Feasibility of endoscopic submucosal dissection for cecal tumors involving the ileocecal valve or appendiceal orifice.

BACKGROUND AND AIM: Endoscopic resection of the ileocecal valve lesions (ICVL) and peri-appendiceal orifice lesions (PAOL), is challenging. This study aimed to evaluate the feasibility of endoscopic submucosal dissection (ESD) for ICVLs and PAOLs compared with other cecal lesions (OCEL). METHODS: This was a multicenter, retrospective cohort study conducted at a cancer center hospital and two community hospitals. Non-pedunculated cecal lesions that were intended to be treated by ESD followed by at least one surveillance colonoscopy were included. The main outcome was curative resection defined as en-bloc resection and R0 resection without risk factors of metastases. The secondary outcome was co lon preservation. RESULTS: A total of 206 patients with 206 cecal lesions, including 37 ICVL, 27 PAOL, and 142 OCEL, who were to be treated with ESD were included in this study. Curative resection rates were 75.7% for ICVL, 70.4% for PAOL, and 77.5% for OCEL (P = 0.67). In the multivariate analysis of predictors of curative resection, tumor size (<40 mm) (odds ratio [OR] 2.40; 95% confidence intervals [CI], 1.14-5.04; P = 0.02) and a negative non-lifting sign (OR 6.12; 95% CI, 2.55-14.60; P < 0.01) were significant. Colon preservation was achieved for 91.9% of the ICVL, 92.6% of the PAOL, and 90.8% of the OCEL (P = 0.947). CONCLUSIONS: Based on curative resection and colon preservation rates, ESD was found to be feasible for ICVL and PAOL. Large tumor size (≥ 40 mm) and positive non-lifting signs were significant factors for non-curative resection.

Safety and efficacy of endoscopic submucosal dissection of rectal tumors extending to the dentate line.

BACKGROUND AND STUDY AIMS: Unique anatomical features render endoscopic resection for rectal tumors extending to the dentate line (RTDL) technically challenging. The aim of this study was to evaluate the feasibility of endoscopic submucosal dissection (ESD) for RTDLs. PATIENTS AND METHODS: This retrospective study compared ESD for RTDLs with proximal rectal tumors between September 2002 and June 2012. En bloc resection rate, R0 resection rate, complications, and tumor recurrences were assessed. RESULTS: A total of 45 RTDLs (median age 69 years; 15 males; median lesion size 38.4 mm) and 94 proximal rectal tumors were identified. En bloc resection and R0 resection rates were 95.6 % (43/45) and 53.3 % (24/45), respectively. The perforation rate was 4.4 %. Compared with proximal rectal ESD, ESD for RTDLs showed longer procedure time (104 vs. 60 minutes; P < 0.001), lower R0 resection rate (53.3 % vs. 70.2 %; P = 0.019), and more frequent high grade fever (22.2 % vs. 4.3 %; P = 0.002). No residual adenoma was observed at the first surveillance colonoscopy. Recurrence rate did not differ significantly between the two groups. CONCLUSIONS: ESD for RTDLs demonstrated safety and effectiveness comparable to ESD in proximal rectal lesions.

Irritant-induced cyclooxygenase-2 is involved in the defense mechanism of the gastric mucosa in mice.

BACKGROUND: Endogenous and exogenous prostaglandins (PGs) have been shown to contribute to reducing the gastric injury caused by irritants given subsequently. The aim of this study was to clarify whether cyclooxygenase-2 (COX-2) protein induced by pretreatment was involved in the prevention of subsequent ethanol-caused gastric injury in mice. METHODS: Mice were pretreated with acidified ethanol or saline and then COX-2 protein expression in the stomach was immunohistochemically determined every 8h. Mice were administered 95% ethanol 24h after the acidified ethanol pretreatment, and gastric mucosal damage was evaluated macroscopically and histologically. The effects of NS-398 or indomethacin on the 95% ethanol-caused damage were also examined. RESULTS: Acidified ethanol pretreatment induced COX-2 protein expression in lamina propria macrophages of the gastric mucosa, with a peak level 24h after the pretreatment. The 95% ethanol treatment caused gastric mucosal damage. The degree of the damage was not different between mice pretreated with acidified ethanol and those pretreated with saline. However, NS-398 aggravated the ethanol-caused damage only in mice pretreated with acidified ethanol, while indomethacin aggravated the damage, evaluated histologically, irrespective of the pretreatment. CONCLUSIONS: Pretreatment-induced COX-2, in addition to COX-1, seemed to be involved in the defense mechanism through minimizing the damage caused by a subsequent irritant.

