Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

Tumor necrosis factor-α (TNF-α)-driven inflammatory reaction plays a crucial role in the initiation of liver fibrosis. We herein attempted to design genetically engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-α inhibitor), and to determine the anti-fibrotic potential of the secretome released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we generated the etanercept-synthesizing ASCs by transfecting the ASCs with mini-circle plasmids containing the gene insert encoding for etanercept. We subsequently collected the secretory material released from the etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in TAA-treated mice) models of liver fibrosis. We observed that while etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration of the etanercept-secretome induced significant reduction in the expression of both fibrosis-related and inflammation-related markers compared to the control group (all Ps < 0.05). The etanercept-secretome group also showed significantly lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such as TNF-α (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver showed the highest reduction in the degree of fibrosis in the entanercept-secretome group (p = 0.006). Our results suggest that the administration of etanercept-secretome improves liver fibrosis by inhibiting TNF-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.

BACKGROUND The role of smoking in the incidence of colorectal cancer (CRC) or gastric cancer (GC) in populations undergoing cholecystectomy has not been investigated. AIM To evaluate the effect of smoking on CRC or GC development in cholecystectomy patients. METHODS A total of 174874 patients who underwent cholecystectomy between January 1, 2010 and December 31, 2017 were identified using the Korean National Health Insurance Service claims database. These patients were matched 1:1 with members of a healthy population according to age and sex. CRC or GC risk after cholecystectomy and the association between smoking and CRC or GC risk in cholecystectomy patients were evaluated using adjusted hazard ratios (HRs) and 95%CIs. RESULTS The risks of CRC (adjusted HR: 1.15; 95%CI: 1.06-1.25; P = 0.0013) and GC (adjusted HR: 1.11; 95%CI: 1.01-1.22; P = 0.0027) were significantly higher in cholecystectomy patients. In the population who underwent cholecystectomy, both CRC and GC risk were higher in those who had smoked compared to those who had never smoked. For both cancers, the risk tended to increase in the order of non-smokers, ex-smokers, and current smokers. In addition, a positive correlation was observed between the amount of smoking and the risks of both CRC and GC. CONCLUSION Careful follow-up and screening should be performed, focusing on the increased risk of gastrointestinal cancer in the cholecystectomy group, particularly considering the individual smoking habits.

Background: Although laparoscopic radical resection for gallbladder (GB) cancer has been attempted, only a limited number of studies have evaluated its outcomes using a per‐protocol analytical approach. Methods: Between January 2010 and December 2019, 213 patients underwent surgery for gallbladder (GB) cancer at three institutions, of whom 203 consecutive patients with T2 or T3 disease were retrospectively analyzed. Protocol‐adherent radical resection (per‐protocol) was defined as wedge liver resection or IVb/V bisegmentectomy with the procurement of at least four lymph nodes. Propensity score matching was performed to compare the laparoscopic and open approaches. Results: Protocol‐adherent radical resection was achieved in 14 of 76 patients (18.4%) in the laparoscopic group and in 76 of 127 patients (59.8%) in the open surgery group. The primary unmet criterion for radical resection was an insufficient lymph node yield (60/76, 78.9%) in the laparoscopic group. After 1:1 propensity score matching (54 pairs), the 5‐year overall survival (OS) rate did not differ between the laparoscopic and open approaches (46.1% vs. 49.9%; hazard ratio 0.90, 95% confidence interval 0.55–1.47; p = 0.668), whereas the disparity in oncological adequacy persisted (protocol‐adherent radical resection 20.4% vs. 70.4%). Among patients who achieved protocol‐adherent radical resection ( N = 90), the exploratory comparison of 5‐year OS between the laparoscopic ( N = 14) and open ( N = 76) groups showed no significant difference (61.5% vs. 53.3%; p = 0.288). Multivariate analysis in patients with protocol‐adherent radical resection identified N stage and elevated CA 19‐9 levels as independent prognostic factors for OS. Conclusions: Regardless of whether a laparoscopic or open approach is used, radical surgery—including appropriate hepatic resection with the retrieval of at least four lymph nodes—is essential for improving long‐term prognosis in patients with GB cancer. N stage and elevated CA 19‐9 levels were independently associated with overall survival.