Naoki Ohmiya

OBJECTIVES: We determined the efficacy of fecal microbiota transplantation (FMT) and subsequent changes in fecal microbiota and short-chain fatty acid (SCFA) levels in patients with ulcerative colitis (UC), Crohn's disease (CD), and recurrent Clostridioides difficile infection (rCDI). METHODS: A filtered solution of Japanese donor feces was endoscopically administered. The efficacy of FMT was evaluated after 8 weeks using the Mayo score, Crohn's Disease Activity Index (CDAI), and the absence of diarrhea with stool toxin negativity in patients with active UC, CD, and rCDI, respectively. For fecal microbiota analysis, the 16S ribosomal RNA gene was sequenced, and fecal SCFA levels were measured. RESULTS: Clinical response was achieved in 5/20 (25%), 3/4 (75%), and 4/4 (100%) patients with UC, CD, and rCDI, respectively. Clinical remission was achieved in 4/20 (20%) and 1/4 (25%) patients with UC and CD, respectively. Linear discriminant analysis illustrated that UC responders had lower counts of Clostridium cluster XIVa before FMT and higher counts after FMT. Higher Fusicatenibacter saccharivorans counts in donors were significantly correlated with 8-week clinical remission. Patients with CD exhibited lower Blautia, Dorea, and Eubacterium counts before FMT and higher Collinsella, Dorea, and Eubacterium counts after FMT, accompanied by functional profiles predictive of SCFA fermentation and elevated fecal butyrate concentrations. Patients with rCDI displayed significantly lower abundances of Clostridium clusters IV and XIVa before FMT and higher abundances after FMT accompanied by elevated fecal propionate concentrations. CONCLUSIONS: FMT exhibited various efficacy against UC, CD, and rCDI by altering the gut microbiota and SCFA production.

BACKGROUND: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC. METHODS: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0. RESULTS: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (- 9.3 ± 1.2 vs. - 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM. CONCLUSIONS: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM. CLINICAL TRIAL REGISTRY: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp .

Study aims: The PillCam patency capsule (PPC) is an Agile tag-less patency capsule used to evaluate gastrointestinal (GI) patency. We determined the appropriate use of PPC to preclude subsequent small bowel capsule endoscopy (SBCE) retention. Methods: This prospective multicenter study consecutively enrolled patients indicated for SBCE with suspected or established small bowel stenosis. Excretion of an intact PPC or its radiologic visualization in the large bowel was considered GI patency. Primary and secondary study endpoints were SBCE retention rates in patients with confirmed patency and identification of factors associated with patency and SBCE retention, respectively. Results: Of 1096 patients enrolled in the study, patency was confirmed in 976 (89.1％). PPC excretion occurred in 579 patients. Of the remaining 517 patients, patency was confirmed using imaging modalities in 401 (77.5％). SBCE retention occurred in five (0.51％) of 963 patients who underwent SBCE: 1.0％ in established Crohn's disease (CD) patients, 0％ in suspected CD, 0％ in tumors, and 1.6％ in patients with obscure GI bleeding, for which PPC localization had been radiographically misinterpreted. The non-confirmation of patency was associated with established CD, stenosis identified using imaging modalities, abdominal fullness, serum albumin levels &lt 4.0g/dL, and previous small bowel obstruction (adjusted odds ratios: 4.21, 2.60, 2.47, 2.12, and 2.00 95％ confidence intervals: 2.62-6.78, 1.62-4.17, 1.43-4.27, 1.32-3.40, and 1.15-3.47, respectively). Conclusions: The PillCamTM patency capsule helped preclude SBCE retention in most patients, but its accurate localization was essential for cases without excretion (Study registered the University Hospital Medical Information Network, #UMIN000010513).

BACKGROUND: Patency confirmation is useful for avoiding the retention of capsule endoscopy (CE). We first evaluated the clinical utility of the tag-less PillCamTM Patency Capsule (PPC) for up to 72 h after ingestion prospectively. METHODS: Excretion of an intact capsule or intact body within 72 h, or positive PPC image in the colon or negative PPC image by abdominal X-ray at 30 h was defined as confirmed functional patency. In patients with unconfirmed functional patency, balloon-assisted enteroscopy was performed to evaluate the reason. RESULTS: Functional patency was confirmed in 44 of 57 patients. Patency was confirmed in 38 patients (66.7%) at 30 h. In 6 of 19 patients (31.6%) in whom patency was not confirmed at 30 h, patency was confirmed within 72 h and no capsule retention (CR) occurred. The rate of pan-enteroscopy did not differ between patients whose patency was confirmed at 30 h and those whose patency was confirmed within 72 h. Excretion time of the PPC significantly correlated with that of the capsule (r = 0.650). Severe adhesions (>5 cm) interfered with PPC passage in 2 patients, despite the absence of critical stricture. The rate of no CR in patients with functional patency confirmed by prior PPC was 97.7%. Misjudgment of the location of the PPC is a risk for CR. CONCLUSIONS: Extending the time to confirm functional patency to 72 h may be acceptable and increase the possibility to perform CE safely in whom CE can perform intrinsically. University Hospital Medical Information Network registration No: 000002564.

