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In Japan, with the increasing prevalence of gastroesophageal reflux disease (GERD) and growing public interest, the Japanese Society of Gastroenterology issued Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009 and a revised 2nd edition in 2015. A number of studies on GERD were subsequently conducted in Japan and abroad, and vonoprazan, a potassium-competitive acid blocker (P-CAB), became available for the first time in Japan in February 2015. The revised 3rd edition (Japanese edition), which incorporates new findings and information, was published in April 2021. These guidelines are summarized herein, particularly sections related to the treatment of GERD. The important clinical issues addressed in the present revision are (i) the introduction of treatment algorithms that classify GERD into reflux esophagitis and non-erosive reflux disease, (ii) the clarification of treatment algorithms based on to the severity of reflux esophagitis, and (iii) the positioning of vonoprazan in the treatment for GERD. The present guidelines propose vonoprazan as the initial/maintenance treatment for severe reflux esophagitis. They also recommend vonoprazan or PPI as an initial treatment for mild reflux esophagitis and recommended PPI and proposed vonoprazan as maintenance treatment. These updated guidelines offer the best clinical strategies for GERD patients in Japan and hope that they will be of global use for the diagnosis and treatment for GERD.

BackgroundAdditional surgery for all patients with noncurative resection after endoscopic resection (ER) for early gastric cancer (EGC) may be excessive due to the relatively low rate of lymph node metastasis (LNM) in such patients. However, the prevalence and risk factors for LNM after noncurative ER have not been consistent across studies.MethodsWe performed a systematic review of electronic databases through August 10, 2018 to identify cohort studies with patients who underwent additional surgery after noncurative ER for EGC. The prevalence of LNM in such patients was extracted for all studies. Odds ratios (ORs) were combined using random-effects meta-analyses to assess the risk of LNM, when possible.ResultsWe identified 24 studies comprising 3877 patients with 311 having LNM (pooled prevalence, 8.1%). The risk of LNM was significantly increased in lymphatic invasion (OR [95% confidence interval] = 4.22 [2.88–6.19]), lymphovascular invasion (LVI) (4.17 [2.90–5.99]), vascular invasion (2.38 [1.65–3.44]), positive vertical margin (2.16 [1.59–2.93]), submucosal invasion depth of ≥ 500 μm (2.14 [1.48–3.09]), and tumor size > 30 mm (1.77 [1.31–2.40]). In contrast, there was no significant association between undifferentiated-type or ulceration (scar) and LNM. When studies were restricted to those that evaluated the adjusted OR, the risk of vascular invasion for LNM did not reach statistical significance.ConclusionsSeveral pathological factors, most notably lymphatic invasion and LVI, were associated with LNM in patients with noncurative resection after ER for EGC. Lymphatic and vascular invasion should be assessed separately instead of LVI (PROSPERO CRD42018109996).

BackgroundWe aimed to elucidate the risk of metastatic recurrence after endoscopic resection (ER) without additional treatment for esophageal squamous cell carcinomas (ESCCs) with tumor invasion into the muscularis mucosa (pT1a-MM) or submucosa (T1b-SM).MethodsWe retrospectively enrolled patients with pT1a-MM/pT1b-SM ESCC after ER at 21 institutions in Japan between 2006 and 2017. We compared metastatic recurrence between patients with and without additional treatment, stratified into category A (pT1a-MM with negative lymphovascular invasion [LVI] and vertical margin [VM]), B (tumor invasion into the submucosa ≤ 200 µm [pT1b-SM1] with negative LVI and VM), and C (others). Subsequently, using multivariate Cox analysis, we evaluated risk factors for metastatic recurrence after ER without additional treatment.ResultsWe enrolled 593 patients, and metastatic recurrence occurred in 38 patients. Metastatic recurrence after additional treatment was significantly lower than that after no additional treatment in category C (9.1% vs. 23.6% in 5 years, p = 0.001), whereas no significant difference was noted in categories A (0.0% vs. 2.6%) and B (0.0% vs. 4.3%). In patients without additional treatment after ER, risk factors for metastatic recurrence were lymphatic invasion (hazard ratio [HR], 5.61), positive VM (HR, 4.55), and tumor invasion into the submucosa > 200 μm (HR, 3.25), and, but near half of the patients with metastatic recurrence had no further recurrence after salvage treatment, resulting in excellent 5-year disease-specific survival in categories A (99.6%) and B (100.0%).ConclusionsClosed follow-up with no additional treatment may be an acceptable option after ER in pT1a-MM/pT1b-SM1 ESCC with negative LVI and VM.

ObjectiveBleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC.DesignThis retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration.ResultsA prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a c-statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01).ConclusionsIn this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.

Background The cancer risk for each length of Barrett’s esophagus (BE) in Japanese is unknown. This nationwide, multi-institutional study aims to clarify the cancer risk by length of BE in the general Japanese population. Methods Consecutive subjects who underwent upper endoscopic screening at 17 centers between 2013 and 2017 and had at least one follow-up endoscopy by December 2022 were included. The presence/absence of BE and, if present, its length were retrospectively assessed using the retrieved endoscopic images recorded at baseline. Information on the subsequent occurrence of esophageal adenocarcinoma and other upper gastrointestinal cancers was also collected. Cancer incidence was calculated and expressed as %/year. Results A total of 33,478 subjects were enrolled, and 17,884 (53.4%), 10,641 (31.8%), 4889 (14.6%), and 64 (0.2%) were diagnosed as absent BE, BE < 1 cm, 1–3 cm, and ≥ 3 cm, respectively. During a median follow-up of 80 months, 11 cases of esophageal adenocarcinoma developed. The annual incidence of esophageal adenocarcinoma is 0%/year for absent BE, 0.0032 (0.00066–0.013)%/year for BE < 1 cm, 0.026 (0.011–0.054)%/year for 1–3 cm, and 0.58 (0.042–2.11)%/year for ≥ 3 cm, respectively. Meanwhile, the incidence of esophageal squamous cell carcinoma and gastric cancer were 0.039 (0.031–0.049)%/year and 0.16 (0.14–0.18)%/year, respectively. Conclusions By enrolling a large number of subjects with long-term follow-up, this study demonstrated that the risk of cancer increased steadily with increasing length of BE in the Japanese population. Therefore, it is important to consider the length of BE when determining the management strategy for BE.

BackgroundDelayed bleeding is the major adverse event in upper gastrointestinal endoscopic treatment (UGET). We aimed to investigate the efficacy of vonoprazan, which is the novel strong antisecretory agent, to reduce the risk for delayed bleeding in comparison with proton pump inhibitors (PPIs) in UGET.MethodsThis retrospective population-based cohort study used the Diagnosis Procedure Combination database in Japan. We included patients on vonoprazan or PPI in UGET between 2014 and 2019. The primary outcome was delayed bleeding. We conducted propensity score matching to balance the comparison groups, and logistic regression analyses to compare the bleeding outcomes.ResultsWe enrolled 124,422 patients, in which 34,822 and 89,600 were prescribed with vonoprazan and PPI, respectively. After propensity score matching, the risk for delayed bleeding was lower in vonoprazan than in PPI (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.71–0.80), consistent with sensitivity analysis results. In the subgroup analyses of seven UGET procedures, vonoprazan was significantly advantageous in esophageal endoscopic submucosal dissection (E-ESD) (OR, 0.71; 95% CI, 0.54–0.94) and gastroduodenal endoscopic submucosal dissection (GD-ESD) (OR, 0.70; 95% CI, 0.65–0.75), although correction for multiple testing of the outcome data removed the significance in E-ESD. These results were also consistent with sensitivity analysis results. In the five other procedures, no significant advantage was found.ConclusionsThis nationwide study found that, compared with PPI, vonoprazan can reduce delayed bleeding with approximately 30% in GD-ESD. Vonoprazan has the possibility to become a new treatment method for preventing delayed bleeding in this procedure.

