the treatment of an intraparenchymal brain tumor.

Animals↗
PubMed1993

Effect of D,L-alpha-difluoromethylornithine (DFMO) enhanced [3H]putrescine uptake on 9L tumor cell growth and colony forming efficiency.

PURPOSE: This study explored the possible use of D,L- alpha-difluoromethylornithine (DFMO) to enhance the uptake of [3H] putrescine in order to selectively kill brain tumor cells. METHODS AND MATERIALS: Gliosarcoma cells (9L) were grown for 4 or 20 day periods in monolayer cultures with or without [3H] putrescine and/or DFMO. Cells in culture incubated for 20 days were replated at 4-day intervals. Cells were counted on a Coulter Electronic Particle Counter and percent viability was determined by eosin dye exclusion. Survival of cells with proliferative capacity was assayed by their colony. Forming ability and surviving fraction was calculated. The radioactive counts due to [3H] putrescine were measured in 9L cells and in medium and expressed as cpm/100 cells or cpm/ml, respectively. RESULTS: As previously reported (15), DFMO treatment resulted in termination of cell proliferation that was reversible by the addition of exogenous putrescine. Specifically, after 4 days in culture, cell counts in groups exposed to 10 mM DFMO were 55% of those in control groups and addition of 3 mM putrescine reversed the DFMO effects. Uptake of [3H] putrescine into untreated cells increased in proportion to the amount of exogenous putrescine present during 4 days of culture (range 0.01 nmol to 100 nmol) and the presence of DFMO in the medium enhanced the uptake 9 fold throughout these ranges. At activities greater than 100 cpm/100 cells the cell count was reduced to 23 to 48% of control after 4 days in culture. Extending the treatment to 20 days of incubation increased the killing of 9L cells. During the 20-day incubation, control cells increased from 5 x 10(5) to 13 x 10(12) of which 90% were colony forming cells. Treatment with either 25 microCi [3H] putrescine or 1 mM DFMO for 4 days followed by removal of these agents and incubation for an additional 16 days for a total of 20 days resulted in 31 x 10(8) or 18 x 10(7) colony forming cells, respectively. Combining [3H] putrescine and DFMO treatments during the first 4 days of the 20 day incubation reduced the colony forming cells to 21 x 10(5) (surviving fraction to 67%). When the DFMO treatment was present during the entire 20 days, it became cytotoxic since the colony forming cells were reduced to 35 x 10(3) (surviving fraction was 17%). The combination of the 4-day [3H putrescine and the 20 day DFMO treatments resulted in only 1200 surviving colony forming cells (surviving fraction was only 2%). CONCLUSION: DFMO treatment of 9L cells for 20 days resulted in increased uptake of [3H] putrescine, a 10(10) fold inhibition of colony forming cells and extensive 9L cell killing relative to untreated controls.

Animals↗
PubMed1993

Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model.

PURPOSE: We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model. METHODS AND MATERIALS: On day 10 following intracranial inoculation of the 9L gliosarcoma, Fischer 344 rats were treated with radiation therapy (Cesium-137 source irradiator) and/or chemotherapy delivered either systemically (intraperitoneal or intravenous), or intracranially directly into the tumor in a volume of 5 microliters. Increased life spans were calculated relative to the median survival time for the control (ILS-C) or to the median survival time for radiation therapy only (ILS-RT) group. RESULTS: Median survival time for untreated rats was 22 +/- 3 days for seven experiments. Radiation therapy (16 Gy) produced a significant (p < 0.002) improvement in survival, with an average ILS-C of 75 +/- 19%. Systemic AZQ (1 or 5 intravenous injections of 0.5 mg/kg) produced ILS's of 0 and 23%, the latter being significant (p = 0.002). When added to radiation therapy, there were further improvements (ILS-RT's of 47 and 72%), but these were not significant. Intratumor AZQ (40 or 50 micrograms intracranially) produced significant ILS-C's of 30 and 33% (p = 0.01 and 0.0002, respectively). Added to radiation therapy, intracranial AZQ produced improvements (ILS-RT's of 5 and 102%), with only the latter being significantly improved (p = 0.009). Cis-platinum (3 micrograms intracranially) produced ILS-C's of 13 and 6%, neither significantly different from controls. Added to radiation therapy, cisplatinum caused improvements (ILS-RT's of 18 and 64%), with only the latter significant (p = 0.049). CONCLUSION: These results demonstrate that AZQ delivered systemically, and AZQ and cis-platinum delivered intracranially, can produce statistically significant improvements in the survival of rats burdened with the 9L brain tumor. The agents delivered intracranially significantly potentiated the prolongation of survival obtained by radiation therapy. This preclinical evidence suggests that combining radiation therapy with these cytotoxic chemotherapeutic agents may benefit patients with high-grade malignant brain tumors.

