Side Effects of COVID-19 Vaccines in Patients with Inflammatory Bowel Disease in Japan.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are recommended to receive the coronavirus disease 2019 (COVID-19) vaccine. However, a recent survey showed that patients with IBD are more hesitant to receive the vaccine than the general population. Detailed information on the side effects of the COVID-19 vaccine is necessary to encourage vaccination among patients with IBD. AIM: To investigate the frequency of side effects following COVID-19 vaccination in patients with IBD in Japan. STUDY DESIGN: a cross-sectional survey was conducted using a questionnaire administered to adult patients with IBD in a tertiary medical facility. RESULTS: Among the participants who answered the questionnaire, 92.6%, 91.5%, and 41.5% of the participants had received their first, second, and third doses of the COVID-19 vaccine, respectively. Of the vaccinated participants, 88.3%, 86.3%, and 89.0% experienced side effects after receiving the first, second, and third doses of the vaccine, respectively. The incidences of fever, chills, and headaches were significantly higher among female participants than among male participants (p < 0.05). However, the frequencies of most side effects were comparable between the BNT162b2 mRNA and mRNA-1273 vaccines. CONCLUSION: The findings of our survey can help encourage patients with IBD to receive the COVID-19 vaccine.

Efficacy and predictor of anti-TNFα agents in patients with intestinal Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a recurrent multisystem inflammatory disease. Anti-tumor necrosis factor (TNF) α agents have been used to treat patients with intestinal BD with severe disease activity or those who are resistant to conventional treatments; however, the long-term efficacy of anti-TNFα agents in intestinal BD remains unclear. In the present study, we investigated the clinical outcomes and predictors of discontinuation of anti-TNFα agents in patients with intestinal BD. METHODS: We reviewed the medical records of patients with intestinal BD who received first-line anti-TNFα agents between January 2009 and June 2020. The primary outcome was the percentage of patients who continued anti-TNFα therapy for 48 weeks. Secondary outcomes included the percentage of patients who achieved marked improvement, complete remission, and mucosal healing, as well as predictors of discontinuation of anti-TNFα agents. RESULTS: A total of 29 patients were included in the study. Twenty-two (75.9%) patients continued anti-TNFα therapy for 48 weeks. The percentage of patients who achieved marked improvement, complete remission, and mucosal healing at week 48 was 48.3%, 37.9%, and 48.3%, respectively. At week 96, 11 (37.9%) patients achieved marked improvement, complete remission, and mucosal healing. A higher C-reactive protein level (CRP; ≥ 1 mg/dL) at baseline was a predictor of discontinuation of anti-TNFα agents. CONCLUSIONS: The 48-week continuation rate of anti-TNFα agents was 75.9% in bio-naïve patients with intestinal BD. However, a higher baseline CRP level (≥ 1 mg/dL) was associated with discontinuation of anti-TNFα agents.

GPR43 Suppresses Intestinal Tumor Growth by Modification of the Mammalian Target of Rapamycin Complex 1 Activity in ApcMin/+ Mice.

OBJECTIVE: G protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using ApcMin/+, a murine model of intestinal tumors. MATERIALS AND METHODS: Using GPR43-/- ApcMin/+ and GPR43+/- ApcMin/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways. RESULTS: Our results revealed that GPR43 deficiency resulted in increased tumor numbers in ApcMin/+ mice. Ki67 was highly expressed in GPR43-/- mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088). CONCLUSION: Collectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway.

The Kobe University Human Intestinal Microbiota Model for gut intervention studies.

The human gut harbors a complex microbial community that performs a range of metabolic, physiological, and immunological functions. The host and its inhabiting microorganisms are often referred to as a "superorganism." Dysbiosis of gut microflora has been associated with the pathogenesis of intestinal disorders including inflammatory bowel disease, colorectal cancer, and extra-intestinal disorders such as cardiovascular disease. Therefore, gut microbiome interventions are important for the prevention and treatment of diseases. However, ethical, economic, scientific, and time constraints limit the outcome of human intervention or animal studies targeting gut microbiota. We recently developed an in vitro batch fermentation model (the Kobe University Human Intestinal Microbiota Model, KUHIMM) that is capable of hosting a majority of gut microbial species in humans and also detects the metabolites produced by microorganisms in real time. In this mini review, we elucidated the characteristics of the KUHIMM and its applicability in analyzing the effect of diet, drugs, probiotics, and prebiotics on intestinal bacteria. In addition, we introduce as examples its application to disease models, such as ulcerative colitis, in which intestinal bacteria are intricately involved in the process of pathogenesis. We also discuss the potential of the KUHIMM in precision medicine. KEY POINTS: • In vitro gut fermentation model to simulate human colonic microbiota • Screening of potential prebiotics and probiotic candidates in healthy model • Construction of disease models of ulcerative colitis and coronary artery disease.

Adrenic acid induces oxidative stress in hepatocytes.

Adrenic acid (ADA), which is an endogenously synthesized polyunsaturated free fatty acid, was significantly increased in nonalcoholic fatty liver disease (NAFLD) patients and NAFLD-model mice compared with the corresponding controls in our previous study. To elucidate the involvement of ADA in NAFLD and nonalcoholic steatohepatitis (NASH), we examined ADA-induced lipotoxicity in human hepatocarcinoma HepG2 cells. The ROS production in HepG2 cells was increased by exposure to ADA. It was also shown that the treatment with ADA decreased cell viability in a dose-dependent manner. The N-Acetyl-L-Cysteine pretreatment counteracted this ADA-induced ROS production and cell death. Furthermore, ADA modulated the expressions of SOD2, HO-1 and Gpx1 as antioxidant enzymes. These findings suggest that ADA could induce oxidative stress accompanied by cell death, providing new insights into lipotoxicity that is involved in the pathogenesis of NAFLD and NASH.

Bacillus coagulans SANK 70258 suppresses Enterobacteriaceae in the microbiota of ulcerative colitis in vitro and enhances butyrogenesis in healthy microbiota.

The aim of this study was to clarify the effect of the spore-forming and lactic acid-producing probiotic strain, Bacillus coagulans SANK 70258, on human colonic microbiota of healthy subjects and ulcerative colitis patients. A model culture system was employed to construct the in vitro human colonic microbiota, to retain the bacterial species richness and simulate the patient's disordered composition, from the fecal inoculum. Bacterial 16S rRNA gene sequencing confirmed that administration of B. coagulans SANK 70258 (at an initial concentration of 4 × 107-total cells/mL) suppressed bacteria related to the family Enterobacteriaceae in the microbiota models for both healthy subjects (P = 0.016) and ulcerative colitis patients (P = 0.023). In addition, administration of B. coagulans SANK 70258 increased bacteria related to the family Lachnospiraceae (P = 0.031), thereby enhancing butyrate production (P = 0.031) in the microbiota models of healthy subjects. However, these changes were not observed in the microbiota models of ulcerative colitis patients, likely owing to the low abundance of Lachnospiraceae species. This study demonstrates the potential of B. coagulans SANK 70258 to exhibit antimicrobial activity against harmful organisms in patients with ulcerative colitis, while improving the intestinal microenvironment by increasing butyrogenesis in healthy persons. KEY POINTS: • B. coagulans SANK 70258 treatment reduced colonic Enterobacteriaceae species. • B. coagulans SANK 70258 treatment enhanced butyrogenesis in healthy individuals. • B. coagulans SANK 70258 treatment increased Lachnospiraceae in healthy persons. • B. coagulans SANK 70258 improves the colonic microenvironment in ulcerative colitis.

Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis.

BACKGROUND: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. METHODS: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. RESULTS: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei. CONCLUSIONS: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

Role of eosinophils in a murine model of inflammatory bowel disease.

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), which is triggered spontaneously by unknown mechanisms and manifests as chronic and relapsing inflammatory conditions in the colon. Eosinophil infiltration is often observed in the colonic tissue of ulcerative colitis patients. However, the role of eosinophils in the disease has not been well defined. The aim of this study is to investigate the role of eosinophils in colonic inflammation using the murine model of spontaneous colitis. CC chemokine receptor type 3 (CCR3) and interleukin (IL)-10 double knockout mice (CCR3-/-;IL-10-/-) were utilized to evaluate the function of eosinophils in colitis. The levels of colitis were evaluated by colonoscopy, histology, and real-time PCR measurements to determine expression levels of inflammatory cytokines in the colonic tissue. The levels of cytokines produced by T cells in mesenteric lymph nodes were evaluated by ELISA. There was no significant difference in endoscopic and histological scores between the groups of CCR3-/-;IL-10-/- mice and control CCR3+/-;IL-10-/- mice. There was also no significant difference in the expression levels of pro-inflammatory cytokines in the intestinal tissue between the two groups. Similar results were found for IL-17A and interferon gamma (IFN-γ) production from mesenteric lymph node-derived T cells. Our data indicate that eosinophils do not play a significant role in the immunopathology of colitis in IL-10-/- mice.

Novel per-oral endoscopic myotomy method preserving oblique muscle using two penetrating vessels as anatomic landmarks reduces postoperative gastroesophageal reflux.

BACKGROUND AND AIM: One of the main concerns related to peroral endoscopic myotomy (POEM) is postoperative gastroesophageal reflux (GER). The two penetrating vessels (TPVs) that are found at the boundary between the circular and oblique muscles in the posterior cardia wall have been suggested to be a good indicator of the optimal distal extent of POEM. However, the effect of performing myotomy using the TPVs as an anatomical reference on the frequency of post-POEM GER has not been studied. METHODS: This study involved consecutive patients who underwent POEM for the treatment of achalasia between April 2015 and June 2017. All enrolled patients underwent POEM in the 5 o'clock position and were divided into two groups: the conventional line group (CL group, n = 31), in which the TPVs were not exposed during submucosal tunnel dissection in the cardia, and the TPVs line group (TPVs group, n = 83), in which the TPVs were exposed and gastric myotomy was performed along the right side of the TPVs to preserve the oblique muscle. Examinations for post-POEM GER were conducted 3 months after the POEM. RESULTS: The frequency of grade B or higher reflex esophagitis was 26/83 (31.3%) in the TPVs group and 18/31 (58.1%) in the CL group (P = 0.017). Nine of 83 patients (10.8%) had GER symptoms in the TPVs group, and six of 31 (19.4%) had GER symptoms in the CL group (P = 0.23). CONCLUSIONS: The novel myotomy method preserving oblique muscle using TPVs as anatomical landmarks significantly reduced the frequency of post-POEM GER.

Pancreatic inflammation and atrophy are not associated with pancreatic cancer concomitant with intraductal papillary mucinous neoplasm.

BACKGROUND: Inflammation-induced carcinogenesis in pancreatic ductal adenocarcinoma (PDAC) has been reported; however, its involvement in PDAC with intraductal papillary mucinous neoplasm (IPMN) remains unclear. We herein investigated the relationship between pancreatic atrophy and inflammation and the incidence of PDAC concomitant with IPMN. METHODS: This study included 178 consecutive patients who underwent surgical resection for PDAC with IPMN (N = 21) and IPMN (N = 157) between April 2001 and October 2016. A multivariable logistic regression analysis was conducted to assess the relationship between pancreatic inflammation and atrophy and the incidence of PDAC concomitant with IPMN, with adjustments for clinical characteristics and imaging features. Pathological pancreatic inflammation and atrophy were evaluated in resected specimens. RESULTS: High degrees of pancreatic inflammation and atrophy were not associated with the incidence of PDAC with IPMN (multivariable odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.07 to 3.33, P = .52, adjusted by clinical characteristics, OR = 0.9, 95% CI = 0.10 to 5.86, P = .91, adjusted by imaging studies; OR = 0.2, 95% CI = 0.009 to 1.31, P = .10, adjusted by clinical characteristics, OR = 0.2, 95% CI = 0.01 to 1.43, P = .12, adjusted by imaging studies, respectively). CONCLUSIONS: Pancreatic inflammation and atrophy were not associated with pancreatic cancer concomitant with IPMN.

Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria.

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it. METHODS: Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration. RESULTS: Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution. CONCLUSIONS: Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.

Two penetrating vessels as a novel indicator of the appropriate distal end of peroral endoscopic myotomy.

BACKGROUND AND AIM: One of the challenges during peroral endoscopic myotomy (POEM) is ensuring the appropriate length of myotomy on the gastric side. To determine the appropriate distal end of the gastric myotomy, we focused on the two penetrating vessels (TPVs) found in the gastric cardia during POEM. In the present study, we evaluated whether the TPVs could serve as an accurate indicator of the appropriate distal end of the gastric myotomy. METHODS: All patients who underwent POEM between March and August 2016 were included for this study. When making the submucosal tunnel in the 5 o'clock direction into the stomach, two vessels penetrating through the circular muscle along the edge of oblique muscle in the cardia can be exposed. We designated these two vessels as TPVs. The myotomy was extended until the second TPVs was exposed. The anal end of the submucosal tunnel was confirmed by the double-scope POEM technique, and the length from the gastroesophageal junction to the anal side end of the myotomy was measured by the scale on the endoscope. RESULTS: Among 37 patients who underwent myotomy in the 5 o'clock position, TPVs were found in 34 patients (91.2%). Sufficient submucosal tunneling on the gastric side was confirmed by the double-scope POEM technique in these 34 patients. Median length of the gastric myotomy was 3.0 cm (range 2-4 cm). CONCLUSION: TPVs appears to be a simple and reliable indicator to determine the appropriate distal end of myotomy.

Indigo Naturalis Ameliorates Oxazolone-Induced Dermatitis but Aggravates Colitis by Changing the Composition of Gut Microflora.

BACKGROUND: Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. METHODS: A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. RESULTS: IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. CONCLUSIONS: Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions).

Efficacy of a new hemostatic forceps during gastric endoscopic submucosal dissection: A prospective randomized controlled trial.

BACKGROUND AND AIM: Currently, endoscopic submucosal dissection (ESD) is a widely accepted standard treatment for early gastric cancer, but one challenging aspect of ESD is hemostasis. We developed a new hemostatic forceps (FD-Y0007) with the aim of achieving more effective hemostasis and investigated the hemostatic ability of the FD-Y0007 during gastric ESD in humans. METHODS: This study was a prospective randomized controlled trial, which was conducted at a cancer referral center. Sixty-six patients who were scheduled to undergo ESD were enrolled and randomly assigned to either the Coagrasper or the FD-Y0007, which was used for hemostasis throughout the case. The primary end point was the time required to obtain hemostasis, which was measured for the first episode of bleeding during each case. RESULTS: Hemostasis time for the first bleeding episode during ESD was 73.0 s for the Coagrasper and 21.5 s for the FD-Y0007 (P < 0.001). When all episodes of bleeding were included, hemostasis time was 56.8 s in the Coagrasper group and 25.5 s in FD-Y0007group (P < 0.0001). The frequency of adverse events (perforation: 3.4% vs 7.1%; delayed bleeding: 0% vs 0%) was not significantly different between the two groups. CONCLUSIONS: Compared with the Coagrasper, the FD-Y0007 efficiently reduces the hemostatic time during gastric ESD with no increase in adverse events.

Predictive value of low serum pancreatic enzymes in invasive intraductal papillary mucinous neoplasms.

BACKGROUND: Despite evidence suggesting a role of chronic pancreatitis in pancreatic carcinogenesis, its relationship with invasive intraductal papillary mucinous neoplasms (IPMN) remains unclear. Low levels of pancreatic enzymes are predictive markers of advanced chronic pancreatitis. We investigated whether low pancreatic enzyme levels were associated with a higher incidence of invasive IPMN. METHODS: This study included 146 consecutive patients who underwent surgical resection of IPMN between April 2001 and October 2014. Multivariable logistic regression analysis was conducted to assess the association between serum pancreatic enzymes and the incidence of invasive IPMN, with adjustment for clinical characteristics including alcohol consumption. The association of serum pancreatic enzymes with pathological pancreatic atrophy and inflammation in areas adjacent to or distant from the tumor was also evaluated. RESULTS: Low serum levels of pancreatic amylase and lipase were associated with a higher incidence of invasive IPMN (multivariable odds ratio [OR] = 9.6, 95% confidence interval [CI] = 2.99 to 35.1, P = 0.0001; OR = 14.2, 95% CI = 2.77 to 112, P = 0.001, respectively). Low serum pancreatic amylase and lipase levels were also associated with higher grade pancreatic atrophy in areas adjacent to the tumor (P = 0.011 and P = 0.017, respectively) and in areas distant from the tumor (P = 0.0002 and P = 0.001, respectively). Furthermore, low serum pancreatic amylase and lipase levels were associated with higher grade inflammation in areas distant from the tumor (P < 0.0001 and P = 0.001, respectively). CONCLUSIONS: Low serum pancreatic enzymes may be a predictive marker of invasive IPMN. Excessive alcohol consumption did not influence the association of low pancreatic enzyme levels with invasive IPMN.

Feasibility and safety of endoscopic submucosal dissection for lesions involving the ileocecal valve.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) has been applied to treat early colorectal cancers. The aim of this study was to clarify the clinical course of ESD for lesions involving the ileocecal valve (ICV) by evaluating the successful resection rates, and the risk and frequency of adverse events. PATIENTS AND METHODS: The outcome of ESD on 38 ICV lesions was compared with the outcome of 132 cecal lesions that did not involve the ICV or appendiceal orifice during the same study period. The factors related to longer procedure time, postoperative stricture development, and tumor recurrence were investigated for ESD of ICV lesions. RESULTS: There was no significant difference between the ICV and non-ICV groups in the en block resection rates. The median procedure time was significantly longer in the ICV group than in the non-ICV group, with a point estimate of the difference of 37 minutes (95 % confidence interval [CI] 20.00 to 56.00; P  < 0.01). None of the patients developed symptomatic post-ESD stricture or tumor recurrence. ESD procedure duration was ≥ 120 minutes in 16 lesions and < 120 minutes in 22 lesions of the ICV group. A specimen diameter of ≥ 40 mm and tumor extension into terminal ileum were factors related to a longer procedure time (odds ratio [OR] 8.40, 95 %CI 1.53 to 46.10, P = 0.01; OR 10.60, 95 %CI 2.17 to 51.40, P  < 0.01, respectively). CONCLUSIONS: ICV lesions can be resected by ESD without major adverse events or causing symptomatic stricture development. However, ESD for ICV lesions should be performed only by expert endoscopists, as the procedure requires accomplished endoscopic skill and experience.

Risk of stricture after endoscopic submucosal dissection for large rectal neoplasms.

BACKGROUND AND STUDY AIMS: Improvements in the endoscopic submucosal dissection (ESD) technique have made circumferential ESD in the rectum possible. However, little is known about the clinical course after extensive ESD in the rectum. The aim of this study was to determine the stricture risk in the rectum after total or subtotal circumferential ESD. PATIENTS AND METHODS: A total of 69 patients with 69 rectal tumors that required ≥ 75 % circumferential resection were identified at Kobe University Hospital and an affiliated hospital between April 2005 and May 2014. Among the patients, 61 were available for evaluation of stricture development, either by follow-up colonoscopy or by surgical specimens. The rate and possible risk factors of post-ESD strictures were investigated. RESULTS: Post-ESD rectal strictures developed in 12 patients (19.7 %). Patients who underwent total circumferential ESD developed a stricture (5/7, 71.4 %) more frequently than those with subtotal (≥ 90 %) ESD (7/16, 43.8 %). Patients undergoing an ESD procedure that involved < 90 % of the circumference did not develop strictures. The strictures were membranous or < 10 mm long in all cases. Of the patients with stricture, 11 received endoscopic balloon dilation and one received bougie with short-caliber-tip transparent hood; all strictures improved following dilation therapy. Statistical analysis revealed that ≥ 90 % circumferential resection was an independent risk factor for stricture, whereas morphology and size were not. CONCLUSIONS: Patients who underwent total or subtotal circumferential ESD of a rectal tumor had a high risk of stricture formation. Dilation helped to alleviate the stenosis.Study registered at University Hospital Medical Information Network (UMIN 000016559).

Endoscopic submucosal dissection of cecal lesions in proximity to the appendiceal orifice.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is performed for treatment of various gastrointestinal lesions; however, the cecum in proximity to the appendiceal orifice remains a challenging area. We reviewed our experience with cecal ESD near the appendiceal orifice in order to clarify whether this procedure is a safe and effective therapeutic option. PATIENTS AND METHODS: We retrospectively reviewed ESD for lesions within approximately 12 mm of the appendiceal orifice at Kobe University Hospital and an affiliated hospital between January 2003 and December 2014. Lesions were classified as: Type 0, proximity to the appendiceal orifice but does not reach it; Type 1, reaches border of the appendix, but does not enter orifice; Type 2, enters orifice, and transition to normal appendiceal mucosa is discernible on inspection of the appendiceal lumen; and Type 3, enters orifice deeply and tumor edge cannot be observed. ESD was not performed for Type 3 lesions unless appendectomy was performed prior to ESD. RESULTS: A total of 76 lesions satisfied the inclusion criteria (47 Type 0 lesions, 20 Type 1, 6 Type 2, and 3 Type 3). En bloc resection was achieved in 72 lesions (94.7 %). Median specimen size was 49 mm (range 15 - 114 mm), and median tumor size was 35.5 mm (10 - 110 mm). One patient experienced postoperative bleeding, which was treated by endoscopic hemostasis. Another patient who experienced intraoperative perforation and was treated by clip closure later developed appendicitis; he underwent emergency ileocecal surgical resection. Another patient experienced postoperative appendicitis and recovered with antibiotic treatment. CONCLUSIONS: ESD in close proximity to the appendiceal orifice seems safe and effective.

Disseminated nocardiosis during systemic steroid therapy for the prevention of esophageal stricture after endoscopic submucosal dissection.

An 85-year-old man underwent endoscopic submucosal dissection for a large superficial esophageal epithelial neoplasm, which required removal of 95% of the circumference of the esophageal mucosa. Steroids were given orally to prevent esophageal stricture starting on day 3 postoperatively. In the 6th week of steroid treatment, he developed high fever without other symptoms. Chest computed tomography revealed a nodular lesion in the lung. Sputum sample showed Gram-positive, branching, filamentous bacteria, and a diagnosis of nocardiosis was suspected. Brain magnetic resonance imaging revealed multiple focal lesions which indicated dissemination of nocardiosis. Trimethoprim-sulfamethoxazole was immediately started, which led to the disappearance of pulmonary and cerebral nocardiosis with alleviation of fever. Recently, oral steroid treatment has been widely used for the prevention of esophageal stricture. However, the present case indicates the risk of life-threatening infection and the importance of close monitoring of this treatment.

Metabolomics-based search for therapeutic agents for non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the commonest form of chronic liver disease in developed countries. Non-alcoholic steatohepatitis (NASH), which represents advanced stage NAFLD, is increasingly being recognized as a major cause of liver-related morbidity and mortality. However, no effective drugs against NASH have yet been developed. Therefore, we searched for candidate therapeutic agents based on the changes in levels of hepatic metabolites via gas chromatography mass spectrometry (GC/MS)-based metabolome analysis of livers from methionine-choline deficient (MCD) diet-fed mice, a mouse model of NASH. METHODS: The metabolites were extracted from the livers of the MCD diet-fed mice and then analyzed using GC/MS. Subsequently, the MCD diet-fed mice were supplemented with hypotaurine, and the therapeutic effects of hypotaurine against steatohepatitis were evaluated. RESULTS: Ninety-nine metabolites were detected in the livers of the MCD diet-induced steatohepatitis model mice. Among these metabolites, hypotaurine exhibited the greatest decrease in its concentration in the mice. Supplementation with 2 mmol/kgBW hypotaurine attenuated liver injuries and fat accumulation caused by the MCD diet-induced steatohepatitis. Furthermore, 10 mmol/kgBW hypotaurine supplementation ameliorated fibrosis and oxidative stress induced by the MCD diet. CONCLUSION: The present metabolome analysis-based study demonstrated that hypotaurine is a novel candidate therapeutic agent for NASH.