Outcomes of the Conventional versus Pocket-Creation Method for Endoscopic Submucosal Dissection of Gastric Body Tumors Using a Dual Knife: A Retrospective Study.

Background/Aims: Various endoscopic submucosal dissection (ESD) methods for gastric tumors have been tried. However, no studies have yet compared results according to the ESD method for gastric body tumors using a dual knife. The objective of this study was to compare outcomes of two ESD methods for gastric body tumors: the pocket-creation method and conventional method. Methods: Patients who underwent ESD for a gastric body tumor were retrospectively reviewed. Patients were divided into two groups according to the ESD method: the conventional method (group I) and pocket-creation method (group II). Characteristics of patients and tumors, hospitalization period, incidence of complications, resection margin status, incidence of surgical operation, procedure time, and laboratory findings were investigated. Results: Of the total of 100 patients, 52 belonged to group I and 48 to group II. All tumors were successfully resected en bloc. Resection margin involvement was found in six (11.5%) of group I and six (12.5%) of group II. Complications were observed in seven (13.5%; major complication five, minor two) of group I and eight (16.7%; major two, minor six) of group II. There were no significant differences in ESD outcomes such as hospitalization period, incidence of complications, resection margin status, incidence of surgical operation, procedure time, or inflammatory response after ESD between the two groups. Conclusions: Both methods are suitable for treating gastric body tumors with adequate treatment success rates and comparable complication rates.

Underwater Versus Conventional Endoscopic Mucosal Resection for Superficial Non-ampullary Duodenal Epithelial Tumors: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Duodenal underwater endoscopic mucosal resection (UEMR) has been suggested as a feasible treatment option for superficial non-ampullary duodenal epithelial tumors (SNADETs). However, its efficacy and safety have not been fully established yet. Thus, the objective of this systematic review and meta-analysis was to determine the efficacy and safety of UEMR as compared with conventional endoscopic mucosal resection (CEMR) in the treatment of SNADETs. METHODS: We conducted a comprehensive literature search in PubMed, EMBASE, the Cochrane Library. Studies comparing CEMR and UEMR for the resection of SNADET were included. Outcomes included en-bloc and complete resection rates, adverse events, and procedure time. RESULTS: A total of six studies with 2454 lesions were included in the quantitative synthesis. En-bloc and complete resection rates were not significantly different between UEMR and CEMR (OR for en-bloc resection: 0.997 [95% CI 0.439-2.266]; OR for complete resection: 0.960 [95% CI 0.628-1.468]). There was no significant risk difference for perforation (risk difference: - 0.002; 95% CI - 0.009 to 0.005) or delayed bleeding (risk difference: - 0.001; 95% CI - 0.014 to 0.011). Procedure time was significantly shorter in the UEMR (standardized mean difference: - 1.294; 95% CI - 2.461 to - 0.127). The risk of recurrence was not significantly different between UEMR and CEMR (risk difference: 0.001; 95% CI - 0.041 to 0.044). CONCLUSION: Although our results did not show any superiority of UEMR over CEMR in the treatment of SNADETs, UEMR showed equivalent efficacy and safety as compared with CEMR and was associated with a shorter procedure time.

Indication, Location of the Lesion, Diagnostic Yield, and Therapeutic Yield of Double-Balloon Enteroscopy: Seventeen Years of Experience.

Double-balloon enteroscopy (DBE) has become one of the standard methods in the diagnosis and treatment of small bowel (SB) disease. However, previous studies for DBE have limitations due to heterogeneity of indications and operators. The aim was to investigate the indication, location of the lesion, diagnostic yield, and therapeutic yield of DBE based on long-term data from a single operator. A retrospective study was performed by reviewing medical records of subjects who had received DBE at our unit in the past 17 years. Overall diagnostic yield was 78.7% (210/267). The diagnostic yield for obscure gastrointestinal bleeding (OGIB) was 68.3% (84/123). The diagnostic yield for OGIB was significantly lower (p < 0.001) than that for other indications. Therapeutic yield was 24.7% (66/267). Complications occurred in 7 (2.6%). Crohn's disease, intestinal tuberculosis, nonsteroidal anti-inflammatory drug enteropathy, and diverticular lesions were mainly found in the ileum. Vascular lesions, non-specific inflammation, and neoplastic lesions were found more frequently in the jejunum. DBE is an excellent and safe endoscopic method for the diagnosis and treatment of SB lesions. DBE has a lower diagnostic rate for OGIB than for other indications. The location where a lesion is commonly found depends on the type of the lesion.

