Cognitive awareness after treatment for high-grade glioma.

OBJECTIVE: In patients with brain lesion, awareness of cognitive deficits is an important aspect of disease awareness. Glioblastoma (GBM) and anaplastic astrocytoma (AA) can cause cognitive deficits, but, to date, awareness of these deficits has not been documented. This study aimed to test cognitive awareness in these patients after the end of treatment. METHODS: Fifty patients with GBM or AA were assessed using the Multiple Ability Self-Report Questionnaire (MASQ), State-Trait Anxiety Inventory (STAI), Self Rating Depression Scale (SRDS), and memory, attention, mental speed, abstract reasoning, and flexibility neuropsychological tests. Cognitive awareness was calculated as the concordance between the composite score of neuropsychological performance (PEC) and the total MASQ score. The controls were 48 healthy subjects. Analysis of variance and regression analysis compared subject groups and explored variables predicting perceived abilities. RESULTS: Patients with GBM or AA showed similar attention, memory, and executive deficits compared with controls. Cognitive awareness was fair/full in 64% of patients. In the entire patients group, the worst MASQ scores were associated with neuropsychological deficits, anxiety, depression, and glioma location in the right hemisphere . In patients with fair/full awareness, MASQ scores were related to affective status and neuropsychological performance, whereas, in those with scarce/no awareness, they were related only to affective status. CONCLUSIONS: After treatment, many patients with GBM or AA are aware of their cognitive deficits. Anxiety, depression, and right hemisphere tumour exacerbate the perceived difficulties. This neurocognitive approach expands the behavioural phenotypes of high-grade gliomas and may have therapeutic implications over the course of the disease.

Cisplatinum and BCNU chemotherapy in primary glioblastoma patients.

BACKGROUND: The prognosis of patients with glioblastoma is very poor with a mean survival of 10-12 months. Currently available treatment options are multimodal, which include surgery, radiotherapy, and chemotherapy. However, these have been shown to improve survival only marginally in glioblastoma multiforme (GBM) patients. Methylated methylguanine methyltransferase (MGMT) promoter is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. METHODS: A retrospective analysis on 160 adult patients (> or =16 years) treated for histologically confirmed GBM between 2003 and 2005 at our Institution was performed. All patients were treated with conventional fractionated radiotherapy and a combined chemotherapy treatment with Cisplatin (CDDP) (100 mg/sqm on day 1) and carmustine (BCNU) (160 mg/sqm on day 2); the treatment was repeated every 6 weeks for five cycles. Toxicity, progression free survival and overall survival were assessed. RESULTS: The median number of chemotherapy cycles delivered to each patient was 5 (range 3-6), with no patients discontinuing treatment because of refusal or toxicity. Dose reduction was required in 16 patients (10%), and all patients completed radiotherapy, whereas 5 patients discontinued chemotherapy before completing all planned cycles for disease progression. The primary toxicities were: neutropenia (grade 3-4: 23%), thrombocytopenia (grade 3-4: 18.5%), and nausea and vomiting (13%). Median progression-free survival times and 1-year progression free survival were 7.6 months (95% CI 6.6-8.5) and 17.3%, respectively. OS was 15.6 months (95% CI 14.1-17.1). CONCLUSIONS: Our results for PFS and overall survival are comparable with those obtained with temozolomide, but the toxicity occurring in our series was more frequent and persistent. The toxicity, and mainly the modalities of administration associated with cisplatin and BCNU combination, argues against future use in the treatment of patients with GBM.

Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma.

