Endoscopic screening for gastric cancer in Japan: Current status and future perspectives.

The revised 2014 Japanese Guidelines for Gastric Cancer Screening approved gastric endoscopy for use in population-based screening. Thus, it is expected that gastric cancer will be detected earlier, and gastric cancer mortality further decreased, with the widespread use of endoscopy and Helicobacter pylori eradication therapy. However, due to an increasingly aging population and relatively low gastric cancer screening rates, gastric cancer remains the leading cause of cancer death in Japan. While the era of endoscopic gastric cancer screening has begun, it does present challenges, such as limited/varying regional availability of endoscopists. This review describes the history of gastric cancer screening in Japan, achievements in endoscopic gastric cancer screening in Japan and Korea, efforts underway to improve screening by stratifying individuals according to gastric cancer risk, and initiatives by the Japan Gastroenterological Endoscopy Society aimed at improving screening, including the implementation of a board certification program for screening endoscopists.

The "caterpillar sign": a novel endoscopic indicator of eosinophilic esophagitis.

BACKGROUND: Although several endoscopic findings of eosinophilic esophagitis (EoE), such as the EoE endoscopic reference score (EREFS), have been reported thus far, these endoscopic findings exhibit low specificity. Furthermore, most of these endoscopic findings were evaluated solely in patients from Western nations. We have recently noted a fragile, protruded mucosal lesion sandwiched between longitudinal furrows (similar to caterpillar tracks) on the esophagus in patients with EoE. We have termed this novel finding the "caterpillar sign". This study evaluated the clinical significance of the caterpillar sign and the EREFS for diagnosis of EoE in Japanese patients. METHODS: We retrospectively analyzed endoscopic images from 165 consecutive patients who underwent tissue collection on suspicion of EoE. We compared the clinical significance between the EREFS and the caterpillar sign. We defined EoE as the presence of ≥ 15 eosinophils on esophageal mucosa per high-power field; control images had < 15 eosinophils per high-power field. For evaluation of endoscopic diagnosis capacity using the total EREFS, 2 points was set as the cutoff value. The presence or absence of the caterpillar sign was evaluated. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of total EREFS ≥ 2 for the diagnosis of EoE were 100%, 56.2%, 56.6%, and 100%; for the caterpillar sign, those values were 83.3%, 98.1%, 96.2%, and 91.2%, respectively. Interobserver agreement for identification of the caterpillar sign was substantial (κ = 0.80) CONCLUSIONS: The caterpillar sign could be a novel reliable indicator for endoscopic diagnosis of EoE.

Multicenter study of autoimmune gastritis in Japan: Clinical and endoscopic characteristics.

BACKGROUND AND AIM: In Japan, the prevalence of autoimmune gastritis (AIG) is assumed to be very low. With the recent rapid decrease in Helicobacter pylori (Hp) prevalence, reports on AIG are increasing. This multicenter registry study aimed to clarify the characteristics of AIG, especially its endoscopic appearance. METHODS: A total of 245 patients with AIG from 11 institutions in Japan from January 2010 to October 2016 were included, and their clinical and endoscopic findings were evaluated. RESULTS: Mean age was 67.2 ± 11.4 years, and 63.7% of the participants were women. The most common approach to diagnose AIG was endoscopic examination. Repeated incorrect treatment for Hp infection, due to a false-positive result in 13 C-urea breath test, ranked third among the basis for diagnosis of AIG. Associated gastric lesions were type 1 neuroendocrine tumor (11.4%), adenocarcinoma (9.8%), and hyperplastic polyps (21.1%). Corpus pan-atrophy was the most common appearance (90.1%); however, remnant oxyntic mucosa was found in 31.5% of the patients (flat, localized type, 48.6%). Sticky adherent dense mucus and scattered minute whitish protrusions were also observed in approximately 30% of the patients. Despite the prevailing presumption of the antral mucosa remaining normal, 42.3% of the patients presented with various extents of atrophy, and patchy redness and circular wrinkle-like patterns were both observed in approximately 20% of the patients. CONCLUSIONS: The present study showed some prominent clinical characteristics and endoscopic findings of AIG. We believe that our study will facilitate the diagnosis of potential AIG.

Guidelines for endoscopic diagnosis of early gastric cancer.

