Pancreatic ductal adenocarcinoma (PDAC) is still the fourth leading cause of cancer-related deaths in Western countries, with increasing incidence. Neither effective prognostic markers nor therapies exist for this cancer. MicroRNAs are potent inhibitors of protein translation, and aberrantly expressed in many cancers. Because let-7 microRNA targets the K-ras oncogene, we aimed to characterize let-7 expression and function in PDAC in vitro and in vivo. Let-7 expression was quantified by real-time RT-PCR from resected tumors and matching adjacent tissue, and in endoscopic ultrasound-guided fine needle aspiration material from patients with PDAC. Let-7 is detected by reverse transcription in situ PCR in a PDAC tissue microarray. PDAC-derived cells were transfected with plasmid-based synthetic microRNAs or by lentiviral transduction, in vitro and in vivo. Let-7 microRNA expression is strongly reduced in PDAC samples, as compared with adjacent tissue. Let-7 is present in normal acinar pancreatic cells, and lost in poorly differentiated cancer samples. In addition, let-7 expression was repressed in patients with PDAC not eligible for surgery. Restoring let-7 levels in cancer-derived cell lines strongly inhibits cell proliferation, K-ras expression, and mitogen-activated protein kinase activation, but fails to impede tumor growth progression after intratumoral gene transfer or after implantation of Capan-1 cells stably overexpressing let-7 microRNA. We describe here for the first time the extensive loss of expression of let-7 in PDAC. In addition, this study provides the initial steps for a microRNA replacement therapy for this cancer.

Endoscopic papillectomy of selected ampullary tumors is curative in 81.0 % of cases. It must be considered to be the first-line treatment for early tumors of the ampulla of Vater without intraductal invasion.

SUMMARY Endoscopic sphincterotomy has gained wide acceptance in the treatment of biliary lithiasis. We attempted endoscopic sphincterotomy in 443 patients and were successful in 407 (92%). Sphincterotomy was carried out with the gall bladder in situ in 234 cases (57%) of advanced age or high surgical risk. Immediate complications occurred in 7%, of which haemorrhage was the most frequent. The mortality rate was 1-5%. Three hundred and sixteen endoscopic sphincterotomies were performed more than six months before writing and follow up was available for 226 (72%) from six to 78 months. Late complications were observed in 16 patients with gall bladder 'in situ' (12%); the most frequent was cholecystitis in 6%. In five patients of the group without gall bladder, four had cholangitis related to retained or recurrent stones, and one restenosed. No episodes of cholangitis were observed in patients without stones despite reflux of barium up the biliary tree as observed during a barium meal examination.Endoscopic sphincterotomy is one of the most important advances in the treatment of common bile duct stones. This technique has gained wide acceptance since Classen, Demling, and Kawai' 2 performed the first successful procedure in 1974.Several publications describe the technique and its immediate complications-9 but few give information on long term results. "11The aim of the present investigation was to evaluate the nature and frequency of long term complications particularly the incidence of acute cholecystitis and reflux cholangitis, which are indications for cholecystectomy and could question the appropriateness of the endoscopic sphincterotomy technique. Methods PATIENTSIn all cases endoscopic sphincterotomy was performed with an 'Olympus' duodenoscope JFB2, JFB3 or JF1T and the Demling and Classen sphincterotome.

In rats after portacaval anastomosis (an animal model of chronic liver disease), transport of tryptophan and other members of the large neutral amino acid group from blood to brain was markedly enhanced. Increased transport activity was apparently restricted to the neutral amino acid transport system, since brain uptake of glucose, inulin, and tyramine was unaffected while blood-brain arginine transport was significantly reduced. These results strikingly confirm the hypothesis that carrier-mediated blood-brain transport is the limiting factor determining the availability of the neutral amino acids to the brain. The encephalopathy associated with cirrhosis may be the result of abnormal neurotransmitter metabolism and neurotransmission secondary to increased neutral amino acid transport activity and an increased brain content of members of the neutral amino acid group.