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Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities. Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities. Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%–50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs. Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff.

OBJECTIVES: The usefulness of non-magnifying endoscopy with narrow-band imaging (NBI; NM-NBI) in the screening of early esophageal squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN) remains unclear. Here, we aimed to compare NM-NBI and chromoendoscopy with iodine staining (CE-Iodine) in terms of the diagnostic performance, and to evaluate the usefulness of NM-NBI in detecting early esophageal SCC. METHODS: We prospectively enrolled 202 consecutive patients (male/female=180/22; median age, 67 years) with high-risk factors for esophageal SCC. All patients received endoscopic examination with NM-NBI and CE-Iodine to screen for early esophageal SCC or HGIN. We conducted the examinations sequentially, and calculated the accuracy, sensitivity, and specificity through a per-lesion-based analysis. A propensity score matching analysis was performed to reduce the effects of selection bias, and we compared the respective outcomes according to NM-NBI and CE-Iodine after matching. RESULTS: The accuracy, sensitivity, and specificity of NM-NBI were 77.0, 88.3, and 75.2%, respectively, and those for unstained areas by CE-Iodine were 68.0, 94.2, and 64.0, respectively. The accuracy and specificity of NM-NBI were superior to those of CE-Iodine (P=0.03 and P=0.01, respectively). However, the sensitivity did not significantly differ between NM-NBI and CE-Iodine (P=0.67). The accuracy and specificity of NM-NBI before matching were superior to those of CE-Iodine after matching (P=0.04 and P=0.03). CONCLUSIONS: NM-NBI was useful and reliable for the diagnosis of esophageal SCC and can be a promising screening strategy for early esophageal SCC.

OBJECTIVE. Enteric bacteria play a significant role in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal damage. However, the association between small intestinal bacterial overgrowth (SIBO) and NSAID-induced small intestinal damage remains unclear. The aim of the study was to examine the association between SIBO and the presence of NSAID-induced severe small intestinal damage or its symptoms in chronic NSAID users. MATERIALS AND METHODS. Forty-three patients who had been using NSAIDs for over 3 months were enrolled. They were examined by capsule endoscopy and a lactulose hydrogen breath test (LHBT). We defined severe small intestinal damage as the presence of more than four small erosions or large erosions/ulcers. The LHBT result was considered positive if there was an increase in the level of breath hydrogen gas of20 ppm above baseline. RESULTS. Out of 43 patients, 22 (51%) had severe small intestinal damage. The LHBT was positive in 5 of 21 patients (24%) without severe small intestinal damage and in 13 of 21 patients (59%) with severe small intestinal damage. Multiple logistic regression analysis showed that an LHBT-positive result was significantly associated with increased odds ratio for severe small intestinal damage (OR, 6.54; 95% CI, 1.40-30.50). There was no significant difference in the presence of symptoms between the LHBT-positive and LHBT-negative patients with severe small intestinal damage. CONCLUSION. SIBO might have a role in the development of severe small intestinal damage in chronic NSAID users.

A 59-year-old woman and a 69-year-old man had esophageal strictures that were refractory to over 10 therapeutic attempts with endoscopic balloon dilation (EBD) after endoscopic submucosal dissections (ESD) for superficial esophageal carcinoma (SEC). The strictured lesions in both patients improved remarkably with a new endoscopic modality (endoscopic radial incision and cutting [ERIC]), which was carried out one to three times, and stricture recurrence was not noted throughout the follow-up period. ERIC is a safe and efficient method for treating refractory strictures after EBD caused by ESD for SEC.

Release of high mobility group box 1 (HMGB1) from damaged cells, which is involved in many types of tissue injuries, activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor 2 (TLR2), TLR4, and receptor for advanced glycation end-products (RAGE). Our objective was to determine the role of HMGB1 in nonsteroidal anti-inflammatory drug (NSAID)-induced damage of the small intestine. Oral indomethacin (10 mg/kg) induced damage to the small intestine and was associated with increases in intestinal HMGB1 expression and serum HMGB1 levels. In wild-type mice, recombinant human HMGB1 aggravated indomethacin-induced small intestinal damage; enhanced the mRNA expression levels of tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1, and KC; activated nuclear factor kappa B; and stimulated phosphorylation of the mitogen-activated protein kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). In contrast, blocking HMGB1 action with neutralizing antibodies prevented damage and inhibited both inflammatory cytokine overexpression and activation of these intracellular signaling pathways. TLR2-knockout (KO) and RAGE-KO mice exhibited high sensitivities to indomethacin-induced damage, similar to wild-type mice, whereas TLR4-KO mice exhibited less severe intestinal damage and lower levels of TNF-α mRNA expression. Exogenous HMGB1 aggravated the damage in TLR2- and RAGE-KO mice but did not affect the damage in TLR4-KO mice. Thus, our results suggest that HMGB1 promotes NSAID-induced small intestinal damage through TLR4-dependent signaling pathways.