STUDY AIMS: The PillCam patency capsule (PPC) is an Agile tag-less patency capsule used to evaluate gastrointestinal (GI) patency. We determined the appropriate use of PPC to preclude subsequent small bowel capsule endoscopy (SBCE) retention. METHODS: This prospective multicenter study consecutively enrolled patients indicated for SBCE with suspected or established small bowel stenosis. Excretion of an intact PPC or its radiologic visualization in the large bowel was considered GI patency. Primary and secondary study endpoints were SBCE retention rates in patients with confirmed patency and identification of factors associated with patency and SBCE retention, respectively. RESULTS: Of 1096 patients enrolled in the study, patency was confirmed in 976 (89.1%). PPC excretion occurred in 579 patients. Of the remaining 517 patients, patency was confirmed using imaging modalities in 401 (77.5%). SBCE retention occurred in five (0.51%) of 963 patients who underwent SBCE: 1.0% in established Crohn's disease (CD) patients, 0% in suspected CD, 0% in tumors, and 1.6% in patients with obscure GI bleeding, for which PPC localization had been radiographically misinterpreted. The non-confirmation of patency was associated with established CD, stenosis identified using imaging modalities, abdominal fullness, serum albumin levels <4.0 g/dL, and previous small bowel obstruction (adjusted odds ratios: 4.21, 2.60, 2.47, 2.12, and 2.00; 95% confidence intervals: 2.62-6.78, 1.62-4.17, 1.43-4.27, 1.32-3.40, and 1.15-3.47, respectively). CONCLUSIONS: The PillCam™ patency capsule helped preclude SBCE retention in most patients, but its accurate localization was essential for cases without excretion (Study registered the University Hospital Medical Information Network, #UMIN000010513).

BACKGROUND: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses. SUMMARY: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts' opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.

Introduction: Polyethylene glycol-electrolyte lavage solution plus ascorbic acid (PEG-ELS-Asc) has been recommended for colonoscopy, but little is known about the safety of PEG-ELS-Asc in patients with chronic kidney disease (CKD). The aim of this study was to determine its safety and efficacy in CKD patients. Methods: Blood and urine samples prospectively collected before and after same-day bowel preparation for colonoscopy with the conventional volume of PEG-ELS-Asc, vital signs before and after colonoscopy, and adverse events within 30 days postcolonoscopy were analyzed in consenting patients with CKD. The cleansing level was evaluated with the Boston bowel preparation score (BBPS) from colonoscopic findings. Results: Of 57 patients enrolled, 1 was excluded for refusal. Serum bicarbonate significantly dropped, and blood hemoglobin, serum total protein, albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total bilirubin, and uric acid significantly rose after bowel preparation, although these changes were not clinically important. Only in nondialysis patients did the platelet count and potassium significantly rise, although these changes were not clinically important either. Renal function, such as the urea, creatinine, and estimated glomerular filtration rate, was not significantly altered. An adequate bowel cleansing score, BBPS ≥ 6, was achieved in 94% of patients. The blood pressure and heart rate were not significantly different between before and after colonoscopy in either nondialysis (n = 32) or dialysis (n = 19) patients. There were no adverse events associated with bowel preparation and colonoscopy within 30 days postcolonoscopy. Conclusions: The conventional volume of same-day bowel preparation with PEG-ELS-Asc may be safe and effective in CKD patients.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is useful for pathologically diagnosing gastrointestinal stromal tumor (GIST) before surgery. However, its role in mutation analysis remains unclear. To examine the feasibility of analyzing GIST mutations using mRNA obtained with EUS-FNA, we prospectively enrolled 41 patients with subepithelial lesion from which EUS-FNA was successfully acquired tissue sample. Thirty-two, 5, and 4 subepithelial lesions were diagnosed as GISTs, schwannomas, and leiomyomas, respectively. After RNA was extracted from FNA sample, RNA was converted to cDNA. Full-length sequence of the KIT cDNA amplified via the polymerase chain reaction (PCR) was successful in 31 (96.9%) out of 32 GIST and three out of 9 non-GIST (33.3%). The KIT mutation statuses of 31 GISTs in which KIT cDNA was amplified were successfully determined through directional sequencing. Furthermore, 15 of 16 surgically excised GISTs exhibited the same mutation status in both the EUS-FNA and resected samples. In vitro experiment, the minimum number of cells required to amplify full-length of KIT cDNA from RNA was one-tenth of that required to amplify KIT exon11 gene from DNA. This study clarifies that mutation analysis using RNA obtained with EUS-FNA is feasible and reliable. Moreover, our data would support that RNA-based mutation is superior to DNA-based mutation analysis in GIST.

BACKGROUND: Evidence for endoscopic balloon dilation of small intestinal strictures in Crohn's disease (CD) using balloon-assisted enteroscopy is scarce. AIM: To evaluate endoscopic balloon dilation for the treatment of small intestinal CD strictures using balloon-assisted enteroscopy. METHODS: Citations in Embase, MEDLINE, and Cochrane were systematically reviewed. In a meta-analysis of 18 studies with 463 patients and 1189 endoscopic balloon dilations, technical success was defined as the ability to dilate a stricture. Individual data were also obtained on 218 patients to identify outcome-relevant risk factors. RESULTS: In the pooled per-study analysis, technical success rate of endoscopic balloon dilation was 94.9%, resulting in short-term clinical efficacy in 82.3% of patients. Major complications occurred in 5.3% of patients. During follow-up, 48.3% of patients reported symptom recurrence, 38.8% were re-dilated and 27.4% proceeded to surgery. On the per-patient-based multivariable analysis, that patients with disease activity in the small intestine had lower short-term clinical efficacy (odds ratio 0.32; 95% confidence interval 0.14-0.73, P = 0.007). Patients with concomitant active disease in the small and/or large intestine had an increased risk to proceed toward surgery (hazard ratio 1.85; 95% confidence interval 1.09-3.13, P = 0.02 and hazard ratio 1.77; 95% confidence interval 1.34-2.34, P < 0.001). CONCLUSIONS: Balloon-assisted enteroscopy for dilatation of CD-associated small intestinal strictures has high short-term technical and clinical efficacy and low complication rates. However, up to two-thirds of patients need re-dilation or surgery.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted. METHODS: This study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival. RESULTS: Two hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonitis. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P = 0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P < 0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs (P < 0.01, p < 0.01). Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy. CONCLUSION: Although the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.

BACKGROUND AND AIM: Ustekinumab is a human monoclonal antibody to the p40 subunit of human IL-12/IL-23. The purpose of this report is to verify the newly developed immunoassays for serum ustekinumab and anti-ustekinumab antibody (AUA) concentrations and assess their clinical utility. METHODS: Serum ustekinumab trough levels and AUA levels were measured using new immunoassays in 38 patients with Crohn's disease under ustekinumab maintenance injection. RESULTS: Mean ustekinumab trough levels were 2.54 ± 2.1 μg/mL, and 3 of 38 patients (7.9%) were positive for AUAs. There was no association between ustekinumab trough levels and AUA levels. The optimal trough level of ustekinumab to maintain negative C-reactive protein levels (≤ 0.3 mg/dL) was 1.67 μg/mL determined by receiver operating characteristic curve analysis. Ustekinumab trough level negatively but significantly correlated with C-reactive protein, erythrocyte sedimentation rate, and Crohn's disease activity index and positively and significantly correlated with serum albumin levels. Ustekinumab trough levels were significantly higher in biologics-naïve patients than in biologics-experienced patients, although there was no difference in AUA levels. CONCLUSIONS: We developed new assays for serum ustekinumab trough and AUA levels. These assays might provide new insights into therapeutic drug monitoring-based management of Crohn's disease patients under ustekinumab therapy.

© 2020 by the authors. Gastrointestinal endoscopy is widely conducted for the early detection of gastric cancer. However, it is often difficult to detect early gastric cancer lesions and accurately evaluate the invasive regions. Our study aimed to develop a detection and segmentation method for early gastric cancer regions from gastrointestinal endoscopic images. In this method, we first collected 1208 healthy and 533 cancer images. The gastric cancer region was detected and segmented from endoscopic images using Mask R-CNN, an instance segmentation method. An endoscopic image was provided to the Mask R-CNN, and a bounding box and a label image of the gastric cancer region were obtained. As a performance evaluation via five-fold cross-validation, sensitivity and false positives (FPs) per image were 96.0% and 0.10 FP/image, respectively. In the evaluation of segmentation of the gastric cancer region, the average Dice index was 71%. These results indicate that our proposed scheme may be useful for the detection of gastric cancer and evaluation of the invasive region in gastrointestinal endoscopy.

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BACKGROUND AND AIM: Needle-based confocal laser endomicroscopy (nCLE) allows for real-time optical biopsies during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Little is known about nCLE imaging of gastrointestinal subepithelial lesions (GI-SEL); therefore, we determined its feasibility. METHODS: We carried out EUS, nCLE, and finally FNA in 25 patients with GI-SEL between November 2015 and December 2018. We retrospectively compared nCLE findings with pathological findings of EUS-FNA or surgical specimens. For concordance analysis, two endoscopists independently validated representative nCLE images 5 months or more after examinations. RESULTS: Adequate sample acquisition rate of EUS-FNA was 67% per needle pass and 96% per patient. EUS-FNA was diagnostic in 80% (20/25), suspicious in 4% (1/25), and nondiagnostic in 16% (4/25). nCLE image acquisition rate was 100% and its concordance rate with final pathology was 88% (22/25), which was not significantly different from diagnostic and suspicious EUS-FNA. nCLE could differentiate GI stromal tumors (GISTs) from leiomyoma, in that GISTs were characterized by contrast-enhanced densely populated spindle cell tumors with unenhanced rod-shaped nuclei in 93% of 14 patients, whereas leiomyomas were characterized by narrower spindle cell tumors with fewer and smaller unenhanced nuclei in 100% of three patients. In rectal metastasis from lung adenocarcinoma, some pleomorphic dark nests were observed. At concordance analysis between the two endoscopists' validation results, κ value was 0.560 (P < 0.001), indicating moderate agreement. There were no adverse events associated with nCLE and EUS-FNA. CONCLUSION: Needle-based confocal laser endomicroscopy can be safe and useful for on-site detection of abnormalities of GI-SEL (UMIN 000013857).

GOALS: We determined whether full-spectrum endoscopy (FUSE) improved the visualization rates of blind spots in a single-center case control study. BACKGROUND: FUSE provides a 210-degree angle of view with a left side-viewing camera in addition to a forward-viewing camera. FUSE can improve the detectability of blind spots in conventional forward-viewing esophagogastroduodenoscopy (EGD), such as the major duodenal papilla (MDP) and the anal side of the pyloric ring. STUDY: Between April 2016 and May 2017, successful visualization rates of the whole MDP and anal side of the pyloric ring were compared between 103 participants who underwent FUSE and 1045 participants who underwent EGD. Pain and discomfort at insertion and during and after the examination were assessed using a visual analog scale in 38 participants who underwent FUSE with a previous examination history of EGD. RESULTS: The successful visualization rates of MDP and the anal side of the pyloric ring in the FUSE group were significantly higher than those in the conventional EGD group; 83.4% versus 35.1% for MDP (P<0.001) and 86.4% versus 7.1% for the anal side of the pyloric ring (P<0.001), respectively. The visual analog scale were not significantly different between FUSE and previous EGD in a portion of the FUSE group. In addition, the detection rate of the periampullary diverticula was also significantly higher in the FUSE group than that in the conventional EGD group (8.7% vs. 1.6%, P<0.001). CONCLUSIONS: This study provides evidence supporting that FUSE is superior to EGD for precise visualization of blind spots in the duodenum.

BACKGROUND: We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness. METHODS: In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5-2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8. RESULTS: The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8. CONCLUSIONS: In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.

Small-bowel bleeding accounts for the majority of obscure gastrointestinal bleeding, but it is caused by various types of small bowel disease, upper gastrointestinal disease, and colorectal disease. For the diagnosis, history taking and physical examination are required, leading to a determination of what diseases are involved. Next, cross-sectional imaging, such as computed tomography, should be carried out, followed by the latest enteroscopy such as small bowel capsule endoscopy and deep enteroscopy according to the severity of hemorrhage and patient condition. After a comprehensive diagnosis, medical, enteroscopic, or surgical treatment should be selected. This article reviews recent advances in the endoscopic diagnosis of obscure gastrointestinal bleeding and compares perspectives of the management of obscure gastrointestinal bleeding in Japan with that in other countries.

OBJECTIVE: The underlying microbial basis, predictors of therapeutic outcome and active constituent(s) of faecal microbiota transplantation (FMT) mediating benefit remain unknown. An international panel of experts presented key elements that will shape forthcoming FMT research and practice. DESIGN: Systematic search was performed, FMT literature was critically appraised and a 1-day round-table discussion was conducted to derive expert consensus on key issues in FMT research. RESULTS: 16 experts convened and discussed five questions regarding (1) the role of donor and recipient microbial (bacteria, viruses, fungi) parameters in FMT; (2) methods to assess microbiota alterations; (3) concept of keystone species and microbial predictors of FMT, (4) influence of recipient profile and antibiotics pretreatment on FMT engraftment and maintenance and (5) new developments in FMT formulations and delivery. The panel considered that variable outcomes of FMT relate to compositional and functional differences in recipient's microbiota, and likely donor-associated and recipient-associated physiological and genetic factors. Taxonomic composition of donor intestinal microbiota may influence the efficacy of FMT in recurrent Clostridioides difficile infections and UC. FMT not only alters bacteria composition but also establishes trans-kingdom equilibrium between gut fungi, viruses and bacteria to promote the recovery of microbial homeostasis. FMT is not a one size fits all and studies are required to identify microbial components that have specific effects in patients with different diseases. CONCLUSION: FMT requires optimisation before their therapeutic promise can be evaluated for different diseases. This summary will guide future directions and priorities in advancement of the science and practice of FMT.

Background and study aims  Endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors (SNADETs) has not been established. Probe-based confocal laser endomicroscopy (pCLE: Cellvizio) provides real-time endomicroscopic analysis. We developed and validated a new pCLE classification of SNADET based on abnormal findings. Patients and methods  pCLE scanning of 20 SNADET lesions including 16 adenomas and four carcinomas was retrospectively evaluated to explore abnormal pCLE findings in relation to histological features. Diagnostic yield of pCLE findings was prospectively evaluated in an additional 20 SNADET lesions including 16 adenomas and four carcinomas. Results  In a retrospective study, we identified four abnormal pCLE findings of SNADETs: (1) dark epithelium, (2) columnar cells irregularly extending to the lumen, (3) distorted crypt structure, and (4) fluorescein leakage. Dark epithelium distinguished neoplastic lesions (adenomas and carcinomas) from non-neoplastic duodenal mucosa with a sensitivity of 90 % and a specificity of 100 %. Distorted crypt structure distinguished carcinomas from adenomas and non-neoplastic duodenal mucosa with a sensitivity of 100% and a specificity of 94 %. In the prospective study, the sensitivity and the specificity of the dark epithelium for the diagnosis of neoplastic lesions (adenomas + carcinomas) was 75% and 100 %. Sensitivity and the specificity of the distorted crypt structure for discrimination of carcinoma from adenoma were 100 % and 94 %, respectively. Conclusions  The pCLE findings correlated with the histopathology of the SNADETs. Dark epithelium and distorted crypt structure were informative pCLE findings to predict presence of neoplasia and cancer in the SNADET, respectively. UMIN-CTR UMIN000013857 TRIAL REGISTRATION: Single-Center, prospective observational trial UMIN000013857 at upload.umin.ac.jp.

Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods: LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori-related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori-related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.

Predicting Helicobacter pylori (Hp) status by endoscopic finding would be useful in recent clinical condition that the use of proton-pump inhibitors, anti-platelet, and anti-coagulant have become widespread. We aimed to elucidate the diagnostic accuracy of magnifying narrow-band imaging (M-NBI) endoscopy in distinguishing Hp status in patients with or without history of successful Hp eradication and compare this accuracy to the diagnostic accuracy of conventional white light (WL) endoscopy.Two hundred seven endoscopic examinations before and after Hp eradication were performed in prospective 163 patients. Endoscopic images by using the M-NBI and conventional WL were stored electronically and randomly allocated to 2 readers for evaluation. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were assessed by reference to Hp status assessed by conventional clinical test.Sensitivity, specificity, PPV, NPV, and accuracy for predicting Hp status for the conventional WL was 72.2%, 75.5%, 72.2%, 75.5%, and 73.9% for the first reader; 86.6%, 57.3%, 64.1%, 82.9%, and 71.0% for the second reader. On the other hand, sensitivity, specificity, PPV, NPV, and accuracy for predicting Hp status for the M-NBI was 96.9%, 93.6%, 93.1%, 97.1%, and 95.2% for the first reader; 92.8%, 93.6%, 92.8%, 93.6%, and 93.2% for the second reader, respectively. The diagnostic accuracy of M-NBI was significantly higher than that of WL (P < .0001 for both readers). Inter-observer agreement of M-NBI (k = 0.83) was also better than that of WL (k = 0.53).M-NBI was capable of distinguishing Hp status before and after eradication therapy.