Bismuth-Based Quadruple Therapy versus Metronidazole-Intensified Triple Therapy as a First-Line Treatment for Clarithromycin-Resistant Helicobacter pylori Infection: A Multicenter Randomized Controlled Trial.

Background/Aims: Clarithromycin resistance is a main factor for treatment failure in the context of Helicobacter pylori infection. However, the treatment regimen for clarithromycin-resistant H. pylori infection has not yet been determined. We aimed to compare the efficacy and cost-effectiveness of 14-day bismuth-based quadruple therapy versus 14-day metronidazole-intensified triple therapy for clarithromycin-resistant H. pylori infection with genotypic resistance. Methods: This was a multicenter, randomized, controlled trial. A total of 782 patients with H. pylori infection examined using sequencing-based clarithromycin resistance point mutation tests were recruited between December 2018 and October 2020 in four institutions in Korea. Patients with significant point mutations (A2142G, A2142C, A2143G, A2143C, and A2144G) were randomly assigned to receive either 14-day bismuth-based quadruple therapy (n=102) or 14-day metronidazole-intensified triple therapy (n=99). Results: The overall genotypic clarithromycin resistance rate was 25.7% according to the sequencing method. The eradication rate of 14-day bismuth-based quadruple therapy was not significantly different in the intention-to-treat analysis (80.4% vs 69.7%, p=0.079), but was significantly higher than that of 14-day metronidazole-intensified triple therapy in the per-protocol analysis (95.1% vs 76.4%, p=0.001). There were no significant differences in the incidence of side effects. In addition, the 14-day bismuth-based quadruple therapy was more cost-effective than the 14-day metronidazole-intensified triple therapy. Conclusions: Fourteen-day bismuth-based quadruple therapy showed comparable efficacy with 14-day metronidazole-intensified triple therapy, and it was more cost-effective in the context of clarithromycin-resistant H. pylori infection.

Inter-observer variability of experts and trainees for the diagnosis of reflux esophagitis: Comparison of linked color imaging, blue laser imaging, and white light imaging.

OBJECTIVES: Diagnosis of reflux esophagitis according to the Los Angeles classification minimal change (LA-M) has a low inter-observer agreement. We aimed to investigate whether the inter-observer agreement of reflux esophagitis was better when expert endoscopists read the endoscopic images, or when the linked color imaging (LCI) or blue laser imaging (BLI)-bright mode was used. In addition, whether the inclusion of LA-M in the definition of reflux esophagitis affected the consistency of the diagnosis was investigated. METHODS: During upper endoscopy, endoscopic images of the gastroesophageal junction were taken using white light imaging (WLI), BLI-bright, and LCI modes. Four expert endoscopists and four trainees reviewed the images to diagnose reflux esophagitis according to the modified LA classification. RESULTS: The kappa values for the inter-observer variability for the diagnosis of reflux esophagitis were poor to fair among the experts (κ = â€Š0.22, 0.17, and 0.27 for WLI, BLI-bright, and LCI, respectively) and poor among the trainees (κ = â€Š0.18, 0.08, and 0.14 for WLI, BLI-bright, and LCI). The inter-observer variabilities for the diagnosis of reflux esophagitis excluding LA-M were fair to moderate (κ = â€Š0.42, 0.35, and 0.42 for WLI, BLI-bright, and LCI) among the expert endoscopists and moderate among the trainees (κ = 0.48, 0.43, and 0.51 for WLI, BLI-bright, and LCI). CONCLUSIONS: The inter-observer agreement for the diagnosis of reflux esophagitis was very low for both the expert endoscopists and the trainees, even using BLI-bright or LCI mode. However, when reflux esophagitis LA-M was excluded from the diagnosis of esophagitis, the degree of inter-observer agreement increased.

