Naoki Ohmiya

BACKGROUND & AIMS: Indigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. METHODS: We performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with a value >1. Mucosal healing was also assessed at week 8. RESULTS: The trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6 months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0 g IN; and 81.0% to 2.0 g IN) (Cochran-Armitage trend test P < .0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, P = .0004) and the 2.0 g IN group (38.1%, (P = .0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% in the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed. CONCLUSIONS: In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/).

The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P < 0.05). Samples from EGC body group showed shorter telomere length than the samples from cancer-free body groups (P < 0.05). Conversely, samples from EGC ADJ group showed rather longer telomere length compared to the EGC body group (P < 0.05), which was also confirmed by the comparison of 35 matched samples (P = 0.0007). Among the samples after H. pylori eradication, shorter telomere length was associated with higher expression of IL-1B and NF-kB (P < 0.0001, 0.0006, respectively). Longer telomere length was also associated with higher expression of TNF-A (P = 0.01). Telomere shortening seems to be important initial steps in gastric cancer predisposition after H. pylori eradication, while it might shift to lengthening to acquire more aggressive pathway to develop cancer.

BACKGROUND AND AIM: Although several drugs may induce small-bowel mucosal injuries, it is unclear whether these injuries contribute to overt small-bowel bleeding. This study was designed to evaluate the associations between drug use and small-bowel mucosal injury and between these mucosal injuries and overt bleeding in a disease-relevant population. METHODS: We retrospectively studied patients with suspected small-bowel diseases who underwent capsule endoscopy between 2010 and 2013. Drug exposure, Charlson Comorbidity Index, smoking, and alcohol consumption were assessed before capsule endoscopy. Adjusted odds ratios (AOR) and confidence intervals (CI) were estimated for small-bowel mucosal injury and small-bowel overt bleeding. RESULTS: In total, 850 patients were analyzed during the study period. Median age was 64 years, and 544 patients (64.0%) were men. Among the patients with small-bowel mucosal injury (n = 60) and without mucosal injury (n = 705), use of non-steroidal anti-inflammatory drugs (NSAIDs) (AOR 1.8, 95% CI 1.01-3.31) was significantly associated with an increased risk of small-bowel mucosal injury compared with non-use. Patients with small-bowel mucosal injury with overt bleeding (n = 85) and without overt bleeding (n = 60) were compared, and no significant difference between the groups in the usage rates for NSAIDs, thienopyridine, other antiplatelets, anticoagulants, acetaminophen, tramadol hydrochloride, or steroids was revealed, even after adjusting for confounders. CONCLUSION: Although the use of NSAIDs was significantly associated with an increased risk of small-bowel mucosal injury, no significant associations were observed between the use of such drugs and small-bowel overt bleeding.

BACKGROUND AND AIM: Early-stage gastric cancer (EGC) found after H. pylori eradication often has non-tumorous epithelium on the tumorous tissue and/or surface differentiation of tumors, which may confuse endoscopic and histologic diagnosis. We investigated the diagnostic reliability of EGC using conventional white light endoscopy (WLE), chromoendoscopy (CE) using indigo carmine, and magnifying endoscopy with narrow band imaging (ME-NBI) in patients with EGC with or without history of prior H. pylori eradication therapy. METHODS: Diagnostic reliability of EGC by using the WLE, CE and ME-NBI was investigated in 71 EGC lesions diagnosed after successful H. pylori eradication (eradication group) and 115 EGC lesions with current H. pylori infection (control group). RESULTS: Diagnostic reliability of EGC was lower in the eradication group than in the control group using all three modalities. In particular, the diagnostic accuracy of CE in the eradication group was especially lower compared to that of the control group (WLE: 74.6% vs. 86.1%, P=0.05; CE: 64.8% vs. 91.3%, P<0.0001; ME-NBI: 88.7% vs. 98.2%, P=0.01). The ME-NBI scored better in comparison with WLE and CE in the eradication group (both P<0.05). The indistinct EGC lesions in the eradicated group by using CE were associated with the presence of histological changes such as non-tumorous epithelium on the tumor and/or surface differentiation of tumors (P=0.005). CONCLUSIONS: It should be noted that the diagnostic reliability of EGC after H. pylori eradication becomes lower especially using CE. Indistinguishable cases using CE are associated with histological findings such as non-tumorous epithelium on the tumor and/or surface differentiation of tumors.

Small intestinal ulcers include mucosal damage caused by drugs, particularly nonsteroidal anti-inflammatory drugs [NSAIDs], infectious diseases, and idiopathic inflammatory bowel disease. Previously, a group of Japanese investigators reported an unusual and uncommon type of enteritis and referred to the condition as chronic nonspecific multiple ulcers of the small intestine [CNSU]. CNSU is characterised by chronic blood and protein loss through persistent small intestinal ulcers. Recently, four candidate mutations in the solute carrier organic anion transporter family, member 2A1 [SLCO2A1] gene, encoding a prostaglandin transporter, were identified by whole-exome sequencing in patients with CNSU. However, because the name 'CNSU' was somewhat ambiguous, the more appropriate nomenclature of 'chronic enteropathy associated with the SLCO2A1 gene' [CEAS] has been suggested. CEAS ulcers are characterised by multiple, circular or eccentric oblique, shallow lesions with discrete margins. The most frequently affected site of CEAS is the ileum, in contrast to 'cryptogenic multifocal ulcerous stenosing enteritis [CMUSE]', for which the most frequent site is the jejunum. Impaired prostaglandin utilisation is thought to cause the small intestinal mucosal damage observed in CEAS, CMUSE, and NSAID-induced enteropathy. This review article focuses on endoscopic and clinical features of genetically diagnosed CEAS, accumulated in a nationwide survey, and illustrates the observations in the format of an atlas.

BACKGROUND AND AIM: Fusobacterium enrichment has been associated with colorectal cancer development. Ulcerative colitis (UC) associated tumorigenesis is characterized as high degree of methylation accumulation through continuous colonic inflammation. The aim of this study was to investigate a potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in UC. METHODS: In the candidate analysis, inflamed colonic mucosa from 86 UC patients were characterized the methylation status of colorectal a panel of cancer related 24 genes. In the genome-wide analysis, an Infinium HumanMethylation450 BeadChip array was utilized to characterize the methylation status of >450,000 CpG sites for fourteen UC patients. Results were correlated with Fusobacterium status. RESULTS: UC with Fusobacterium enrichment (FB-high) was characterized as high degree of type C (for cancer-specific) methylation compared to other (FB-low/neg) samples (P<0.01). Genes hypermethylated in FB-high samples included well-known type C genes in colorectal cancer, such as MINT2 and 31, P16 and NEUROG1. Multivariate analysis demonstrated that the FB high status held an increased likelihood for methylation high as an independent factor (odds ratio: 16.18, 95% confidence interval: 1.94-135.2, P=0.01). Genome-wide methylation analysis demonstrated a unique methylome signature of FB-high cases irrespective of promoter, outside promoter, CpG and non-CpG sites. Group of promoter CpG sites that were exclusively hypermethylated in FB-high cases significantly codified the genes related to the catalytic activity (P=0.039). CONCLUSION: Our findings suggest that Fusobacterium accelerates DNA methylation in specific groups of genes in the inflammatory colonic mucosa in UC.