The Japan Gastroenterological Endoscopy Society developed the Guideline for Endoscopic Diagnosis of Early Gastric Cancer based on scientific methods. Endoscopy for the diagnosis of early gastric cancer has been acknowledged as a useful and highly precise examination, and its use has become increasingly more common in recent years. However, the level of evidence in this field is low, and it is often necessary to determine recommendations based on expert consensus only. This clinical practice guideline consists of the following sections to provide the current guideline: [I] Risk stratification of gastric cancer before endoscopic examination, [II] Detection of early gastric cancer, [III] Qualitative diagnosis of early gastric cancer, [IV] Diagnosis to choose the therapeutic strategy for gastric cancer, [V] Risk stratification after endoscopic examination, and [VI] Surveillance of early gastric cancer.

Optimal Criteria and Diagnostic Ability of Serum Pepsinogen Values for Helicobacter pylori Infection.

BACKGROUND: Practical criteria for the use of serum pepsinogen (PG) values in diagnosing Helicobacter pylori infection have not yet been determined. METHODS: The results of gastric endoscopies, H. pylori infection tests, and PG values were retrospectively reviewed. Subjects were assigned to groups, including never-infected (with neither infection nor gastric mucosal atrophy), infected (with atrophy or findings indicating infection in endoscopy and positive infection tests except for antibody tests), and ex-infected (with gastric mucosal atrophy and negative infection tests, except for antibody tests). The optimal criteria with combined use of the PG II concentrations and the PG I/PG II ratio were investigated separately for PG measurements obtained with the chemiluminescent magnetic particle immunoassay (CLIA) and latex agglutination (LA) methods, such that the specificity was greater than 70% and the sensitivity was no less than 95% among the never-infected and infected subjects. Similar analyses were performed by combining the data from ex-infected and infected subjects. RESULTS: For the CLIA (LA) method, the optimal criterion among 349 (397) never-infected and 748 (863) infected subjects was a PG II value of at least 10 (12) ng/mL or a PG I/PG II ratio no more than 5.0 (4.0), which produced 96.3% (95.1%) sensitivity and 82.8% (72.8%) specificity. When 172 (236) ex-infected subjects were included, the optimal criterion was the same, and the sensitivity was 89.1% (86.9%). CONCLUSIONS: The above criteria may be practical for clinical use, and PG tests using these criteria might prevent unnecessary endoscopic examinations for never-infected subjects.

Characteristics of gastric cancer in negative test of serum anti-Helicobacter pylori antibody and pepsinogen test: a multicenter study.

BACKGROUND AND AIM: The serological risk prediction system combines the pepsinogen test and anti-Helicobacter pylori (H. pylori) antibody determination. In this system, chronic atrophic gastritis (CAG) is diagnosed using the pepsinogen test. Patients who are H. pylori negative and pepsinogen negative are classified into group A, are assumed to be H. pylori uninfected, and are at an extremely low risk for gastric cancer. However, gastric cancers are detected in this group. The aim of this study is to clarify the clinicopathological status of group A patients with gastric cancer. METHODS: A total of 109 gastric cancer patients classified as group A were enrolled in a multicenter study. Group A patients were divided into two subgroups: group AN (H. pylori uninfected) and group AP (H. pylori infected). They were compared to 183 H. pylori-infected gastric cancer patients who were not in group A. RESULTS: Of the 109 patients, only 7 were classified as group AN; the other 102 were classified as group AP. The clinicopathological features of group AP included older age, predominantly differentiated type cancer, endoscopically visualized CAG, and pepsinogen (PG) I/II ratio lower than that of group AN. In group AN, the depressed type was dominant, and the PG I/II ratio was higher than in those gastric cancer patients who were infected with H. pylori. CONCLUSION: Patients in group AP had CAG, and their gastric cancers were similar to those of H. pylori-eradicated patients. Concerning the recent ABC classification system, advanced decision criteria should be proposed to decrease the false-negative evaluation of gastric cancer risk.

Establishment of disseminated intravascular coagulation (DIC) model by a single iv administration of Escherichia coli-derived lipopolysaccharide (LPS) to cynomolgus monkeys and evaluation of its pathophysiological status.

