Backgrounds/Aims: Endoscopic submucosal dissection (ESD) of early cancer allows precise staging and avoids recurrence or surgery. Tutored by experts, ESD has rapidly spread in Japan, but still demands untutored learning in Western countries. A step-up approach starts with easiest gastric neoplasias, but fails on their low prevalence in Western countries. A prevalence-based approach includes challenging colonic neoplasias. Methods: We analyzed an untutored series of initial 50 ESD procedures by an experienced endoscopist on consecutive lesions referred according to prevalence. Results: Overall, 48 lesions (20% upper gastrointestinal, 80% colorectal; 2 hyperplastic (inflammatory) lesions, 46 neoplasms) were completely resected intention-to-treat with ESD, 2 required a second ESD. Neoplasias were resected 76% en-bloc (46% ESD, 30% ESD with snaring), 17% by ESD with snaring in 2-3 pieces, and 6.5% as ESD with snaring in multiple pieces. None of 15 neoplasias with high-grade intraepithelial neoplasia or an early esophageal cancer (R0) had recurred. Complications were 2 bleedings (4%) and 7 perforations (14%), 5 clipped and 2 (4%) operated. All patients were discharged within 9 days without long-term morbidity. Conclusion:Untutored learning of ESD is feasible on colonic lesions. We propose to establish ESD in Europe with structured training and a prevalence-of-lesions-based approach.

BackgroundThe green tea catechin epigallocatechin gallate (EGCG) was shown to effectively inhibit tumor growth in various types of cancer including biliary tract cancer (BTC). For most BTC patients only palliative therapy is possible, leading to a median survival of about one year. Chemoresistance is a major problem that contributes to the high mortality rates of BTC. The aim of this study was to investigate the cytotoxic effect of EGCG alone or in combination with cisplatin on eight BTC cell lines and to investigate the cellular anti-cancer mechanisms of EGCG.MethodsThe effect of EGCG treatment alone or in combination with the standard chemotherapeutic cisplatin on cell viability was analyzed in eight BTC cell lines. Additionally, we analyzed the effects of EGCG on caspase activity, cell cycle distribution and gene expression in the BTC cell line TFK-1.ResultsEGCG significantly reduced cell viability in all eight BTC cell lines (p < 0.05 or p < 0.01, respectively, for most cell lines and EGCG concentrations > 5 μM). Combined EGCG and cisplatin treatment showed a synergistic cytotoxic effect in five cell lines and an antagonistic effect in two cell lines. Furthermore, EGCG reduced the mRNA levels of various cell cycle-related genes, while increasing the expression of the cell cycle inhibitor p21 and the apoptosis-related death receptor 5 (p < 0.05). This observation was accompanied by an increase in caspase activity and cells in the sub-G1 phase of the cell cycle, indicating induction of apoptosis. EGCG also induced a down-regulation of expression of stem cell-related genes and genes that are associated with an aggressive clinical character of the tumor, such as cd133 and abcg2.ConclusionsEGCG shows various anti-cancer effects in BTC cell lines and might therefore be a potential anticancer drug for future studies in BTC. Additionally, EGCG displays a synergistic cytotoxic effect with cisplatin in most tested BTC cell lines.Graphical abstractSummary illustration

BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 μM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.