BACKGROUND: Gastric cancer develops after successful H. pylori eradication in patients with severe atrophic gastritis. We classified atrophic and non-atrophic mucosa of gastric body using magnifying NBI endoscopy in patients after successful H. pylori eradication. MATERIALS AND METHODS: One hundred and twenty-five patients after successful H. pylori eradication (median period after eradication: 36 months) were enrolled. Magnifying NBI patterns in the uninvolved gastric body were divided into the following: restored-small, round pits, accompanied with honeycomb-like subepithelial capillary networks; atrophic-well-demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels. The subjects were also classified into the three types: Grade 0-restored pattern is shown in all or almost the entire area of gastric body; Grade 1-mixture of restored and atrophic pattern, there is a considerable portion of the atrophic area in the lesser curvature; Grade 2-atrophic pattern is shown in all or almost the entire area of the gastric body. RESULTS: Sensitivity and specificity for atrophic type for detection of histological intestinal metaplasia were 95.9 and 98.3%, respectively. No association was observed between the prevalence of Grades 0, 1 and 2 and duration after eradication, while grades 1 and 2 were significantly frequent in gastric cancer patients diagnosed both before (27/35: 77%) and after (23/31: 74%) eradication, compared to the cancer-free subjects (15/59: 25%) (P < 0.001). The grades 1 and 2 were also common in patients who underwent H. pylori eradication for gastric ulcer. CONCLUSIONS: Magnifying the NBI pattern well correlates with pathological status of gastric mucosa after H. pylori eradication and may predict gastric cancer occurrence.

Chromoendoscopy, narrow-band imaging (NBI), and confocal laser endomicroscopy (CLE) have been introduced in ulcerative colitis (UC)-associated neoplasia surveillance. We aimed to determine the ability of CLE to differentiate among UC-associated neoplasia (differentiated type or undifferentiated type), sporadic adenoma, and circumscribed regenerative lesions. Of 665 patients with UC, we carried out probe-based CLE (pCLE) on 12 patients with suspected UC-associated neoplasia in addition to magnifying chromoendoscopy with crystal violet and NBI. We compared pCLE findings with pathological diagnoses. pCLE could differentiate UC-associated differentiated cancer from other pathologies such as solitary adenoma and non-neoplastic circumscribed regenerative lesions on the basis of back-to-back orientation of crypts (P = 0.048), and UC-associated undifferentiated cancer from other pathologies on the basis of dark trabecular architecture (P = 0.015). Sensitivity, specificity, and accuracy of combination of back-to-back orientation of crypts and dark trabecular architecture for carcinoma or dysplasia were 100%, 83%, and 92%, respectively. In vivo microscopic observation with pCLE was helpful to evaluate the suspected UC-associated neoplasia.

Management of small bowel diseases has evolved since the advent of capsule endoscopy (CE) and balloon-assisted enteroscopy (BAE). One of the most common indications for enteroscopy is obscure gastrointestinal bleeding (OGIB), followed by small bowel stenosis, tumors, and inflammatory bowel disease. Although enteroscopes have been regarded as useful tools, correct guidelines are required to ensure that we manipulate these enteroscopes safely and efficiently in clinical practice. Herein, the Japanese Gastroenterological Endoscopy Society has developed 'Clinical Practice Guidelines for Enteroscopy' in collaboration with the Japanese Society of Gastroenterology, the Japanese Gastroenterological Association, and the Japanese Association for Capsule Endoscopy. These guidelines are based on the evidence available until now, but small bowel endoscopy is a relatively new technology, so the guidelines include recommendations based on a consensus reached among experts when the evidence has not been considered sufficient. These guidelines were not designed to be disease-based, but focus on how we should use small bowel CE and BAE in everyday clinical practice.

Residual DNA methylation in the gastric mucosa after Helicobacter pylori (H. pylori) eradication may have a role in gastric carcinogenesis. We examined the association between morphologic features and promoter methylation status of non-neoplastic gastric mucosa especially after H. pylori eradication. A total of 140 gastric specimens from 99 participants who had at least 6 months of post-eradication period were examined. The magnifying narrow-band imaging (NBI) endoscopic feature of gastric mucosa was divided into two types: restored-small, round pits, accompanied with honeycomb-like subepithelial capillary networks; atrophic-well-demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels. Methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA, and PRDM5) were examined by bisulfite pyrosequencing. The atrophic type, informative endoscopic features of intestinal metaplasia, demonstrated higher methylation levels in all five genes compared to the restored type (all P < 0.0001). In the restored type, methylation levels were significantly lower among the samples with longer post-eradication period (for all genes, P < 0.0001), which was not observed in atrophic type (for all genes, P > 0.1). Multivariate analysis demonstrated that atrophic type or presence of intestinal held an independent factor for hyper methylation (odds ratio: 24.69, 95% confidence interval: 6.95-87.76, P < 0.0001). The atrophic type by the magnifying NBI and presence of intestinal metaplasia are the morphologic characteristics of residual DNA methylation of after H. pylori eradication, regardless of the post-eradication period and it might be considered as the epigenetic irreversible point with H. pylori eradication.

BACKGROUND AND STUDY AIMS:  Probe-based confocal laser endomicroscopy (pCLE) enables real-time optical biopsy. Little is known about pCLE imaging deep inside the small bowel, therefore the aim of this study was to determine its usefulness. PATIENTS AND METHODS:  Between April 2014 and January 2016, we performed 38 pCLE examinations during double-balloon enteroscopy with intravenous fluorescein in 37 patients with: tumors (n = 10), vascular disorders (n = 6), inflammatory diseases and drug injuries (n = 13), other disorders (n = 4), and normal findings (n = 4). We measured the calibers of capillary and lymphatic vessels at 15 different sites and compared the calibers between pCLE images and histopathology. We also compared pCLE findings with pathologic diagnosis. RESULTS:  The inner diameters of capillary vessels beneath the epithelium and in the middle of villi were 16.2 ± 3.0 µm and 14.5 ± 3.1 µm, respectively, in the pCLE images, but these were not consistent with formalin-fixed paraffin-embedded histology. In tumors, larger capillary vessels were observed in aggressive malignant lymphoma and metastasis, and a "soccer ball-like pattern" constituting homogenous dark cells packed with polygonal, narrower capillary vessels was characteristic in pCLE images of a malignant lymphoma follicle. Hereditary hemorrhagic telangiectasia and angiodysplasia contained anastomosis of capillary vessels of different calibers. In IgA vasculitis, segmental capillary strictures were observed. Intestinal lymphangiectasia with protein-losing enteropathy contained a reticular network of lymphatic vessels and dilated lymphatic ducts accompanied by numerous cell gaps. pCLE findings corresponded to pathologic diagnosis in 32 examinations (91 %). CONCLUSIONS:  pCLE is useful for in vivo analysis of abnormalities of the capillary and lymphatic vessels and epithelium, and for diagnosis in various small-bowel diseases.

DNA methylation is associated with "field defect" in the gastric mucosa. To characterize "field defect" morphologically, we examined DNA methylation of non-neoplastic gastric mucosa in relation to their morphology seen by narrow-band imaging (NBI) with magnifying endoscopy. Magnifying NBI of non-neoplastic gastric body was classified as follows: normal-small and round pits with uniform subepithelial capillary networks; type 1-a little enlarged round pits with indistinct subepithelial capillary networks; type 2-remarkably enlarged pits with irregular vessels; and type 3-clearly demarcated oval or tubulovillous pits with bulky coiled or wavy vessels. Methylation of nine candidate genes (MYOD1, SLC16A12, GDNF, IGF2, MIR 124A1, CDH1, PRDM5, RORA and MLF1) were determined by bisulfite pyrosequencing. Infinium HumanMethylation450 array was used to characterize the methylation of >450,000 CpG sites. Mean Z score methylation of nine genes positively correlated with the changes of mucosal patterns from normal to types 1, 2, and 3 (P < 0.0001). Genome-wide analysis showed that development of mucosal patterns correlated with methylation accumulation especially at CpG islands. Genes with promoter CpG islands that were gradually methylated with the development of mucosal patterns significantly enriched the genes involved in zinc-related pathways. The results indicates that gastric mucosal morphology predicts a "field defect" in this tissue type. Accumulation of DNA methylation is associated with "field defect" in the non-neoplastic gastric mucosa. Endoscopic identification of "field defect" has important implications for preventing gastric cancer. Our results suggest that magnifying NBI of gastric mucosal morphology predicts a "field defect" in the gastric mucosa.

Neoadjuvant chemotherapy may improve outcomes for patients with locally advanced gastric cancer (GC). To explore useful predictive factors for the response of advanced GC to neoadjuvant chemotherapy, tumor responses were assessed using computed tomography (CT) with histological based criteria. A total of 78 patients with advanced GC undergoing neoadjuvant chemotherapy were included. CT-based response assessment was performed following 2 courses of treatment. Histological evaluation of resected specimens was also performed according to the Japanese classification of gastric carcinoma. Grade 1b, 2 and 3 (viable tumor cells remaining in <2/3 of the tumorous area) were defined as histological responders. The results were associated with overall survival (OS) and progression-free survival (PFS). The majority of the cases underwent tegafur/gimeracil/oteracil based preoperative chemotherapy as the first line of treatment (n=76, 96%). A total of 25 (32%) and 29 (37%) cases were considered to be CT and histological responders, respectively. CT-based evaluation was not associated with OS or PFS, while histological evaluation was significantly associated with OS and PFS. Histological based evaluation was not associated with CT and GI X-ray or endoscopy-based evaluation of primary lesions. Multivariate survival analysis using Cox's regression model demonstrated that histological non-response was an independent prognostic factor for predicting worse OS. Histological-based evaluation of primary lesions was independently associated with prognosis in patients with GC who underwent neoadjuvant chemotherapy.

BACKGROUND/AIM: Telomere shortening in leukocytes has been thought to be associated with reduced immune response capacity and increased chromosome instability. Several studies indicate that telomere length in the peripheral blood leukocyte DNA can predict clinical outcome of several cancers. We evaluated the potential association between telomere shortening in the leukocyte DNA and clinicopathological features and prognosis of gastric cancer (GC) in Japanese patients. MATERIALS AND METHODS: Telomere length in leukocyte DNA was measured using quantitative real-time polymerase chain reaction (PCR) in 207 GC patients. The association between telomere length and clinicopathological features and prognosis was evaluated. RESULTS: These short-telomere group was significantly associated with advanced stage (p=0.015), worse overall survival (OS) and progression-free survival (PFS) (p=0.046 and 0.026, respectively). The same group was also weakly associated with overall and peritoneal recurrences (p=0.052 and 0.059, respectively). CONCLUSION: Telomere shortening in leukocyte DNA is associated with advanced stage and poor prognosis of GC, which may reflect their reduced immune response capacity or increased chromosome instability.

Helicobacter pylori (Hp) infection is a major cause of gastric cancer. The use of proton-pump inhibitors, anti-platelet and anti-coagulant has become widespread in the clinic. Thus, it would be clinically useful to distinguish Hp-positive stomachs by endoscopic findings alone. Blue laser imaging (BLI) is a new image-enhanced endoscopy technique that utilizes a laser light source developed for narrow-band light observation. We investigated the diagnostic ability of magnifying BLI endoscopy to distinguish Hp-positive stomach in cancer free subjects. The data were also compared to the diagnostic ability of magnifying narrow-band imaging (NBI) endoscopy. In total, 215 participants were randomly assigned to the NBI (n=112) and BLI (n=113) groups. The greater curvature of the gastric middle and upper corpus were carefully evaluated with magnifying NBI or BLI. Small, round pits, accompanied with regular honeycomb-like subepithelial capillary networks (SECNs), being regularly interspersed with collecting venules were considered as Hp infection negative, while enlarged or elongated pits with unclear SECNs or dense fine irregular vessels were considered as Hp infection positive. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of Hp infection for the NBI group was 0.97, 0.81, 0.87 and 0.95, respectively. Sensitivity, specificity, PPV and NPV for the BLI group was 0.98, 0.92, 0.93 and 0.98, respectively. There was no significant difference among the values for the NBI and BLI groups (all P&gt 0.2). In conclusion, the diagnostic ability of magnifying BLI is acceptable, since it is similar to that of magnifying NBI.

INTRODUCTION: Aberrant DNA methylation frequently occurs in the inflammatory mucosa in ulcerative colitis (UC) and is involved in UC-related tumorigenesis. We performed comprehensive DNA methylation profiling of the promoter regions of the inflamed rectal mucosae of patients with UC. DESIGN: The methylation status of the promoter CpG islands (CGIs) of 45 cancer/inflammation or age-related candidate genes and the LINE1 repetitive element were examined in the colonic mucosae of 84 cancer-free patients with UC by bisulfite pyrosequencing. Methylation status of selected genes (DPYS, N33, MIR1247, GSTP1, and SOX11) was also determined in 14 neoplastic lesions (5 with high-grade dysplasia and 9 with carcinoma) and 8 adjacent tissues derived from 12 patients. An Infinium HumanMethylation450 BeadChip array was used to characterize the methylation status of >450,000 CpG sites for 10 patients with UC. RESULTS: Clustering analysis based on the methylation status of the candidate genes clearly distinguished the inflammatory samples from the noninflammatory samples. The hypermethylation of the promoter CGIs strongly correlated with increased disease duration, which is a known risk factor for the development of colon cancer. Genome-wide methylation analyses revealed a high rate of hypermethylation in the severe phenotype of UC, particularly at the CGIs. Exclusively hypermethylated promoter CGIs in the severe phenotypes were significantly related to genes involved in biosynthetic processes, the regulation of metabolic processes, and nitrogen compound metabolic processes. CONCLUSION: Our findings suggest the potential utility of DNA methylation as a molecular marker and therapeutic target for UC-related tumorigenesis.

BACKGROUND: Chemotherapy may improve outcomes in gastric cancer (GC), especially for the patients with advanced stage. To explore useful predictive factor for GC performing chemotherapy, we compared the tumor responses assessed using computed tomography (CT) with endoscopy based criteria. METHODS: 192 GC patients performing chemotherapy were retrospectively studied. CT based response assessment was performed after 2 courses of treatment. Endoscopic evaluation according to The Japanese classification of gastric carcinoma was also performed at same period. Data were correlated with overall survival (OS) and progression-free survival (PFS). RESULTS: Majority of the cases (n = 178, 93%) received S-1 based chemotherapy as the first line treatment. 55 (29%) and 91 (47%) cases were considered to be CT and endoscopic responders. Endoscopic responder was more clearly associated with better OS and PFS compared to CT based responder by the log-rank test (P<0.0001 vs. 0.01 and P<0.0001 vs. 0.008, respectively). The association was more striking among patients performing neoadjuvant chemotherapy (P<0.0001 vs. 0.15 and P<0.0001 vs. 0.1, respectively). Multivariate survival analysis using Cox's regression model revealed that endoscopic non-responder was the independent predictive factor, being more strongly associated with worse OS when compared to CT non-responder (hazard ratio: 4.60 vs. 1.77, 95% confidence interval: 2.83-7.49 vs.1.08-2.89, P<0.0001 vs. 0.02). More advanced T, N stage and cases who had peritoneal dissemination were significantly associated with endoscopic non-responder (all P values <0.01). CONCLUSION: Endoscopy based evaluation of primary lesions are clearly associated with prognosis in patients with GC who perform chemotherapy.