Animals↗
PubMed1992

Rat glioma cell lines C6 and 9L synthesize type 1 collagen in vitro.

Glial cell lines (C6, a glioma and 9L, a gliosarcoma) grown in vitro produce type 1 collagen which is detectable in the extracellular matrix by immunocytochemistry. Northern blot analysis using a cDNA specific for the proalpha2 (I) chain of procollagen indicates the presence of a single transcript with an apparent size of 4.8 kb in the C6 cell line, whereas two transcripts with apparent sizes of 5.8 and 4.8 kb are visualized in the 9L cells. The stimulatory effect of ascorbic acid on collagen production is detectable by a 20-27% increase in the concentration of hydroxyproline in the culture medium from the two glioma cell lines. Therefore these glioma cell lines provide a valuable model system for comparative investigations on the regulation of type 1 collagen synthesis by nonmesenchymal cells of neuroepithelial origin.

Animals↗
PubMed1991

Gd HP-DO3A--experimental evaluation in brain and renal MR.

GD HP-DO3A, a neutral (nonionic) IV MR contrast agent presently in clinical trials, was evaluated with respect to imaging characteristics in rats. Following administration of 0.25 mmol/kg I.V., 58 +/- 19%, i.e. (n = 6) enhancement was noted in a brain gliosarcoma model. Meningeal spread of neoplasia could be identified due to its enhancement (69 +/- 26%) in nine animals. The time course of renal enhancement was quantitated at two dosages, 0.05 (n = 4) and 0.25 mmol/kg (n = 8). At the higher dose, enhancement of both cortex and medulla plateaued between 9 and 23 min postinjection. At the lower dose, enhancement of renal medulla was maximum at 2 min postinjection. These enhancement characteristics (both brain and kidney), at equivalent contrast dosages, are comparable to that previously published for Gd-DTPA. However, Gd HP-DO3A has the potential to be utilized clinically at higher doses than Gd-DTPA, with no reported adverse effects in initial trials employing up to 0.3 mmol/kg.

Animals↗
PubMed2006

Differential expression of Hsp90 isoforms in geldanamycin-treated 9L cells.

In mammals, two major Hsp90 isoforms (Hsp90alpha and Hsp90beta) have been identified and found to be highly conserved among different species. However, the expression control of Hsp90 isoforms at both transcriptional and translational levels is largely unknown. Herein, we quantitatively investigate the changes in the total mRNA and inductive protein levels of Hsp90alpha and Hsp90beta in rat gliosarcoma cells treated with geldanamycin (GA). The stability of mRNA and protein was estimated. The translational efficiency of Hsp90 isoforms was measured employing in vitro translation techniques. It was found that Hsp90alpha was more inducible than Hsp90beta after GA treatment, whereas the hsp90alpha mRNA level was lower than that of hsp90beta. In addition, higher translational efficiency of hsp90alpha mRNA was observed, suggesting that translational control played an important role. Taken together, our results indicate that differential expression between Hsp90alpha and Hsp90beta is a consequence of both distinct mRNA profiles and differential translation processes.

Animals↗
PubMed2006

Thalidomide enantiomers: determination in biological samples by HPLC and vancomycin-CSP.

Thalidomide is a racemate with potentially different pharmacokinetics and pharmacodynamics of the component (+)-(R)- and (-)-(S)-thalidomide enantiomers. As part of a project on the adjunctive effects of thalidomide and cytotoxic agents, a method for the chiral separation and quantitation of thalidomide was developed and validated. Thalidomide in relevant serum and tissue homogenate samples was stabilized by buffering with an equal volume of citrate-phosphate buffer (pH 2, 0.2M), and stored at -80 degrees C pending assay. The thalidomide enantiomers, extracted from the samples with diethyl ether, were well separated on a chiral HPLC column of vancomycin stationary phase and a mobile phase of 14% acetonitrile in 20 mM ammonium formate adjusted to pH 5.4; their concentrations were determined with phenacetin as internal standard at 220 nm detection. Over a thalidomide concentration range of 0.1-20 microg/ml, assay precision was 1-5% (CV) for both enantiomers, and calibration curves were linear with all correlation coefficients being >0.99. The estimated limit of quantification for both enantiomers was 0.05 microg/ml with 0.2-0.6 ml serum samples. Thalidomide in rat and human serum, acidified and stored as described above, was found to be chemically and chirally stable over 1 year. The method has been successfully applied to serum samples from human patients undergoing thalidomide treatment for mesothelioma, and to serum, blood and tissue samples from a laboratory rodent model using transplanted 9l gliosarcoma. Enantioselectivity in thalidomide pharmacokinetics has been found, thereby reinforcing the need for considering the relevance of chirality in thalidomide pharmacology.