This prospective study aimed to evaluate the feasibility and safety of locoregional mitomycin C (MMC) injection to treat refractory esophageal strictures after endoscopic submucosal dissection (ESD) for superficial esophageal carcinoma. Patients with dysphagia and strictures that were refractory to repeated endoscopic balloon dilation (EBD) were eligible. After EBD, MMC was injected into the dilated site. Between June 2009 and August 2010, five patients were recruited. The treatment was performed once in two patients and twice in three patients with recurrent dysphagia or restenosis. In all patients, passing a standard endoscope through the site was easy and the dysphagia grade improved (grade 3→1 in 3 patients, grade 4→2 in 2 patients). No serious complications were noted. During the observation period of 4.8 months, neither recurrent dysphagia nor re-stricture appeared in any of the patients. The combination of locoregional MMC injections and EBD is feasible and safe for the treatment of esophageal strictures after ESD. Recently, endoscopic submucosal dissection (ESD) has been developed and accepted as a new endoscopic treatment for gastrointestinal tumors. ESD is a promising treatment for superficial esophageal carcinoma (SEC), and it has a reliable en bloc resection rate. However, the application of ESD for widespread lesions is challenging because of the high risk of the development of severe strictures, which lead to a low quality of life after ESD. Although endoscopic balloon dilation (EBD) is effective for benign strictures, it needs to be performed frequently until the dysphagia disappears 1 . Mitomycin C (MMC), which is a chemotherapeutic agent derived from some Streptomyces species 2 , reduces scar formation when topically applied to a surgical lesion. MMC has been applied to treat strictures in a variety of anatomical locations, including a variety of organs 3 . The aim of this study was to prospectively evaluate both the feasibility and the safety of locoregional MMC injection therapy in patients with refractory esophageal strictures after ESD for SEC.

Background There is no clinical predictor for the enlargement potential of gastric GI stromal tumors (GISTs) during the follow-up observation period. Objective The aim of our study was to identify predictive markers for the enlargement potential of gastric GISTs on the basis of various endosonographic features determined at the initial examination. Design Single-center retrospective analysis. Setting Academic university hospital in Japan. Patients All patients (n = 74) with histologically diagnosed GISTs in the stomach underwent EUS. Intervention EUS. Main Outcome Measurements We analyzed the following endoscopic and EUS features: mucosal ulceration, irregular shape, irregular border, heterogeneity, internal hyperechoic spot, hypoechoic area, and anechoic area of gastric GISTs in 3 groups according to tumor size. Furthermore, we compared the characteristics between increased growth and unchanged growth of GISTs, that were defined on the basis of the novel tumor growth index: changes in tumor volume/follow-up interval (days between initial EUS and second EUS) (mm3/day). Results The presence of heterogeneity (P = .016) and anechoic area (P = .003) was significantly highest in the group with the largest tumor size. The increased growth group had a higher presence of hypoechoic area than did the unchanged growth group (84.2% vs 51.9%, P = .023). Multivariate analysis showed that the presence of a hypoechoic area was an enlargement-associated factor (odds ratio 5.38; 95% confidence interval 1.19-24.39; P = .029). Limitations Retrospective design of the study. Conclusions The internal hypoechoic area determined by EUS may be a predictor for the enlargement potential of gastric GISTs.

Background and Aim: Proton-pump inhibitor (PPI) therapy is the first-line treatment for gastroesophageal reflux disease; however, there are some reports of PPI failure in cases of non-erosive reflux disease (NERD). Among the pathogenic factors associated with PPI-refractory NERD, reflux other than acid reflux can not be detected by conventional pH monitoring. The purpose of this study was to clarify the usefulness of multichannel intraluminal impedance-pH (MII-pH) monitoring for PPI-refractory NERD patients and examine the pathogenesis. Methods: We used MII-pH monitoring to examine 29 PPI-refractory NERD patients on PPI treatment. Reflux parameters, symptom index (SI: positive if ≥ 50%), and proximal migration were analyzed. The acidity of the reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified into reflux-related disease (abnormal reflux parameters or positive SI) and non-reflux-related disease (normal reflux parameters and negative SI). Results: Of the 29 subjects, 21 were diagnosed with reflux-related disease, including 6 with acid reflux type and 15 with non-acid reflux type, and 8 were diagnosed with non-reflux-related disease. Of the total 1816 liquid reflux episodes, 834 showed proximal migration, which was more common in symptomatic reflux than in asymptomatic reflux. Conclusions: MII-pH monitoring could distinguish reflux-related disease (especially non-acid type) from PPI-refractory NERD. Proximal migration was associated with symptomatic reflux in PPI-refractory NERD patients.

Barrett’s esophagus is characterized by a distinct Th-2-predominant cytokine profile, unlike the pro-inflammatory nature of reflux esophagitis. The aim of this study was to examine the role of Th-2 cytokines during the development of Barrett’s esophagus, using a rat model. Barrett’s esophagus was induced by Levrat’s esophagojejunostomy technique in Brown-Norway (BN) rats. Rats were killed at 8, 15, 30, and 50 weeks after the operation. We studied the incidences of esophagitis and Barrett’s esophagus, and the mRNA expression of cytokines and CDX2 by real-time reverse transcriptase-polymerase chain reaction and immunohistochemical staining. Finally, we compared the incidence of Barrett’s esophagus in BN rats with that in Sprague-Dawley (SD) rats. Esophagitis was found in all rats. Barrett’s esophagus appeared 8 weeks after the operation, and its incidence and length increased over time. Levels of Th-2 cytokines such as interleukin (IL)-4, IL-10, and IL-13 were significantly increased in Barrett’s esophagus as compared to those in non-Barrett’s esophagus, while there were no differences in the levels of pro-inflammatory cytokines. The peak of elevated IL-4 mRNA was observed before that of CDX2 mRNA. IL-4 was co-localized in CD4-positive cells and CDX2-positive goblet cells. The incidence of Barrett’s esophagus was more common in BN rats (8/10, 80%) than in SD rats (2/7, 28%) at 30 weeks. Th-2 cytokines, especially IL-4, may play a crucial role in the development of Barrett’s esophagus in an early phase. These results provide understanding of the pathogenesis of Barrett’s esophagus from the aspect of the Th-2 immune response.

Prostaglandin E(2) plays an important role in the maintenance of gastric mucosal integrity. The level of biologically active prostaglandin E(2) in the tissue is regulated by the balanced expression of its synthetic enzymes, such as cyclooxygenase, and its catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase. We examined the effect of rebamipide, a mucoprotective drug, on prostaglandin E(2) production and metabolism in the gastric tissue and its effect on indomethacin-induced gastric mucosal injury in mice. Rebamipide suppressed indomethacin-induced gastric mucosal injury. Suppressive effect of rebamipide on indomethacin-induced gastric mucosal injury was also observed in cyclooxygenase-2-knockout mice. The mice that were treated with rebamipide showed a 2-fold increase in cyclooxygenase-2 mRNA expression in the gastric tissue, whereas 15-hydroxyprostaglandin dehydrogenase mRNA expression markedly decreased as compared to vehicle-treated control mice. Rebamipide did not affect the expression of cyclooxygenase-1 in the gastric tissue. Rebamipide did not increase prostaglandin E(2) production in the gastric tissue; however, it induced a 1.4-fold increase in the concentration of prostaglandin E(2) in the gastric tissue as compared to vehicle-treated control mice. These results suggest that the suppressive effect of rebamipide on non-steroidal anti-inflammatory drugs-induced gastric mucosal injury can be attributed to reduced 15-hydroxyprostaglandin dehydrogenase expression, which increases the prostaglandin E(2) concentration in the gastric tissue.

Recent studies using small bowel endoscopy revealed that non-steroidal anti-inflammatory drugs including low-dose aspirin, can often induce small bowel injury. Non-steroidal anti-inflammatory drugs-induced small bowel mucosal injury involves various factors such as enterobacteria, cytokines, and bile. Experimental studies demonstrate that both mitochondrial disorders and inhibition of cyclooxygenases are required for development of non-steroidal anti-inflammatory drugs-induced small bowel injury. Mitochondrion is an organelle playing a central role in energy production in organisms. Many non-steroidal anti-inflammatory drugs directly cause mitochondrial disorders, which are attributable to uncoupling of oxidative phosphorylation induced by opening of the mega channel called mitochondrial permeability transition pore on the mitochondrial membrane by non-steroidal anti-inflammatory drugs. Bile acids and tumor necrosis factor-α also can open the permeability transition pore. The permeability transition pore opening induces the release of cytochrome c from mitochondrial matrix into the cytosol, which triggers a cascade of events that will lead to cell death. Therefore these mitochondrial disorders may cause disturbance of the mucosal barrier function and elevation of the small bowel permeability, and play particularly important roles in early processes of non-steroidal anti-inflammatory drugs-induced small bowel injury. Although no valid means of preventing or treating non-steroidal anti-inflammatory drugs-induced small bowel injury has been established, advances in mitochondrial studies may bring about innovation in the prevention and treatment of this kind of injury.

Summary Ulcerative colitis (UC) is a chronic inflammatory bowel disease featuring infiltration by plasma cells producing immunoglobulins. We have reported previously the specific and significant proliferation of immature plasma cells in the inflamed colonic and pouch mucosa of UC patients. The aim of this study was to characterize peripheral blood immature plasma cells and the migration mechanisms of such immature plasma cells to inflamed sites in UC. The characteristics of peripheral blood immature plasma cells and chemokine receptor expression were examined by flow cytometry. Expression of mucosal chemokine was quantified using real-time reverse transcription–polymerase chain reaction and immunohistochemistry. The number of peripheral blood immature plasma cells was significantly higher in patients with active UC and active Crohn's disease (CD) than in healthy controls. The proportion of immature plasma cells was correlated positively with clinical activities of UC and CD. Many peripheral blood immature plasma cells were positive for CXCR3, CXCR4, CCR9 and CCR10. Expression of CXCR3 and CXCR4 in UC patients was significantly higher than in controls. CXCL9, CXCL10 and CXCL11 mRNA levels in colonic mucosa of inflamed IBD were higher than in controls. Immunofluorescence study also showed abundant CXCR3-positive immature plasma cells in the inflamed colonic mucosa of UC. Increased numbers of immature plasma cells may migrate towards inflammatory sites of UC via the CXCR3 axis, and may participate in UC pathogenesis.

Background and Aim: Leptin, a key hormone in regulation of food intake and energy expenditure, exerts pleiotropic cytokine-like biological effects. Its role in gastric ulcer healing is unclear. In this study, we investigated the role of leptin in gastric ulcer healing. Methods: Experimental gastric ulcer was induced by focal serosal application of acetic acid in leptin-deficient ob/ob mice and wild-type mice. Healing of gastric ulcer and angiogenesis in the ulcer tissue was evaluated. Results: Gastric ulcer healing was delayed in ob/ob mice compared with that in wild-type mice. The impairment of ulcer healing observed in ob/ob mice was characterized by reduced expression of vascular endothelial growth factor (VEGF) and impairment of angiogenesis. Systemic administration of leptin to ob/ob mice reversed the impairment of gastric ulcer healing; this reversal was accompanied by an increase in VEGF expression and angiogenesis. Although mRNA for leptin was not expressed in normal gastric mucosa and not induced in ulcerous tissue, leptin receptor expression was markedly upregulated in gastric epithelial cells at ulcer margins, and was colocalized with VEGF. Conclusion: These findings suggest that leptin promotes gastric ulcer healing by induction of angiogenesis in the granular tissue of ulcers via upregulation of VEGF expression.

