Open Access

Background: The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease. Methods: In this study we analysed five compounds with suggested inhibitory effects on Wnt signalling (DMAT, FH535, myricetin, quercetin, and TBB) for their cytotoxic efficiency, mode of cell death, time- and cell line-dependent characteristics as well as their effects on Wnt pathway activity in nine different BTC cell lines. Results: Exposure of cancer cells to different concentrations of the compounds results in a clear dose-dependent reduction of viability for all drugs in the order FH535 > DMAT > TBB > myricetin > quercetin. The first three substances show high cytotoxicity in all tested cell lines, cause a direct cytotoxic effect by induction of apoptosis and inhibit pathway-specific signal transduction in a Wnt transcription factor reporter activity assay. Selected target genes such as growth-promoting cyclin D1 and the cell cycle progression inhibitor p27 are down- and up-regulated after treatment, respectively. Conclusions: Taken together, these data demonstrate that the small molecular weight inhibitors DMAT, F535 and TBB have a considerable cytotoxic and possibly Wnt-specific effect on BTC cell lines in vitro. Further in vivo investigation of these drugs as well as of new Wnt inhibitors may provide a promising approach for targeted therapy of this difficult-to-treat tumour.

Background and aims Transfer of ESD technique for early gastrointestinal cancer from Japan requires expert-supervised experimental training before unsupervised implementation of clinical ESD. Aims To evaluate unsupervised implementation of ESD-intention-to-treat (-ITT). Methods ESD Workshops (in-vivo porcine model) lasted 3.3 days including one day theory for 177 participants from 135 Western referral centers. A questionnaire was sent to the senior participant of all 135 centers. Design Cross-sectional questionnaire survey. Main outcome measurements Performance, organ distribution, severe adverse events of ESD-ITT. Results Feedback was received from 113 centers (84%), i.e. 73 (54%) ESD centers and 40 centers (30%) with zero ESD; 10 (7%) had published ESD; no feedback from 12 (9%) centers with unknown status. Altogether, 83 centers (61.5%) perform ESD: 21 (16%) had >150 ESD (professional category), 33 (24%) had 31-150 ESD (competent category), and 29 (21.5%) had ≤ 30 ESD (initial learning category). Most implemented ESD centers (91%, 72 of 79) were analyzed: Centers on initial learning (420 ESD) compared to centers with >30 ESD (5676 ESD) performed en-bloc ESD in 64% vs. 84%, hybrid-ESD in 26% vs.11% and piecemeal-EMR in 10% vs. 5.2%. Majority of ESD (66-68%) were in colorectum, overall with low risk (30-day mortality 0.03%, surgical repair 3.5% vs. 1.7%) and satisfactory outcome (oncosurgery 7.4% vs. 5.2%, local recurrence 1.5% vs. 0.3%). Conclusions Beyond guideline recommendations, unsupervised implementation of ESD was successful in colorectum with step-up approach. Now, Western ESD centers have to aim for professional (i.e. >80%) curative ESD.