Tomoregulin ectodomain shedding by proinflammatory cytokines.

The shedding mechanism for the tomoregulin (TR) ectodomain, which contains two follistatin modules and a single epidermal growth factor (EGF)-like domain, remains unclear. Our study provides the first evidence that proinflammatory cytokines, IL-1beta and TNF-alpha, induce TR-ectodomain shedding in cultured A172 human glioma cells, without affecting TR mRNA expression. In addition, it appears that this shedding process is induced via activation of the NF-kappaB signaling pathway; with consequent increase in the production of metalloproteinases. Furthermore, since due to erbB4 tyrosine phosphorylation TR may have functions similar to EGF/neuregulin (NRG) family growth factors, our results suggest that following inflammation-induced injury, increases in TR shedding may contribute to tissue growth and repair in the central nervous system.

Induced microsomal PGE synthase-1 is involved in cyclooxygenase-2-dependent PGE2 production in gastric fibroblasts.

We have previously shown that the cyclooxygenase (COX)-2/PGE2 pathway plays a key role in VEGF production in gastric fibroblasts. Recent studies have identified three PGE synthase (PGES) isozymes: cytosolic PGES (cPGES) and microsomal PGES (mPGES)-1 and -2, but little is known regarding the expression and roles of these enzymes in gastric fibroblasts. Thus we examined IL-1beta-stimulated mPGES-1 and cPGES mRNA and protein expression in gastric fibroblasts by quantitative PCR and Western blot analysis, respectively, and studied both their relationship to COX-1 and -2 and their roles in PGE2 and VEGF production in vitro. IL-1beta stimulated increases in both COX-2 and mPGES-1 mRNA and protein expression levels. However, COX-2 mRNA and protein expression were more rapidly induced than mPGES-1 mRNA and protein expression. Furthermore, MK-886, a nonselective mPGES-1 inhibitor, failed to inhibit IL-1beta-induced PGE2 release at the 8-h time point, while totally inhibiting PGE2 at the later stage. However, MK-886 did inhibit IL-1beta-stimulated PGES activity in vitro by 86.8%. N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398), a selective COX-2 inhibitor, totally inhibited PGE2 production at both the 8-h and 24-h time points, suggesting that COX-2-dependent PGE2 generation does not depend on mPGES-1 activity at the early stage. In contrast, NS-398 did not inhibit VEGF production at 8 h, and only partially at 24 h, whereas MK-886 totally inhibited VEGF production at each time point. These results suggest that IL-1beta-induced mPGES-1 protein expression preferentially coupled with COX-2 protein at late stages of PGE2 production and that IL-1beta-stimulated VEGF production was totally dependent on membrane-associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) superfamily proteins, which includes mPGES-1, but was partially dependent on the COX-2/PGE2 pathway.

COX-1 and COX-2 conversely promote and suppress ischemia-reperfusion gastric injury in mice.

