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Glioblastoma multiforme (GBM) carries a dismal prognosis. However, a range of survival times exists, and parameters that define prognostic groups may help to optimize treatment. To identify such prognostic groups, we analyzed tumor tissue from 110 cases of newly diagnosed GBM from two clinical protocols. Similar to other studies, we found no association of epidermal growth factor receptor (EGFR) overexpression (as assessed by immunohistochemistry), p53 immunopositivity, or p53 mutation with survival in the entire sample. However, EGFR overexpression showed trends toward worse prognosis in patients younger than the median age, but better prognosis in patients older than the median age. This interaction of EGFR with age group was statistically significant and led us to focus our further analyses on the younger patients. In this group, a statistically significant association of EGFR overexpression with worse survival was identified in the p53-negative but not p53-positive tumors. We found a similar result after screening these cases for mutations in p53: EGFR overexpression was negatively associated with survival only in the p53 wild-type cases. To confirm this unexpected result, this finding was reproduced in a validation sample of an additional 42 tumors from younger patients on the same two clinical protocols. This complex relationship between EGFR and p53 in younger patients remained in a multivariate analysis that incorporated additional prognostic variables. The results suggest that analysis of prognostic markers in GBM is complex, and maximal information may require analysis of subgroups based on age and the status of specific markers such as p53. In addition, they suggest a specific group of patients on which to focus promising therapies targeting EGFR.

Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha [6 x 10(6) U subcutaneously three times per week] and tamoxifen (240 mg/m2/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23-61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m2/day. Although the initial tamoxifen dose was reduced to 120 mg/m2/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.

It is often assumed that a cerebral lesion that is nonenhancing on a magnetic resonance imaging study with gadolinium contrast is a low grade tumor. Some physicians recommend observation rather than biopsy for such lesions.The authors prospectively evaluated the incidence of anaplastic tumor histology in a consecutive series of patients who presented to a neuro-oncology service with a nonenhancing mass of the cerebral hemisphere.During a 5-month period, the authors evaluated 31 patients who had a nonenhancing lesion in the cerebral hemisphere on initial magnetic resonance images. Thirty patients underwent stereotactic biopsy (27%) or open resection (73%). The median patient age was 36 years (range, 6-63 years). There was no mortality or permanent neurologic morbidity from surgery. Twenty-eight patients had pathologic confirmation of diagnosis while their lesions were still nonenhancing. Of these patients, 9 (32%) had Grade 3 lesions (anaplastic astrocytoma or oligoastrocytoma), 13 (43%) had Grade 2 lesions (astrocytoma, oligodendroglioma, or oligoastrocytoma), and 2 (7%) had Grade 1 lesions (dysembryoplastic neuroepithelial tumors). Two additional patients (ages 33 and 59 years) who developed enhancement within their lesions during preoperative periods of observation had glioblastomas at surgery. Logistic regression was used to relate patient age to the risk of anaplasia in a nonenhancing cerebral mass lesion. Older age predicted a significantly higher risk of anaplasia (P = 0.025). The model predicted that nonenhancing cerebral masses in patients older than 44 years were more likely to be anaplastic tumors than low grade tumors. There was no "safe" age below which low grade histology could be confidently assumed.Magnetic resonance-nonenhancing cerebral lesions may be histologically anaplastic, even in young patients. The risk of anaplasia in magnetic resonance-nonenhancing lesions increases significantly with patient age.

After intensive initial radiation therapy for malignant glioma, magnetic resonance imaging (MRI) and computerized tomography (CT) cannot distinguish tumor progression from radiation injury.The authors studied the prognostic value of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in 55 patients with malignant glioma for whom MRI obtained after initial surgery and radiation therapy demonstrated enlarging, enhancing lesions consistent with either tumor progression or radiation necrosis. Forty patients (73%) had an initial diagnosis of Grade 4 malignant glioma and 15 (27%) had Grade 3 malignant glioma. The FDG-PET scans were graded visually on a four-level scale at the time of acquisition.In univariate analysis, the FDG-PET score was a significant predictor of survival time after FDG-PET scanning (P = 0.005). Median survival was 10 months for patients with FDG-PET scores of 2 or 3 (glucose uptakeor = adjacent cortex) and 20 months for those with scores of 0 or 1 (glucose uptakeadjacent cortex). In multivariate proportional hazards analysis, the FDG-PET score was a significant predictor of survival (P = 0.019) in a model that included patient age, recurrence number, and FDG-PET score. There was no significant difference in the FDG-PET score hazard ratio for patients with Grade 3 or 4 tumors at initial diagnosis, first or later suspected recurrence, initial photon irradiation given with standard fractions or hyperfractionation, or stereotactic irradiation prior to FDG-PET scanning.This analysis demonstrates that FDG-PET scanning has prognostic value in a cohort limited to patients with suspected recurrent high grade glioma.

