Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas.

Treatment of recurrent malignant glioma, which has a poor patient prognosis, has not been standardised. Moreover, it is unclear whether repeated treatment with temozolomide is effective in patients who received previous temozolomide treatment before developing a recurrence. Here, we present the results of a high-dose individually adapted 21-day regimen demonstrating that rechallenge is effective even in patients expressing O6-methylguanine-DNA methyltransferase (MGMT) in the tumor. Twenty-one patients with recurrent malignant gliomas pre-treated with temozolomide, 18 WHO IV glioblastoma (GBM) and 3 WHO III patients, received 100 mg/m2 temozolomide on days 1-21/28. The GBM patients had a median Karnofsky performance status of 60% and a median age of 54.8 years. Blood counts decreased continuously, enabling a gradual dose adaptation. When blood counts dropped below normal values, temozolomide was applied on days 1-5/7. Dosage was reduced to 50-75 mg/m2 in 11 patients and gradually increased up to 130 mg/m2 in 3 patients. WHO grade 3/4 toxicity was hematological in 3 patients and non-hematological in 3 patients. In GBM patients (n=18), response after >3 months was complete in 3 patients, partial in 1 (22%), stable disease in 7 (39%) and progressive disease in 7 (39%). Progression-free survival at 6 months (PFS-6M) was 39%. Median survival was 9.1 months from relapse and 17.9 months overall. Of the patients with unmethylated MGMT promoter, 2/7 were progression-free for >6 (15 and 19) months. The data indicate that rechallenge with near-continuous, higher-dose temozolomide (100 mg/m2 on days 1-21/28 or days 1-5/7 with individual dose adaptation) is also feasible in patients with critical blood counts. Objective responses can be achieved even after relapse during a conventional 5/28-day regimen. The resistance of tumors characterized by unmethylated MGMT promoter may be overcome by near continuous temozolomide administration, which is probably most effective with a 5/7-day schedule. In spite of the relatively poor clinical prognosis, the data indicate that rechallenge with temozolomide with a dose-dense and long-lasting administration protocol is tolerable and comparable with other reported treatment protocols involving temozolomide.

Three-dimensional reconstruction and volumetry of intracranial haemorrhage and its mass effect.

Intracerebral haemorrhage still causes considerable disability and mortality. The studies on conservative and operative management are inconclusive, probably due to inexact volumetry of the haemorrhage. We investigated whether three-dimensional (3-D), voxel-based volumetry of the haemorrhage and its mass effect is feasible with routine computed tomography (CT) scans. The volumes of the haemorrhage, ventricles, midline shift, the intracranial volume and ventricular compression in CT scans of 12 patients with basal ganglia haemorrhage were determined with the 3-D slicer software. Indices of haemorrhage and intracranial or ventricular volume were calculated and correlated with the clinical data. The intended measures could be determined with an acceptable intra-individual variability. The 3-D volumetric data tended to correlate better with the clinical course than the conventionally assessed distance of midline shift and volume of haemorrhage. 3-D volumetry of intracranial haemorrhage and its mass effect is feasible with routine CT examination. Prospective studies should assess its value for clinical studies on intracranial space-occupying diseases.

The impact of progesterone receptor expression on relapse in the long-term clinical course of 93 benign meningiomas.

BACKGROUND: Previous clinicopathological observations have pointed towards an impact of progesterone receptor (PgR) expression on the clinical course of meningiomas. MATERIALS AND METHODS: EXpression of PgR and the proliferation marker MIB-1 was assessed by immunohistochemistry in the primary tumours of 30 cases of benign, completely resected, recurrent meningiomas and compared with 63 cases of meningioma without recurrence for 14 or more years. RESULTS: Univariate analysis showed a significantly higher risk for recurrence (odds ratio 3.533) for tumours with a low expression of PgR. A tendency for a higher risk for tumours with higher proliferation rate (odds ratio 6.889) was not significant. In 20 cases in which the primary tumour could be compared with its recurrence, no consistent changes of PgR expression were observed. CONCLUSION: Our findings support previous studies that found an association of low or absent expression of PgR with a higher risk of recurrence. This encourages attempts at a hormonal therapy for patients with PgR-positive meningioma.

Galectin-3: cellular distribution and correlation with WHO-grade in human gliomas.

In order to elucidate the reason for conflicting results that have been published previously on galectin-3 expression in human gliomas, we used single labeling and double labeling immunohistochemistry experiments to identify cellular origin and extent of galectin-3 positivity in 53 glioma-samples (16 glioblastomas, 21 anaplastic astrocytomas, 16 low-grade astrocytomas). Galectin-3 positivity was observed in neoplastic astrocytes, macrophages/microglial cells. endothelial cells and some B- and T-lymphocytes. The quantitative analysis showed that the percentage of galectin-3 positive cells was significantly higher in the tumor parenchyma of glioblastomas than in anaplastic (p = 0.0371) and low-grade astrocytomas (p = 0.0042). Single labeling with anti-CD68 antibodies revealed a significant correlation between CD68 and galectin-3 immunoreactivity (p = 0.0092). Endothelial cells were labeled in all low-grade and anaplastic astrocytomas, but only in 10/16 glioblastomas (p = 0.0003). This detailed analysis demonstrates that galectin-3 positivity in human gliomas is considerably influenced by tumor-infiltrating macrophages. The differential expression on endothelial cells raises the question if galectin-3 plays a role in tumor angiogenesis of human gliomas.

Localization of endostatin in rat and human gliomas.

BACKGROUND: Endostatin is a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. Its occurrence and localization has not yet been examined in human brain tumors. The authors report the production of a monoclonal antibody and detection of endostatin in rat and human gliomas by immunohistochemistry. METHODS: The authors analyzed localization and tissue distribution of endostatin in 41 paraffin embedded glioma samples (18 glioblastoma multiforme, 7 WHO Grade III astrocytomas, 13 fibrillary, and 3 protoplasmic WHO Grade II astrocytomas) of human origin and 21 rat C6 gliomas by immunohistochemistry. Double labeling experiments confirmed the origin of endostatin-labeled cells. RESULTS: Endostatin immunoreactivity was detected in tumor cells, endothelial cells, macrophages, and lymphocytes of both rat and human gliomas. The percentage of cells labeled with the endostatin antibody was significantly lower (P = 0.0126) in the tumor parenchyma of human glioblastomas than in WHO Grade II astrocytomas. CONCLUSIONS: Endostatin was present in various cell types in rat and human gliomas in vivo. Lower levels in glioblastomas than in WHO Grade II astrocytomas might have reflected the shift of a probable regulatory balance between promoters and inhibitors of angiogenesis towards facilitation of neovascularization.

A case of spinal glioblastoma multiforme: immunohistochemical study and review of the literature.

A 31-year old female underwent subtotal resection of a spinal glioblastoma multiforme (GBM) at level D 10/11 in June 1997. Immunohistochemistry revealed increased MIB-1 labeling index and accumulation of p53 protein. Routine MRI in February 1998 showed multiple tumors of the lumbar spinal cord. At open biopsy, diffuse infiltration of multiple radices was seen. Histologically and immunohistochemically, the tumor was similar to the primary. In May 1998, MRI revealed multiple intracranial metastases and meningeal involvement. The patient died in June 1998, 13 months after the onset of symptoms. The lifes of patients with spinal gliomas are not endangered by direct compression of the brain stem, and systemic metastases are extremely uncommon with gliomas. Yet, survival times in the reported case and in the literature are not better than with cerebral localization. Analysis of the present case and a survey of the literature indicate that CSF involvement and consecutive intracranial seeding determine the prognosis of patients with spinal GBM. Thus, regular monitoring of CSF-cytology and/or spinal MRI appear to be advisable in spinal GBM.

Heat shock protein expression in human gliomas.

BACKGROUND: Heat shock proteins (HSP) are cytoprotective, antiapoptotic proteins which may predict clinical prognosis in various types of cancer. Here, we asked whether the differential response to radiochemotherapy and different overall prognosis for astrocytic and oligodendroglial tumours can be accounted for by differences in HSP expression. MATERIAL AND METHODS: We examined aB-crystallin, HSP27, HSP70, HSC70 (HSP73) and HSP90 expression in 44 human gliomas (5 anaplastic and 5 low-grade astrocytomas, 5 anaplastic and 5 low-grade oligodendrogliomas and 24 glioblastomas) by immunohistochemistry. RESULTS: HSP were expressed in the tumour parenchyma of all high-grade and most low-grade gliomas, including oligodendrogliomas. Endothelial cells were more often positive for HSC70 and HSP90, but more often negative for HSP27, in glioblastomas than in the other tumours. HSP were also observed in macrophages/microglial cells, but not in a tumour-specific pattern. CONCLUSION: Different patterns of HSP expression seem not to account for the differential response of these tumours to adjuvant cytotoxic therapy.