Reliable data on large cohorts of patients with glioblastoma are needed because such studies differ importantly from trials that have a strong bias toward the recruitment of younger patients with a higher performance status. We analyzed the outcome of 676 patients with histologically confirmed newly diagnosed glioblastoma who were treated consecutively at a single institution over a 7-year period (1997-2003) with follow-up to April 30, 2006. Survival probabilities were 57% at 1 year, 16% at 2 years, and 7% at 3 years. Progression-free survival was 15% at 1 year. Prolongation of survival was significantly associated with surgery in patients with a good performance status, whatever the patient's age, with an adjusted hazard ratio of 0.55 (p < 0.001) or a 45% relative decrease in the risk of death. Radiotherapy and chemotherapy improved survival, with adjusted hazard ratios of 0.61 (p = 0.001) and 0.89 (p = 0.04), respectively, regardless of age, performance status, or residual tumor volume. Recurrence occurred in 99% of patients throughout the follow-up. Reoperation was performed in one-fourth of these patients but was not effective, whether performed within 9 months (hazard ratio, 0.86; p = 0.256) or after 9 months (hazard ratio, 0.98; p = 0.860) of initial surgery, whereas second-line chemotherapy with procarbazine, lomustine, and vincristine (PCV) or with temozolomide improved survival (hazard ratio, 0.77; p = 0.008). Surgery followed by radiotherapy and chemotherapy should be considered in all patients with glioblastoma, and these treatments should not be withheld because of increasing age alone. The benefit of second surgery at recurrence is uncertain, and new trials are needed to assess its effectiveness. Chemotherapy with PCV or temozolomide seems to be a reasonable option at tumor recurrence.

Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival.

PURPOSE: Recent data suggest that methylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase (MGMT), by increasing the chemosensitivity of glioblastoma multiforme, is significantly associated with improved prognosis. Results in contradiction with these findings, however, are present in the literature and the clinical and genetic context framing MGMT methylation is poorly characterized. EXPERIMENTAL DESIGN: To address these issues, we have investigated the MGMT methylation status, clinical and magnetic resonance imaging characteristics, and relevant genetic features (loss of heterozygosity on 17p and 19q, EGFR amplification, and p53 mutations) in a retrospective study on 86 patients affected by glioblastoma multiforme: 72 patients had a clinical history indicating de novo insurgence of the tumor and the remaining 14 were secondary glioblastoma multiforme. RESULTS: MGMT methylation was detected by methylation-specific PCR in 41 of 86 cases (47.7%; Meth+). Progression-free survival and overall survival were significantly longer in Meth+ than in Meth- patients [10 versus 7 months (P=0.003, log-rank test) and 18 versus 14 months (P=0.0003, log-rank test), respectively]. Mixed-nodular enhancement at magnetic resonance imaging was significantly more frequent in Meth+ and secondary glioblastoma multiforme and ring enhancement in Meth- and primary glioblastoma multiforme (P<0.005). MGMT methylation was more present in secondary glioblastoma multiforme (P=0.006) and associated with loss of heterozygosity on 17p and/or 19q (P=0.005). CONCLUSIONS: These observations suggest that MGMT methylation is part of a genetic signature of glioblastomas that developed from lower-grade gliomas.

Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines.

Valproic acid (VPA) has been recently investigated for its anticancer properties in different tumors, including malignant gliomas. The aim of the present work was to evaluate the effects of VPA, alone or in combination with other chemotherapeutic drugs, on in vitro growth of human glioma cell lines. A172, U373, U138, U87, and SW1783 were treated with VPA alone or in combination with mitoxantrone, etoposide, or 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU). The effects of treatments on cell growth were assessed with crystal violet staining and analyzed using the combination index (CI). The percentage of apoptotic cells and the DNA content for cell cycle phases detection were also investigated by flow cytometry. Despite a certain variability, glioma cell lines were rather resistant to the drugs tested. Addition of VPA decreased the IC50 of the chemotherapeutic agents in all cell lines tested. This effect was more evident with BCNU. The synergic effect of the association of VPA and BCNU was related to an increased block of cell cycle with accumulation in S-G2/M phases of cell cycle rather than an increased programmed cell death. In our experimental model, VPA showed anticancer properties per se on human glioma cell lines and our data support the hypothesis that, if used in association with conventional chemotherapy, it might improve the effects of single chemotherapeutic agents.

Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas.

Both clinical and biological features have been reported as prognostic factors in low-grade gliomas. Among these, histotype, tumor size, enhancement, age and genetic pattern. Microvessel density (MVD) has been correlated to clinical outcome in astrocytomas, but its impact in oligodendrogliomas and mixed tumors is not sure. The pro-angiogenic chemokine stromal cell-derived factor (SDF-1/CXCL12) and its receptor CXC chemokine receptor 4 (CXCR4) have been described in low-grade gliomas, with a correlation between CXCL12 expression and shorter time to progression (TTP). The intermediate filament Nestin is expressed in proliferating vessels. Platelet-derived growth factor B (PDGF-B) and its receptor PDGFR-beta are also involved in angiogenesis and malignant progression in gliomas.

Production and post-surgical modification of VEGF, tPA and PAI-1 in patients with glioma.

Malignant gliomas are associated with risk of thromboembolism, but the molecular link between tumor and peripheral pro-coagulant status has not been elucidated. Vascular Endothelial Growth Factor (VEGF), tissue-type Plasminogen Activator (tPA), Plasminogen Activator Inhibitor-1 (PAI-1) and lipoprotein (lp) (a) influence the pro-coagulant status. To assess whether the presence of the tumor influenced the peripheral levels of VEGF, tPA, PAI-1 and lp(a), we studied the expression and secretion of VEGF, tPA, PAI-1 and lp(a) in glioma specimens, in peripheral blood and in primary glioma-derived cultures. We also measured lp(a), VEGF, tPA and PAI-1 in the peripheral circulation of patients, before and after surgery for glioma. VEGF, tPA and PAI-1 were expressed in glioma specimens. Glioma cells were indeed a major source of tPA and PAI-1; these molecules were significantly more expressed in glioma than in patient's blood cells. Lp(a) was rarely expressed in glioma specimens and not expressed in blood cells. In glioma, VEGF, tPA and PAI-1 were localized mainly in tumor cells; tPA was localized also in the extracellular matrix and PAI-1 in tumor vascular lumen. Glioma cells were indeed able to produce and release VEGF, tPA and PAI-1. After surgery, peripheral levels of VEGF and PAI-1 were increased, while tPA and lp(a) were unchanged. The great amount of VEGF, tPA and PAI-1 produced by glioma could influence peripheral levels of these molecules. The partial resection of the tumor by surgery was not able to decrease plasma levels of these molecules.

In vitro study of low molecular weight heparin effect on cell growth and cell invasion in primary cell cultures of high-grade gliomas.

Heparins represent the first choice for prevention and treatment of venous thromboembolism. In particular, low molecular weight heparins (LMWHs) provide pharmacokinetic advantages compared to unfractionated heparin (UFH): longer half-life, better bioavailability, and lower binding to plasma proteins. In the last years results of preclinical and clinical studies have suggested that LMWH may be able to inhibit cell growth, cell invasion, and angiogenesis, which are key mechanisms involved in tumor progression, possibly influencing favorable clinical outcome in at least a proportion of cancer patients. In this work we investigated the effect of LMWH (enoxaparin) on cell growth and cell invasion in primary cell cultures obtained from high-grade glioma specimens: 5 anaplastic astrocytoma (AA) and 13 glioblastoma multiforme (GBM). Apoptosis and expression of the thrombin receptor PAR1 were also assessed. A significant decrease in tumor cell growth was observed after treatment with 10 U/ml (-21%; p = 0.001) and 100 U/ml (-26%; p < 0.001); tumor cells from AA (grade III; WHO) were more affected by LMWH treatment compared to cell lines from GBM (grade IV; WHO). The antiproliferative effect was more pronounced in cell cultures displaying higher expression of PAR1. Glioma cell cultures were able to invade a model of basement membrane (Matrigel matrix) in standard culture conditions, but migration was not modulated significantly by LMWH treatment at any of the concentrations tested (1, 10, 100 U/ml). In conclusion, our results confirm the antineoplastic effect of LMWH, suggesting a potential direct role on tumor cell growth in high grade gliomas.

Genetic and plasma markers of venous thromboembolism in patients with high grade glioma.

