Dietary N-3 polyunsaturated fatty acids decrease biliary cholesterol saturation in gallstone disease

Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n-1 monounsaturated or n-6 polyunsaturated fatty acids with n-3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n-3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n-3 polyunsaturated fatty acids. Intake of n-3 polyunsaturated fatty acids increased (p < 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p < 0.001) and arachidonic acids (p < 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p < 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 ± 0.44 to 1.24 ± 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile

The green tea catechin epigallocatechin gallate induces cell cycle arrest and shows potential synergism with cisplatin in biliary tract cancer cells

BACKGROUND: The 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. METHODS: The 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. RESULTS: EGCG 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. CONCLUSIONS: EGCG 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. [Figure: see text

Influence of Five Potential Anticancer Drugs on Wnt Pathway and Cell Survival in Human Biliary Tract Cancer Cells

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

The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

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

Implementation of endoscopic submucosal dissection in Europe: survey after ten ESD expert training workshops 2009 – 2018

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

Systematic Review on Optical Diagnosis of Early Gastrointestinal Neoplasia

Background: Meticulous endoscopic characterization of gastrointestinal neoplasias (GN) is crucial to the clinical outcome. Hereby the indication and type of resection (endoscopically, en-bloc or piece-meal, or surgical resection) are determined. By means of established image-enhanced (IEE) and magnification endoscopy (ME) GN can be characterized in terms of malignancy and invasion depth. In this context, the statistical evidence and accuracy of these diagnostic procedures should be elucidated. Here, we present a systematic review of the literature. Results: 21 Studies could be found which met the inclusion criteria. In clinical prospective trials and meta-analyses, the diagnostic accuracy of &gt;90% for characterization of malignant neoplasms could be documented, if ME with IEE was used in squamous cell esophageal cancer, stomach, or colonic GN. Conclusions: Currently, by means of optical diagnosis, today’s gastrointestinal endoscopy is capable of determining the histological subtype, exact lateral spread, and depth of invasion of a lesion. The prerequisites for this are an exact knowledge of the anatomical structures, the endoscopic classifications based on them, and a systematic learning process, which can be supported by training courses. More prospective clinical studies are required, especially in the field of Barrett’s esophagus and duodenal neoplasia