Atorvastatin Induces FXR and CYP7A1 Activation as a Result of the Sequential Action of PPARγ/PGC-1α/HNF-4α in Hep3B Cells.

Backgrounds/Aims: PPARγ, farnesoid X receptor (FXR) and CYP7A1 are associated with solubility of bile. This study was performed to understand a mechanism and interactions of statin-induced PPARγ, PGC-1α and HNF-4α related to the statin-induced activation of FXR and CYP7A1, and verify whether the mevalonate pathway is involved in the mechanism. Methods: MTT assays were performed using cultured human Hep3B cells to determine the effect of atorvastatin on the cell proliferation. Expression levels of indicated proteins were measured using Western blotting assays by inhibiting the protein expression or not. Results: Atorvastatin increased expression of PPARγ, PGC-1α, HNF-4α, FXR, and CYP7A1 in Hep3B cells. PPARγ ligand of troglitazone upregulated the expression of PGC-1α, HNF-4α, FXR, and CYP7A1 in Hep3B cells. Silencing of PPARγ, PGC1α, and HNF4α using respective siRNA demonstrated that atorvastatin-induced FXR and CYP7A1 activation required sequential action of PPARγ /PGC-1α/HNF-4α. The silencing of PPARγ completely inhibited atorvastatin-induced PGC-1α expression, and the PGC1α silencing partially inhibited atorvastatin-induced PPARγ expression. The inhibition of HNF4α did not affect atorvastatin-induced PPARγ expression, but partially inhibited atorvastatin-induced PGC-1α expression. Besides, mevalonate completely reversed the effect of atorvastatin on PPARγ, PGC-1α, HNF-4α, FXR, and CYP7A1. Conclusions: Atorvastatin induces FXR and CYP7A1 activation as a result of sequential action of PPARγ/PGC-1α/HNF-4α in human hepatocytes. We propose that atorvastatin enhances solubility of cholesterol in bile by simultaneously activating of FXR and CYP7A1.

Diagnostic Accuracy of Fecal Calprotectin for the Detection of Small Bowel Crohn's Disease through Capsule Endoscopy: An Updated Meta-Analysis and Systematic Review.

Background/Aims: The diagnosis of small bowel Crohn's disease with negative ileocolonoscopic findings has been challenging. Fecal calprotectin (FC) has been used to detect colonic inflammation, but its efficacy for detecting small bowel inflammation is less established. We performed an updated meta-analysis to evaluate the diagnostic accuracy of FC to detect active small bowel inflammation observed during capsule endoscopy. Methods: We conducted a systematic literature search for studies that evaluated the correlation between small bowel inflammation and FC in patients with suspected/established Crohn's disease. We calculated the pooled sensitivity, specificity, and diagnostic odds ratios (DORs) and constructed hierarchical summary receiver operating characteristic curves for FC cutoffs of 50, 100, and 200 µg/g. Results: Fourteen studies were eligible for the final analysis. The DORs of all FC cutoffs were significant. The highest DOR was observed at 100 µg/g (sensitivity, 0.73; specificity, 0.73; and DOR, 7.89) and was suggested as the optimal diagnostic cutoff. If we analyzed only studies that included patients with suspected Crohn's disease, the DOR was 8.96. If we analyzed only studies that included patients with a Lewis score ≥135 as a diagnostic criterion for active disease, the DOR was 10.90. Conclusions: FC has significant diagnostic accuracy for detecting small bowel inflammation, and an FC cutoff of 100 µg/g can be used as a tool to screen for small bowel Crohn's disease.

Effect of Nonsteroidal Anti-inflammatory Agents on Small Intestinal Injuries as Evaluated by Capsule Endoscopy.