PURPOSE: Deep venous thrombosis/pulmonary embolism (DVT/PE) is a frequent complication in the course of cancer, particularly in brain tumors. We investigated genetic and plasma factors possibly associated with risk of DVT/PE in patients with high-grade glioma. EXPERIMENTAL DESIGN: In a case-control study, we studied polymorphisms of the genes coding for factor II (G20210A), factor V (G1691A), methylenetetrahydrofolate-reductase (C677T), tissue-type plasminogen activator (tPA; insertion/deletion), plasminogen activator inhibitor-1 (PAI-1; 4G/5G), and vascular endothelial growth factor (VEGF; C936T). We also measured plasma levels of D-dimer, lipoprotein (lp) (a), homocysteine, VEGF, tPA, and PAI-1, comparing healthy control patients with patients with glioma or with patients with neurological nonneoplastic disease (multiple sclerosis). RESULTS: Genotype frequencies of polymorphisms analyzed were similar in patients with glioma and in healthy matched population. D-dimer, lp (a), homocysteine, VEGF, tPA, and PAI-1 plasma levels were significantly higher in patients with glioma than in healthy controls, whereas patients having neurological nonneoplastic disease had plasma values of these molecules not significantly different from healthy controls. VEGF, tPA, and PAI-1 were also found at high-plasma levels in patients carrying genotypes that, in healthy controls, were associated with "low-producing" phenotypes. CONCLUSIONS: Genetic risk factors alone did not explain the high incidence of DVT/PE observed in patients with glioma. Higher plasma levels of molecules influencing the coagulation pathways indicate that the tumor itself might confer an increased risk of DVT/PE; thus, D-dimer, homocysteine, lp (a), VEGF, tPA, and PAI-1 look like good candidates to be evaluated as DVT/PE prognostic factors.

Methylprednisolone acts on peripheral blood mononuclear cells and endothelium in inhibiting migration phenomena in patients with multiple sclerosis.

BACKGROUND: Intravenous methylprednisolone hemisuccinate is administered to patients with multiple sclerosis (MS) during exacerbations to improve the rate of recovery. Corticosteroids could be beneficial in MS exacerbations also by decreasing transmigration of peripheral blood mononuclear cells (PBMNCs) through the blood-brain barrier. OBJECTIVES: To evaluate how in vivo intravenous methylprednisolone treatment in patients with MS could influence transmigration of PBMNCs in an in vitro model; to perform transmigration experiments through a methylprednisolone-treated endothelium with PBMNCs from untreated healthy control subjects to evaluate putative selective effects of corticosteroids on endothelium; concomitantly, to quantify the concentration of matrix metalloproteinases 2 and 9 in supernatants of PBMNCs and in serum samples from methylprednisolone-treated patients with MS; to evaluate monokine induced by interferon-gamma release in the supernatants of human umbilical vein endothelial cells treated with interferon-gamma alone or interferon-gamma and methylprednisolone; and to perform gene expression studies of matrix metalloproteinases 2 and 9 in human umbilical vein endothelial cells and PBMNCs from methylprednisolone-treated patients with MS. PATIENTS: Eight patients with MS in exacerbation were studied before and 3 and 24 hours after intravenous methylprednisolone treatment, 1 g. RESULTS: The absolute number of transmigrated PBMNCs from methylprednisolone-treated patients with MS significantly (P<.01) decreased at 3 hours and increased again at 24 hours, reaching values higher than those before treatment onset. Methylprednisolone was also able to significantly (P<.03) reduce the number of PBMNCs from healthy controls migrating through interferon-gamma-stimulated or unstimulated endothelium. In vitro methylprednisolone treatment decreased monokine induced by interferon-gamma production in human umbilical vein endothelial cells. CONCLUSIONS: Methylprednisolone may be able to decrease transmigration of PBMNCs through the blood-brain barrier, exerting its inhibitory effects on PBMNCs and endothelium. A "rebound" of transmigration at 24 hours suggests that a single infusion is not optimal for achieving a persistent reduction in transmigration.

Fas/CD95-mediated apoptosis in human glioblastoma cells: a target for sensitisation to topoisomerase I inhibitors.

The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.

Effect of association of temozolomide with other chemotherapic agents on cell growth inhibition in glioma cell lines.

Despite progresses in surgery and treatments of malignant gliomas, prognosis of these tumors remains poor, with a median life expectancy of 12 months in glioblastomas. Chemotherapy (mostly with nitrosoureas) has been demonstrated to prolong overall survival, but the entity of this improvement is slight and disease recurrence/progression is the rule, stressing the need for multimodality treatment. In this work we investigated the effect of association of temozolomide (TMZ), an orally bioavailable alkylating agent, with three chemotherapeutic drugs, liposomal doxorubicin (DOXO), cis-platinum (CDDP). and topotecan (TP), on cell growth of A 172, U373, U138, U87, and SW1783 (all human glioma cell lines). Results indicate a synergistic effect (CI < 1) of TMZ in association with liposomal DOXO and CDDP on cell growth inhibition in most of the studied cell lines (A172, U373, U138, U87). Synergistic effect also has been obtained after treatment of A 172 and U373 with TMZ and TP in association. In conclusion, our results confirm the potential effect of association of chemotherapic drugs with different mechanisms of action in the treatment of gliomas.

