Purpose: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH₂-terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications. Experimental Design: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance <1 cm (second area), and between 1 and 3.5 cm (third area) from the macroscopic tumor border. The relationships between patients' age, Karnofsky performance status, gender, protein expression, and survival were analyzed. Results: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/tJNK)/nestin ratios in the second area were ≥2.619 and ≥0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis. Conclusions: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.

The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the KLRC1 (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of “apparently normal” cells presenting a gene profile compatible with a precancerous state or even “quiescent” cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.

✓ Chronic subdural hematomas (SDHs) generally occur in elderly patients. Its pathogenesis is usually related to head trauma with tearing and rupture of the bridging veins, although in some cases a history of trauma is not recognizable. There are many reports regarding the association between spontaneous chronic SDHs and an alteration in coagulative parameters. A coagulative disorder should be suspected when an unexplained hemorrhage occurs, especially in a young patient. The authors report on three young men with a deficiency in coagulation factor XIII (FXIII) who underwent surgery for chronic SDHs. The role of FXIII in the pathogenesis of chronic SDH is emphasized. In patients with unexplained chronic SDH all coagulation parameters and factors should be screened to identify an eventual coagulative disorder.