BACKGROUND: Currently, because the population is aging, use of medications has been increasing, including use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antithrombotic agents. AIMS: This study aims to investigate whether NSAIDs can cause damage to the small bowel (SB) mucosa. METHODS: Endoscopic videos of subjects who had undergone capsule endoscopy (CE) were evaluated by three experts in order to identify SB injury. All medications taken within 2 weeks from the time of CE were investigated. Cases with a final diagnosis of intestinal tuberculosis, inflammatory bowel disease, Behcet's disease, Peutz-Jeghers syndrome, small bowel lymphoma, or Henoch-Schönlein purpura were excluded from the analysis. RESULTS: Among the 273 subjects, 125 (45.8%) had SB erosions or ulcers (erosion group) and the remaining 148 (54.2%) did not (no erosion group). SB erosions or ulcers were more common in females, patients aged > 60 years, and subjects taking NSAIDs (p = 0.048, 0.032, and < 0.001, respectively). No statistically significant differences were found between the two groups in the following variables: history of cancer and GI surgery, reasons for the test, comorbidities, and use of anticoagulants and antiplatelet agents. Multivariate analysis showed that use of NSAIDs [OR 4.191 (95% CI 1.858-9.458), p < 0.001] was an independent risk factor for SB erosions or ulcers. CONCLUSIONS: Use of NSAIDs is the only independent risk factor for SB injury identified in this study. Antithrombotic agents do not cause or exacerbate damage to the SB, according to our results. CLINICAL TRIAL REGISTRATION: KCT0004795.

The Protective Effect of 5-Aminosalicylic Acid Against Non-Steroidal Anti-Inflammatory Drug-Induced Injury Through Free Radical Scavenging in Small Intestinal Epithelial Cells.

Background and objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) have been among the major causes of small intestinal injury in clinical practice. As such, the current study investigated the protective effect of 5-aminosalicylic acid (5-ASA) against an NSAID-induced small intestinal injury. Materials and Methods: IEC-6 cells were treated with various concentrations of indomethacin with or without 5-ASA in a serum-free medium, after which an 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Dromide (MTT) assay, a cell apoptosis assay, a caspase-3 activity assay, a reactive oxygen species (ROS) content and Superoxide dismutase 2 (SOD2) activity measurement, a Western blotting for occludin and zonula occludens-1 (ZO-1) and a wound healing assay were conducted. Results: 5-ASA ameliorated indomethacin-induced cell apoptosis and an increase in the intracellular ROS content while augmenting the indomethacin-induced suppression of SOD2 activity in IEC-6 cells. Moreover, 5-ASA reversed the indomethacin-induced attenuation of occludin and ZO-1 expression and promoted faster wound healing effects in IEC-6 cells following an indomethacin-induced injury. Conclusion: Our results suggested that 5-ASA protects small intestinal cells against an NSAID-induced small intestinal injury by scavenging free radicals. Therefore, 5-ASA could be a potential treatment for an NSAID-induced small intestinal injury.

The role of linked color imaging in endoscopic diagnosis of Helicobacter pylori associated gastritis.

OBJECTIVE: Linked color imaging (LCI), a novel image-enhanced endoscopy, can make it easy to recognize differences in mucosal color. It may be helpful for diagnosing H. pylori associated gastritis and H. pylori infection status. We investigated whether LCI could improve the diagnostic accuracy of H. pylori associated gastritis. MATERIALS AND METHODS: Upper endoscopy was performed for 100 patients using white light imaging (WLI) and LCI. During the exam, endoscopic video was recorded. It was then analyzed by four expert endoscopists. They reviewed these videos for endoscopic diagnosis of atrophic gastritis, metaplastic gastritis, nodular gastritis and H. pylori infection. Tissue biopsies with rapid urease test were done to confirm H. pylori infection status and intestinal metaplasia. RESULTS: Kappa values for the inter-observer variability among the four endoscopists were fair to moderate under WLI and fair to good under LCI. Sensitivity, specificity, positive predictive value and negative predictive value for diagnosing H. pylori infection using WLI were 32.4%, 93.3%, 85.2% and 53.6%, respectively, while those for LCI were 57.4%, 91.3%, 88.7% and 64.3%, respectively. Total diagnostic accuracies for diagnosing H. pylori infection using WLI/LCI were 70.8%/78.8%. The accuracy and sensitivity of LCI for diagnosing H. pylori infection were significantly higher than those of WLI (p < .001 for both). However, there were no significant differences in the accuracy, sensitivity or specificity for diagnosing metaplastic gastritis between LCI and WLI. CONCLUSIONS: LCI has better diagnostic accuracy for H. pylori infection status than WLI. Clinical trial registration number: KCT0003674.