Genome-wide association study identified two functional SNPs associated with gastric cancer especially the diffuse type. The first was a polymorphism (rs2294008) in prostate stem cell antigen (PSCA), and the other was a polymorphism (rs4072037) in mucin 1 (MUC1). DNA methylation is associated with gastric cancer and Helicobacter pylori (H. pylori)-induced gastritis, while hypermethylation of promoter CpG island (CGI) is a common characteristic of enlarged-fold gastritis induced by H. pylori, a risk factor of diffuse-type gastric cancer. We evaluated the association between PSCA and MUC1 polymorphisms with H. pylori--related promoter CGI methylation in the nonneoplastic gastric mucosa. PSCA rs2294008 C/T and MUC1 rs4072037 A/G polymorphisms were genotyped in 410 cancer-free subjects in relation to promoter CGI methylation status of three candidate genes, of which the methylation status is associated with H. pylori infection (IGF2, MYOD1, and SLC16A12). Methylation levels of all three genes were significantly higher in subjects with PSCA rs2294008 T/T compared with the PSCA rs2294008 C/C (all P < 0.05). Such associations were more enhanced in H. pylori-positive subjects (all P < 0.01). The multivariate analysis demonstrated that PSCA C/T [OR, 2.37; 95% CI (confidence interval), 1.06-5.29; P = 0.035] and T/T genotypes (OR, 3.2; 95% CI, 1.41-7.25; P = 0.005) were significantly associated with methylation-high gastric mucosa as independent factors. MUC1 rs4072037 A/G polymorphism was not associated with methylation status of all three genes. PSCA C/T and T/T genotypes are associated with H. pylori-related promoter DNA methylation in the gastric mucosa.Impact: Our observations provided the evidence that PSCA polymorphism influence the susceptibility to gastric cancer through DNA methylation induction.

Drug resistance makes treatment difficult in cancers. The present study identifies and analyzes drug resistance-related miRNA in colorectal cancer. We established 4 types of 5-fluorouracil (5-FU)-resistant colon cancer cell lines in vitro and in vivo. We then analyzed the miRNA expression profile by miRNA array in these 4 cell lines, and identified the drug resistance-related miRNAs. We examined the expression levels of the identified miRNA in 112 colorectal tumor samples from the patients. We identified 12 possible miRNAs involved in 5-FU resistance by miRNA arrays. We then examined the relationship between miR-31, which was the most promising among them, and drug resistance. The ectopic expression of mimic miR-31 showed significant 5-FU resistance in the parental DLD-1 cells, while anti-miR-31 caused significant growth inhibition in DLD/F cells; that is, 5-FU-resistant colon cancer cell line DLD-1 under exposure to 5-FU. When we exposed high doses of 5-FU to parent or 5-FU-resistant cells, the expression levels of miR-31 were raised higher than those of controls. Notably, the expression levels of miR-31 were positively correlated with the grade of clinical stages of colorectal tumors. The protein expression levels of factors inhibiting hypoxia-inducible factor 1 were downregulated by transfection of mimic miR-31 into DLD-1 cells. This study provides evidence supporting the association of miR-31 with 5-FU drug resistance and clinical stages of colorectal tumors.

BACKGROUND & AIMS: We aimed to establish a comorbidity index for small bowel vascular diseases (SBVD) associated with small bowel bleeding (SBB) and recurrent bleeding. METHODS: We performed a retrospective analysis of 404 patients diagnosed with SBB via double-balloon enteroscopy, at 2 hospitals in Japan from June 2003 through July 2016. We collected data on comorbidities, computed Charlson Comorbidity Index and anticoagulation and risk factors in atrial fibrillation (ATRIA) scores, and analyzed associations with SBVD, rebleeding, and overall survival associated with bleeding and/or comorbidities. We used these data to develop a comorbidity index to identify patients at risk for SBVD, rebleeding, and reduced survival time. We validated our findings in a separate, prospective cohort of 88 patients with SBB. RESULTS: We developed a weighted index (the Ohmiya index) that identified patients who developed SBVD with an area under the receiver operating characteristic (AUROC) curve of 0.7758; this value was higher than that of the Charlson index score (0.6828; P < .0001) or ATRIA score (0.6728; P < .0001) alone. Among the 51 patients taking oral anticoagulants, there was no significant difference in AUROCs for the Ohmiya score (0.5254) vs the outcomes registry for better informed treatment score (0.5857; P = .4300). In the retrospective cohort, the Ohmiya index identified patients with SBVD with 68% sensitivity (93/137), 84% specificity (223/267), and 78% accuracy (316/404); in the validation cohort, these values were 63% (22/35), 85% (45/53), and 76% (67/88), respectively. Onset age <50 years and index score <2 identified patients with Meckel's diverticulum and Crohn's disease with 53% accuracy. Onset age ≥50 years and index score <2 identified patients with inflammatory diseases, drug-induced injuries, or tumors with 72% accuracy. An index score ≥2 identified patients with SBVD with 68% accuracy, regardless of age. Among patients with Ohmiya index scores ≥2, 33% had rebleeding; among patients with scores <2, 15% had rebleeding (hazard ratio for score ≥2, 1.729; 95% CI, 1.038-2.882; P = .0355). CONCLUSION: We developed an index, based on comorbidities and age of onset of SBB, that identified patients at risk for rebleeding and vascular disease (for example, enteroscopic hemostasis for SBVD, medication for inflammatory diseases, surgery with enteroscopic tattooing for tumors and diverticula). UMIN: 000025693.

