Objective: Pancreatic stellate cells (PSC) promote oncogenesis by modulating cell proliferation. Aim-To evaluate the early activation of PSC in case of hypoxia in normal human pancreas. Method: An organotypic culture model of thick sections of human pancreas has been developed and validated. Slices of pancreas (300 μm) were prepared from surgical specimens and cultured in hyperoxia conditions. Half of the samples underwent an initial phase of culture in normoxia (21 % O2) to reproduce hypoxia. The total duration of culture was 72 h. Cell viability, hypoxia, apoptosis and activation were monitored. Results: 30 sections per specimen were cultured. Analysis was performed at baseline, 24 h, 48 h and 72 h. Morphological analysis showed gradual appearance of ductal/acinar dedifferentiation. At 72 h, foci of necrosis were identified. Hypoxia was confirmed by the expression of HIF1 and CA9 at 48 h (10 % and 50 % of labeled cells). Apoptosis was limited, acinar cells expressed caspase 3 at 48 and 72 h. Analysis of proliferation using Ki67 index showed significant activation of PSC at 48 h (×5/baseline) and at 72 h (×6/ baseline). Activation of PSC was confirmed by smooth muscle actin immunochemistry. Conclusion: Organotypic culture of normal human pancreas is possible with optimized cell viability at 72 h. Hypoxiainduced activation of PSC occurs very early. Objective: IPN are still poorly characterized precursor lesions of bile duct adenocarcinoma. We present a multicenter study with focus on morphology, subtyping and prognosis and provide a detailed molecular analysis in the stepwise progression from low-grade to high-grade lesions and invasive carcinoma. Method: Fourty-five patients with biliary IPN were included into the cohort, twenty-two patients with conventional adenocarcinoma of the bile duct served as control cohort. Subtyping was performed based on histomorphology and expression profile of mucins and cdx2 expression. Furthermore, low grade lesions (n=14), high-grade lesions (n=38) and invasive components (n=13) of IPN as well as conventional bile duct adenocarcinomas (n=22) were investigated individually for alterations of common oncogenic pathways using immunohistochemistry, real-time polymerase chainreaction and direct sequencing. Results: IPN are mainly detected at preinvasive stage (71 %), pancreato-biliary and intestinal type are the most common subtypes (36 and 29 %, respectively). Detailed molecular analysis showed that p53 overexpression, k-ras mutation, loss of heterozygosity of p16 locus and nuclear ßcatenin expression are early events and loss of smad4 and overexpression of EGFR and HER2 are later events in the tumor progression of IPN. Conclusion: Stepwise alterations of common oncogenic pathways are required for progression of biliary IPN from non-invasive precursors to invasive carcinoma.