Metformin Induces Apoptosis and Inhibits Proliferation through the AMP-Activated Protein Kinase and Insulin-like Growth Factor 1 Receptor Pathways in the Bile Duct Cancer Cells.

Background/Aims: Metformin has been found to have antineoplastic activity in some cancer cells. This study was performed to determine whether metformin inhibits the proliferation of bile duct cancer cells by inducing apoptosis and its effects on the expression of gene-related proteins involved in cancer growth. Methods: Human extrahepatic bile duct cancer cells (SNU-245 and SNU-1196) were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were performed to determine the effect of metformin on the cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and a caspase-3 activity assay. Expression levels of various proteins, with or without specific small interfering ribonucleic acid-induced gene disruption, were measured by Western blot analysis. The migratory activity of the cancer cells was evaluated by wound healing assay. Results: Metformin suppressed cell proliferation in bile duct cancer cells by inducing apoptosis. Metformin inhibited mammalian target of rapamycin (mTOR) by activation of tuberous sclerosis complex 2 (TSC-2) through phosphorylation of adenosine monophosphate-activated protein kinase at threonine-172 (AMPKThr172). Hyperglycemia impaired metformin-induced AMPKThr172 activation and enhanced phosphorylation of AMPK at serine-485 (AMPKSer485). Metformin blocked the inhibitory effect of insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor substrate 1 (IRS-1) pathway on TSC-2, and hyperglycemia impaired metformin-induced inhibition of IGF-1R/IRS-1 pathway and modulated the invasiveness of bile duct cancer cells; however, this effect was impaired by hyperglycemia. Conclusions: Metformin has antineoplastic effects in bile duct cancer, and hyperglycemic environment interrupts the effect of metformin. In addition, AMPK and IGF-1R play a key role in the proliferation of bile duct cancer cells.

Effect of ilaprazole on the healing of endoscopic submucosal dissection-induced gastric ulcer: randomized-controlled, multicenter study.

BACKGROUND: The optimal treatment regimen or the duration of treatment for an endoscopic submucosal dissection (ESD)-induced gastric ulcer has not been established. The aim of this study was to assess the efficacy of novel proton-pump inhibitor, ilaprazole, for the treatment of ESD-induced gastric ulcer. METHODS: This was a prospective, open-label, randomized multicenter study. Between June 2015 and March 2018, a total of 176 patients (178 lesions) who underwent ESD for a gastric neoplasm were randomly allocated to receive the oral proton-pump inhibitor ilaprazole 20 mg or rabeprazole 20 mg daily for 8 weeks. The primary outcome was the ulcer healing rate at 4 and 8 weeks. RESULTS: A total of 155 (157 lesions) and 154 patients (156 lesions) were included in the modified intention-to-treat (mITT) and per-protocol analyses, respectively. There was no significant difference in the ulcer healing rate (ilaprazole vs. rabeprazole, 97.4% vs. 97.0 p = 0.78 at 4 weeks, 100% vs. 100%, p = 0.95 at 8 weeks in the mITT analysis) or stage of ulcer (scar stage, 25.6% vs. 17.7%, p = 0.25 at 4 weeks, 92.3% vs. 88.6%, p = 0.59 at 8 weeks in the mITT analysis) between the treatment groups. The quality of ulcer healing was not significantly different between the two groups. No independent predictive factor for higher-quality ulcer healing was found in the multivariate analysis. CONCLUSIONS: According to this trial, ilaprazole and rabeprazole showed no significant difference in the healing of artificial gastric ulcers. Most of the ulcers achieved complete healing within 4-8 weeks. TRIAL REGISTRATION: ClinicalTrial.gov NCT02638584.