BACKGROUND AND AIM: Extensive use of laxatives and incomplete excretion rates are problematic for colon capsule endoscopy (CCE). The aim of the present study was to determine the effectiveness of castor oil as a booster. METHODS: At four Japanese hospitals, 319 examinees undergoing CCE were enrolled retrospectively. Before and after the introduction of castor oil, other preparation reagents were unchanged. RESULTS: Of 319 examinees who underwent CCE, 152 and 167 examinees took regimens with castor oil (between November 2013 and June 2016) and without castor oil (between October 2015 and September 2017), respectively. Capsule excretion rates within its battery life in the groups with and without castor oil were 97% and 81%, respectively (P < 0.0001). Multivariate analysis showed that ages younger than 65 years (adjusted odds ratio [OR], 3.00; P = 0.0048), male gender (adjusted OR, 3.20; P = 0.0051), and use of castor oil (adjusted OR, 6.29; P = 0.0003) were predictors of capsule excretion within its battery life. Small bowel transit time was shorter and total volume of lavage and fluid intake was lower with castor oil than without (P = 0.0154 and 0.0013, respectively). Overall adequate cleansing level ratios with and without castor oil were 74% and 83%, respectively (P = 0.0713). Per-examinee sensitivity for polyps ≥6 mm with and without castor oil was 83% and 85%, respectively, with specificities of 80% and 78%, respectively. CONCLUSION: Bowel preparation with castor oil was effective for improving capsule excretion rate and reducing liquid loading.

BACKGROUND: Capsule endoscopy can be used to identify the early stage of small bowel Crohn's disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD. METHODS: We retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups. RESULTS: Under SBCE, cobblestone appearance (33% vs. 2%, p < 0.0001), longitudinal ulcers (78% vs. 20%, p < 0.0001), and irregular ulcers (84% vs. 60%, p < 0.01) were more frequently found in patients with CD. Linear erosion (90% vs. 38%, p < 0.0001) and irregular erosion (89% vs. 64%, p < 0.005) were also more frequent in patients with CD. Furthermore, circumferential (75% vs. 9%, p < 0.0001) and longitudinal (56% vs. 7%, p < 0.0001) alignment of diminutive lesions, mainly observed in the 1st tertile of the small bowel, was more frequent in patients with CD. Good intra-observer agreement was found for ulcers, cobblestone appearance, and lesion alignment. However, inter-observer agreement of SBCE findings differed among observers. CONCLUSIONS: Circumferential or longitudinal alignment of diminutive lesions, especially in the upper small bowel, may be a diagnostic clue for CD under SBCE, while inter-observer variations should be cautiously considered when using SBCE.

Both genetic and epigenetic abnormalities play important roles in gastric cancer (GC) development. We investigated whether the molecular subtypes of gastric cancer by combining genetic and epigenetic anomalies define its clinicopathological features and prognosis. The CpG island methylator phenotype (CIMP), MLH1 methylation, TP53, and KRAS mutation statuses were characterized in 214 GCs in relation to their clinicopathological features and prognosis. The molecular subtypes based on CIMP and TP53 hot spot mutation status (R175, G245, R248, R273, and R282) best predicted prognosis of GC. These subtypes contained 120 CIMP-positive (CIMP+) TP53 hot spot mutation-negative (TP53 hot spot-) cases, 81 CIMP-negative (CIMP-) TP53 hot spot- cases, 8 CIMP+TP53 hot spot mutation-positive (TP53 hot spot+) cases, and 5 CIMP- TP53 hot spot+ cases. The CIMP-TP53 hot spot+ group presented the worst overall survival (OS) and progression-free survival (PFS), followed by the CIMP+TP53 hot spot+, CIMP-TP53 hot spot- and CIMP+TP53 hot spot- groups (both P < 0.0001). These subtypes also correlated well with several aggressive clinicopathological features in that order. The molecular subtypes were independent factors for predicting overall survival (hazard ratio = 1.66, 95% CI = 1.07-2.57, P = 0.006). The molecular subtypes combining the CIMP and TP53 hot spot mutation status provide distinct clinicopathological features and prognostic impacts in GC.

Background and Aim: Extensive use of laxatives and incomplete excretion rates are problematic for colon capsule endoscopy (CCE). The aim of the present study was to determine the effectiveness of castor oil as a booster. Methods: At four Japanese hospitals, 319 examinees undergoing CCE were enrolled retrospectively. Before and after the introduction of castor oil, other preparation reagents were unchanged. Results: Of 319 examinees who underwent CCE, 152 and 167 examinees took regimens with castor oil (between November 2013 and June 2016) and without castor oil (between October 2015 and September 2017), respectively. Capsule excretion rates within its battery life in the groups with and without castor oil were 97% and 81%, respectively (P＜0.0001). Multivariate analysis showed that ages younger than 65 years (adjusted odds ratio [OR], 3.00 P=0.0048), male gender (adjusted OR, 3.20 P=0.0051), and use of castor oil (adjusted OR, 6.29 P=0.0003) were predictors of capsule excretion within its battery life. Small bowel transit time was shorter and total volume of lavage and fluid intake was lower with castor oil than without (P = 0.0154 and 0.0013, respectively). Overall adequate cleansing level ratios with and without castor oil were 74% and 83%, respectively (P = 0.0713). Per-examinee sensitivity for polyps ≥ 6 mm with and without castor oil was 83% and 85%, respectively, with specificities of 80% and 78%, respectively. Conclusion: Bowel preparation with castor oil was effective for improving capsule excretion rate and reducing liquid loading.