Animals↗
PubMed1998

[Gene therapy of cerebral glioblastoma by adenovirus vector. Experimental model in the rat].

Our aim was to test the therapeutic effects of adenovirus-mediated gene therapy in an animal brain tumor model which was obtained by stereotactic injection of 9L gliosarcoma cells into the caudate nucleus of rat brains. Seven days after the implantation of tumor cells, adenovirus vectors bearing the Escherichia coli beta-galactosidase gene (ADVbgal) or the herpes simplex virus thymidine kinase gene (ADVtk) were stereotactically injected into the tumor. Injection of the ADVbgal resulted in the expression of the marker gene in 11 animals. Transfer of the ADVtk was followed, 3 days later, by intraperitoneal injection of ganciclovir (GCV) for 10 days. A control group was treated with saline instead of GCV. We observed a significant regression of the tumors in the rats treated with ADVtk and GCV as compared with control animals. In four cases the tumor completely disappeared after treatment. These results demonstrate the potential efficacy of adenovirus-mediated transfer of the HSVtk gene following by GCV administration for the treatment of glioblastomas.

Adenoviridae↗
PubMed2003

Identification of novel enzyme-prodrug combinations for use in cytochrome P450-based gene therapy for cancer.

Gene-directed enzyme prodrug therapy can be used to increase the therapeutic activity of anti-cancer prodrugs that undergo liver cytochrome P450 (CYP)-catalyzed prodrug to active drug conversion. The present report describes a cell-culture-based assay to identify CYP gene-CYP prodrug combinations that generate bystander cytotoxic metabolites and that may potentially be useful for CYP-based gene therapy for cancer. A panel of rat liver microsomes, comprising distinct subsets of drug-inducible hepatic CYPs, was evaluated for prodrug activation in a four-day 9L gliosarcoma cell growth inhibition assay. A strong NADPH- and liver microsome-dependent increase in 9L cytotoxicity was observed for the CYP prodrugs cyclophosphamide, ifosfamide, and methoxymorpholinyl doxorubicin (MMDX) but not with three other CYP prodrugs, procarbazine, dacarbazine, and tamoxifen. MMDX activation was potentiated approximately 250-fold by liver microsomes from dexamethasone-induced rats (IC(50) (MMDX) approximately 0.1nM), suggesting that dexamethasone-inducible CYP3A enzymes contribute to activation of this novel anthracycline anti-tumor agent. This CYP3A dependence was verified in studies using liver microsomes from uninduced male and female rats and by using the CYP3A-selective inhibitors troleandomycin and ketoconazole. These findings highlight the advantages of using cell culture assays to identify novel CYP prodrug-CYP gene combinations that are characterized by production of cell-permeable, cytotoxic metabolites and that may potentially be incorporated into CYP-based gene therapies for cancer treatment.

Animals↗
PubMed1994

Thromboembolism in patients with high-grade glioma.

OBJECTIVE: To identify factors related to increased or decreased risk of thromboembolism (TE) in patients with high-grade glioma. DESIGN: We performed a retrospective analysis of 64 patients enrolled in two prospective clinical trials of chemotherapy and radiation therapy for newly diagnosed high-grade glioma. MATERIAL AND METHODS: The 64 patients were 18 years of age or older and had histologically confirmed grade 3 or 4 astrocytoma, mixed astrocytoma-oligodendroglioma, or gliosarcoma. The diagnosis of TE was confirmed by impedance plethysmography, venography, duplex ultrasonography, ventilation-perfusion lung scanning, or pulmonary angiography. For statistical analysis, the study group was divided into those with and those without TE. RESULTS: TE developed in 18 of the 64 patients (28%). Of the 18 patients, 11 had deep venous thrombosis of a lower extremity, 5 had pulmonary emboli, and 2 had superficial thrombophlebitis. A paretic arm (P = 0.017), a paretic leg (P = 0.026), or a history of TE before the diagnosis of glioma (P = 0.076) was more common in patients with TE than in those without TE. Ten patients in the group without TE were using aspirin preoperatively in comparison with no patient in the TE group (P = 0.05). No significant differences were noted in duration of survival (median, 39.4 weeks and 46 weeks for the TE and non-TE groups, respectively). One patient with apparently excessive anticoagulation had a fatal intracerebral hemorrhage. CONCLUSION: This study suggests that TE in patients with newly diagnosed high-grade glioma might be associated with a history of TE or with a paretic extremity; however, no evidence of worse survival was noted in the TE group. Treatment with heparin followed by warfarin sodium was associated with infrequent bleeding complications. An intriguing finding was that the use of aspirin before operation was associated with a decreased risk of TE. Thus, a prospective study with use of aspirin in patients with high-grade glioma at risk for TE would be reasonable.

Adolescent↗