Efficacy and safety of etomidate-based sedation compared with propofol-based sedation during ERCP in low-risk patients: a double-blind, randomized, noninferiority trial.

BACKGROUND AND AIMS: Etomidate is a short-acting intravenous hypnotic with a safety profile that is superior to alternative drugs such as propofol. However, there is a lack of evidence on the safety of etomidate in ERCP. The objective of this study was to compare efficacy and safety profiles of etomidate and propofol for endoscopic sedation. METHODS: This single-center, randomized, double-blind, noninferiority trial included patients with American Society of Anesthesiologists (ASA) physical status I to II who had been scheduled for ERCP. All patients received .05 mg/kg midazolam intravenously as pretreatment before receiving etomidate or propofol. Either etomidate or propofol was then administered according to group allocation. The primary endpoint was an overall respiratory event. A noninferiority margin of 10% was assumed. RESULTS: Sixty-three and 64 patients were enrolled in the etomidate and propofol groups, respectively. Respiratory events were identified in 10 patients (15.6%) in the etomidate group and 16 patients (25.4%) on the propofol group, with a rate difference of -9.8% (1-sided 97.5% confidence interval, -∞ to 4.2%). The overall incidence of cardiovascular events tended to be higher in the etomidate group (67.2% vs 50.8%, P = .060). In particular, tachycardia (heart rate > 100 beats/min) was more common in the etomidate group than in the propofol group (64.1% vs 34.9%, P = .001). Transient hypotension tended to be less common in the etomidate group (6.3 vs 15.9%, P = .084). CONCLUSIONS: Etomidate-based sedation during ERCP was noninferior to propofol-based sedation in terms of the overall incidence of respiratory events in patients with ASA physical status I to II. (International Clinical Trials Registry Platform number: KCT0001926.).

Safety and efficacy of early feeding based on clinical assessment at 4 hours after ERCP: a prospective randomized controlled trial.

BACKGROUND AND AIMS: The optimal timing of refeeding after ERCP is unknown. Some practices keep the patient fasting for 24 hours after ERCP, whereas others resume feeding earlier. We aimed to evaluate the risk of post-ERCP pancreatitis (PEP) in patients who initiate early feeding, based on their clinical assessment, including serum amylase testing performed at 4 hours after ERCP. METHODS: Patients who were scheduled for ERCP were recruited. Patients without abdominal pain and tenderness and a serum amylase level within 1.5-fold the upper limit of normal at 4 hours after ERCP were randomly assigned to either the 4-hour fasting or 24-hour fasting group. Patients from the 4-hour fasting group started oral intake 4 hours after ERCP, whereas those from the 24-hour fasting group fasted for 24 hours after ERCP. RESULTS: Among the 276 enrolled, PEP was identified in 3 (2.2%) from the 4-hour fasting group and in 5 (3.6%) from the 24-hour fasting group, with a rate difference of -1.4% (1-sided 97.5% confidence interval, -∞ to 2.5%). Four-hour fasting was non-inferior to 24-hour fasting in terms of PEP incidence. The total medical costs for treatment-related ERCP were significantly lower in the 4-hour fasting group than in the 24-hour fasting group (1157.20 ± 311.90 vs 1311.20 ± 410.70 U.S. dollars; P = .032). CONCLUSION: Early feeding in patients without abdominal pain and tenderness and a serum amylase level <1.5-fold the upper limit of normal at 4 hours after ERCP does not increase the incidence of PEP after ERCP and decreases medical costs. (Clinical trial registration number: KCT0002354.).

Etomidate versus propofol sedation for complex upper endoscopic procedures: a prospective double-blinded randomized controlled trial.