A submucosal hematoma in the colon is rare. Here we report a case of submucosal hematoma in the colon during anticoagulation therapy. An 80-year-old man was admitted to a previous hospital due to hematochezia. He had taken a direct oral anticoagulant, Edoxaban, for chronic atrial fibrillation. Because the bleeding continued in spite of stopping the anticoagulant, he was transferred to our hospital on the third day of hospitalization. On emergency colonoscopy, several protruded submucosal hematomas with mucosal exfoliations were observed from the sigmoid colon to the descending colon. It was impossible to insert the endoscope to the proximal side because of obstruction by hematomas. Conservative therapy including discontinuation of Edoxaban was administered. The hematochezia stopped and anemia did not progress. On the second day, the patient had a high fever with septic shock and two sets of blood culture tests both showed positivity for Clostridium perfringens. In addition to intravenous antibiotic therapy, intensive cares were provided. After his general condition recovered, follow-up colonoscopy was conducted on the 9th day. The submucosal hematomas had completely disappeared and changed to a wide longitudinal ulcer. The patient was discharged without any sequela such as stricture. Anticoagulants may be a risk factor for submucosal hematoma in the colon, and it is necessary to keep in mind the characteristic endoscopic findings.

Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp-), gastric body without cancer after H. pylori eradication (cancer-free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer-free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome-wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication.

OBJECTIVE: Helicobacter pylori eradication is expected to prevent gastric cancer. However, morphological alterations after eradication often hinder accurate diagnosis. Therefore, we evaluated endoscopic and histological changes in gastric tumors after eradication of H. pylori in a time-dependent manner. METHODS: We classified 144 cases of endoscopic submucosal dissection (ESD) of early gastric cancer into the following categories: (i) patients positive for H. pylori with no eradication history, (ii) patients positive for H. pylori who underwent ESD 2 months after eradication, (iii) patients negative for H. pylori with an eradication history of at least 6 months before ESD, and (iv) patients negative for H. pylori with an unknown history. We compared endoscopic and histological factors between the groups. RESULTS: The characteristics of cancers positive for H. pylori were exploding shape, superficial high-grade atypical epithelium, and a surface proliferating zone. H. pylori eradication induced a series of endoscopic and histological changes, including shape -depression, appearance of surface regenerative and lower-grade atypical epithelium, and a downward shift of the proliferative zone within a period as short as 2 months. CONCLUSION: H. pylori eradication rapidly causes cancer regression and leads to tumor shrinkage, diminished atypism, and shortened proliferative zone, resulting in drastic morphological changes.

To investigate the molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication, expression of miR-124a, miR-34b, and miR-34c was examined in nonneoplastic gastric specimens after successful H. pylori eradication. The magnifying narrow-band imaging (NBI) endoscopic features of gastric mucosa were also examined. The atrophic type, an informative endoscopic feature for histological intestinal metaplasia, showed lower expression of miR-124a. Lower expression of miR-124a correlated with hypermethylation of the miR-124a3 locus. The atrophic type represents gastric microarchitectures associated with irreversibility with H. pylori eradication and downregulation of miR-124a.

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 nonsteroidal 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 confound-ers. 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.

[This corrects the article DOI: 10.1016/j.vgie.2018.04.010.].

BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a hereditary disease caused by mutations in the SLCO2A1 gene and characterized by multiple small intestinal ulcers of nonspecific histology. SLCO2A1 is also a causal gene of primary hypertrophic osteoarthropathy (PHO). However, little is known about the clinical features of CEAS or PHO. METHODS: Sixty-five Japanese patients recruited by a nationwide survey of CEAS during 2012-2016 were enrolled in this present study. We reviewed the clinical information of the genetically confirmed CEAS patients. RESULTS: We identified recessive SLCO2A1 mutations at 11 sites in 46 patients. Among the 46 patients genetically confirmed as CEAS, 13 were men and 33 were women. The median age at disease onset was 16.5 years, and parental consanguinity was present in 13 patients (28%). Anemia was present in 45 patients (98%), while a single patient experienced gross hematochezia. All patients showed relatively low inflammatory markers in blood tests (median CRP 0.20 mg/dl). The most frequently involved gastrointestinal site was the ileum (98%), although no patient had mucosal injuries in the terminal ileum. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO. CONCLUSIONS: The clinical features of CEAS are distinct from those of Crohn's disease. Genetic analysis of the SLCO2A1 gene is therefore recommended in patients clinically suspected of having CEAS.

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 previously reported to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. In this report, we focused on colorectal adenoma (tubular or tubulovillous adenoma), or tubular early carcinoma or type 2 adenocarcinoma, familial adenomatous polyposis (FAP), ulcerative colitis-associated tumor (UCAT), and sessile serrated adenoma/polyp (SSA/P). We tried to clarify the relationship between the expression of the miRNAs and the colorectal tumor development. The expression levels of miR-143, -145, and -34a were reduced in most of the polypoid and FAP tumors compared with those in the flat elevated, UCAT, SSA/P ones. In type 2 adenocarcinomas, the expression profile of these miRNAs was similar to those of the polypoid and FAP tumors. The expression levels of miR-7 and -21 were up-regulated in non-granular type of laterally spreading tumor, UCAT, and SSA/P compared with those in polypoid and FAP tumors. These findings indicated that the expression of onco-related miRNAs was closely associated with the development and endoscopic appearance of colorectal tumors.

