Helicobacter pylori infection associated DNA methylation in primary gastric cancer significantly correlates with specific molecular and clinicopathological features.

Helicobacter pylori induces DNA methylation in gastric mucosa, which links to gastric cancer (GC) risk. In contrast, CpG island methylator phenotype (CIMP) is defined as high levels of cancer-specific methylation and provides distinct molecular and clinicopathological features of GC. The association between those two types of methylation in GC remains unclear. We examined DNA methylation of well-validated H. pylori infection associated genes in GC and its adjacent mucosa and investigated its association with CIMP, various molecular subtypes and clinical features. We studied 50 candidate loci in 24 gastric samples to identify H. pylori infection associated genes. Identified loci were further examined in 624 gastric tissue from 217 primary GC, 217 adjacent mucosa, and 190 mucosae from cancer-free subjects. We identified five genes (IGF2, SLC16A2, SOX11, P2RX7, and MYOD1) as hypermethylated in H. pylori infected gastric mucosa. In non-neoplastic mucosa, methylation of H. pylori infection associated genes was higher in patients with GC than those without. In primary GC tissues, higher methylation of H. pylori infection associated genes correlated with CIMP-positive and its related features, such as MLH1 methylated cases. On the other hand, GC with lower methylation of these genes presented aggressive clinicopathological features including undifferentiated histopathology, advanced stage at diagnosis. H. pylori infection associated DNA methylation is correlated with CIMP, specific molecular and clinicopathological features in GC, supporting its utility as promising biomarker in this tumor type.

Prospective study of diagnostic yields of flexible spectral imaging color enhancement installed in colon capsule endoscopy for colorectal polyps and tumors.

BACKGROUND AND AIMS: We prospectively determined the efficacy of flexible spectral imaging color enhancement (FICE) used with second-generation colon capsule endoscopy (CCE) for colorectal polyps and tumors (CRTs). METHODS: This study included optical colonoscopy within 4 months after CCE. Two colonoscopists independently reviewed CCE using white-light images (CCE-WL) and CCE using FICE images (CCE-FICE), respectively. Based on colonoscopic findings as the criterion standard, the diagnostic accuracy for CRTs was compared between CCE-WL and CCE-FICE. RESULTS: Of 89 enrolled patients (65 men and 24 women; 75 with CRTs including 36 with serrated lesions, 63 with adenomas, and 9 with adenocarcinomas), the per-patient detectability of CCE-FICE for the representative CRTs was significantly higher than that of CCE-WL: overall CRTs (CCE-WL, 79%; CCE-FICE, 88%; P = .0001), 6- to 9-mm CRTs (CCE-WL, 63%; CCE-FICE, 94%; P = .0055), and ≥6-mm CRTs (CCE-WL, 78%; CCE-FICE, 93%; P = .0159). The per-lesion sensitivity of CCE-FICE was significantly higher than that of CCE-WL for CRTs: overall (CCE-WL, 61%; CCE-FICE, 79%; P < .0001), <6 mm (CCE-WL, 53%; CCE-FICE, 69%; P < .0001), 6- to 9-mm CRTs (CCE-WL, 65%; CCE-FICE, 93%; P = .0007), slightly elevated CRTs (CCE-WL, 53%; CCE-FICE, 75%; P < .0001), tubular adenomas (CCE-WL, 61%; CCE-FICE, 79%; P < .0001), and serrated polyps (CCE-WL, 57%; CCE-FICE, 74%; P = .0022). Both modes detected all adenocarcinomas. No significant differences were found between CCE-WL and CCE-FICE of the per-lesion sensitivity for ≥10-mm CRTs (CCE-WL, 81%; CCE-FICE, 94%; P = .1138) or protruding CRTs (CCE-WL, 77%; CCE-FICE, 86%; P = .0614). Kappa coefficients for overall CRTs for CCE-WL and CCE-FICE were .66 and .64, respectively, which indicated substantial agreement. CONCLUSIONS: CCE-FICE improved the detection rates for all CRTs except adenocarcinomas, ≥10-mm polyps, and protruding polyps when compared with CCE-WL. (Clinical trial registration number: UMIN 000021125.).

Nationwide multicenter study on adverse events associated with a patency capsule: Additional survey of appropriate use of patency capsule study.

BACKGROUND AND AIM: The PillCam patency capsule (PC) without a radio frequency identification tag was released to preclude retention of the small bowel capsule endoscope (CE) in Japan in 2012. We conducted a multicenter study to determine tag-less PC-related adverse events (AEs). METHODS: We first conducted a retrospective survey using a standardized data collection sheet for the clinical characteristics of PC-related AEs among 1096 patients collected in a prospective survey conducted between January 2013 and May 2014 (Cohort 1). Next, we retrospectively investigated additional AEs that occurred before and after Cohort 1 within the period June 2012 and December 2014 among 1482 patients (Cohort 2). RESULTS: Of the 2578 patients who underwent PC examinations from both cohorts, 74 AEs occurred among 61 patients (2.37%). The main AEs were residual parylene coating in 25 events (0.97%), PC-induced small bowel obstruction, suspicious of impaction, in 23 events (0.89%), and CE retention even after patency confirmation in 10 events (0.39%). Residual parylene coating was significantly associated with Crohn's disease (P < 0.01). Small bowel obstruction was significantly associated with physicians with less than 1 year of experience handling the PC and previous history of postprandial abdominal pain (P < 0.01 and P < 0.03, respectively). CE retention was ascribed to erroneous judgment of PC localization in all cases. CONCLUSIONS: This large-scale multicenter study provides evidence supporting the safety and efficiency of a PC to preclude CE retention. Accurate PC localization in patients without excretion and confirmation of previous history of postprandial abdominal pain before PC examinations is warranted (UMIN000010513).

Injury to the muscle layer, increasing the risk of post-colorectal endoscopic submucosal dissection electrocoagulation syndrome.

BACKGROUND AND AIM: In colorectal endoscopic submucosal dissection (ESD), post-ESD electrocoagulation syndrome (PECS) has been recognized as one of the major complications. There are no reports on the relationships between ESD findings and PECS. This study aims to evaluate the risk factors for PECS, including ESD findings such as muscularis propria exposure. METHODS: We performed a retrospective cohort study of patients who underwent colorectal ESD between January 2017 and December 2021 in Japan. The grade of injury to the muscle layer caused by ESD was categorized as follows: Grade 0, no exposure of muscularis propria; Grade 1, muscularis propria exposure; Grade 2, torn muscularis propria; and Grade 3, colon perforation. The risk factors for PECS, including injury to the muscle layer, were analyzed by univariate and multivariate analyses. RESULTS: Out of 314 patients who underwent colorectal ESD, PECS occurred in 28 patients (8.9%). The multivariate analysis showed that female sex (odds ratio [OR] 3.233; 95% confidence interval [95% CI]: 1.264-8.265, P = 0.014), large specimen size (≥ 40 mm) (OR 6.138; 95% CI: 1.317-28.596, P = 0.021), long procedure time (≥ 90 min) (OR 2.664; 95% CI: 1.053-6.742, P = 0.039), and Grade 1 or 2 injury to the muscle layer (OR 3.850; 95% CI: 1.090-13.61, P = 0.036) were independent risk factors for PECS. CONCLUSIONS: Injury to the muscle layer, such as exposure or tear, was identified as a novel independent risk factor for PECS. We should perform colorectal ESD carefully to avoid injuring the muscle layers.

Multicenter epidemiological survey of pneumatosis intestinalis in Japan.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome. METHODS: We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion. RESULTS: We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02-1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04-167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80-152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02-15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82-145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31-144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10-72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07-140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053-131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09-189.48, P = 0.0425). DISCUSSION: Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis.

Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial.

BACKGROUND AND AIM: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS: This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION: In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.

Safety and efficacy of the endoscopic delivery of capsule endoscopes in adult and pediatric patients: Multicenter Japanese study (AdvanCE-J study).