We prepared a DIC model by administrating LPS to cynomolgus monkeys, and investigated its potential for evaluations of new medicines for DIC therapy. Peripheral blood mononuclear cells (PBMC) collected from cynomolgus monkeys were incubated with LPS (8 types), and TNF-α levels in the media were measured. LPS from Escherichia coli (K-235) was most appropriate in terms of larger increases and smaller variation in TNF-α levels. PBMC from rats, cynomolgus monkeys or humans were incubated with LPS (K-235), and the TNF-α response to LPS was investigated. The response was comparable between cynomolgus monkeys and humans but small in rats. In an in vivo experiment, LPS (K-235) was administered once intravenously to cynomolgus monkeys with or without recombinant human thrombomodulin (rhTM) to investigate any changes in coagulation and fibrinolysis biomarkers and the suppressive effect of rhTM. The liver, kidney, and lung were examined histopathologically. Almost all of the changes resembled the pathophysiological status of human DIC and were suppressed by co-administration of rhTM. The DIC model resembling human DIC was established by LPS (K-235) treatment in cynomolgus monkeys, and therapeutic effect of rhTM was noted, suggesting that this model is useful in evaluations of the efficacy of new medicines for DIC therapy.

The Ameliorating Effect of Lactobacillus gasseri OLL2716 on Functional Dyspepsia in Helicobacter pylori-Uninfected Individuals: A Randomized Controlled Study.

BACKGROUND/AIMS: Probiotics appear to improve Helicobacter pylori-associated dyspepsia via an inhibitory effect on H. pylori; however, uncertainty exists regarding their effects in H. pylori-uninfected individuals. We evaluated the efficacy of Lactobacillus gasseri OLL2716 (L. gasseri OLL2716) on H. pylori-uninfected individuals with functional dyspepsia (FD). METHODS: A double-blind, parallel-group, placebo-controlled, randomized, controlled trial was performed. Participants were randomly assigned to ingest L. gasseri OLL2716-containing yogurt (L. gasseri OLL2716 group) or L. gasseri OLL2716-free yogurt (placebo group) for 12 weeks. Participants completed questionnaires that dealt with a global assessment as well as symptom severity. The per-protocol (PP) population was evaluated for efficacy in accordance with a plan prepared beforehand. RESULTS: Randomization was performed on 116 individuals; the PP population consisted of 106 individuals (mean age 42.8 ± 9.0). The impressions regarding the overall effect on gastric symptoms were more positive in the L. gasseri OLL2716 group compared to that in the placebo group (statistical trend; p = 0.073). The elimination rate for major FD symptoms was 17.3 and 35.3% in the placebo and L. gasseri OLL2716 groups respectively (p = 0.048). CONCLUSION: L. gasseri OLL2716 has beneficial effects on FD without H. pylori involvement.

Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice.

Intrathecal (i.t.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) induces long-lasting nociceptive behaviors for more than 60 min in mice, while the involvement of PACAP type1 receptor (PAC1-R) has not been clarified yet. The present study investigated signaling mechanisms of the PACAP-induced prolonged nociceptive behaviors. Single i.t. injection of a selective PAC1-R agonist, maxadilan (Max), mimicked nociceptive behaviors in a dose-dependent manner similar to PACAP. Pre- or post-treatment of a selective PAC1-R antagonist, max.d.4, significantly inhibited the nociceptive behaviors by PACAP or Max. Coadministration of a protein kinase A inhibitor, Rp-8-Br-cAMPS, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor, PD98059 or a c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly inhibited the nociceptive behaviors by Max. Immunohistochemistry and immunoblotting analysis revealed that spinal administration of Max-induced ERK phosphorylation and JNK phosphorylation, and also augmented an astrocyte marker, glial fibrillary acidic protein in mouse spinal cord. Furthermore, an astroglial toxin, l-α-aminoadipate, significantly attenuated the development of the nociceptive behaviors and ERK phosphorylation by Max. These results suggest that the activation of spinal PAC1-R induces long-lasting nociception through the interaction of neurons and astrocytes.

Number of Gastrointestinal Symptoms is a Useful Means of Identifying Patients with Cancer for Dysphagia.

Dysphagia is a symptom suggestive of severe underlying pathology, although its causes include organic and non-organic disorders. The epidemiology of dysphagia is, however, poorly understood. We evaluated the prevalence of dysphagia in outpatients in Japan, measured the proportion ultimately found to have an organic cause, and recorded the nature of their symptoms and the underlying disorder. Of 5362 consecutive outpatients attending the Digestive Center at our hospital between June 1, 2010 and December 31, 2012, 186 patients (3.5 %) had dysphagia with a frequency score of ≥5 out of 6. The most common diagnosis was cancer (34 patients, 18.3 %), followed by gastroesophageal reflux disease (24 patients, 12.9 %). An esophageal motility disorder was diagnosed in 21 patients (11.3 %); the causes in the remaining 107 patients (57.5 %) were miscellaneous. Multivariable analysis identified the following predictors of cancer: age ≥ 54 years, weight loss, being a drinker of alcohol, and ≤2 gastrointestinal symptoms. Our findings can be used to inform the prioritization of referrals from primary care for investigation and treatment for patients with cancer for dysphagia.