Background Little is known about the specific risks of metastasis in esophageal adenocarcinoma in relation to invasion depth or other pathologic factors. Methods We conducted a multicenter retrospective study in 13 high-volume centers in Japan from January 2000 to October 2014 to elucidate the risk of metastasis of esophageal adenocarcinoma. A total of 458 patients (217 surgically resected and 241 endoscopically resected) with esophageal adenocarcinoma or esophagogastric adenocarcinoma involving the esophagus were included. Metastasis was considered positive if there was histologically confirmed metastasis in the surgical specimen or clinically confirmed metastasis during follow-up. Metastasis was considered negative if no metastasis was identified in resected specimens and during follow-up in patients treated surgically or no metastasis during follow-up for >5 years in patients treated by endoscopic resection. Results Metastasis was identified in 72 patients. Multivariate analysis confirmed lymphovascular involvement [odds ratio (OR) 6.20; 95 % confidence interval (CI) 3.12–12.32; p  < 0.001], a poorly differentiated component (OR 3.69; 95 % CI 1.92–7.10; p  < 0.001), and lesion size >30 mm (OR 3.12; 95 % CI 1.63–5.97; p  = 0.001) as independent risk factors for metastasis. No metastasis was detected in patients with mucosal cancer without lymphovascular involvement and a poorly differentiated component (0/186 lesions) or in patients with cancer invading the submucosa (1–500 µm) without lymphovascular involvement, a poorly differentiated component, and ≤30 mm (0/32 lesions). Conclusions Mucosal and submucosal cancers (1–500 µm invasion) without risk factors have a low incidence of metastasis and may thus be good candidates for endoscopic resection.

Binding peptides for given target molecules are often selected in vitro during drug discovery and chemical biology research. Among several display technologies for this purpose, complementary DNA (cDNA) display (a covalent complex of a peptide and its encoding cDNA linked via a specially designed puromycin-conjugated DNA) is unique in terms of library size, chemical stability, and flexibility of modification. However, selection of cDNA display libraries often suffers from false positives derived from non-specific binding. Although rigorous washing is a straightforward solution, this also leads to the loss of specific binders with moderate affinity because the interaction is non-covalent. To address this issue, herein, we propose a method to covalently link cDNA display molecules with their target proteins using light irradiation. We designed a new puromycin DNA linker that contains a photocrosslinking nucleic acid and prepared cDNA display molecules using the linker. Target proteins were also labeled with a short single-stranded DNA that should transiently hybridize with the linker. Upon ultraviolet (UV) light irradiation, cDNA display molecules encoding correct peptide aptamers made stable crosslinked products with the target proteins in solution, while display molecules encoding control peptides did not. Although further optimization and improvement is necessary, the results pave the way for efficient selection of peptide aptamers in multimolecular crowding biosystems.

BackgroundRecent epidemiological studies suggested correlation between gastric cancer (GC) and periodontal disease.AimsWe aim to clarify involvement of lipopolysaccharide of Porphyromonas gingivalis (Pg.), one of the red complex periodontal pathogens, in the GC development.MethodsTo evaluate barrier function of background mucosa against the stimulations, we applied biopsy samples from 76 patients with GC using a Ussing chamber system (UCs). K19-Wnt1/C2mE transgenic (Gan) mice and human GC cell-lines ± THP1-derived macrophage was applied to investigate the role of Pg. lipopolysaccharide in inflammation-associated carcinogenesis.ResultsIn the UCs, Pg. lipopolysaccharide reduced the impedance of metaplastic and inflamed mucosa with increases in mRNA expression of toll-like receptor (TLR) 2, tumor necrosis factor (TNF) α, and apoptotic markers. In vitro, Pg. lipopolysaccharide promoted reactive oxidative stress (ROS)-related apoptosis as well as activated TLR2-β-catenin-signaling on MKN7, and it increased the TNFα production on macrophages, respectively. TNFα alone activated TLR2-β-catenin-signaling in MKN7, while it further increased ROS and TNFα in macrophages. Under coculture with macrophages isolated after stimulation with Pg. lipopolysaccharide, β-catenin-signaling in MKN7 was activated with an increase in supernatant TNFα concentration, both of which were decreased by adding a TNFα neutralization antibody into the supernatant. In Gan mice with 15-week oral administration of Pg. lipopolysaccharide, tumor enlargement with β-catenin-signaling activation were observed with an increase in TNFα with macrophage infiltration.ConclusionsLocal exposure of Pg. lipopolysaccharide may increase ROS on premalignant gastric mucosa to induce apoptosis-associated barrier dysfunction and to secrete TNFα from activated macrophages, and both stimulation of Pg. lipopolysaccharide and TNFα might activate TLR2-β-catenin-signaling in GC.