OBJECTIVE: Neutrophil activation followed by free radical production is a feature that is common to the various forms of gastric injury. However, the roles of cyclooxygenase (COX)-1 and -2 in neutrophil activation have yet to be clarified in the gastric mucosa. We examined the roles of both COX-1 and COX-2 in neutrophil activation and free radical production in ischemia-reperfusion (IR) injury in the gastric mucosa of mice. MATERIAL AND METHODS: Ischemia was induced by clamping the celiac artery for 30 min, then removing the clamp for 90 min. SC-560, a selective COX-1 inhibitor; NS-398, a selective COX-2 inhibitor; or rebamipide, a mucoprotective agent, was administered to mice 60 min before ischemia. Gastric damage was evaluated histologically and by measuring myeloperoxidase (MPO) activity. Expressions of COX protein and intercellular adhesion molecule (ICAM)-1 were evaluated by Western blot analysis and ELISA, respectively. Effects of these drugs on thiobarbituric acid reactive substances (TBARS) and gastric blood flow were also evaluated. RESULTS: COX-2 expression was induced in gastric mucosa 60 min after reperfusion, whereas COX-1 expression remained unaltered. Localization of COX-1 and ICAM-1 in IR-injured mucosa was observed mainly in endothelial cells, while COX-2 expression was detected in mesenchymal cells such as mononuclear cells, spindle-like cells and endothelial cells. SC-560 significantly decreased gastric blood flow at the reperfusion point and reduced gastric mucosal injury in IR mice. Furthermore, SC-560 pretreatment significantly reduced MPO activity, TBARS levels and ICAM-1 expression. In contrast, NS-398 significantly increased ICAM-1 expression, MPO activity and TBARS levels, and aggravated gastric damage in IR mice. Rebamipide pretreatment reduced both COX-2 expression and IR injury. CONCLUSIONS: In IR mice, COX-2 protects the gastric mucosa by down-regulating ICAM-1 expression, whereas COX-1 is involved in up-regulating reperfusion flow, thereby aggravating the mucosa.

Rebamipide reduces indomethacin-induced gastric injury in mice via down-regulation of ICAM-1 expression.

Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric mucosal injury occurs through subsequent events following free radical production derived from activated neutrophils. In this study, we hypothesized that rebamipide, a novel anti-ulcer agent, exerts a protective effect on NSAID-induced gastric injury through its antioxidant properties. The protective effect of rebamipide in a mouse model of indomethacin-induced gastric injury and mechanisms for this effect were investigated. Pre-treatment with rebamipide significantly inhibited indomethacin-induced gastric mucosal injury in mice. Gastric thiobarbituric acid reactive substances (TBARS) levels and myeloperoxidase (MPO) activity substantially increased 3 hr after indomethacin administration. These increases were significantly inhibited by pre-treatment with rebamipide. Furthermore, rebamipide pre-treatment notably decreased intercellular adhesion molecule-1 (ICAM-1) expression that was up-regulated in gastric tissue treated with indomethacin. Therefore, rebamipide may reduce indomethacin-induced gastric mucosal injuries through its antioxidant effect, which inhibits the neutrophil activation step following up-regulation of ICAM-1 expression on endothelial cells.

Teprenone, but not H2-receptor blocker or sucralfate, suppresses corpus Helicobacter pylori colonization and gastritis in humans: teprenone inhibition of H. pylori-induced interleukin-8 in MKN28 gastric epithelial cell lines.

BACKGROUND: The role of teprenone in Helicobacter pylori-associated gastritis has yet to be determined. To investigate the effect of teprenone on inflammatory cell infiltration, and on H. pylori colonization of the gastric mucosa in H. pylori-infected patients, we first compared the effect of teprenone with that of both histamine H2 receptor antagonists (H2-RA) and sucralfate on the histological scores of H. pylori gastritis. We then examined its in vitro effect on H. pylori-induced interleukin (IL)-8 production in MKN28 gastric epithelial cells. MATERIALS AND METHODS: A total of 68 patients were divided into three groups, each group undergoing a 3-month treatment with either teprenone (150 mg/day), H2-RA (nizatidine, 300 mg/day), or sucralfate (3 g/day). All subjects underwent endoscopic examination of the stomach before and after treatment. IL-8 production in MKN28 gastric epithelial cells was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Following treatment, the teprenone group showed a significant decrease in both neutrophil infiltration and H. pylori density of the corpus (before vs. after: 2.49 +/- 0.22 vs. 2.15 +/- 0.23, p =.009; 2.36 +/- 0.25 vs. 2.00 +/- 0.24, p =.035, respectively), with no significant differences seen in either the sucralfate or H2-RA groups. Teprenone inhibited H. pylori-enhanced IL-8 production in MKN28 gastric epithelial cells in vitro, in a dose-dependent manner. CONCLUSIONS: Teprenone may modify corpus H. pylori-associated gastritis through its effect on neutrophil infiltration and H. pylori density, in part by its inhibition of IL-8 production in the gastric mucosa.