BACKGROUND/AIM: In the colorectum, lymphoid follicles hyperplasia (LH) is sometimes observed as small, round, yellowish-white nodules. The novel image-enhanced endoscopy system named blue laser imaging (BLI) provides enhanced the contrast of surface vessels using lasers for light illumination. We investigated the endoscopic features of LH observed by using BLI endoscopy and its association with chronic bowel symptoms. PATIENTS/METHODS: 300 participants undergoing colonoscopy for various indications were enrolled. Entire colorectum was observed by using BLI-bright mode with non-magnification view. LH was defined as well demarcated white nodules. Elevated LH with erythema was distinguished as LH severe. RESULTS: LHs were observed more clearly by using BLI-bright mode compared to conventional white light colonoscopy and were also histologically confirmed as intense infiltration of lymphocytes or plasmacytes. LH was observed in 134 subjects (44.6%) and 67 (22.3%) were LH severe. LH was associated younger age (Odds ratio (OR) = 1.05, 95%Confidence Interval (95%CI) = 1.03-1.07, P<0.0001) and chronic bowel symptoms including constipation, hard stools, diarrhea and loose stools (all LH: OR = 4.03, 95%CI = 2.36-6.89, P<0.0001, LH severe: OR = 5.31, 95%CI = 2.64-10.71, P<0.0001). LH severe was closely associated with both constipation associated symptoms (OR = 3.94, 95%CI = 1.79-8.66, P = 0.0007) and diarrhea associated symptoms (OR = 5.22, 95%CI = 2.09-13.05, P = 0.0004). In particular, LH severe in the ascending colon was strongly associated with bowel symptoms (P<0.0001). CONCLUSION: LH, visualized by using BLI endoscopy was associated with bowel symptom, raising the possibility of pathogenic role of this endoscopic finding in the functional lower gastrointestinal disorders.

BACKGROUND: Previous studies have reported that the suppression of acid secretion by using proton pump inhibitors (PPIs) results in dysbiosis of the small-bowel microbiota, leading to exacerbated small-bowel injuries, including erosions and ulcers. This study was designed to assess the association between PPI therapy and small-bowel lesions after adjustment for the differences in baseline characteristics between users and non-users of PPIs. METHODS: We retrospectively studied patients suspected to be suffering from small-bowel diseases, who underwent capsule endoscopy between 2010 and 2013. We used propensity matching to adjust for the differences in baseline characteristics between users and non-users of PPIs. The outcomes included the prevalence of small-bowel lesions: erosion, ulcer, angioectasia, varices, and tumor. RESULTS: We selected 327 patient pairs for analysis after propensity matching, and found no significant differences in the prevalence of small-bowel injuries, including erosions and ulcers, between users and non-users of PPIs. Two subgroup analyses of the effect of the type of PPI and the effect of PPI therapy in users and non-users of nonsteroidal anti-inflammatory drugs indicated no significant differences in the prevalence of small-bowel injuries in these two groups. CONCLUSION: PPI therapy did not increase the prevalence of small-bowel injury, regardless of the type of PPI used and the use of nonsteroidal anti-inflammatory drugs.

BACKGROUND AND STUDY AIMS: Olympus recently developed a new algorithm called Omni mode that discards redundant video capsule endoscopy (VCE) images. The current study aimed to demonstrate the non-inferiority of the Omni mode in terms of true positives (TPs) and the superiority of the Omni mode with regard to reading time against a control (ordinary ES-10 system). PATIENTS AND METHODS: This multicenter prospective study included 40 patients with various small bowel diseases. VCE images were evaluated by 7 readers and 3 judging committee members. Two randomly allocated readers assessed the VCE images obtained using the 2 modalities for each patient. The order of the modalities was switched between the 2 readers and the interval between readings by the same reader was 2 weeks. The judging committee predefined clinically relevant lesions as major lesions and irrelevant lesions as minor lesions. The number of TPs for major and minor lesions and the reading times were compared between the modalities. The predefined non-inferiority margin for the TP ratio of the Omni mode compared with the control was 0.9. RESULTS: The estimated TP ratios and 95 % confidence intervals for total, major, and minor lesions were 0.87 (0.80 - 0.95), 0.93 (0.83 - 1.04), and 0.83 (0.74 - 0.94), respectively. Although non-inferiority was not demonstrated, the rate of detection of major lesions was not significantly different between the modalities. The reading time was significantly lower when using the Omni mode than when using the control. CONCLUSIONS: The Omni mode may be only appropriate for the assessment of major lesions.

BACKGROUND: Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa. METHODS: Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive elementResults: We identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=-0.39, P<0.0001) and four of these locus (IGF2: R=-0.35, P=0.0003, SLC16A12: R=-0.35, P=0.0002, P2RX7: R=-0.29, P=0.003, and MYOD1: R=-0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016). CONCLUSION: Potential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa.

BACKGROUND AND AIM: TP53 gene is frequently mutated in gastric cancer (GC), but the relationship with clinicopathological features and prognosis is conflicting. Here, we screened TP53 mutation spectrum of 214 GC patients in relation to their clinicopathological features and prognosis. RESULTS: TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5'-CpG-3' sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P=0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P=0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P=0.001). METHODS: Matched biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing. CONCLUSION: Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients.

Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03 ± 0.3 vs. 2.82 ± 0.19 vs. 0.82 ± 0.07 vs. 0.29 ± 0.09, P < 0.0001). In non-neoplastic mucosa of GC patients, shorter telomeres were found significantly more often than in that of GC free subjects (age, sex, and H. pylori adjusted odds ratio = 7.81, 95 % confidence interval = 4.71-12.9, P < 0.0001). Telomere shortening in non-neoplastic mucosa was associated with chronic inflammation (P = 0.0018) and intestinal metaplasia (P < 0.0001). No significant associations were found between relative telomere length and clinicopathological features of GC and overall survival. Telomere shortening in gastric mucosa reflects a field effect in an early stage of carcinogenesis and is associated with an increased risk of GC. Telomere length in GC is not associated with clinicopathological features or prognosis.

Background and Aim: Double-balloon endoscopy (DBE) has enabled direct, detailed examination of the entire small bowel with interventional capabilities. Although its usefulness is recognized, efficacy and safety have not been extensively evaluated by prospective multicenter studies. To evaluate the efficacy and safety of DBE carried out by expert and non-expert endoscopists, a prospective, multicenter study was conducted in five university hospitals and a general hospital in Japan. Methods: A total of 120 patients who underwent 179 procedures were enrolled in the study. Experts carried out 129 procedures and non-experts carried out 50 procedures. Primary and secondary end points were evaluation of safety, the rate of achievement of procedural objectives, namely, identification of a new lesion, detailed examination to establish a therapeutic strategy, or exclusion of significant lesions by total enteroscopy, and rate of successful examination of the entire small bowel and evaluation of safety. Results: Overall rate of achievement of procedural objectives was 82.5% (99/120). Overall success rate for examination of the entire small bowel was 70.8% (34/48). Incidence of adverse events was 1.1% (a mucosal injury and an episode of pyrexia in two of 179 examinations). No severe adverse events were encountered. There were no significant differences in any of the outcome measures comparing expert and non-expert operators. Conclusions: DBE is effective and safe for patients with suspected small bowel diseases, and can be safely carried out even by a non-expert under the supervision of an expert, following a simple training program.