Quality of life and brain tumors: what beyond the clinical burden?

This study analyzed the subjective facets of quality of life (QoL) and their relation to the type of brain tumor (BT) and phase of disease. Two hundred and ninety-one patients with pinealoblastoma, medulloblastoma, low-grade glioma, anaplastic astrocytoma, or glioblastoma were evaluated. With respect to 110 healthy controls, patients in the phases of radiotherapy/chemotherapy, stable disease, or tumor recurrence were significantly more anxious and depressed compared with patients in the early postoperative period. All patients were impaired in mental flexibility and memory, with preservation of abstract reasoning. The Functional Living Index-Cancer (FLIC), previously validated in cancer and BT patients, yielded six subjective factors (disease perception, affective well-being, role and leisure, personal base, nausea, sharing). None of the FLIC factors were predicted by tumor type, which only related to the physical and cognitive performances and mood scores. Affective well-being, role and leisure, and sharing were predicted by the phase of disease. Personal base, including self-perception and confidence, was independent on tumor progression and treatment. To conclude, QoL encompasses different subjective aspects, which vary in relation to the phase of disease and clinical burden. However, some person-related facets appear independent on tumor progression and treatment, indicating individual resources. Knowing this may guide tailored interventions supporting QoL.

Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients.

The purpose of this study was to evaluate safety and efficacy of Procarbazine (PCB) and fotemustine (FTM) combination in the treatment of pre-temozolomide treated, recurrent GBM patients. The primary end-point was progression free survival at 6 months (PFS-6). Secondary end-points were overall survival, response rates (CR + PR) and toxicity. About 54 patients (41 men and 13 women) aged 26-68 years (median age, 53.5 years) with recurrent GBM were treated. PCB was administered as an oral dosage of 450 mg on days 1-2 and a total dose of 300 mg on day 3. FTM was administered on day 3, 3 h after the last PCB intake at a dose of 110 mg/mq/BSA. The treatment was repeated every 5 weeks. Treatment was continued for a maximum of six cycles or until disease progression. After two cycles of chemotherapy: 6 patients (11.2%) experienced a neuroradiographic partial response (PR), 29 patients (53.7%) had stable disease (SD), and 19 patients (35.1%) had progressive disease (PD). For the whole group of patients, the median PFS was 19.3 weeks (95% CI, 14.1-24.4 weeks), and PFS-6 was 26.7% (95% CI, 10.6-42.8%). Overall MST from the beginning of PCB + FTM chemotherapy was 28.7 weeks (95% CI, 24.8-32.7 weeks). At 6 and 12 months, 64.4% (95% CI, 51.5-77.3%) and 23.6% (95% CI, 10.1-37.1%) of patients were alive. The median survival time calculated from the first diagnosis was 20.8 months (95% CI, 16.7-24.8). We concluded that the PCB + FTM combination as done in the current trial for patients with recurrent GBM after treatment with TMZ showed some benefit with regards to increased survival and that a Phase III trial is warranted.

Treatment of recurrent glioblastoma: can local delivery of mitoxantrone improve survival?

