Hisatsugu Noda

G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells.

Background:Short-chain fatty acids (SCFAs), which are produced by the fermentation of dietary fiber by intestinal microbiota, may positively influence immune responses and protect against gut inflammation. SCFAs bind to G protein-coupled receptor 43 (GPR43). Here, we show that SCFA–GPR43 interactions profoundly affect the gut inflammatory response. Methods:Colitis was induced by adding dextran sulfate sodium to the drinking water of GPR43 knockout (−/−) and wild-type mice. Results:Dextran sulfate sodium–treated GPR43−/− mice exhibited weight loss, increased disease activity index (a combined measure of weight loss, rectal bleeding, and stool consistency), decreased hematocrit, and colon shortening, resulting in significantly worse colonic inflammation than in wild-type mice. Tumor necrosis factor alpha and interleukin 17 protein levels in the colonic mucosa of GPR43−/− mice were significantly higher than in wild-type mice. Treatment of wild-type mice with 150 mM acetate in their drinking water markedly improved these disease indices, with an increase in colon length and decrease in the disease activity index; however, it had no effect on GPR43−/− mice. Mononuclear cell production of tumor necrosis factor alpha after lipopolysaccharide stimulation was suppressed by acetate. This effect was inhibited by anti-GPR43 antibody. Conclusions:SCFA–GPR43 interactions modulate colitis by regulating inflammatory cytokine production in mononuclear cells.

Predictive Factors for Intractability to Endoscopic Hemostasis in the Treatment of Bleeding Gastroduodenal Peptic Ulcers in Japanese Patients

Background/Aims Despite improvements in endoscopic hemostasis and pharmacological therapies, upper gastrointestinal (UGI) ulcers repeatedly bleed in 10% to 20% of patients, and those without early endoscopic reintervention or definitive surgery might be at a high risk for mortality. This study aimed to identify the risk factors for intractability to initial endoscopic hemostasis. Methods We analyzed intractability among 428 patients who underwent emergency endoscopy for bleeding UGI ulcers within 24 hours of arrival at the hospital. Results Durable hemostasis was achieved in 354 patients by using initial endoscopic procedures. Sixty-nine patients with Forrest types Ia, Ib, IIa, and IIb at the second-look endoscopy were considered intractable to the initial endoscopic hemostasis. Multivariate analysis indicated that age ≥70 years (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.07 to 4.03), shock on admission (OR, 5.26; 95% CI, 2.43 to 11.6), hemoglobin <8.0 mg/dL (OR, 2.80; 95% CI, 1.39 to 5.91), serum albumin <3.3 g/dL (OR, 2.23; 95% CI, 1.07 to 4.89), exposed vessels with a diameter of ≥2 mm on the bottom of ulcers (OR, 4.38; 95% CI, 1.25 to 7.01), and Forrest type Ia and Ib (OR, 2.21; 95% CI, 1.33 to 3.00) predicted intractable endoscopic hemostasis. Conclusions Various factors contribute to intractable endoscopic hemostasis. Careful observation after endoscopic hemostasis is important for patients at a high risk for incomplete hemostasis.

Gastric calcifying fibrous tumor removed by endoscopic submucosal dissection.

The World Health Organization describes calcifying fibrous tumors (CFTs) as rare, benign lesions characterized by hypocellular, densely hyalinized collagenization with lymphoplasmacytic infiltration. These tumors rarely involve the gastrointestinal (GI) tract. A routine endoscopic upper gastrointestinal screen detected a 10-mm submucosal tumor (SMT) in the lesser curvature of the lower corpus of the stomach of an apparently healthy, 37-year-old woman with no history of Helicobacter pylori infection. Endoscopic ultrasonography (EUS) localized the internally isoechoic, homogeneous SMT mainly within the submucosa. Malignancy was ruled out using endoscopic submucosal dissection (ESD). A pathological examination confirmed complete resection of the SMT, and defined a hypocellular, spindle-cell tumor with a densely hyalinized, collagenous matrix, scattered lymphoplasmacytic aggregates as well as a few psammomatous, dystrophic calcified foci. The mass was immunohistochemically positive for vimentin and negative for CD117 (c-kit protein), CD34, desmin, smooth muscle actin (SMA) and S100. Therefore, the histological findings were characteristic of a CFT. To date, CFT resection by ESD has not been described. This is the first case report of a gastric calcifying fibrous tumor being completely resected by ESD after endoscopic ultrasonography.