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. We measured average telomere length using quantitative real-time PCR in non-neoplastic gastric mucosa and assessed its relationship to H. pylori-related gastritis, DNA methylation, ulcer disease, and nonsteroidal anti-inflammatory drug (NSAID) usage. Gastric biopsies were obtained from 151 cancer-free subjects including 49 chronic NSAID users and 102 nonusers. Relative telomere length in genomic DNA was measured by real-time PCR. H. pylori infection status, histological severity of gastritis, and serum pepsinogens (PGs) were also investigated. E-cadherin (CDH1) methylation status was determined by methylation-specific PCR (MSP). Average relative telomere length of H. pylori-infected subjects was significantly shortened when compared to H. pylori-negative subjects (p = 0.002) and was closely associated with all histological parameter of gastritis (all p values <0.01) and CDH1 methylation (p = 0.0002). In H. pylori-negative subjects, NSAID users presented significantly shorter telomere length than nonusers (p = 0.028). Shorter telomere length was observed in duodenal and gastric ulcer patients compared with non-ulcer subjects among NSAID users. Telomere shortening is closely associated with severity of H. pylori-induced gastritis and CDH1 methylation status. Also, telomere shortening is accelerated by NSAID usage especially in H. pylori-negative subjects.

Background. Gastric cancer is discovered even after successful eradication of H. pylori. We investigated clinic pathological features of early gastric cancers after H. pylori eradication. Methods. 51 early gastric cancers (EGCs) from 44 patients diagnosed after successful H. pylori eradication were included as eradication group. The clinic-pathological features were compared with that of 131 EGCs from 120 patients who did not have a history of H. pylori eradication (control group). Results. Compared with control group, clinic-pathological features of eradication group were characterized as depressed (p < 0.0001), reddish (p = 0.0001), and smaller (p = 0.0095) lesions, which was also confirmed in the comparison of six metachronous lesions diagnosed after initial ESD and subsequent successful H. pylori eradication. Prevalence of both SM2 (submucosal invasion greater than 500 μm) and unexpected SM2 cases tended to be higher in eradication group (p = 0.077, 0.0867, resp.). Prevalence of inconclusive diagnosis of gastric cancer during pretreatment biopsy was also higher in the same group (26.0% versus 1.6%, p < 0.0001). Conclusions. Informative clinic pathological features of EGC after H. pylori eradication are depressed, reddish appearances, which should be treated as a caution because histological diagnosis of cancerous tissue is sometimes difficult by endoscopic biopsy.

BACKGROUND: The effect of H. pylori eradication in gastric cancer prevention can be attributed to the improvement of atrophic gastritis, which is a known risk of gastric cancer. However, gastric cancer has also been diagnosed after long-term H. pylori eradication. This study aimed to clarify the association between gastric atrophy and gastric cancer after H. pylori eradication, including its clinicopathological features. METHODS: A total of 55 consecutive patients with 64 early gastric cancers (EGCs) diagnosed after H. pylori eradication were enrolled. The degree of endoscopic atrophy and the histological degrees of mononuclear cell infiltration, atrophy, and metaplasia in the corpus and adjacent mucosa of the EGCs were determined and scored. RESULTS: The majority of EGCs (63/64) were located within the endoscopically assessed atrophic mucosa or along the atrophic border. The adjacent mucosa of the EGCs presented significantly higher degrees of all histological parameters than in the corpus (mononuclear cell infiltration, 0.86+/-0.09 vs. 0.51+/-0.11, P = 0.016; atrophy, 1.77+/-0.13 vs. 0.65+/-0.14, P<0.0001; metaplasia, 1.68+/-0.13 vs. 0.48+/-0.1, P<0.0001). The degree of endoscopic atrophy improved in the patients with longer post-H. pylori eradication periods; however, this trend was not observed for the histological parameters, and high degrees of atrophy and metaplasia were observed in the adjacent mucosa of the EGCs compared with the corpus during all periods (all P<0.05). The histological degrees of atrophy and metaplasia in the adjacent mucosa were particularly higher in the patients who underwent eradication due to gastric ulcers. CONCLUSIONS: Severe gastric atrophy remained in the adjacent mucosa of the EGCs after H. pylori eradication, which may be linked to gastric carcinogenesis.

The aim of this study was to investigate the effect of consuming small amounts of beer or a nonalcoholic beer taste beverage (non-beer) on gastric emptying and the polymorphisms in alcohol metabolism-related enzyme-encoding genes. Twenty male healthy volunteers were questioned regarding their alcohol consumption status, and body measurement was performed. The genetic polymorphisms in ADH1B (rs1229984, Arg47His) and ALDH2 (rs671 Glu487Lys) were analyzed. The subjects consumed 150 mL of beer or non-beer once per week, followed by the ingestion of 200 kcal of the test nutrient containing 13C-acetate 15 min later, after which the subjects' exhalations were collected up to 120 min. The concentration peak of 13C was measured as Tmax. Diamine oxidase (DAO) activity for the marker of small intestinal function activity was also measured the day after the test. Gastric emptying was significantly slower in the group that consumed a small amount of beer, and in daily beer consumption group, and also in the ADH1B *2/*2, ALDH2 *1/*2 genotypes compared to non-beer drinking group. DAO values were not significantly changed between beer and non-beer group. The consumption of even a small amount of beer and the polymorphisms in ADH1B / ALDH2 affects gastric motility.

BACKGROUND: Colon capsule endoscopy (CCE) is a new procedure for colon imaging. Limited information is available regarding visualization of flat colon lesions and patient acceptability in Japan. OBJECTIVE: The aims of this study were to evaluate the sensitivity of CCE in detecting polyps and other lesions compared with optical colonoscopy (OC) and to evaluate its safety and acceptability in a cohort of Japanese patients. DESIGN: A prospective, open-label, clinical study in Japan. SETTING: Multicenter. PATIENTS: Patients referred for OC because of personal history of polyps ≥6 mm or any other colon lesion that required endoscopic or surgical treatment. INTERVENTIONS: CCE followed by therapeutic colonoscopy. MAIN OUTCOME MEASUREMENTS: The primary endpoint was per-patient sensitivity of CCE in detecting significant colon lesion. The secondary endpoints were CCE safety and patient acceptability. RESULTS: Sixty-six of the 72 patients enrolled in the study were evaluated for efficacy. The per-patient sensitivity was 94% (95% confidence interval [CI], 88.2%-99.7%). The per-polyp sensitivity was 86.6% (95% CI, 81.3%-91.9%) when pathology-confirmed polyps were considered true positives. There were no adverse events related to CCE, and the acceptability of CCE was high. LIMITATIONS: All patients had previously confirmed colon lesions, which may have falsely elevated the sensitivity of CCE. CONCLUSION: CCE had a high sensitivity for detecting significant colon lesions. CCE was safe and had a high level of patient acceptability. ( CLINICAL TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network, UMIN000007258.).

OBJECTIVES: The aim of this study was to investigate the relationship between pancreas and small intestine evaluating the endoscopic and histopathologic findings of the proximal small intestine in pancreatic diseases. METHODS: Fifty patients (18 patients with chronic pancreatitis, 17 patients with pancreatic cancer, 15 control subjects) underwent enteroscopy using a prototype enteroscope. The villous height of the jejunum on bioptic specimens was measured, and the mean values of the villi were compared among the 3 groups. Exocrine function was calculated by the pancreatic function diagnostic test, and the correlation between the recovery rate of p-aminobenzoic acid and the villous height was assessed. Finally, the distribution of the K cells secreting glucose-dependent insulinotropic polypeptide and the L cells secreting glucagon-like peptide 1 in the duodenum and jejunum was investigated using immunohistochemistry for glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. RESULTS: The mean villous height in chronic pancreatitis (328 ± 67 μm) was significantly lower than that in pancreatic cancer (413 ± 57 μm) and control subjects (461 ± 97 μm) (P = 0.004 and P < 0.0001, respectively). A positive correlation was found between the recovery rate of p-aminobenzoic acid and the villous height (r = 0.52, P = 0.0001). The presence of K and L cells was verified in the duodenum and the jejunum. CONCLUSIONS: Close relationship between pancreas and small intestine was demonstrated.

Background There are few reports on the short- and long-term follow-up of endoscopic retrograde cholangiography (ERC) in adult patients with hepaticojejunostomy (HJS) stricture after living-donor liver transplantation (LDLT). Methods Nine LDLT recipients underwent ERC with the use of double-balloon endoscopy (DBE) for HJS stricture at Nagoya University Hospital. We assessed the rate of reaching biliary anastomosis, procedure success rate, procedure duration, complications, improvement in liver function test results, and biliary anastomosis patency. Results In total, 19 ERC procedures with the use of DBE were performed for 9 adult LDLT recipients with HJS stricture from June 2006 to September 2014. Balloon dilation with the use of DBE was successfully performed in 5 of the 9 patients during the 1st procedure. Of the 4 patients in whom DBE-ERC failed to be completed, 3 patients underwent 2nd procedures successfully. Liver function test results were significantly improved in the successful cases. Four patients underwent 2nd DBE-ERC for stricture recurrence at a mean time of 2.3 years after the 1st successful procedure. Of those, 2 patients required 3rd procedures for stricture recurrence after the 2nd procedure. Conclusions DBE-ERC is promising as a treatment for HJS stricture in adult LDLT recipients in the short term. However, the DBE-ERC procedure may have a considerable risk of restenosis.

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. To clarify the clinical importance of telomere shortening in colonic mucosa in ulcerative colitis (UC), we measured average telomere length using quantitative real-time PCR in non-neoplastic colonic mucosa in UC patients and assessed its relationship to various clinical subtypes. Relative telomere length in genomic DNA was measured in colonic biopsies obtained from rectal inflammatory mucosa from 86 UC patients as well as paired non-inflammatory proximal colonic mucosae from 10 patients. Data were correlated with various clinical phenotypes. In paired samples, average relative telomere length of rectal inflammatory mucosa was shortened compared to normal appearing proximal colon in eight out of ten cases (p = 0.01). Telomere length shortening was significantly associated with more severe Mayo endoscopic subscore (p < 0.0001) and cases needing surgery due to toxic megacolon or cancer occurrence (p = 0.043). When the severe clinical phenotype was defined as having at least one of following phenotypes, more than two times of hospitalization, highest Mayo endoscopic subscore, steroid dependent, refractory, or needing operation, average relative telomere length was significantly shortened in the same phenotypes than the others (p = 0.003). Telomere shortening is associated with more severe clinical phenotypes of UC, reflecting severe inflammatory state in the colonic mucosa.

Interleukin (IL)‑1β, and tumor necrosis factor (TNF)‑α have significant roles in the mediation of inflammatory immune responses and are also potent inhibitors of gastric acid secretion in the stomach. The present study aimed to investigate the associations between polymorphisms at position ‑31 (T>C) of the IL‑1β gene and ‑857 (C>T) of the TNF‑α gene with dyspeptic symptoms. Polymorphisms at position ‑31 (T>C) of the IL‑1β gene and ‑857 (C>T) of the TNF‑α gene were genotyped in 261 subjects, including 126 subjects without symptoms and 135 subjects exhibiting symptoms of dyspepsia. The IL‑1β ‑31 CC genotype was inversely associated with dyspeptic symptoms in all subjects, as determined by the Fisher's exact test [odds ratio (OR), 0.57; 95% confidence interval (CI), 0.34‑0.96; P=0.046]; however, this association was not detected following logistic regression analysis. Within the subgroups of symptoms, the CC genotype was also inversely associated with upper abdominal pain (OR, 0.28; 95% CI, 0.12‑0.67; P=0.003) and epigastric pain syndrome (EPS)‑like symptoms (OR, 0.14; 95% CI, 0.07‑0.28; P=0.003), according to the Rome III classifications. These associations were also found following logistic regression analysis (upper abdominal pain: OR, 0.34; 95% CI, 0.14‑0.80; P=0.014; and EPS‑like symptoms: OR, 0.41; 95% CI, 0.20‑0.84; P=0.015). No significant associations were identified between the TNF‑α ‑857 polymorphism and dyspeptic symptoms, including amongst the various subtypes analyzed. In conclusion, the IL‑1β ‑31 CC genotype was inversely associated with susceptibility to dyspeptic symptoms, in particular, upper abdominal pain and EPS‑like symptoms.

BACKGROUND: To assess the diagnostic ability and safety of endoscopic retrograde cholangiopancreatography (ERCP) in in-depth preoperative examination of children patients with pancreaticobiliary maljunction (PBM). METHODS: In 63 patients with a definite diagnosis of PBM, the ability to visualize the bile and main pancreatic ducts was compared between ERCP, which was performed in 63 patients with a definite diagnosis of PBM, and magnetic resonance cholangiopancreatography (MRCP), which was performed before ERCP in 29 patients. For ERCP, its complications were also evaluated. RESULTS: The intrahepatic bile ducts could be visualized using ERCP in 44 patients (69.8%) and using MRCP in 18 (62.1%). The extrahepatic bile ducts could be visualized using ERCP in 59 patients (93.7%) and using MRCP in 29 (100%). The rates of the visualization of the main pancreatic duct and pancreaticobiliary ductal union were significantly higher in using ERCP than in using MRCP (96.8 vs. 41.4% and 90.5 vs. 37.9%, respectively; P<0.0001). As complications, hyperamylasemia developed in 12 patients (19%), but no other severe complications such as pancreatitis were observed. CONCLUSIONS: ERCP as part of an in-depth preoperative examination of children with PBM is useful and safe.

BACKGROUND AND AIM: Double-balloon endoscopy (DBE) has enabled direct, detailed examination of the entire small bowel with interventional capabilities. Although its usefulness is recognized, efficacy and safety have not been extensively evaluated by prospective multicenter studies. To evaluate the efficacy and safety of DBE carried out by expert and non-expert endoscopists, a prospective, multicenter study was conducted in five university hospitals and a general hospital in Japan. METHODS: A total of 120 patients who underwent 179 procedures were enrolled in the study. Experts carried out 129 procedures and non-experts carried out 50 procedures. Primary and secondary end points were evaluation of safety, the rate of achievement of procedural objectives, namely, identification of a new lesion, detailed examination to establish a therapeutic strategy, or exclusion of significant lesions by total enteroscopy, and rate of successful examination of the entire small bowel and evaluation of safety. RESULTS: Overall rate of achievement of procedural objectives was 82.5% (99/120). Overall success rate for examination of the entire small bowel was 70.8% (34/48). Incidence of adverse events was 1.1% (a mucosal injury and an episode of pyrexia in two of 179 examinations). No severe adverse events were encountered. There were no significant differences in any of the outcome measures comparing expert and non-expert operators. CONCLUSIONS: DBE is effective and safe for patients with suspected small bowel diseases, and can be safely carried out even by a non-expert under the supervision of an expert, following a simple training program.

Small-bowel bleeding comprises a majority of obscure gastrointestinal bleeding, but is caused by various kinds of diseases. For its diagnosis, history-taking and physical examination is requisite, leading to a suspicion of what diseases are involved. Next, cross-sectional imaging such as computed tomography should be done, followed by the latest enteroscopy, videocapsule endoscopy and deep enteroscopy according to the severity of hemorrhage and patient conditions. After comprehensive diagnosis, medical, enteroscopic, or surgical treatment should be selected.

Double-balloon endoscopy (DBE) can be used to treat disorders of the small intestine and can also be used to retrieve foreign bodies from the small intestine without surgery. We describe the findings of 22 cases in which DBE was used to try and retrieve foreign bodies from the small intestine. The foreign bodies included 12 capsule endoscopes, 3 artificial teeth, 3 medical tubes, 2 worms, 1 press-through packet of medicine, and 1 intestinal stone. The retrieval success rate was 86.3% (19/22), and there were no complications related to the retrieval procedures. Snare forceps were the most useful device for grasping the foreign bodies, and DBE was usually performed via an oral route. If an anal route is selected in cases involving stenosis of the small intestine, endoscopic balloon dilation will be necessary to reach the target. In conclusion, DBE is very useful for extracting foreign bodies from the small intestine, and the careful selection of the DBE route and the removal device are important for successfully retrieving foreign bodies.

Double-balloon endoscopy (DBE) can be used to treat disorders of the small intestine and can also be used to retrieve foreign bodies from the small intestine without surgery. We describe the findings of 22 cases in which DBE was used to try and retrieve foreign bodies from the small intestine. The foreign bodies included 12 capsule endoscopes, 3 artificial teeth, 3 medical tubes, 2 worms, 1 press-through packet of medicine, and 1 intestinal stone. The retrieval success rate was 86.3% (19/22), and there were no complications related to the retrieval procedures. Snare forceps were the most useful device for grasping the foreign bodies, and DBE was usually performed via an oral route. If an anal route is selected in cases involving stenosis of the small intestine, endoscopic balloon dilation will be necessary to reach the target. In conclusion, DBE is very useful for extracting foreign bodies from the small intestine, and the careful selection of the DBE route and the removal device are important for successfully retrieving foreign bodies.

Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We examined the expression of onco-related miRNAs in 131 sporadic exophytic adenomas or early cancers and in 52 sporadic flat elevated adenomas or early cancers to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. The expression levels of miR-143, -145, and -34a were significantly reduced in most of the exophytic tumors compared with those in the flat elevated ones. In type 2 cancers, the miRNA expression profile was very similar to that of the exophytic tumors. The expression levels of miR-7 and -21 were significantly up-regulated in some flat elevated adenomas compared with those in exophytic adenomas. In contrast, in most of the miR-143 and -145 down-regulated cases of the adenoma-carcinoma sequence and in some of the de novo types of carcinoma, the up-regulation of oncogenic miR-7 and/or -21 contributed to the triggering mechanism leading to the carcinogenetic process. These findings indicated that the expression of onco-related miRNA was associated with the morphological appearance of colorectal tumors.

AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders. METHODS: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion. All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy. Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL. Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score, with a reduction of ≥ 5 considered to indicate a response. Among responders, we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine. Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex, age, disease duration, clinical activity index score, C-reactive protein level, hemoglobin level, disease extent, endoscopic findings, and clinical course. RESULTS: Cyclosporine was not discontinued due to side effects in any patient. Nineteen (65.5%) of 29 patients were considered responders. A statistically significant (P = 0.004) inverse association was observed between an endoscopic finding of "mucosal bleeding" and responsive cases. Fifteen (9 males, 6 females) of these 19 patients were followed for 5 years or more, of whom 9 (60%) exhibited long-term efficacy of cyclosporine. Of the 10 non-responders, 9 (90%) underwent surgery within 6 mo of cyclosporine therapy. None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex, age, duration of disease, clinical activity index score, C-reactive protein level, hemoglobin level, extent of disease, endoscopic findings, or clinical course. In contrast, a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy (P = 0.0014). CONCLUSION: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.

BACKGROUND AND AIM: The Agile patency capsule (PC; Given Imaging Ltd, Yoqneam, Israel) is used as a dummy prior to capsule endoscopy (CE) to avoid retention of the CE capsule. However, impaction of the PC's inner radio frequency identification (RFID) tag in a stricture could cause small-bowel ileus. Recently, the RFID tag-less PC was introduced into clinical practice. Herein, we aimed to retrospectively evaluate the usefulness of the tag-less PC. METHODS: Of 154 patients who were scheduled to undergo CE, 100 consecutive patients (65%) who underwent PC evaluation were enrolled in the present study. Primary study end point was the retention rate of the CE capsule after successful passage of the PC. Secondary end point was analysis of the significant factors affecting the passage of the PC. RESULTS: In total, 87 patients (87%) had bowel patency confirmed by PC evaluation. There was no capsule retention in any of these 87 patients during CE. Abnormal findings were obtained from 60 CE, and 41 patients received new or modified treatment. Multivariate analysis of factors related to the confirmation of patency demonstrated that stenosis on imaging was the most influential factor (P = 0.002, odds ratio 16.387). The results confirmed that passage of the PC depends on stenosis on imaging. CONCLUSIONS: Use of the tag-less PC confirmed gastrointestinal tract patency for most of the patients who did not have stenosis on imaging and allowed estimation of the patency for patients who did have stenosis on imaging.

BACKGROUND AND AIMS: Fusobacterium species are part of the gut microbiome in humans, but some species have been recognized as opportunistic pathogens implicated in inflammatory diseases including inflammatory bowel diseases. Here, we performed prevalence screening of Fusobacterium in ulcerative colitis (UC) in Japanese patients. METHODS: We examined Fusobacterium nucleatum (F. nucleatum) and whole Fusobacterium species (Pan-fusobacterium) by quantitative real-time PCR in 163 inflamed mucosae from 152 UC patients. Data were correlated with clinical subtypes of UC. RESULTS: In an initial prevalence screen, F. nucleatum and Pan-fusobacterium were detected in 6.3 % (4/64) and 53.1 % (34/64). For all 163 mucosae, the prevalence of Pan-fusobacterium was 54.6 % (89/163). Pan-fusobacterium status was concordant in inflamed and normal adjacent samples, and the matched cases during 1-year follow-up colonoscopy. The higher amount of Pan-fusobacterium was observed in chronic continuous type compared to one attack and relapse/remitting type (p = 0.039). The higher amount of Pan-fusobacterium was also associated with rather mild clinical course of disease, such as non-steroid dependency (p = 0.015), non-refractory phenotype (p = 0.013), and non-severe phenotype (p = 0.04). Based on the distribution of Pan-fusobacterium measurable cases, we identified 10 cases as having a high amount of Pan-fusobacterium (FB-high). The clinicopathological features of FB-high UC cases were also highlighted by chronic continuous type and mild phenotypes of disease. CONCLUSION: Whole Fusobacterium species, but not F. nucleatum, are common in UC patients and have a role in persistence of colonic inflammation in UC. However, Fusobacterium infection is associated with rather mild clinical phenotypes of UC.

To our knowledge, this is the first report of Cowden syndrome complicated by a gastrointestinal stromal tumor (GIST) of the small bowel. A 42-year-old female patient was found to have an abdominal mass that was diagnosed as the cause of anemia and was surgically extracted. The surgical specimen was found to be a GIST. During the same period, the patient underwent an endoscopic examination of the entire gastrointestinal tract. She was also diagnosed as having Cowden syndrome based on gastrointestinal polyps and skin, thyroid and breast lesions. Cowden syndrome is associated with germline mutations in the tumorsuppressor gene PTEN. PTEN expression may be essential to tumor growth and is a predictive biomarker of the prognosis of both diseases. The present report of such a case is expected to further the analysis of Cowden syndrome.

BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) have been associated with various malignancies and their prognoses. We evaluated the associations of three selected SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) with the prognosis of advanced gastric cancers (GCs) treated by chemotherapy. MATERIALS AND METHODS: The rs11614913 (T>C), rs2910164 (C>T), and rs3746444 (A>G) SNPs were genotyped in 130 advanced GCs performing chemotherapy. Survival and response evaluation was based on overall survival (OS) and progression-free survival (PFS). Response rate (RR) was also evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: 63 patients performed gastrectomy after chemotherapy (neoadjuvant chemotherapy) and the remaining cases performed chemotherapy alone as treatment (chemotherapy alone). The majority of cases performed S-1-based chemotherapy as the first line treatment (n=119, 92%). The rs3746444 (A>G) SNP was significantly associated with OS by the log-rank test (p=0.018), while other SNPs were not associated with OS. The rs3746444 (A>G) SNP was also associated with OS and PFS among cases of neoadjuvant chemotherapy (p=0.038, 0.024, respectively). Multivariate survival analysis using the Cox's regression model revealed that non-responder by the RECIST (Hazard ratio (HR): 2.14 95%CI 1.06-4.19), upper third cancer (HR: 2.48 95%CI 1.12-5.49) and more advanced stage (HR: 4.12 95%CI 1.06-16.02) were predictive factors for worse OS, while the rs3746444 A allele carrier was predictive factor for better OS (HR: 0.33 95%CI 0.18-0.75). CONCLUSION: The rs3746444 A allele carrier in the hsa-mir-499 is associated with better prognosis in advanced GC performing chemotherapy.

Endoscopic exploration of the small bowel after pelvic radiation has limitations related to strong abdominal adhesion. It is often difficult to demonstrate the findings of radiation enteritis endoscopically, even with video capsule endoscopy (VCE) or double-balloon enteroscopy (DBE). We present our experience with three cases of radiation enteritis that were diagnosed using VCE and DBE, including their effective aspects. Radiation enteritis has not been diagnosed using conventional methods, and DBE may not accomplish deeper insertion into the ileum, although it is capable of both diagnosis and hemostasis. Therefore, VCE is thought to be the initial tool for the diagnosis of radiation enteritis when small bowel stenosis has not been previously detected and the risk of retention has been discussed.

BACKGROUND AND AIM: Transabdominal ultrasonography (US) is commonly used for the initial screening of bilio-pancreatic diseases in Asian countries due to its widespread availability, the non-invasiveness and the cost-effectiveness. However, it is considered that US has limits to observe the area, namely the blind area. The observation of the pancreatic tail is particularly difficult. The goal of this study was to examine the pancreatic tail region that cannot be visualized on transverse scanning of the upper abdomen using US with spatial positional information and factors related to visualization, and observation of the tail from the splenic hilum. METHODS: Thirty-nine patients with pancreatic/biliary tract disease underwent CT and US with GPS-like technology and fusion imaging for measurement of the real pancreatic length and the predicted/real unobservable (PU and RU) length of the pancreatic tail. RU from US on transverse scanning and the real pancreatic length were used to determine the unobservable area (UA: RU/the real pancreatic length). Relationships of RU with physical and hematological variables that might influence visualization of the pancreatic tail were investigated. RESULTS: The real pancreatic length was 160.9 ± 16.4mm, RU was 41.0 ± 17.8mm, and UA was 25.3 ± 10.4%. RU was correlated with BMI (R=0.446, P=0.004) and waist circumferences (R=0.354, P=0.027), and strongly correlated with PU (R=0.788, P<0.001). The pancreatic tail was visible from the splenic hilum in 22 (56%) subjects and was completely identified in 13 (33%) subjects. CONCLUSIONS: Combined GPS-like technology with fusion imaging was useful for the objective estimation of the pancreatic blind area.

Endoscopic exploration of the small bowel after pelvic radiation has limitations related to strong abdominal adhesion. It is often difficult to demonstrate the findings of radiation enteritis endoscopically, even with video capsule endoscopy (VCE) or double-balloon enteroscopy (DBE). We present our experience with three cases of radiation enteritis that were diagnosed using VCE and DBE, including their effective aspects. Radiation enteritis has not been diagnosed using conventional methods, and DBE may not accomplish deeper insertion into the ileum, although it is capable of both diagnosis and hemostasis. Therefore, VCE is thought to be the initial tool for the diagnosis of radiation enteritis when small bowel stenosis has not been previously detected and the risk of retention has been discussed.

BACKGROUND: An accurate diagnosis of pancreatic fibrosis is clinically important and may have potential for staging chronic pancreatitis. The aim of this study was to diagnose the grade of pancreatic fibrosis through a quantitative analysis of endoscopic ultrasound elastography (EUS-EG). METHODS: From September 2004 to October 2010, 58 consecutive patients examined by EUS-EG for both pancreatic tumors and their upstream pancreas before pancreatectomy were enrolled. Preoperative EUS-EG images in the upstream pancreas were statistically quantified, and the results were retrospectively compared with postoperative histological fibrosis in the same area. For the quantification of EUS-EG images, 4 parameters (mean, standard deviation, skewness, and kurtosis) were calculated using novel software. Histological fibrosis was graded into 4 categories (normal, mild fibrosis, marked fibrosis, and severe fibrosis) according to a previously reported scoring system. RESULTS: The fibrosis grade in the upstream pancreas was normal in 24 patients, mild fibrosis in 19, marked fibrosis in 6, and severe fibrosis in 9. Fibrosis grade was significantly correlated with all 4 quantification parameters (mean r = -0.75, standard deviation r = -0.54, skewness r = 0.69, kurtosis r = 0.67). According to the receiver operating characteristic analysis, the mean was the most useful parameter for diagnosing pancreatic fibrosis. Using the mean, the area under the ROC curves for the diagnosis of mild or higher-grade fibrosis, marked or higher-grade fibrosis and severe fibrosis were 0.90, 0.90, and 0.90, respectively. CONCLUSIONS: An accurate diagnosis of pancreatic fibrosis may be possible by analyzing EUS-EG images.