In this study, the records of 276 adult patients with recurrent glioblastoma (GBM) treated at recurrence at our institution between 2004 and 2006 were reviewed for progression-free survival (PFS), overall survival (OS), and toxicity. At recurrence, all patients underwent systemic treatment with temozolomide (200 mg/sqm on days 1-5 every 28 days) until tumor progression. Patients, whose tumor was judged resectable without risk of adjunctive neurological deficit, underwent a second surgery with or without positioning of a Rickam/Ommaya reservoir. The reservoir was used for locoregional chemotherapy with mitoxantrone. Two hundred seventy-six rGBL patients (pts) were divided into three subgroups: A 161 pts treated only with temozolomide, B 50 pts re-operated-on +temozolomide, and C 65 pts re-operated on + temozolomide + locoregional CHT. For group A, the 6 month PFS and 6 month survival (ST) were 39.3 and 43%, respectively, with a median survival time (mST) of 5 months (range 4-6) and 25% of pts alive at 9 months. For group B, the 6 month PFS and 6 month survivors were 64 and 74.1%, respectively, with a mST of 8 months (range 6-10) and 25% of pts alive at 12 months. For group C, the 6 month PFS and 6 month survivors were 70.7 and 87.7%, respectively, with a mST of 11 months (range 9-13) and 25% of pts alive at 18 months (A vs. B vs. C, log-rank P < 0.001) (B vs. C, P = 0.041) (A vs. B P = 0.009). Cox proportional hazard model was used to obtain Hazard Ratio (HR) for type of treatment corrected by age and time (in months) between diagnosis and first recurrence: second tumor debulking was statistically effective for survival, reducing by 36% the risk of death (HR = 0.64; 0.46-0.89), but the most significant favorable prognostic factor for survival was the local delivery of mitoxantrone which reduced the risk of death to 50% (HR = 0.50; 0.38-0.68).

Surgifoam and mitoxantrone in the glioblastoma multiforme postresection cavity: the first step of locoregional chemotherapy through an ad hoc-placed catheter: technical note.

OBJECTIVE: To investigate the safety and feasibility of a novel form of treatment offered by the direct intraoperative application of a Surgifoam-mitoxantrone mix into a glioblastoma multiforme postresection cavity. A technique for the placement of an intracavity catheter connected with a subcutaneous reservoir for further locoregional mitoxantrone administration is also described. METHODS: Between January and December 2004, 22 consecutive recurrent glioblastoma multiforme patients (14 men, 8 women; age, 56-72 yr; average, 64 yr; median, 65 yr) were enrolled in this study. All patients underwent image-assisted gross total resection of the pathological tissue. A Surgifoam-mitoxantrone mix (1 g Surgifoam powder, 3 ml physiological solution, and 12 mg mitoxantrone in 6 ml) was used to fill the surgical cavity. A ventricular catheter, connected to a Rickham subcutaneous reservoir, was then positioned in the surgical cavity for future mitoxantrone administration. RESULTS: Toxic effects caused by mitoxantrone administration were not observed in any patients during the first postoperative month. On postoperative Days 1, 7, and 30, computed tomographic scans excluded surgical complications. In three patients, residual tumor was disclosed. CONCLUSION: A mix of Surgifoam and mitoxantrone could be safely applied intraoperatively into the post-glioblastoma multiforme resection cavity without any observable side effects. This technique may benefit both the surgeon and the patient by taking advantage of the drug's hemostatic and cytostatic properties.

Reclassification of oligoastrocytomas by loss of heterozygosity studies.

Oligoastrocytomas (OAs) are WHO grade II or III tumors composed of a mixture of 2 neoplastic cell types morphologically resembling the cells in oligodendrogliomas and diffuse astrocytomas. Investigations on the genetic profile of OAs may yield important information for their classification and help for their clinical management. We have studied, in 94 OAs (46 WHO grade II and 48 WHO grade III), the patterns of loss of heterozygosity (LOH) of 4 genomic regions: 1p, 19q, 17p and 10q. Results were as follows: LOH 1p was present in 46% of the tumors; LOH 19q in 45%; LOH 17p in 22%; LOH 10q in 16%. LOH 1p and 19q were associated in 32%, other LOH associations were rare (<3%). Patients had a median follow-up of 30 months. Patients without LOH on 1p had shorter progression free survival than patients with LOH on 1p: 30 vs. 132 months, p < 0.0001. MRI indicated that tumors without LOH on 1p were often temporal (p < 0.02), and showed signal inhomogeneity on T1 and T2 images (p < 0.02) and contrast enhancement (p < 0.04). Thus, LOH on 1p identifies two subgroups of OAs. OAs without LOH on 1p behave like WHO grade II or III diffuse astrocytomas: they have shorter survival, MRI characteristics implying malignancy and genetic alterations associated with tumor progression. OAs with LOH on 1p, on the other hand, behave like WHO grade II or III oligodendrogliomas with 1p loss: they are associated with longer survival and do not have MRI or genetic alterations associated with malignancy. These findings suggest that the definition of OAs or mixed gliomas could be reshaped in agreement with the genetic information.