Many pathologists require the presence of tumor necrosis within an astrocytic neoplasm to establish the diagnosis of glioblastoma multiforme (GM). Two new grading systems for astrocytic neoplasms allow a tumor to be diagnosed at the highest level of anaplasia without requiring the presence of tumor necrosis.To determine whether GMs without necrosis had biologic behavior most compatible with a diagnosis of GM or of anaplastic astrocytoma (AA), we examined the survival of 299 patients whose tumors were diagnosed as GM because they contained endothelial proliferation and who were treated according to prospective clinical protocols. Multivariate proportional-hazards survival analysis was used to assess the importance of tumor necrosis after adjustment for other prognostic factors.Of 275 patients with GMs containing endothelial proliferation, 88% had tumor necrosis. Absence of necrosis was associated with younger age and with less extensive surgical resection. The absence of necrosis predicted longer survival in univariate analysis (P = 0.02) and after adjustment for age, Karnofsky performance score, and extent of resection in a multivariate analysis (P = 0.04). However, the magnitude of the survival difference was not clinically important: patients without tumor necrosis had a median survival of 12.5 months, and those with tumor necrosis had a median survival of 10.9 months. Kaplan-Meier survival rates two years after diagnosis were 13.0% for patients with necrosis and 27.1% for patients without necrosis; the difference in 2-year survival was not statistically significant (difference in survival rates = 14.1%, 95% confidence interval -2.2% to 30.4%).The survival of patients with astrocytic neoplasms containing endothelial proliferation and no necrosis conforms best to the pattern expected for patients with GM rather than AA. This supports the classification of these tumors as GM in the revised World Health Organization grading system and as grade 4 astrocytomas in the St. Anne-Mayo grading system.

Recent years have seen rapid progress in our understanding of the molecular basis of brain tumors, particularly malignant astrocytomas. Translation of these advances from basic molecular genetics into the clinical arena is now underway. Molecular markers that correlate with prognosis in individual patients are being sought, and work is beginning on the identification of individuals who are at increased risk for developing a malignant brain tumor. Goals for the future include the development of more effective treatment strategies based on a clearer understanding of the pathogenesis of these tumors.

The placement of the atrial portion of a ventriculoatrial shunt is occasionally rendered difficult by a tendency of the shunt catheter to pass into the contralateral jugular vein or into a subclavian vein instead of into the atrium. We report a simple flow-directed technique that may resolve this problem.

Thromboembolic complications are a major cause of postoperative morbidity and mortality in the neurosurgical patient. Prophylaxis with lower extremity pneumatic compression boots (PCBs) reduces the incidence of lower extremity deep vein thrombosis (DVT) but has not been shown to affect the incidence of pulmonary embolism (PE). Prophylaxis with low-dose heparin has consistently reduced the incidence of both DVT and PE in studies on general surgical patients but has not been adopted for use in neurosurgery primarily for fear of causing catastrophic hemorrhage. We report on a series of 138 consecutive adult patients who underwent major neurosurgical procedures on a general neurosurgical service at our institution. Patients were treated with intraoperative PCBs and, starting on the morning of the first postoperative day, with a regimen of 5000 U of heparin administered subcutaneously twice daily. This treatment was continued until patients were fully ambulatory. PCBs were discontinued 24 hours after the first administration of heparin. None of the heparin-treated patients suffered postoperative hemorrhage. We compared this series with a control group of 473 adult patients who had previously undergone major neurosurgical procedures on the same neurosurgical service. These patients had been treated with intraoperative and postoperative PCBs alone. The control group had a 3.2% incidence of thromboembolic complications (15 of 473; eight DVT, seven PE). Prophylaxis with PCBs plus heparin significantly (P = 0.020) reduced the incidence of thromboembolic complications: no PCBs/heparin-treated patient exhibited clinical evidence of PE or DVT (0%, 0/138). We conclude that a combination of intraoperative PCBs and postoperative low-dose heparin is a safe and effective method by which to reduce thromboembolic complications in the neurosurgical patient.