Nonsteroidal anti-inflammatory drug-induced visible and invisible small intestinal injury

Permeation of the small intestinal mucosa is a key mechanism in the induction of enteropathy. We investigated the effect of rebamipide in healthy subjects with diclofenac-induced small intestinal damage and permeability. In this crossover study, each treatment period was 1 week with a 4-week washout period. Diclofenac (75 mg/day) and omeprazole (20 mg/day) plus rebamipide (300 mg/day) or placebo were administered. Capsule endoscopy and a sugar permeability test were performed on days 1 and 7 in each period. Ten healthy subjects were enrolled. Small intestinal injuries were observed on day 7 in 6 of 10 subjects in both groups. Urinary excretion of administered lactulose increased from 0.30% to 0.50% of the initial dose during the first treatment period in the placebo group, and from 0.13% to 0.33% in the rebamipide group. Despite recovery from small-intestinal mucosal damage, the increased permeability in both groups resulted in sustained high levels of lactulose (0.50% to 1.06% in the placebo group and 0.33% to 1.12% in the rebamipide group) through the 4-week washout period. Diclofenac administration induced enteropathy and hyperpermeability of the small intestine. The sustained hyperpermeability during the washout period may indicate the presence of invisible fragility.

Serum-Derived Hyaluronan-Associated Protein Is a Novel Biomarker for Inflammatory Bowel Diseases

Background/Aims: We evaluated the role of serum-derived hyaluronan-associated protein (SHAP) in inflammatory bowel disease (IBD) pathogenesis and its potential as a novel IBD biomarker. Methods: We studied the SHAP expression in a mouse model of colitis and in human intestinal samples of IBD and compared serum concentrations with normal controls. Results: SHAP was expressed in the connective tissue derived from inflamed regions of the intestine. In mice, serum levels of SHAP-hyaluronic acid (SHAP-HA) were positively correlated with the histological damage of the colon (r = 0.566, p < 0.001). Serum concentration of SHAP-HA complex was significantly higher in patients with active ulcerative colitis than in those in remission, and this value was positively correlated with the erythrocyte sedimentation rate, serum level of tumor necrosis factor (TNF)-α, and endoscopic damage (r = 0.568, p < 0.001; r = 0.521, p < 0.001, and r = 0.641, p < 0.001). In patients with Crohns disease, the serum SHAP-HA level correlated only with TNF-α (r = 0.630, p = 0.002). Conclusion: SHAP is a novel IBD biomarker that is related to disease activity in certain types of colitis, and it may affect disease pathogenesis. Future studies are needed to evaluate the therapeutic potential of this complex.

Risk factors for bleeding evaluated using the Forrest classification in Japanese patients after endoscopic submucosal dissection for early gastric neoplasm.

Background/aims Bleeding remains a serious complication after endoscopic submucosal dissection (ESD). Second-look endoscopy for hemostasis helps prevent post-ESD bleeding. We investigated the relationships between patient characteristics, tumor characteristics, and the Forrest classification for exposed vessels on artificial ulcers after ESD and evaluated whether hemostasis during second-look endoscopy was useful for preventing post-ESD bleeding. Patients and methods We analyzed 250 patients (265 lesions) who underwent ESD for gastric neoplasms. Vessels classified by Forrest classifications during scheduled second-look endoscopy were analyzed for associations with patient characteristics, tumor characteristics, and recurrent bleeding. Results Two of 250 patients (0.8%) underwent emergency hemostatic endoscopy before scheduled second-look endoscopy. The remaining 248 patients (99.2%) underwent scheduled second-look endoscopy on the day after ESD. Patients with Forrest classification Ia, Ib, or IIa vessels had a significantly higher risk for recurrent bleeding after scheduled second-look endoscopy compared with patients with IIb or III vessels according to univariate analysis (P<0.05) and multivariate logistic regression analysis (odds ratio: 3.45; 95% confidence interval: 1.04–11.41; P=0.042). Univariate analysis indicated that hemodialysis correlated significantly with the presence of Ia, Ib, or IIa vessels compared with that of IIb or III vessels found during second-look endoscopy (P<0.05). Multivariate analysis indicated a significant relationship between hemodialysis and recurrent bleeding after second-look endoscopy (odds ratio: 10.05; 95% confidence interval: 1.97–51.26; P=0.006). Conclusion Hemodialysis is a risk factor for post-ESD bleeding. Proper classification of exposed vessels within post-ESD ulcers according to the Forrest classification using second-look endoscopy might help predict or prevent recurrent bleeding.