DNA methylation of leukocyte DNA has been proposed to be a biomarker for cancer that can be used to target patients for appropriate clinical implementation. We investigated IGF2 DMR and LINE1 methylation in the leukocyte DNA and their association with clinicopathological features and prognosis of gastric cancer (GC) patients. Methylation status of IGF2 DMR and LINE1 in the leukocyte DNA was quantified using bisulfite pyrosequencing in 207 GC patients. Methylation of both IGF2 DMR and the LINE1 was significantly higher in the undifferentiated histologic type compared to the differentiated histologic type (both P = 0.0002). Hypermethylation of both the IGF2 DMR and the LINE1 was associated with more aggressive features of GC such as advanced stage (IGF2 DMR, P = 0.0002; LINE1, P < 0.0001), lymphatic invasion positive (IGF2 DMR, P = 0.004; LINE1, P = 0.002), venous invasion positive (IGF2 DMR, LINE1, both P = 0.03), lymph node metastasis positive (IGF2 DMR, P = 0.01; LINE1, P = 0.001), peritoneal dissemination positive (IGF2 DMR, P = 0.04; LINE1, P = 0.002), liver metastasis positive (IGF2 DMR, P = 0.008; LINE1, P = 0.001), and other distant metastasis positive (IGF2 DMR, P = 0.04). Our data suggest that high LINE1 and IGF2 DMR methylation status would be a phenomenon that is observed with the progression of GC, supporting their potential utility as a biomarker in GC patients.

Epstein-Barr virus (EBV) infection is involved in a subset of gastric carcinoma (GC) cases, and is associated with distinct clinicopathological features. The present study reports a unique case of EBV-associated early-stage GC compared with the other cases experienced in our hospital. A 72-year-old male receiving treatment for cerebral infarction underwent an esophagogastroduodenoscopy (EGD) for suspicion of gastrointestinal bleeding. EGD revealed a type 0-I protruding lesion in the lesser curvature of the upper gastric corpus. Biopsy indicated well-differentiated adenocarcinoma. As the tumor diameter was >3 cm and the thickness of the tumor suggested submucosal invasion, laparoscopic gastrectomy was performed. Histological assessment revealed polypoid growth of an intramucosal, differentiated, tubular or papillary adenocarcinoma, with dense infiltration of lymphocytes. The carcinoma crypts were found to be EBV-positive on in situ hybridization. A review of the clinicopathological features of 25 EBV-associated GCs from 20 patients treated in our hospital between 2005 and 2014 was performed. All of these tumors, except that in the current case, appeared as shallow, depressed or ulcerative lesions. Thus, the current case appears to represent an unusual growth of EBV-positive GC.

Background and Aims: Endoscopic balloon dilation [EBD] is an alternative to surgery for Crohn's strictures. However, there have been no prospective studies of EBD for small bowel strictures in patients with Crohn's disease [CD]. The aim of this study was to clarify the efficacy and safety of EBD using balloon-assisted enteroscopy for small bowel strictures in CD. Methods: This was a nationwide, multi-centre, open-label, prospective cohort study. The subjects were CD patients with at least one symptom [abdominal pain, abdominal bloating, nausea] attributable to small bowel stricture. The primary endpoint related to short-term outcomes was the level of improvement of symptoms evaluated using a 10-cm visual analogue scale [VAS]. Cases in which VAS scores for all symptoms improved 4 weeks after EBD compared with baseline were considered to have short-term symptomatic improvement. Factors related to short-term treatment outcomes and safety were investigated as secondary endpoints. Results: A total of 112 patients were enrolled. Seventeen were later excluded because they did not meet the criteria, and the analysis was conducted with the remaining 95 patients. Of these 95 patients, procedure failure occurred in six [6.3%], and short-term symptomatic improvement was achieved in 66 patients [69.5%]. Adverse events were seen in five patients [5%] and all of these improved with conservative treatment. A large dilation diameter of the balloon was a factor contributing to the success of EBD. Conclusions: EBD using balloon-assisted enteroscopy for small bowel strictures in CD patients was shown to be an effective and safe procedure. Clinical trial registry: UMIN000005946.

BACKGROUND AND AIM: Early-stage gastric cancer (EGC) found after Helicobacter pylori (Hp) eradication often displays non-tumorous regenerative epithelium and/or maturated tumorous epithelium overlying the cancerous tissue, which may confuse endoscopic and histological diagnosis. Probe-based confocal laser endomicroscopy (pCLE) enables in vivo real-time optical biopsy. We compared the diagnostic yields for these EGC cases using conventional white light endoscopy (WL), magnifying endoscopy with narrow-band imaging (ME-NBI), pCLE, and endoscopic biopsy; we also compared the accuracy of the horizontal extent diagnosis between ME-NBI and pCLE. METHODS: This study enrolled 30 patients with 36 EGC lesions after successful Hp eradication. Diagnostic yields of WL, ME-NBI, pCLE, and endoscopic biopsy were prospectively compared. Four points of cancerous margins (oral, anal, anterior, and posterior sites) were also prospectively evaluated with M-NBI and pCLE to determine the horizontal extent of the EGC. RESULTS: Diagnostic yield was significantly higher with pCLE than with WL and endoscopic biopsy (97 vs 72%, 97 vs 72%, P = 0.0159, 0.0077, respectively), whereas it did not differ from ME-NBI (88.9%, P = 0.371). Height of non-tumorous regenerative epithelium or maturated atypical glands was 104.7 ± 34.2 μm in the pCLE-positive cases, whereas it was 188.3 ± 27.1 μm in a pCLE-negative case (P = 0.0004). Diagnostic accuracy of the horizontal margin of EGC was significantly higher with pCLE than with ME-NBI (92 vs 70%, P = 0.0159). CONCLUSION: pCLE may be helpful for the diagnosis of ambiguous ECG found after Hp eradication because it enables real-time scanning throughout the lesion and detection of subsurface microstructure.