BACKGROUND AND AIMS: Although a growing body of evidence demonstrates that propofol-induced deep sedation can be effective and performed safely, cardiopulmonary adverse events have been observed frequently. Etomidate is a new emerging drug that provides hemodynamic and respiratory stability, even in high-risk patient groups. The objective of this study was to compare safety and efficacy profiles of etomidate and propofol for endoscopic sedation. METHODS: A total of 128 patients undergoing EUS were randomized to receive either etomidate or propofol blinded administered by a registered nurse. The primary outcome was the proportion of patients with any cardiopulmonary adverse events. RESULTS: Overall cardiopulmonary adverse events were identified in 22 patients (34.38%) of the etomidate group and 33 patients (51.56%) of the propofol group, without significant difference (P = .074). However, the incidence of oxygen desaturation (4/64 [6.25%] vs 20/64 [31.25%]; P =.001) and respiratory depression (5/64 [7.81%] vs 21/64 [32.81%]; P =.001) was significantly lower in the etomidate group than in the propofol group. The frequency of myoclonus was significantly higher in the etomidate group (22/64 [34.37%]) compared with the propofol group (8/64 [12.50%]) (P =.012). Repeated measure analysis of variance revealed significant effects of sedation group and time on systolic blood pressure (etomidate group greater than propofol group). Physician satisfaction was greater in the etomidate group than in the propofol group. CONCLUSIONS: Etomidate administration resulted in fewer respiratory depression events and had a better sedative efficacy than propofol; however, it was more frequently associated with myoclonus and increased blood pressure during endoscopic procedures. (Clinical trial registration number: KCT0001701.).

Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer.

Statin has been known not only as their cholesterol-lowering action but also on their pleiotropic effects including anti-inflammatory and anti-oxidant as well as anti-cancer effect. Nrf2 (NF-E2-related factor 2) is a transcription factor to activate cellular antioxidant response to oxidative stress. There are little known whether statins affect activation of Nrf2 and Nrf2 signaling pathway in colon cancer cells. We investigated whether simvastatin stimulates the expression of Nrf2 and nuclear translocation of Nrf2 and which signal pathway is involved in the expression of Nrf2 and antioxidant enzymes. We investigated the effect of simvastatin on the expression of Nrf2 and nuclear translocation of Nrf2 in two human colon cancer cell lines, HT-29 and HCT 116 through cell proliferation assay, Western blotting and immunocytochemical analysis. We evaluated which signal pathway such as ERK or PI3K pathway affect Nrf2 activation and whether simvastatin induces antioxidant enzymes (heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1), γ-glutamate-cysteine ligase catalytic subunit (GCLC)). We demonstrated simvastatin-induced dose-dependent up-regulation of Nrf2 expression and stimulated Nrf2 nuclear translocation in colon cancer cells. We also demonstrated that simvastatin-induced anti-oxidant enzymes (HO-1, NQO1, and GCLC) in HT-29 and HCT 116 cells. PI3K/Akt inhibitor (LY294002) and ERK inhibitor (PD98059) suppressed simvastatin-induced Nrf2 and HO-1 expression in both HT-29 and HCT 116 cells. This study shows that simvastatin induces the activation and nuclear translocation of Nrf2 and the expression of various anti-oxidant enzymes via ERK and PI3K/Akt pathway in colon cancer cells.

Statin induces apoptosis of human colon cancer cells and downregulation of insulin-like growth factor 1 receptor via proapoptotic ERK activation.

Insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) signaling plays an important role in tumor progression in patients with certain gastrointestinal tract cancers. In addition to lowering cholesterol in serum, statins have pleiotropic effects, including anti-oxidative, anti-inflammatory or anti-neoplastic effects. Therefore, the present study investigated whether statins could induce the apoptosis of colon cancer cells and regulate the expression of IGF-1R and its associated signaling pathways in the present study. It was demonstrated that simvastatin and pravastatin suppressed cell proliferation and induced cell death in human HT-29 cells, but simvastatin was more potent than pravastatin. Simvastatin induced apoptosis in a concentration-dependent manner. In addition, simvastatin suppressed the expression of IGF-1R and inhibited the activity of phosphorylated-extracellular signal-regulated kinase (ERK)1/2 and phosphorylated-Akt activated by IGF-1. Simvastatin and IGF-1 each stimulated the activity of phosphorylated ERK1/2. However, simvastatin inhibited cell proliferation and IGF-1 stimulated cell proliferation. Mevalonic acid and PD98059 reversed the ERK activation and apoptosis induced by treatment with simvastatin. It was concluded that simvastatin induces the apoptosis of human colon cancer cells and inhibits IGF-1-induced ERK and Akt expression via the downregulation of IGF-1R expression and proapoptotic ERK activation. Simvastatin may be beneficial for the treatment of colon cancer. The present study suggested that statin may possess therapeutic potential for the treatment of colon cancer.

