Objective-In vitro studies indicate a role of apoptosis regulatory proteins of the BCL-2 family in the resistance of glioblastoma multiforme to irradiation and chemotherapy. To date, no study has compared the expression of these proteins in initial and recurrent tumours. The diVerences of expression of BCL-2, BCL-X, BAX, and MCL-1 proteins of paired first resection and recurrence glioblastoma specimens were examined. Methods-Immunohistochemistry was performed in 37 cases of glioblastoma multiforme with paraYn embedded tissue from first resections and their recurrences in three treatment groups (15 radiochemotherapy, 15 irradiation, seven untreated). Ten high power fields were evaluated with an arbitrary score (< 5%=1, 5-50%=2, >50%=3), and cumulative scores for each antigen calculated. Results-In the whole group, we found a significant up regulation of antiapoptotic BCL-2 (median cumulative score of 15 in the primary, 19 at recurrence; p<0.0001 in the Wilcoxon test), BCLX (median scores 20 and 25, respectively, p<0.0001), and MCL-1 (median scores 11 and 14, p=0.0395), and a significant down regulation of proapoptotic BAX (median scores 14 and 11, p<0.0001). In the subgroups, these trends were also found. No association between protein expression and treatment regimen was found, although significant changes were restricted to the subgroups that received adjuvant chemotherapy. No significant correlation with clinical prognosis was detected with the Kaplan-Meier method. Conclusions-In the development from initial to recurrent glioblastoma multiforme, the BCL-2 family rheostat shifts towards antiapoptotic adjustment in vivo. Importantly, the changes in BCL-2 family protein expression characterised here were also seen in the subgroup of patients who did not receive adjuvant radiotherapy or chemotherapy, suggesting that the changes of BCL-2 family protein expression result not only from radiochemotherapy but also reflect the natural course of disease.

Gliomatosis cerebri is a rare, diffusely growing neuroepithelial tumor characterized by extensive brain infiltration involving more than two cerebral lobes. Among 13 patients with gliomatosis cerebri (median age, 46 years), biopsies showed features of diffuse astrocytoma (n = 4), oligoastrocytoma (n = 1), anaplastic astrocytoma (n = 5), anaplastic oligoastrocytoma (n = 1), or glioblastoma (n = 2). Molecular genetic investigation showed TP53 mutations in three of seven tumors and both PTEN mutation and epidermal growth factor receptor overexpression in one tumor. Amplification of CDK4 or MDM2 or homozygous deletion of CDKN2A was not detected. Three of 10 patients receiving radiotherapy showed a partial response (one patient) or had stable disease (two patients) lasting for more than 1 year. Four of six patients treated with procarbazine, carmustine, vincristine chemotherapy demonstrated partial remission (one patient), minor response (two patients), or stable disease (one patient). Median survival time from diagnosis was 14 months (range, 4-91+ months). Infratentorial involvement was associated with shorter survival. We conclude that (1) the molecular genetic alterations in gliomatosis cerebri resemble those in diffuse astrocytomas; (2) the prognosis of gliomatosis cerebri is variable but for at least 50% of patients as poor as for glioblastoma; and (3) some patients respond to radiotherapy and/or procarbazine, carmustine, vincristine chemotherapy.

Increased concentrations of myo-inositol and glutamine in the contralateral normal-appearing white matter of GBM patients are consistent with mild astrocytosis and suggest the detectability of early neoplastic infiltration by using proton MR spectroscopy in vivo.

High constitutive, as opposed to inducible, expression of HSP may play a role in the primary resistance of human malignant gliomas to cytotoxic radiochemotherapy. Superinduction of HSP levels by hyperthermia in vitro provided no further survival advantage.

Sphingosine-1-phosphate (S1P), the corresponding kinases SphK1-2, and receptors S1P1-3 and S1P5 are involved in cell survival and growth. Pathway components are overexpressed in many tumors including glioblastoma. Previous studies showed that the expression of SphK1 influenced survival of glioblastoma patients, yet the roles of SphK1-2 and receptors S1P1-3 and S1P5 have not been investigated in different forms of glioblastoma. Samples from 59 patients (37 males, 22 females, age 55.1 ± 17.1 years) suffering from primary (n = 35), recurrent (n = 18), and secondary (n = 6) glioblastomas were analyzed using quantitative real-time PCR and immunohistochemistry for expression levels of SphK1 and SphK2 and S1P1-3 and S1P5. Sixteen autopsy nontumorous brain specimens were used as controls. Expression data was correlated with clinical data and patient survival. All markers were overexpressed in the glioblastoma specimens compared to the non-neoplastic brain tissue. SphK1 and all S1P receptors were expressed in increasing order of magnitude from primary, up to recurrent and secondary glioblastomas, with values of up to 44-fold compared to normal brain tissue. In contrast, SphK2 levels were highest in primary tumors (25-fold). Expression of the sphingosine signaling pathway components was influenced by radio/radiochemotherapy in distinct ways. Immunohistochemistry for SphK1 and S1P1 confirmed the overexpression in glioblastoma. Uni- and multivariate survival analyses identified S1P5 messenger RNA levels as an independent prognostic factor of survival. The sphingosine pathway is overexpressed in glioma. Its components show distinct expression patterns in the tumor subgroups. S1P5 is identified as an independent prognostic factor in multivariate analysis, and this pathway promises to be a candidate for targeted therapies.

The most frequent primary brain tumors, anaplastic astrocytomas (AA) and glioblastomas (GBM): tend to invasion of the surrounding brain. Histopathological studies found malignant cells in macroscopically unsuspicious brain parenchyma remote from the primary tumor, even affecting the contralateral hemisphere. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is suspected. The purpose of this study was to investigate the value of DTI as a possible instrument of depicting evidence of tumor invasion into the corpus callosum (CC). Preoperatively, 31 patients with high-grade brain tumors (8 AA and 23 GBM) were examined by MRI at 3 T, applying a high-resolution diffusion tensor imaging (DTI) sequence. ADC- and FA-values were analyzed in the tumor-associated area of the CC as identified by fiber tracking, and were compared to matched healthy controls. In (MR-)morphologically normal appearing CC the ADC values were elevated in the tumor patients (n = 22; 0.978 × 10−3 mm²/s) compared to matched controls (0.917 × 10−3 mm²/s, p < 0.05), and the corresponding relative FA was reduced (rFA: 88 %, p < 0.01). The effect was pronounced in case of affection of the CC visible on MRI (n = 9; 0.978 × 10−3 mm²/s, p < 0.05; rFA: 72 %, p < 0.01). Changes in diffusivity and anisotropy in the CC can be interpreted as an indicator of tumor spread into the contralateral hemisphere not visible on conventional MRI.

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ADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients.