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OBJECTIVES Data on the long-term outcomes of endoscopic submucosal dissection (ESD) performed in elderly patients with early colorectal cancer (CRC) are limited. We analyzed the prognosis of elderly CRC patients, not only from the viewpoint of treatment curability but also from the patients' baseline physical condition assessed by several indexes. METHODS A retrospective analysis of 729 patients aged ≥75 years who underwent ESD for Tis/T1 CRC in 16 institutions was conducted. The patients were classified into three groups based on curability: curative ESD (Group A, n = 582), non-curative ESD with additional surgery (Group B, n = 60), and non-curative ESD without additional surgery (Group C, n = 87). Overall survival (OS) was compared among the groups, and factors associated with reduced OS were investigated. RESULTS The median follow-up periods in Groups A, B, and C were 41, 49, and 46 months, respectively (P = 0.62), during which 92 patients died. Two patients (0.3%) in Group A, none (0%) in Group B, and three (3.4%) in Group C died of CRC. Three-year OS rates in Groups A, B, and C were 93.9%, 96.1%, and 90.1%, respectively, without a significant difference (P = 0.07). Multivariate analysis indicated low (

Background The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. Methods This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, β-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. Results A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30–0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. Conclusion Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Environmental factors are suggested to affect the pathogenesis of several diseases, including inflammatory bowel disease (IBD). The seasonality of disease onset and exacerbation in IBD, however, are not well established. We herein aimed to clarify the disease seasonality and to investigate the underlying characteristics in IBD patients exhibiting seasonality of the disease course. This was a multicenter observational study comprising 20 institutions (Osaka Gut Forum) in Japan. Data were collected from November 2013 to August 2014 using survey forms for physicians and questionnaires for patients. Multivariate analysis was performed to clarify the independent factors affecting disease seasonality. A total of 1055 patients, including 298 patients with Crohn’s disease (CD) and 757 patients with ulcerative colitis (UC), were enrolled. The proportion of CD patients with disease onset in the summer was significantly larger than that in the other seasons, while UC patients exhibited no seasonality of disease onset. More than half of the IBD patients (51.1%) experienced seasonal exacerbation of IBD, and winter was the most common season for disease exacerbation in both CD and UC patients. Seasonality of disease onset and exacerbation was observed in young-onset patients (≤40 years old), but not in elderly-onset patients. Age at onset was independently associated with the seasonality of both disease onset and exacerbation. Seasonality of disease onset and exacerbation was observed especially in young-onset IBD patients. Underlying pathophysiologic triggers for disease initiation and exacerbation may be influenced by age at disease onset.

Background and aims Psychologic stress can affect the pathogenesis of inflammatory bowel disease (IBD), but the precise contribution of psychologic stress to IBD remains unclear. We investigated the association of psychologic stress with disease activity in patients with IBD, especially in terms of mental state and sleep condition. Methods This was a multi-center observational study comprising 20 institutions. Data were collected using survey forms for doctors and questionnaires for patients, and the association of psychologic stress with clinical parameters was investigated. Mental state was evaluated using the Center for Epidemiologic Studies Depression (CES-D) scale, and sleep condition was evaluated by querying patients about the severity of insomnia symptoms. Results A total of 1078 IBD patients were enrolled, including 303 patients with Crohn’s disease and 775 patients with ulcerative colitis. Seventy-five percent of IBD patients believed that psychologic stress triggered an exacerbation of their disease (PSTE group) and 25% did not (non-PSTE group). The CES-D scores were significantly higher for patients with clinically active disease than for those in remission in the PSTE group (median (interquartile range) = 7 (4–9.5) vs. 5 (3–7), p < .0001), but not in the non-PSTE group (5 (2–8) vs. 4 (3–7), p = 0.78). Female sex and disease exacerbation by factors other than psychologic stress were independent factors of psychologic stress-triggered disease exacerbation. Also, patients with insomnia had higher disease activity than those without insomnia, especially in the PSTE group. Conclusions A worsened mental state correlates with disease activity in IBD patients, especially those who believe that their disease is exacerbated by psychologic stress.

Gastric cancer and liver cirrhosis (LC) are often comorbid. However, little is known about the clinical outcomes of gastric endoscopic submucosal dissection (ESD) in patients with comorbid LC. This case–control study used a multicentre retrospective cohort. We identified 69 LC patients from the cohort of patients with early gastric cancer, who underwent gastric ESD at 12 hospitals from March 2003 to November 2010. Using the propensity score matching method, 69 patients without LC were used to compare the short- and long-term outcomes of ESD. Among the 69 LC patients, 53 (77 %) were Child-Pugh grade A (CP-A) and 16 (28 %) had past or present histories of hepatocellular carcinoma (HCC). Short-term outcomes did not differ between the LC patients and controls or between the CP-A and CP-B/C patients. Although the LC patients had significantly worse long-term outcomes than the controls (the 5-year overall survival rates were 60 vs. 91 %, respectively), patients with CP-A liver function without HCC histories had an overall survival almost equivalent to that of patients without LC (controls). LC patients appear to be good candidates for ESD if they have CP-A liver function and no history of HCC. Although their short-term outcomes were not inferior, the patients with Child-Pugh grades B/C or with histories of HCC benefited less from ESD.

Treatment with endoscopic submucosal dissection (ESD) for gastric noninvasive neoplasia (NIN) diagnosed by endoscopic forceps biopsy specimen, whether as a follow-up or "total incisional biopsy", is controversial. To validate the use of ESD for total incisional biopsy in NIN, we examined the underdiagnosis rate of NIN and the rates of complication associated with ESD.This is a cross-sectional multicenter retrospective study from 10 hospitals. Subjects diagnosed with NIN (equivalent to category 3 or 4.1 of the Vienna classification) by endoscopic forceps biopsy and treated with ESD were included. From March 2003 to December 2009, a total of 468 subjects were included and analyzed. The underdiagnosis rate was defined as the proportion of lesions diagnosed with adenocarcinoma after ESD. We assessed the complete en-bloc resection rate and the complication rate of ESD.Among the 468 subjects with NIN, 205 were diagnosed with adenocarcinoma after ESD, with an underdiagnosis rate of 44% (95% confidence interval: 39-49%). Two submucosal cancer lesions had invaded beyond 500 μm and one had lymphatic involvement. The complete en-bloc resection rate was 97%. The incidences of post-ESD bleeding, perforation, and serious complications were 5.5, 4.7, and 0.43%, respectively. There were no procedure-related deaths.In this large-scale, multicenter cross-sectional study, over 40% of the noninvasive gastric neoplasia specimens were determined to have adenocarcinoma, and the ESD-related complication rate was relatively low. Therefore, ESD was useful and may be a therapeutic option for gastric NIN.

Double-balloon endoscopy (DBE) examinations are not yet widely accepted as routine procedures for examining the small bowel of patients with Crohn's disease (CD).To evaluate the feasibility and usefulness of DBE for CD in tertiary-care hospitals.Between July 2004 and September 2008, 1444 DBE procedures were performed for 704 patients in 6 tertiary-care hospitals. Patient profile, indication, diagnosis and treatment of DBE were evaluated using a multicenter database.DBE examinations were most frequently performed in 75 patients with CD, corresponding to 10.5% of all the patients examined by DBE. Fifty patients were diagnosed with CD before DBE, while DBE was performed for the diagnosis of 25 new CD patients. Small bowel lesions were often detected even when the terminal ileum was not involved. In the 75 patients, 21 patients were asymptomatic at the time of DBE examinations. Active inflammatory lesions were detected in 51.2% of the CD patients, and were even detected in 33.3% of the asymptomatic CD patients. The treatment was altered in 53.3% of the CD patients after the DBE evaluation. No severe complications were experienced.DBE procedures can be safely performed in patients with CD and should be considered for the precise evaluation of and to determine the treatment strategy for CD.

Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE2 levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE2 synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE2 levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE2 synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE2 upregulation in rats.

Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis–related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src – or v-H-ras –expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates. GASTROENTEROLOGY 2002;122:331-339

Background and study aims: The number of patients with chronic kidney disease (CKD) is increasing worldwide and gastric cancer sometimes occurs with CKD. However, the safety and feasibility of endoscopic submucosal dissection (ESD) for patients with CKD are not clear. The aim of this study is to clarify the feasibility and safety of gastric ESD for patients with CKD. Patients and methods: This was a multicenter retrospective cohort study. In total, 144 patients with CKD who underwent gastric ESD between May 2003 and October 2012 were enrolled. The patients were divided into three groups: stage 3 (estimated glomerular filtration rate [eGFR]: 30 – 59 mL/min), stage 4 (eGFR: 15 – 29 mL/min), and stage 5 (eGFR

Approximately half of all patients with chronic hepatitis C show an initial biochemical response to interferon, but only 15% to 20% of patients achieve a sustained response. We studied the efficacy of retreatment with interferon for patients with chronic hepatitis C who showed transient biochemical responses to initial treatment. Thirty patients who relapsed were retreated 1 to 52 months (median 14) after the end of initial treatment, according to the previously used regimens. The responses were correlated with the pre-retreatment patient data. The liver histologic grades, compared with those found before the initial treatment, were better in eight (27%) patients but worse in six (20%), whereas the fibrosis stage was improved in five (17%) but worsened in eight (27%). All patients displayed end-of-retreatment biochemical responses. Of the 30 patients, 10 (33%) achieved sustained aminotransferase normalization and serum hepatitis C virus (HCV) RNA clearance, but the remaining 20 patients showed relapse within 1 year after cessation of retreatment. Univariate analysis associated the sustained response with low pre-retreatment viral loads (0.8 +/- 0.7 MEq/mL vs. 9.1 +/- 6.5 MEq/mL; p = 0.006), short treatment intervals (13 +/- 13 months vs. 22 +/- 14 months; p = 0.031), and low histologic grades (1.3 +/- 0.7 vs. 1.9 +/- 0.7; p = 0.039). However, multivariate analysis indicated that only the pre-retreatment viral load was predictive of the sustained response (p = 0.049). These findings suggest that transient responders to interferon are likely to respond to retreatment but the achievement of a sustained response depends on the HCV viral load before retreatment.

Background: Gastric antral vascular ectasia (GAVE), as a cause of upper gastrointestinal bleeding, has been treated surgically, endoscopically and pharmacologically for the past 20 years. Methods: We analyzed the clinical effect of endoscopic treatment for 12 cases of GAVE diagnosed at Osaka National Hospital between January 1993 and October 1998. Results: Eight of the 12 cases were treated endoscopically due to marked anemia and histories of gastrointestinal bleeding. All had chronic liver disease (CLD). Mean age was 69 years on diagnosis. Male to female ratio was 1 : 1. Gastric antral vascular ectasia was a cause of 3.9% of bleeding associated with CLD. The modes of endoscopic treatment of the eight cases were laser photocoagulation (1), electrocautery (3), and heater probe thermocoagulation (4). The initial treatment required an average of 5.1 sessions over a period of 43 days. Initial hemostasis was successful in all cases. Treatments for recurrent bleeding were necessary in six cases within 9.2 months, and endoscopic coagulation was again effective in two cases. Corticosteroids were effective in two of three cases resistant to endoscopic therapy. Mean follow-up period after initial treatment was 2.8 years. The mean total number of therapeutic endoscopy sessions was 9.6. Conclusion: Endoscopic treatments and/or corticosteroids have yielded sufficient results in the hemorrhage of GAVE. Factors affecting the recurrence of GAVE need to be analyzed in CLD patients.

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

G A A b st ra ct s ethical committee and written informed consent was obtained from all patients. Subjects randomly assigned to three treatment groups for 10 days: Standard triple therapy (STT), Esomeprazole (40 mg b.i.d.) + clarithromycin (500 mg b.id.) + amoxicillin (1,000 mg b.i.d.). Levofloxacin triple therapy (LTT): Esomeprazole (40 mg b.i.d.) + levofloxacin (500 mg once a day) + amoxicillin (1,000 mg b.i.d.) and Levo-Clari triple therapy LCT: Esomeprazole (40 mg b.i.d.) + clarithromycin ((500mg b.i.d.) + levofloxacin (500mg once a day). The allocation was concealed. All were H. pylori positive. Antimicrobial susceptibility was determined by agar dilution and by direct sequencing of PCR products. Post treatment H. pylori status was determined by the 13C-UBT at least 8 weeks after the completion of treatment. The results and analysis of clinical trial was by intention-to-treat (ITT) and per-protocol (PP). Results 240 patients were enrolled between February 2008 and February 2011, 80 patients in each treatment group. ITT results were: STT 71% (95% CI 61% 82%), LTT 75% (95% CI 65% -85%) and LCT 79% (95% CI 70% -91%). PP results were 71%, 75% and 83%, respectively (p = n.s.) The most common mutation resulting in clari resistance was A2143G, and for levofloxacin, mutations D91G, N87K and N871. The relative risk (RR) of failure in relation to specific mutations were: for 23S rRNA in STT 6 and 2.9 for LCT. The (RR) for presence of mutations in both gene gyrA and 23S rRNA in LTT was 14. We performed a logistic regression model to estimate the probability of treatment success. The model variables were associated with the presence of A2143G mutation, N87I, D91G. The probability of treatment success in patients without mutation was 98% compared to 13% for those with mutations in both genes. Adverse events occurred in all three treatment groups and were mild or moderate, with no residual effects. Metallic taste was the most common adverse effect, followed by diarrhea, abdominal pain and nausea. 2 patients required stopping treatment for diarrhea in the LCT group. Conclusion Triple standard therapy and triple therapies containing levofloxacin no provided acceptable cure rates in Bogota because of high rates of clarithromycin and levofloxacin resistance.

AIM: To evaluate the efficacy and safety of esomeprazole-based triple therapy compared with lansoprazole therapy as first-line eradication therapy for patients with Helicobacter pylori (H. pylori) in usual post-marketing use in Japan, where the clarithromycin (CAM) resistance rate is 30%. METHODS: For this multicenter, randomized, open-label, non-inferiority trial, we recruited patients (≥ 20 years of age) with H. pylori infection from 20 hospitals in Japan. We randomly allocated patients to esomeprazole therapy (esomeprazole 20 mg, CAM 400 mg, amoxicillin (AC) 750 mg for the first 7 d, with all drugs given twice daily) or lansoprazole therapy (lansoprazole 30 mg, CAM 400 mg, AC 750 mg for the first 7 d, with all drugs given twice daily) using a minimization method with age, sex, and institution as adjustment factors. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. H. pylori eradication was confirmed by a urea breath test from 4 to 8 wk after cessation of therapy. RESULTS: ITT analysis revealed the eradication rates of 69.4% (95%CI: 61.2%-76.6%) for esomeprazole therapy and 73.9% (95%CI: 65.9%-80.6%) for lansoprazole therapy (P = 0.4982). PP analysis showed eradication rate of 76.9% (95%CI: 68.6%-83.5%) for esomeprazole therapy and 79.8% (95%CI: 71.9%-86.0%) for lansoprazole therapy (P = 0.6423). There were no differences in adverse effects between the two therapies. CONCLUSION: Esomeprazole showed non-inferiority and safety in a 7 day-triple therapy for eradication of H. pylori compared with lansoprazole.

Effectiveness of Double Balloon Enteroscopy for Obscure Gastrointestinal Bleeding : a Multicenter Retrospective Cohort Study by Osaka Gut Forum Akira Maekawa*, Masato Komori, Satoshi Egawa, Shinjirou Yamaguchi, Kunio Suzuki, Sachiko Nakajima, Hiroyuki Ogawa, Takashi Ueda, Satoshi Hiyama, Takahiro Inoue, Takuya Yamada, Shinichiro Shinzaki, Tsutomu Nishida, Hideki Iijima, Masahiko Tsujii, Tetsuo Takehara Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Gastroenterology, Osaka Rousai Hospital, Sakai, Japan; Department of Gastroenterology, Kansai Rousai Hospital, Amagasaki, Japan; Department of Gastroenterology, Osaka Police Hospital, Osaka, Japan; Department of Internal Medicine, Saiseikai Senri Hospital, Suita, Japan; Department of Gastroenterology, NTT-West Osaka Hospital, Osaka, Japan; Department of Gastroenterology, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan; Department of Gastroenterology, Yao Municipal Hospital, Yao, Japan Background and Aim: Double-balloon enteroscopy (DBE) enabled endoscopic approaches to the small intestine and is useful to make accurate diagnosis of the responsible lesions of bleeding in patients with obscure gastrointestinal bleeding (OGIB). It is unknown, however, about the efficacy of DBE in association with bleeding condition. We aimed to investigate the efficacy of DBE for the diagnosis of occult and overt OGIB in a multi-center cohort. Methods: We analyzed 323 patients who underwent DBE due to OGIB between June 2004 and September 2012 in tertiary-care hospitals of Osaka Gut Forum. Overt OGIB was defined as with visible GI bleeding, while occult OGIB was with anemia or with a positive fecal occult blood test. Overt OGIB was further differentiated in terms of DBE findings in active overt (i.e., existence of endoscopic ongoing bleeding or bloody residue) and inactive overt bleeding. Results: We performed 430 DBE in 277 patients with overt OGIB (162 male, 115 female; mean age, 67 years; range, 15-91 years) and 46 DBE in 82 patients with occult OGIB (29 male, 17 female; mean age, 66 years; range, 17-84 years). Detection rate of the bleeding lesion was 55% (152/277) in patients with overt OGIB, including ulceration in 53 patients (35%), vascular lesions in 35 patients (23%), and neoplastic lesions in 18 patients (18%). Seventy lesions were diagnosed in oral DBE, while 82 were diagnosed in anal DBE. Detection rate of bleeding lesion was 49% (21/46) in patients with occult OGIB and was similar to that of overt OGIB. These lesions included ulceration in 8 patients (38%), vascular lesions in 4 patients (19%), and neoplastic lesions in 4 patients (19%). Nine lesions were diagnosed in oral DBE, while 12 were diagnosed in anal DBE. In 277 patients with overt OGIB, 49 patients showed endoscopically active bleeding by DBE and 228 did not. The shorter time from bleeding symptom till DBE, the more active bleeding was detected. The proportion of ulcer lesions was lower in active bleeding patients (26%) than in inactive patients (38%). In contrast, vascular lesions were significantly higher in patients with active bleeding (33%) than that of patients with inactive bleeding (19%). Conclusions: The detection rate of the bleeding lesions using DBE was similar between overt and occult OGIB and ulceration is most commonly observed in both overt and occult OGIB. Endoscopists should bear in mind that the types of lesions responsible for bleeding are different in terms of bleeding conditions.