Meta-Analysis for Cyto-Pathological Outcomes in Endoscopic Ultrasonography-Guided Fine-Needle Aspiration With and Without the Stylet.

BACKGROUND: Theoretically, use of the stylet during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) will prevent the tip of the needle from being blocked and the sample from being contaminated, improving the quality and diagnostic yield of specimens. AIM: This meta-analysis aimed to evaluate any benefit from the use of a stylet during EUS-FNA. METHODS: MEDLINE, EMBASE, WEB of SCIENCE, and the Cochrane Central Register of Controlled Trials were searched for articles published through October 2015. A fixed-effects model was used to calculate the pooled effects when there is no heterogeneity and a random-effects model was used in situations with significant heterogeneity. RESULTS: Five prospective randomized controlled studies and two retrospective studies of a total of 5491 specimens (2504 specimens in the S+ group and 2987 specimens in the S- group) were included in this study. The pooled analysis demonstrated no significant differences in the adequate sample rate between the S+ group (2135/2504, 85.26 %) and S- group (2609/2987, 87.35 %) [odds ratio 0.94 (95 % confidence interval 0.79-1.11), p = 0.45]. Furthermore, the rate of cellularity > 50 %, the contamination rate, and the blood contamination rate were not significantly superior in the S+ group when compared with the S- group. CONCLUSIONS: Whether the use of a stylet improves the proportion of adequate specimens or quality of the specimen is questionable. Our results suggest that the use of a stylet dose not guarantee any advantage during EUS-guided tissue sampling.

Synergistic Effects of Simvastatin and Irinotecan against Colon Cancer Cells with or without Irinotecan Resistance.

Aims. We here investigated whether the combination of simvastatin and irinotecan could induce the synergistic effect on colon cancer cells with or without resistance to irinotecan. Methods. We investigated cell proliferation assay and assessed cell death detection ELISA and caspase-3 activity assay of various concentrations of simvastatin and irinotecan to evaluate the efficacy of drug combination on colon cancer cells with or without irinotecan resistance. Results. The IC50 values of simvastatin alone and irinotecan alone were 115.4 ± 0.14 µM (r = 0.98) and 62.5 ± 0.18 µM (r = 0.98) in HT-29 cells without resistance to irinotecan. The IC50 values of these two drugs were 221.9 ± 0.22 µM (r = 0.98) and 195.9 ± 0.16 µM (r = 0.99), respectively, in HT-29 cell with resistance to irinotecan. The results of combinations of the various concentrations of two drugs showed that combined treatment with irinotecan and simvastatin more efficiently suppressed cell proliferation of HT-29 cells even with resistance to irinotecan as well as without resistance. Furthermore, the combination of simvastatin and irinotecan at 2 : 1 molar ratio showed the best synergistic interaction. Conclusion. Simvastatin could act synergistically with irinotecan to overcome irinotecan resistance of colon cancer.

Simvastatin Induces Apoptosis and Suppresses Insulin-Like Growth Factor 1 Receptor in Bile Duct Cancer Cells.

BACKGROUND/AIMS: Statins act as antineoplastic agents through the inhibition of cell proliferation. This study sought to demonstrate the effects of statins on extrahepatic bile duct cancer cell apoptosis and to document the changes in protein expression involved in tumor growth and suppression. METHODS: Human extrahepatic bile duct cancer cells were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of statins on cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and caspase-3 activity assay, and flow cytometry was used to determine the percentage of cells in each phase of the cell cycle. The protein expression of Bax, Bcl-2, insulin-like growth factor 1 (IGF-1) receptor, extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt was measured by Western blot analysis. RESULTS: Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation. CONCLUSIONS: Simvastatin induces apoptosis in bile duct cancer cells, which suggests that it could be an antineoplastic agent for bile duct cancer.