Wirkung von peroral verfüttertem »Novadral« und »Trimanyl« auf die lokale Durchblutung des Gehirns von wachen Hunden und Katzen

Um die Wirkung vasoaktiver Substanzen im Tierversuch unter möglichst gleichen Bedingungen wie beim Menschen zu untersuchen, haben wir Medikamente an wache Tiere verfüttert und die lokale Gehirndurchblutung am wachen, frei beweglichen Tier fortlaufend über viele Tage registriert. (Meßanordnung nach Betz, s. dieses Symposium.) In den Versuchen wurden ein Medikament mit gefäßverengender Wirkung, nämlich das adrenalinverwandte m-Oxyphenylaminoäthanolhydrochlorid, das unter dem Namen »Novadral« im Handel ist, und der Gefäßdilatator 4 ' 4 Diäthylaminoaethoxy hexoestrol, unter dem Namen »Trimanyl« bekannt, einander gegenübergestellt

Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach

Immunohistochemical studies showed that O6-methylguanine-DNA methyltransferase (MGMT) protein expression is negatively associated with survival in glioblastomas treated with alkylating agents in accordance with previous results of methylation-specific PCR. Implementation of this data in routine clinical diagnostics is limited due to often inappropriate study designs, e.g. pooling of tumor entities, WHO grades or primary and secondary glioblastomas, disregard concerning the infiltration zone or various epidemiological factors. The aim of our study was to evaluate MGMT expression and its prognostic value taking into consideration the aforementioned deficiencies. For this, 162 astrocytic tumors WHO II-IV (36 diffuse astrocytomas WHO II, 51 anaplastic astrocytomas, 75 primary glioblastomas) as well as 25 glioblastoma infiltration zones and 19 glioblastoma relapses were analyzed for immunohistochemical MGMT protein expression using tissue microarray technique. Expression of MGMT significantly decreased from WHO grade II (25.6%) to glioblastoma (16.8%, p=0.01) with lowest levels in grade III tumors (10.2%, II/III p<0.0001). Significant negative associations of MGMT and survival were detected for WHO grade II and IV (p=0.003 and 0.013). The optimal cut-off value of MGMT positive nuclei in primary glioblastomas discriminating patients with significantly different survival rates was at 15% (Log-Rank p=0.0002). Individual relapse tumors showed changes of MGMT expression to a varying degree. The infiltration zone demonstrated a significant increase of MGMT (p<0.0001). We conclude that immunohistochemical MGMT assessment has potential as a powerful diagnostic tool but analysis should only be performed in a grade dependent manner, before radio-/chemotherapy and with special attention to the infiltration zone of diffuse astrocytoma

Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach

Immunohistochemical studies showed that O6-methylguanine-DNA methyltransferase (MGMT) protein expression is negatively associated with survival in glioblastomas treated with alkylating agents in accordance with previous results of methylation-specific PCR. Implementation of this data in routine clinical diagnostics is limited due to often inappropriate study designs, e.g. pooling of tumor entities, WHO grades or primary and secondary glioblastomas, disregard concerning the infiltration zone or various epidemiological factors. The aim of our study was to evaluate MGMT expression and its prognostic value taking into consideration the aforementioned deficiencies. For this, 162 astrocytic tumors WHO II-IV (36 diffuse astrocytomas WHO II, 51 anaplastic astrocytomas, 75 primary glioblastomas) as well as 25 glioblastoma infiltration zones and 19 glioblastoma relapses were analyzed for immunohistochemical MGMT protein expression using tissue microarray technique. Expression of MGMT significantly decreased from WHO grade II (25.6%) to glioblastoma (16.8%, p=0.01) with lowest levels in grade III tumors (10.2%, II/III p<0.0001). Significant negative associations of MGMT and survival were detected for WHO grade II and IV (p=0.003 and 0.013). The optimal cut-off value of MGMT positive nuclei in primary glioblastomas discriminating patients with significantly different survival rates was at 15% (Log-Rank p=0.0002). Individual relapse tumors showed changes of MGMT expression to a varying degree. The infiltration zone demonstrated a significant increase of MGMT (p<0.0001). We conclude that immunohistochemical MGMT assessment has potential as a powerful diagnostic tool but analysis should only be performed in a grade dependent manner, before radio-/chemotherapy and with special attention to the infiltration zone of diffuse astrocytoma

Perforin and tumor necrosis factor alpha in the pathogenesis of experimental allergic encephalomyelitis: comparison of autoantigen induced and transferred disease in Lewis rats.

A cell-mediated cytotoxic reaction is believed to be involved in inflammatory lesion formation of experimental allergic encephalomyelitis (EAE). We compared EAE diseased animals which had either been immunized with myelin basic protein (MBP) or adoptively received MBP specific T-cell lines in order to study whether the different courses of disease induction are reflected by quantitative or qualitative differences in the expression of genes encoding putative mediators of tissue damage, i.e. TNF alpha, and the pore-forming protein perforin. With the appearance of signs of paralysis, both genes are induced in cells within the CNS lesions, whereas drastically reduced numbers of TNF alpha- and perforin gene-expressing cells are observed during recovery, despite the presence of high numbers of mononuclear cells in the CNS. Marked differences, however, exist in the gene expression profiles: during the phase of most severe clinical signs TNF alpha expressing cells are 2 to 3 times more frequent in transferred than immunized animals. In animals with MBP-induced EAE the number of perforin expressing cells represents only 1.6% of the IL2R gene expressing cells, while this fraction represents 25% in mice which received autoaggressive T cells. Thus, the presence of a high number of activated killer cells may accelerate tissue damage and progression of disease in passive EAE whereas in actively induced EAE activation of regulatory mechanisms induced by polyclonal activation after immunization may prevent generation of large amounts of activated cytotoxic T cells

Expression of integrins αvß3 and αvß5 and their ligands in primary and secondary central nervous system neoplasms

. Aims: To study the expression of integrins αvß3 and αvß5 and their ligands in tumour, stroma and endothelial cells from human glioblastoma and CNS metastases from breast, lung and skin tumours. Methods and results: Integrin and integrin ligand expression was quantified in frozen tumour surgical specimens (15 glioblastomas and breast carcinoma metastases as well as 16 lung carcinoma and melanoma metastases) using immunohistochemistry. Gene expression profiles were evaluated in glioblastomas (n=424) and in normal brain (n=11). Overall, αvß3 expression was more common than αvß5, except in tumours derived from lung. αvß3 expression was most frequent in glioblastomas and melanoma metastases. Most lung-derived tumours expressed αvß5, but expression was less frequent in other tumours; about 20% of breast-derived tumours strongly expressed αvß5. Melanoma-derived tumours did not express αvß5. Expression of integrin ligands vitronectin, fibrinogen, fibronectin and osteopontin was variable between tumours, although most tumours expressed the ligands to some extent. Marked αvß3, but not αvß5, expression was common in stroma of CNS metastases. In blood vessels, αvß3 expression was more frequent than αvß5 and more pronounced in CNS metastases than in glioblastomas. Integrin ligand expression occurred in blood vessels in most tumours. In glioblastomas, mRNA expression of αvß3, αvß5, osteopontin and fibronectin were significantly upregulated over normal brain. Conclusions: Overall, we report distinct and heterogeneous patterns of integrin expression in primary and secondary brain tumours that may be relevant to the future development of integrintargeting therapeutic approaches to brain tumours