Pancreatic ductal adenocarcinoma (PDAC) is thought to originate from ductal structures, exhibiting strong desmoplastic reaction with stromal pancreatic myofibroblasts (PMF), which are supposed to drive PDAC tumorigenesis. Previously, we observed high expression of the adhesion molecule L1CAM (CD171) in PDAC cells accounting for chemoresistance. Thus, this study aimed to investigate whether PMFs are involved in the induction of tumoral L1CAM and whether this contributes to malignant transformation of pancreatic ductal cells and PDAC tumorigenesis. Immunohistochemistry of tissues from chronic pancreatitis specimens revealed considerable L1CAM expression in ductal structures surrounded by dense fibrotic tissue, whereas no L1CAM staining was seen in normal pancreatic tissues. Using the human pancreatic duct cell line H6c7, we show that coculture with PMFs led to a transforming growth factor-B1 (TGF-B1)-dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in monocultured H6c7 cells after administration of exogenous TGF-B1. Both TGF-B1-and PMF-induced L1CAM expression were independent of Smad proteins but required c-Jun NH 2 -terminal kinase activation leading to the induction of the transcription factor Slug. Moreover, Slug interacted with the L1CAM promoter, and its knockdown abrogated the TGF-B1-and PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-B1-induced L1CAM expression and the resulting phenotype could be verified in the TGF-B1-responsive PDAC cell lines Colo357 and Panc1. Our data provide new insights into the mechanisms of tumoral L1CAM induction and how PMFs contribute to malignant transformation of pancreatic duct cells early in PDAC tumorigenesis. [Cancer Res 2009;69(10):4517-26]

We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.

The authors' data strongly suggest that CSF pathway reclosure is the factor most responsible for ETV failure in obstructive hydrocephalus. According to both their experiences and to studies published in the literature, the formation of new arachnoid membranes or scars plays a far greater role in ETV failure than does poor CSF absorption, at least in aqueductal stenosis. It is hypothesized that infants have a higher tendency to form new arachnoid membranes than do older patients and that this factor may explain (at least in part) the higher ETV failure rate in patients younger than 1 year old.

Factors indicating potential failure of ETV were very young age and etiology other than idiopathic aqueductal stenosis. Probability of success seems to increase during the first 2 or 3 months of life. Ventriculoscopy with the option of a second ETV should be regularly performed after failure of ETV.

We recently reported on continuous tumor-stroma interactions essentially contributing to chemoresistance of pancreatic ductal adenocarinoma (PDAC) cells. As demonstrated here, long-term coculture with pancreatic myofibroblasts representing the main stromal compartment of PDAC resulted in a chemoresistant phenotype in the pancreatic ductal epithelial cell line H6c7 as well as in the chemosensitive PDAC cell line T3M4. This involved a reduced expression of caspases and the caspase inducing transcription factor STAT1, both caused by diminished gene transcription. The DNA-methylation inhibitor 5-azadeoxycytidine enhanced caspase and STAT1 expression in cocultured H6c7 and T3M4 cells along with an increased chemosensitivity, indicating a role for CpG DNA-hypermethylation in the downregulation of these crucial apoptosis mediators. Cocultured H6c7 and T3M4 cells exhibited elevated nuclear levels of DNA-methyltransferase-1 (DNMT1). Silencing of DNMT1 expression by siRNA increased expression of caspases and STAT1 and restored chemosensitivity. In SCID mice, tumors arising from coinoculated T3M4 cells and myofibroblasts (co-tumors) responded less towards chemotherapy than mono-tumors, exhibiting decreased apoptosis, no remission and reduced expression of caspases and STAT1. These data underscore the role of myofibroblasts in chemoresistance of PDAC and point to the importance of caspases as central target structures of epigenetic regulation in this scenario. Furthermore, an activated microenvironment might apparently promote the manifestation of chemoresistance already in premalignant precursor cells at early stages of PDAC tumorigenesis. ' 2008 Wiley-Liss, Inc.Key words: chemoresistance; pancreatic cancer; epigenetic gene silencing; myofibroblasts Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly malignant phenotype associated with rapid tumor progression and metastasis. 1,2 In Western countries, pancreatic cancer is 4th in the rank order of fatal tumor diseases exhibiting a still increasing prevalence. 3 The conventional therapy of PDAC still proves to be very difficult and poorly effective due to the preexisting (innate) or acquired resistance of PDAC cells towards chemotherapeutic drugs. One strategy by which tumor cells can adopt a chemoresistant phenotype is the protection from apoptosis. Because PDAC is largely composed of mesenchymal stromal cells, we recently started to investigate the impact of pancreatic myofibroblasts on the development of chemoresistance in these tumor cells. Using a transwell coculture model including murine pancreatic myofibroblasts and the chemosensitive human PDAC cell lines T3M4 and PT45-P1, we could show that during 1 week of coculture, these tumor cells become highly chemoresistant by an efficient protection from drug-induced apoptosis, apparently mediated by soluble factors released by the myofibroblasts. Since in this model system tumor and stromal cells originated from different species, we were able to distinguish the origin of all soluble factors. In this scenar...

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O(6)-benzylguanine (O(6)BG), sensitizes tumor cells to O(6)-alkylating agents. However, systemic administration of O(6)BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O(6)-alkylating drugs administered together with O(6)BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O(6)BG of a patient suffering from glioblastoma. O(6)BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide (Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O(6)BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O(6)BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O(6)-alkylating drugs) concomitant with O(6)BG without augmenting drug-induced systemic side effects.

In this article, 12 re-ventriculostomies in the treatment for obstructive hydrocephalus are described. The etiology of the hydrocephalus was a benign aqueductal stenosis in 9 patients, a tumor around the aqueduct in 2 patients and intraventricular bleeding in one patient. In all cases the initial ventriculostomy was successful, but after a time interval of 2 weeks to 6 years the patients developed similar clinical symptoms as preoperatively. In all except one case the radiological findings spoke in favour of stoma closure. Intraoperatively the stoma was completely closed in 9 patients and in 3 patients a subtotal closure was observed. In all cases a re-ventriculostomy was performed bluntly with a Fogarty catheter in loco typico at the floor of the third ventricle. Of the 12 patients 6 had an excellent outcome postoperatively, one patient improved and one had a benefit from the re-ventriculostomy although he died of cardiac problems. In the remaining 4 patients the re-ventriculostomy was not successful and the patients needed a shunt operation. In conclusion, after initially successful endoscopic third ventriculostomy, re-ventriculostomy should be considered as a sufficient treatment option in case of suspected stoma dysfunction.