BACKGROUND AND AIM: We retrospectively determined the safety and efficacy of the endoscopic delivery (ED) of capsule endoscopes. METHODS: We enrolled 10,156 patients who underwent small bowel capsule endoscopy (SBCE), 3182 who underwent patency capsule (PC), and 1367 who underwent colon capsule endoscopy (CCE), at 11 gastroenterological and nine pediatric centers. RESULTS: Small bowel capsule endoscopies, PCs, and CCEs were endoscopically delivered to 546 (5.4%), 214 (6.7%), and 14 (1.0%) patients, respectively. Only mild complications occurred for 21.6% (167/774), including uneventful mucosal damage, bleeding, and abdominal pain. Successful ED of SBCE to the duodenum or jejunum occurred in 91.8% and 90.7% of patients aged <16 years and ≥16 years, respectively (P = 0.6661), but the total enteroscopy rate was higher in the first group (91.7%) than in the second (76.2%, P < 0.0001), for whom impossible ingestion (87.3%) was significantly more common than prolonged lodging in the stomach (64.2%, P = 0.0010). Successful PC and CCE delivery to the duodenum occurred in 84.1% and 28.6%, thereafter the patency confirmation rate and total colonoscopy rate was 100% and 61.5%, respectively. The height, weight, and age cutoff points in predicting spontaneous ingestion were 132 cm, 24.8 kg, and 9 years 2 months, respectively, in patients aged <16 years. Patients aged ≥16 years could not swallow the SBCEs mainly due to dysphagia (75.0%); those who retained it in the esophagus due to cardiac disease (28.6%), etc. and in the stomach due to diabetes mellitus (15.7%), etc. CONCLUSIONS: This large-scale study supports the safety and efficacy of ED in adult and pediatric patients. UMIN000042020.

Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures (supplement to the Clinical Practice Guidelines for Enteroscopy).

Balloon-assisted enteroscopy allows endoscopic treatments in the deeper segments of the small bowel. Endoscopic balloon dilation has become a popular minimally invasive alternative for the treatment of Crohn's disease-associated small intestinal strictures. As a supplement to the Clinical Practice Guidelines for Enteroscopy, the Japan Gastroenterological Endoscopy Society's Working Committee has developed the present "Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures," based on new scientific techniques and evidence. The guidelines cover standard procedures for the insertion route of the balloon endoscope, bowel preparation, indications, procedure-related complications, efficacy, target diameter and duration, management of multiple strictures, and the current state of combined and alternative treatments. Unresolved future research questions are also listed in this guideline.

Fecal microbiota transplantation as therapy for recurrent Clostridioides difficile infection is associated with amelioration of delirium and accompanied by changes in fecal microbiota and the metabolome.

Recurrent Clostridioides difficile infection (rCDI) is a frustrating condition that may affect a person's quality of life for months. Microbiome-based therapy such as fecal microbiota transplantation (FMT) has been effective for the treatment of rCDI by correcting the imbalance of the gut microbiota. Appropriate antibiotic treatment is recommended for at least two recurrences before offering FMT. Here, we report the case of a 92-year-old woman who experienced five recurrences of Clostridioides difficile infection (CDI) (six episodes in total) complicated by dementia and delirium, both of which were dramatically improved by FMT, which was associated with alterations in fecal microbiota and the metabolome. Analyses of whole microbial communities and metabolomic analyses were performed on stool specimens collected from the patient on the first episode, the third episode, the day of FMT (before FMT), and 2, 8, and 23 weeks after the FMT and from the donor. The patient had various fecal dysbioses on the first and third episodes and on the day of FMT. Two weeks after FMT, diversity of the gut bacteriome as well as the virome increased dramatically and was reflected in a positive clinical outcome for this patient. Metabolomic analysis revealed that short-chain fatty acids, which have been reported to be associated with improved memory function, were increased after FMT.

A Prospective Study Evaluating the Clinical Utility of the Tag-Less Patency Capsule with Extended Time for Confirming Functional Patency.

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.

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research.

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.

Tag-less patency capsule for suspected small bowel stenosis: Nationwide multicenter prospective study in Japan.

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).

Scientific frontiers in faecal microbiota transplantation: joint document of Asia-Pacific Association of Gastroenterology (APAGE) and Asia-Pacific Society for Digestive Endoscopy (APSDE).

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.

Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody.

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.

Usefulness of Full-spectrum Endoscopy for the Upper Gastrointestinal Tract.

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.

Clinical relevance of innovative immunoassays for serum ustekinumab and anti-ustekinumab antibody levels in Crohn's disease.

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.

Management of obscure gastrointestinal bleeding: Comparison of guidelines between Japan and other countries.

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.

Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy in gastrointestinal subepithelial lesions: Feasibility study.

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).

Molecular subtyping of gastric cancer combining genetic and epigenetic anomalies provides distinct clinicopathological features and prognostic impacts.

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.

DNA methylation accumulation in gastric mucosa adjacent to cancer after Helicobacter pylori eradication.

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.