Inflammatory responses triggered by activation of the lipopolysaccharide (LPS)/Toll-like receptor (TLR) 4 signaling pathway are a key mechanism in nonsteroidal anti-inflammatory drug-induced enteropathy. The aim of this study was to investigate the probiotic effect of Lactobacillus casei strain Shirota (LcS) on indomethacin-induced small intestinal injury. Rats pretreated with viable LcS or heat-killed LcS once or once daily for a week were administered indomethacin by gavage to induce injury. Anti-inflammatory effects of L-lactic acid (1-15 mM) were evaluated in vitro by use of THP-1 cells. One-week treatment with viable LcS prevented indomethacin-induced intestinal injury with increase in the concentration of lactic acid in small intestinal content and inhibited increases in myeloperoxidase activity and expression of mRNA for tumor necrosis factor-alpha (TNF-alpha) while affecting neither TLR4 expression nor the number of gram-negative bacteria in intestinal content, whereas neither heat-killed LcS nor a single dose of viable LcS inhibited intestinal injury. Prevention of this injury was also observed in rats given l-lactic acid in drinking water. Both L-lactic acid and LcS culture supernatant containing 10 mM lactic acid inhibited NF-kappaB activation and increases in TNF-alpha mRNA expression and TNF-alpha protein secretion in THP-1 cells treated with LPS. Western blot analyses showed that both L-lactic acid and LcS culture supernatants suppressed phosphorylation and degradation of I-kappaB-alpha induced by LPS without affecting expression of TLR4. These findings suggest that LcS exhibits a prophylactic effect on indomethacin-induced enteropathy by suppressing the LPS/TLR4 signaling pathway and that this probiotic effect of LcS may be mediated by L-lactic acid.

Although balloon-occluded retrograde transvenous obliteration (B-RTO) is useful for management of gastric varices, worsening of esophageal varices (EV) is the most important complication of B-RTO. The predictive factors of worsening of EV have not been evaluated in detail. This study was designed to evaluate the role of endoscopic color Doppler ultrasonography (ECDUS) in the detection of possible risk factors for worsening of EV after B-RTO.A total of 39 cirrhotic patients with high-risk gastric varices successfully treated by B-RTO were included in this study. All patients underwent ECDUS before B-RTO to measure hemodynamic parameters of gastric varices and regular endoscopic follow-up after B-RTO to detect worsening of EV. The risk factors were analyzed by Cox's proportional hazards regression.Worsening of EV was found in 24 (61.5%) patients. The presence of esophageal varices before B-RTO and a lower degree of liver dysfunction (Child-Pugh class B) were statistically independent risk factors for worsening of EV after B-RTO (hazard ratio, HR, 5.81, 95% confidence interval, CI, 1.71-19.77 and HR 2.92, 95% CI: 1.21-7, respectively). High resistance index (or =0.24), measured by ECDUS, is also an independent risk factor for worsening of EV after B-RTO (HR 4.06, 95% CI: 1.14-14.38) and increase in resistance index is associated with worsening of EV (P for trend=0.028).The presence of EV, higher Child-Pugh class, and higher resistance index assessed by ECDUS before B-RTO were significant risk factors for worsening of EV after B-RTO.

Clinical and experimental studies showed that the reflux of bile into the stomach contributes to the induction of intestinal metaplasia of the stomach and gastric carcinogenesis. Caudal-type homeobox 2 (Cdx2) plays a key role in the exhibition of intestinal phenotypes by regulating the expression of intestine-specific genes such as goblet-specific gene mucin 2 (MUC2). We investigated the involvement of the farnesoid X receptor (FXR), a nuclear receptor for bile acids, in the chenodeoxycholic acid (CDCA)-induced expression of Cdx2 and MUC2 in normal rat gastric epithelial cells (RGM-1 cells). RGM-1 cells were treated with CDCA or GW4064, an FXR agonist, in the presence or absence of guggulsterone, an FXR antagonist. CDCA induced dose-dependent expression of Cdx2 and MUC2 at both the mRNA and protein levels. The maximum stimulation of Cdx2 and MUC2 mRNA induced by CDCA was observed at 3 h and by 6 h, respectively. GW4064 also induced expression of these molecules. The effects of CDCA and GW4064 on expression of Cdx2 and MUC2 were abolished by guggulsterone. These findings suggest that bile acids may induce gastric intestinal metaplasia and carcinogenesis through the FXR.

Helicobacter pylori eradication is useful for improvement of a half of patients with idiopathic thrombocytopenic purpura (ITP), but its long-term therapeutic efficacy has not been elucidated. We investigated the long-term efficacy of H. pylori eradication in 30 cases with ITP that were included in our previous study regarding the association between H. pylori infection and ITP. Twenty-one cases were positive and nine cases were negative for H. pylori infection. H. pylori eradication therapy including secondary regimen was successful in 20 cases, half (responder) of whom showed ITP remission 1 month later. Nine responders could be followed up for a long time and did not show re-infection of H. pylori. Eight of nine needed no medication except for eradication therapy. Another case remained in remission for 1 year but thereafter needed a steroid therapy due to the recurrence. Eight nonresponders could be followed up for a long time. All these cases showed a bad clinical course even though they received the other post-treatments including steroid therapy. Three of nine H. pylori-negative cases underwent eradication therapy after obtaining the written informed consent, but none of them showed improvement. Of these three cases, two cases could be followed up. Only one case remained a remission although receiving corticosteroid as a post-treatment. Conditions of H. pylori-negative ITP cases were usually unstable for a long time. H. pylori eradication has a short-term efficacy for about half of H. pylori-positive ITP patients, and the responders to the eradication therapy may receive a long-term clinical benefit without other therapies.

Background & Aims With capsule endoscopy, the ulcerogenic effect of low-dose enteric-coated aspirin on the small bowel and the therapeutic effect of misoprostol on intestinal injury were evaluated. Methods Eleven patients who developed gastric ulcers while undergoing low-dose enteric-coated aspirin therapy were enrolled. They continued aspirin therapy while taking proton pump inhibitors (PPIs) for 8 weeks to heal the gastric ulcers. Then misoprostol 200 μg 4 times a day was administered instead of PPIs for 8 weeks. When the patients could not tolerate misoprostol as a result of side effects, they received another 8 weeks of PPI therapy. Results Capsule endoscopy performed after 8 weeks of PPI treatment identified red spots and mucosal breaks in 100% (11/11) and 90.9% (10/11) of patients, respectively. In 7 patients who completed the study protocol, misoprostol significantly decreased the median number of red spots and mucosal breaks, with complete disappearance of mucosal breaks in 4 patients. Intestinal lesions tended not to heal in 3 patients who discontinued misoprostol. Conclusions Low-dose enteric-coated aspirin frequently damages the small intestine, and misoprostol is effective in the treatment of aspirin-induced enteropathy.

Wireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE) are new methods enabling diagnostic endoscopy of the entire small intestine. However, which of the two is superior is unclear. We therefore prospectively compared the clinical efficacy of CE and DBE. We prospectively examined 32 patients with obscure gastrointestinal bleeding. CE preceded DBE by 1–7 days, and all patients underwent DBE twice, by antegrade and retrograde approaches, to evaluate the entire small intestine. Physicians evaluating the results of CE and DBE were blind to the results of the other method. We evaluated diagnosis, diagnostic yield of the two methods, and clinical outcomes. CE revealed abnormal findings in 29 (90.6%) of 32 patients. CE definitively or probably detected the sources of bleeding in 23 (71.9%) of the 32 patients, including angioectasias (eight), erosions (seven), ulcers (five), tumor (one), and hemorrhagic polyps (two). DBE definitely or probably detected the sources of bleeding in 21 (65.6%) of the 32 patients, including angioectasias (seven), erosions (four), ulcers (five), tumor (one), hemorrhagic polyps (two) and diverticula (two). CE yielded more abnormal findings than DBE (CE 90.6%, DBE 65.6%) (P = 0.032), although there were no significant differences in diagnostic yield between the methods. We were able to perform additional treatment or biopsy with DBE in 13 patients, including coagulation therapy (ten), endoscopic mucosal resection (one), biopsy (seven), and extraction of retained CE (two). Our results demonstrate the superiority of CE in detecting abnormal lesions, and the superiority of DBE in endoscopic management.

A 74-year-old woman was referred to our department because of epigastralgia. Endoscopic findings revealed yellowish bumpy mucosa from the bulbus to the second portion of the duodenum. The patient was admitted to our hospital for further examinations and treatment for this lesion. Endoscopic mucosal resection (EMR) was performed on part of the lesion to obtain the final diagnosis, and then mucosa-associated lymphoid tissue (MALT) lymphoma of the duodenum was diagnosed using this procedure. In this case, no evidence of Helicobacter pylori infection in the patient's stomach was detected by any of the diagnostic examinations used, such as the urea breath test, histological study, culture, and serological antibody. For this reason, the patient's duodenal MALT lymphoma was treated solely with long-term clarithromycin, which had an inhibitory action on lymphocyte activation. The lesion showed slight improved during the first 12 days of treatment, and complete regression was reached after 6 months of treatment. It is suggested that the long-term use of clarithromycin may be effective for diseases of the gastrointestinal tract associated with the lymphocyte proliferation.

Objective: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. Methods: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0–24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. Results: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0–24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). Conclusion: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.

Complete Remission of Protein-Losing Gastroenteropathy Associated With Sjogren's Syndrome by B Cell-Targeted Therapy With Rituximab

The interpretive skills of medical doctors and medical technologists who examine video capsule endoscopy (VCE) in clinical practice are usually improved through hands-on courses. Such courses require that a large volume of cases be undertaken as part of the training, and they thus consume a considerable amount of the trainees' time. This paper describes an e-learning system that reduces the training time in addition to enhancing the quality of the educational process with regard to reading VCE. To achieve this goal, we focused on organizing training courses in order to appropriate for the laborious conditions that exist when reading VCE. The designed courses help the trainees acquire knowledge of abnormal regions and become familiar with reading VCE before taking examinations under conditions similar to those actual clinical practice. The proposed training modality was developed as an e-learning application on the World Wide Web. Thus, it can be easily extended to a wide range of trainees. In the experiments, 20 participants completed the self-learning training procedures in approximately 3 hours. The proposed system is much faster than conventional hands-on courses, which require a minimum of 8 hours. Furthermore, the trainees' learning performances in the final examinations confirmed that the proposed system is particularly effective for inexperienced examining doctors.

Background There are few comprehensive reports detailing the prevalence of major adverse events associated with a double-balloon enteroscopy procedure. Methods We retrospectively investigated the prevalence of major adverse events in 538 patients (262 males and 276 females; median age, 65 years; age range, 12–95 years) who underwent double-balloon enteroscopy at our Institution between April 2008 and October 2011. Results Of the 17 adverse events recorded (3.2%), acute pancreatitis (n = 5; 0.9%) occurred during both diagnostic (n = 3) and therapeutic (n = 2) anterograde double-balloon enteroscopy, and all of them were treated conservatively. For these cases, the average duration of the examination was 135 min, which was longer than for the other patients (97 min) (P = 0.046). Intestinal bleeding (1.3%) was observed in 6 cases after endoscopic polypectomy and in 1 case following a biopsy procedure during a diagnostic double-balloon enteroscopy. The prevalence rates of intestinal perforation and other complications were 0.2% and 0.7%, respectively. Conclusions The rate of adverse events associated with double-balloon enteroscopy was high compared to that associated with conventional upper/lower gastrointestinal endoscopy (0.042%/0.078%). The occurrence of acute pancreatitis may be significantly dependent on the duration of double-balloon enteroscopy examination.

A 59-year-old woman and a 69-year-old man had esophageal strictures that were refractory to over 10 therapeutic attempts with endoscopic balloon dilation (EBD) after endoscopic submucosal dissections (ESD) for superficial esophageal carcinoma (SEC). The strictured lesions in both patients improved remarkably with a new endoscopic modality (endoscopic radial incision and cutting [ERIC]), which was carried out one to three times, and stricture recurrence was not noted throughout the follow-up period. ERIC is a safe and efficient method for treating refractory strictures after EBD caused by ESD for SEC.

OBJECTIVE: Gastrointestinal stromal tumors (GISTs) are the most frequently occurring mesenchymal tumors of the GI tract. Double-balloon enteroscopy (DBE) and capsule endoscopy (CE) promise the detection and accurate diagnosis of small bowel diseases in patients with obscure GI bleeding (OGIB). The aim of the present study was to analyze the clinical characteristics of small bowel GISTs and the usefulness of DBE, CE and computed tomography (CT). METHODS: Among 705 cases with OGIB examined between December 2003 and January 2011, 12 (1.7%) cases of small bowel GIST were identified. We analyzed endoscopic appearance, tumor-size and location, detection rate by DBE, CE and CT and clinical course in each of these cases. RESULTS: Of the 12 patients with GIST, eight were men. The mean patient age was 53.6 years. The presenting symptoms in most patients included tarry stools and/or anemia. Six patients required blood transfusions. The detection rates of DBE, CE and CT were 92%, 60% and 67%, respectively. All cases, except for one incomplete study, were identified using DBE; however, one case was not diagnosed as a tumor because of the presence of extramural growth. A pathological diagnosis of GIST was obtained using biopsies during DBE in three (45%) of seven cases. Lower detection rates were found in cases with intramural and extramural growth, larger tumors (≥35 mm) detected by CE and intraluminal growth and smaller tumors (

This paper proposes a method to track abnormalities in successive frames in a capsule endoscopic image sequence. Exact tracking of an abnormality in the gastrointestinal tract is useful in preparing the content for educational systems. However, if the abnormality is de-formable over continuous frames and its features are not highly distinct, it is difficult to track abnormalities precisely. The proposed method uses not only the abnormality image features, but also surrounding features, called supporters. In a capsule endoscopic image sequence, however, both the supporters and the target are difficult to track using only their image features, because these features are indistinguishable. Since estimation using only surrounding features is hard, the proposed method uses triangular constraints among supporters as well. The proposed method is able to track successfully even if the target and supporter features are indistinguishable. Finally, we evaluate the proposed method using eight major types of abnormalities.

Proton-pump inhibitor (PPI) therapy is the first-line treatment for gastroesophageal reflux disease; however, there are some reports of PPI failure in cases of non-erosive reflux disease (NERD). Among the pathogenic factors associated with PPI-refractory NERD, reflux other than acid reflux can not be detected by conventional pH monitoring. The purpose of this study was to clarify the usefulness of multichannel intraluminal impedance-pH (MII-pH) monitoring for PPI-refractory NERD patients and examine the pathogenesis.We used MII-pH monitoring to examine 29 PPI-refractory NERD patients on PPI treatment. Reflux parameters, symptom index (SI: positive if ≥ 50%), and proximal migration were analyzed. The acidity of the reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH4). Subjects were classified into reflux-related disease (abnormal reflux parameters or positive SI) and non-reflux-related disease (normal reflux parameters and negative SI).Of the 29 subjects, 21 were diagnosed with reflux-related disease, including 6 with acid reflux type and 15 with non-acid reflux type, and 8 were diagnosed with non-reflux-related disease. Of the total 1816 liquid reflux episodes, 834 showed proximal migration, which was more common in symptomatic reflux than in asymptomatic reflux.MII-pH monitoring could distinguish reflux-related disease (especially non-acid type) from PPI-refractory NERD. Proximal migration was associated with symptomatic reflux in PPI-refractory NERD patients.

Background/Aims: Visceral obesity is commonly involved in the pathogenesis of gastroesophageal reflux disease (GERD) and non-alcoholic fatty liver disease (NAFLD). However, other characteristic factors different from visceral obesity are associated with the pathogenesis of NAFLD. We investigated the prevalence of GERD symptoms in patients with NAFLD and its associated risk factors. Methods: NAFLD (n = 96) and controls (n = 139) were enrolled in this study. GERD symptoms were evaluated by using a frequency scale for the symptoms of GERD. Results: GERD symptom score and its prevalence rate were higher in the NAFLD group (7.4 ± 0.7, 37%) than those seen in the control groups (4.5 ± 0.4, 20%), which was independent of sex, age, and body mass index (BMI). GERD symptoms were correlated with insulin resistance (r = 0.167, p = 0.011), total cholesterol (T-CHO) (r = 0.138, p = 0.034), triglyceride (TG) (r = 0.178, p = 0.006), or immunoreactive insulin (r = 0.173, p = 0.008) but not BMI (r = 0.089, p = 0.175). GERD symptoms of the NAFLD group were significantly severer in the higher group of T-CHO and TG levels than those in the lower group. Multivariate analysis proved that risk factors related to GERD symptoms were TG (OR 3.96, 95% CI 1.31–11.9) and T-CHO (OR 3.39, 95% CI 1.11–10.3). Conclusion: The severity and prevalence of GERD symptoms in patients with NAFLD were high, which was associated with serum levels of TG and T-CHO but not BMI.

This paper describes a technique to enhance a region-of- interest (ROI) in a capsule endoscopy (CE) image. Our aim is to improve distinguishing suspicious regions from normal ones without over-enhancing the image. Given a ROI by physicians, the proposed technique enhances the ROI so that the enhanced region remains as natural as possible. To achieve this, we utilize image features relating to a specific color space dedicated to gastrointestinal (GI) wall regions. The proposed approach starts by utilizing a self-organizing map to handle GI wall color components. The goal of preserving the original color tones is obtainable by using a histogram equalization technique in the proposed color space. As a result, the enhanced images only contain color components inferred from the color gamut of the human small bowel. The results of the proposed method are judged in terms of visual appearance by comparison with images obtained by the conventional enhancement technique.

Background Gastroesophageal reflux disease (GERD), functional dyspepsia (FD), and irritable bowel syndrome (IBS) are common gastrointestinal diseases. Several studies have shown a significant occurrence of overlap among these 3 diseases. The purpose of this study was to examine the factors associated with such disease overlap in Japanese adults. Methods We performed a cross-sectional study on Japanese workers who visited a clinic for a routine health check-up and asked them to fill out a self-report questionnaire. GERD was defined as episodes of heartburn and/or acid regurgitation at least once a week, and the diagnosis of FD and IBS was based on Rome III criteria. A logistic regression model was used to identify risk factors, and odds ratio (OR) was calculated with 95% confidence intervals (CIs). Results Disease overlaps were found in 160 (6.0%) of the 2680 eligible subjects. Female gender was associated with GERD + IBS (OR=1.99; 95% CI, 1.06-3.75), and FD + IBS (OR=1.72; 95% CI, 1.03-2.85), and lower body mass index was negatively associated with FD + IBS (OR=0.54; 96% CI, 0.34-0.87). Cigarette smoking was a common factor associated with the overlaps: GERD + FD (OR=2.14; 95% CI, 1.22-3.76), GERD + IBS (OR=3.16; 95% CI, 1.75-3.71), FD + IBS (OR=2.26; 95% CI, 1.40-3.66), and GERD + FD + IBS (OR=4.08; 95% CI, 1.66-10.07). The associations between smoking habits and overlaps were stronger in smokers who smoked ≥1 pack per day as compared to those who smoked

The traditional Japanese medicine rikkunshito ameliorates the nitric oxide-associated delay in gastric emptying. Whether rikkunshito affects gastric motility associated with 5-hydroxytryptamine (serotonin: 5-HT) receptors or dopamine receptors is unknown. We examined the effects of rikkunshito on the delay in gastric emptying induced by 5-HT or dopamine using the phenol red method in male Wistar rats. 5-HT (0.01–1.0 mg kg−1, i.p.) dose dependently delayed gastric emptying, similar to the effect of the 5-HT3receptor agonist 1-(3-chlorophenyl) biguanide (0.01–1.0 mg kg−1, i.p.). Dopamine also dose dependently delayed gastric emptying. The 5-HT3receptor antagonist ondansetron (0.04–4.0 mg kg−1) and rikkunshito (125–500 mg kg−1) significantly suppressed the delay in gastric emptying caused by 5-HT or 1-(3-chlorophenyl) biguanide. Hesperidin (the most active ingredient in rikkunshito) suppressed the 5-HT-induced delayed gastric emptying in a dose-dependent manner, the maximum effect of which was similar to that of ondansetron (0.4 mg kg−1). The improvement obtained by rikkunshito or ondansetron in delaying gastric emptying was completely blocked by pretreatment with atropine. Rikkunshito appears to improve delay in gastric emptying via the antagonistic action of the 5-HT3receptor pathway.

The total number of elderly persons with gastric ulcers in Japan is increasing with an improvement in the average life expectancy. So far, gastric ulcer in elderly persons is considered proximal gastric ulcer due to corpus-predominant atrophic gastritis. However, the clinical features of the disease will change with a decrease in the number of persons with Helicobacter pylori infection. On the other hand, the numbers of persons with gastric ulcers associated with aging-related diseases and those with gastric ulcers induced by drugs such as nonsteroidal anti-inflammatory drugs and aspirin are increasing. Even recently, there have been no changes in the mortality of patients with severe gastric ulcers. Management based on pathological conditions of gastric ulcers in the elderly persons is required.

Prostaglandin (PG) E2 promotes gastrointestinal carcinogenesis and tumor progression. We determined the correlations between pattern of expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a catabolic enzyme for biological inactivation of PGE2, in gastric adenocarcinoma and various clinicopathological factors and patient outcome in an attempt to elucidate its biological significance. In 35 of 71 cases of gastric adenocarcinoma, expression of 15-PGDH protein was reduced in tumor tissues. Multivariate analysis revealed reduction of 15-PGDH expression to be an independent predictor of poor survival. The proportion of Ki67-positive cells in 15-PGDH-negative adenocarcinoma was higher than that in 15-PGDH-positive adenocarcinoma. No differences were found in clinicopathological parameters between patients with cyclooxygenase-2 (COX-2)-positive tumors and those with COX-2 negative tumors. In an in vitro study, use of specific siRNA to silence 15-PGDH or a specific inhibitor of 15-PGDH enhanced cell proliferation in the gastric cancer cell line AGS, which expresses 15-PGDH. These findings suggest that reduction of 15-PGDH is an independent predictor of poor survival associated with enhancement of cell proliferation in gastric adenocarcinoma. (Cancer Sci 2009)

Helicobacter pylori-induced immune responses are skewed toward a T helper (Th) 1 phenotype. IL-17-producing Th17 cells have recently been discovered, and we examined the role of IL-17A in H. pylori-induced gastritis. Six months after inoculation with H. pylori, the mice received an intraperitoneal injection of recombinant IL-17A, anti-IL-17A antibody or irrelevant IgG(2a) for 3days. H. pylori infection markedly increased mRNA for IL-17A. Double immunofluorescence studies showed that IL-17A proteins were expressed on CD4(+) T cells, macrophages, and dendritic cells. H. pylori infection elevated mRNAs for IL-12, IFN-gamma, and TNF-alpha with increase in myeloperoxidase activity, whereas it did not affect mRNAs for IL-4 and IL-5. Neutralization of IL-17A elevated mRNAs for IFN-gamma and TNF-alpha, and myeloperoxidase activity, whereas recombinant IL-17A had a tendency to reduce these parameters. In conclusion, IL-17A exerts anti-inflammatory effects on H. pylori-induced gastritis through suppression of Th1 differentiation.

Pathogenic bacterial components play critical roles in initiation of gastrointestinal inflammation via activation of intracellular signaling pathways which induce proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Lansoprazole (LANSO), a proton pump inhibitor, has been widely used for the treatment of peptic ulcers and reflux esophagitis due to its potent acid-suppressive effect. It has also been reported to have anti-inflammatory effects. In this study we investigated the effects of LANSO on the production of TNF-alpha and IL-1beta induced by lipopolysaccharide (LPS) and Helicobacter pylori water-soluble extract (HpWE) in the human monocytic cell line (THP-1). LANSO (100 microM) significantly reduced mRNA expression and production of TNF-alpha and IL-1beta by THP-1 cells stimulated by LPS and HpWE. LANSO inhibited phosphorylation and degradation of inhibitory factor kappaB-alpha (IkappaB-alpha) and phosphorylation of extracellular signal-regulated kinase (ERK) induced by LPS and HpWE in THP-1 cells. These findings suggest that LANSO exerts anti-inflammatory effects by suppressing induction of TNF-alpha and IL-1beta via inhibition of nuclear factor (NF)-kappaB and ERK activation.

A 31-year-old man has visited our hospital, complaining diarrhea and leg edema. Blood test showed hypoalbuminea, but we couldn't find the reason by several examinations. Therefore, we performed double balloon enteroscopy, and intestinal lymphangiectasia was diagnosed histologically by biopsy. It's useful and effective to perform double balloon enteroscopy and histological examination for the unknown origin case of protein loosing enteropathy.

Video capsule endoscopy (VCE) and double-balloon enteroscopy (DBE) enable the detection of small intestinal lesions. To examine causes of acute overt gastrointestinal (GI) bleeding and the prevalence of mid-GI bleeding, defined as small intestinal bleeding from the ampulla of Vater to the terminal ileum, in a multi-center experience in Japan in the VCE/DBE era. Data were collected retrospectively from consecutive patients with acute overt GI bleeding in ten participating hospitals. All patients were examined by esophagogastroduodenoscopy and/or colonoscopy. When the source of bleeding was not identified after these procedures, patients suspected to have mid-GI bleeding were referred to our hospital and VCE/DBE was performed to determine the source of bleeding. Of the 1044 patients with acute overt GI bleeding, 524 (50.2%) patients were diagnosed with upper GI bleeding, 442 (42.3%) with lower GI bleeding, and 13 (1.2%) with mid-GI bleeding. Gastric ulcer was the most common cause of bleeding (20.4%). Among cases of mid-GI bleeding, ulcers were found in 4 (30.8%) patients, erosions in 3 (23.1%), angiodysplasia in 3 (23.1%), submucosal tumor in 2 (15.4%), and hemangioma in one (7.7%). Seven lesions were located in the jejunum, 5 in the ileum, and one in both the jejunum and ileum. Analysis of age-related cause showed that the prevalence of mid-GI bleeding among younger patients under 40 years of age was higher (5%) than in other age groups (1–2%). mid-GI bleeding is rare among Japanese patients with acute overt GI bleeding.

Background and Aim: The risk factors for aggravation of esophageal varices (EV) in patients with hepatocellular carcinoma (HCC) are poorly understood. The aim of this study was to evaluate the effects of HCC on the appearance of the red color (RC) sign on EV and also investigate whether risk factors for the appearance of the RC sign differed between patients with and without HCC. Methods: A total of 243 patients with cirrhosis (127 with HCC, 116 without HCC) without the RC sign, with no previous variceal hemorrhage, and not on prophylactic treatment for EV were enrolled. The endpoint was defined as being either when the RC sign was first noted, or when variceal bleeding occurred. In patients without HCC, follow-up was discontinued if HCC was discovered. The risk factors were analyzed by Cox proportional hazards regression. Results: In patients with HCC, portal vein tumor thrombus was a statistically independent risk factor (risk ratio [RR] 4.58, 95% confidence interval [CI] 1.32–15.86), although the presence of HCC was not. A large HCC (≥50 mm) tended to be a risk factor, but this was not statistically significant (RR 2.50, 95%CI 0.98–6.39). Child–Pugh classification and low platelet count were common risk factors regardless of whether HCC was present or not. Conclusions: Portal vein tumor thrombus, but not the presence of HCC, was a significant risk factor for aggravation of EV in patients with HCC. Cirrhotic patients with portal vein tumor thrombus should receive more aggressive management of portal hypertension to prevent aggravation of EV.

In recent years, various endoscopic treatments have become available to treat gastroesophageal reflux disease (GERD) in Western countries. The Stretta procedure, which uses radiofrequency energy, is one type of safe and effective endoluminal treatment for GERD. However, the feasibility, safety, and efficacy of the Stretta procedure in Japanese patients with GERD, who differ from Western peoples in their physiological characteristics, are not known. In 2006, we imported a Stretta system from the United States and investigated important clinical aspects of the system in Japanese patients with GERD. This study was an open-label trial that enrolled patients with GERD who desired to undergo the Stretta procedure. Heartburn scores, medication use, overall satisfaction with the procedure, and adverse events were evaluated. Nine patients received the Stretta treatment between February and September 2006. Esophagogastroduodenoscopy just after treatment revealed a remarkable reduction in the expansion of the gastric cardia and small erosions in all patients. At 3 or 6 months after treatment, heartburn scores were significantly improved compared with pretreatment scores (5.0 ± 1.7 pretreatment vs. 0.7 ± 1.4 posttreatment, P = 0.007). In six of nine patients (66.7%), treatment significantly (P = 0.009) decreased medication use. There were no major adverse events. All patients were satisfied with this treatment. The Stretta procedure safely reduced GERD symptoms and decreased medication use in Japanese patients with GERD. This treatment may thus be very useful for such patients, and it is hoped that a nationwide trial will be undertaken in Japan to obtain more extensive data.