The Influence of Snare Size on the Utility and Safety of Cold Snare Polypectomy for the Removal of Colonic Polyps in Japanese Patients

Background Cold snare polypectomy (CSP) has been recently reported to be useful for the removal of small colonic polyps. However, the relationship between the histologically complete resection rate and snare size used during CSP has not been reported. Our aim was to assess the utility of CSP. Methods We analyzed the histologically complete resection rates and the frequency of complications for 175 colon polyps removed by CSP. Moreover, we examined the histologically complete resection rate associated with different snare sizes used during CSP. Results There was no significant difference in the histologically complete resection rate between endoscopic mucosal resection (EMR) (60.9%) and CSP (53.1%). There were also no significant differences in the frequency of complications including perforation and postoperative bleeding between EMR (perforation: none; postoperative bleeding: two patients) and CSP (perforation: none; postoperative bleeding: none). Histological examination revealed that the complete resection rate of CSP using a short snare (61.6%) was significantly higher than that of CSP using a long snare (44.9%; P < 0.05). There were no significant differences in the frequency of complications between CSP using the short snare and that using the long snare. Conclusions CSP is a safe, useful method for the removal of colonic polyps. CSP using the short snare improved the histologically complete resection rates compared to the long snare. Future studies to further assess the utility of CSP are required.

Thread-Traction with a Sheath of Polypectomy Snare Facilitates Endoscopic Submucosal Dissection of Early Gastric Cancers

Although the thread-traction (TT) method has been found useful during endoscopic submucosal dissection (ESD) for early gastric cancers, the movement of the thread interferes with the movement of the endoscope, and the lesion can only be pulled to the mouth side. We have developed the novel TT method using a sheath of polypectomy snare (TTSPS). The TTSPS method enables free and independent movement of the thread and the endoscope and allows pulling the lesion towards the anal as well as oral side. The median dissection times, numbers of instances of arterial bleeding, and numbers of local injections into the submucosal layer were significantly lower for ESD with TTSPS than for conventional ESD. Countertraction ESD using the TTSPS method is straightforward, safe, easy, noninvasive, and cost effective, and it uses instruments readily available in most hospitals to enhance visualization of cutting lines. Therefore, the TTSPS method can be universally applied in conventional ESD.

Clinical risk factors for delayed bleeding after endoscopic submucosal dissection for colorectal tumors in Japanese patients.

Background Endoscopic submucosal dissection (ESD) is a curative, standard therapy for colorectal neoplasms. Some studies have investigated the risk factors for perforation during colorectal ESD. However, few studies have assessed the risk factors for delayed bleeding after colorectal ESD. We studied patients undergoing ESD for colorectal epithelial neoplasms to identify the risk factors for post-ESD bleeding. Patients and methods We studied 124 consecutive patients undergoing ESD for colorectal epithelial neoplasms. To identify risk factors for delayed bleeding post-ESD, recurrent bleeding post-ESD was compared with patient-related and tumor-related factors. Results Delayed bleeding after ESD occurred in 10 (8.1%) lesions of 124 colorectal tumors, and the median time from the end of ESD to the onset of bleeding was 18.5 h. Delayed bleeding was significantly higher in tumors located in rectums than in colons (P=0.021), and the number of occurrences of arterial bleeding during ESD was significantly higher in the delayed bleeding group than in the nondelayed bleeding group (P=0.002). The procedure time was significantly longer in the delayed bleeding group than in the nondelayed bleeding group (P=0.012). On multivariate logistic regression analysis, tumor location (odds ratio, 10.13; 95% confidence interval, 1.18–87.03; P=0.035) and three or more occurrences of arterial bleeding during ESD (odds ratio, 6.86; 95% confidence interval, 1.13–41.5; P=0.036) were significant independent risk factors for delayed bleeding. Conclusion The presence of lesions in the rectum and three or more arterial bleeding occurrences during ESD were risk factors for post-ESD bleeding. Patients with these risk factors should be followed up carefully after ESD for colorectal epithelial neoplasms.

Successful Endoscopic Submucosal Dissection of a Large Terminal Ileal Lipoma.

A 78-year-old woman who had recurrent right lower abdominal pain for about 1 year underwent computed tomography (CT) because of a follow-up observation 1 year after right breast cancer surgery. CT revealed a tumor in the colon. The patient was referred to our hospital for detailed examinations. An abdominal CT showed a low-density tumor of approximately 30 mm in the ascending colon, and the CT density inside the tumor was same as that of fatty tissues. A subsequent colonoscopy showed a submucosal tumor (SMT) in the proximal ascending colon developing from the terminal ileum. A colonoscopic ultrasonography revealed that the SMT was a high-echoic mass mainly localized in the submucosal layer. Based on the findings from CT, colonoscopy, and colonoscopic ultrasonography, the SMT was diagnosed as a pedunculated lipoma originating from the terminal ileum and treated with endoscopic submucosal dissection (ESD) because of recurrent abdominal pain. The 40-mm tumor was resected en bloc without complications. ESD may be more appropriate than polypectomy and surgery for removal of small intestinal tumors, because ESD allows direct visualization of the cutting line and exactly dissects the submucosal layers without damaging the muscular layers. ESD is a potentially useful treatment to remove intestinal lipomas.