[Jejunal duplication in an adult presenting with hematochezia].

A 56-year-old man was admitted to our hospital with appetite loss, palpitations, orthostatic syncope, and hematochezia. Contrast-enhanced abdominal computed tomography (CT) revealed a proximal jejunal diverticulum with contrast extravasation. We immediately performed transoral double balloon enteroscopy (DBE) to treat the bleed in the jejunum, and this revealed a small ulcer with an exposed vessel at the opening of the jejunal diverticulum. Hemostasis was achieved endoscopically with argon plasma coagulation (APC) and hemoclips. During subsequent surgery, the diverticulum was found on the mesenteric side of the jejunum. We performed laparoscopy-assisted partial resection of the jejunum, and pathological examination showed that the diverticulum shared a common proper muscle layer with the jejunum and was covered by jejunal mucosa with no ectopic mucosa. Therefore, we diagnosed jejunal duplication. After hospital discharge, the patient had no recurrence of hematochezia or anemia. We report a rare case of jejunal duplication presenting with hematochezia, which was diagnosed as jejunal diverticular bleeding by CT and DBE before surgery. Pathological analysis confirmed jejunal duplication after surgery. We suggest that intestinal diverticular bleeding, as well as duplication of the gastrointestinal tract, should be considered as part of the differential diagnosis of obscure gastrointestinal bleeding.

Development of reflux esophagitis after H. pylori eradication therapy.

Several studies showed that H. pylori infection is significantly lower in reflux esophagitis (RE) patients than in elder asymptomatic controls in Japan. It is well known that H. pylori infection induces corporal atrophic gastritis, and suppresses gastric acid secretion. In the other words, H. pylori infection shows a negative association with the development of RE. The relative lack of corpus gastritis might play a role in the pathogenesis of RE through preservation of the acid secretion area. Meanwhile, the occurrence of RE after H. pylori eradication was first report;e' in Europe in 1997. However, no consensus has been reached on whether H. pylori eradication leads to the onset of a de-novo RE. Eradication of H. pylori infection may be a risk factor for de-novo RE, especially in Asian populations. The presence of hiatal hernia and corpus gas- tritis are closely related to the development of RE after H. pylori eradication. RE, which develops after H. pylori eradication, rarely becomes a long-term clinical problem among patients who complete therapy successfully.

Time Trends in Helicobacter pylori Infection and Atrophic Gastritis Over 40 Years in Japan.

BACKGROUND: Helicobacter pylori infection produces progressive mucosal damage that may eventually result in gastric cancer. We studied the changes that occurred in the presence and severity of atrophic gastritis and the prevalence of H. pylori infection that occurred coincident with improvements in economic and hygienic conditions in Japan since World War II. MATERIALS AND METHODS: The prevalence of H. pylori infection and histologic grades of gastric damage were retrospectively evaluated using gastric biopsy specimens obtained over a 40-year period. Gastric atrophy and intestinal metaplasia were scored using the updated Sydney classification system. RESULTS: The prevalence of H. pylori and severity of atrophy were examined in 1381 patients including 289 patients examined in the 1970s (158 men; mean age, 44.9 years), 787 in the 1990s (430 men; 44.2 years), and 305 in the 2010s (163 men; 53.2 years). Overall, the prevalence of H. pylori infection decreased significantly from 74.7% (1970s) to 53% (1990s) and 35.1% (2010s) (p < .01). The prevalence of atrophy in the antrum and corpus was significantly lower in the 2010s (33, 19%, respectively) compared to those evaluated in either the 1970s (98, 82%) (p < .001) or 1990s (80, 67%) (p < .001). The severity of atrophy and intestinal metaplasia also declined remarkably among those with H. pylori infection. CONCLUSIONS: There has been a progressive and rapid decline in the prevalence of H. pylori infection as well a fall in the rate of progression of gastric atrophy among H. pylori-infected Japanese coincident with the westernization and improvements in economic and hygienic conditions in Japan since World War II.

Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation.

Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as a neuroprotective factor through the PACAP type 1 receptor, PAC1. In a previous work, we demonstrated that nerve growth factor augmented PAC1 gene expression through the activation of Sp1 via the Ras/MAPK pathway. We also observed that PAC1 expression in Neuro2a cells was transiently suppressed during in vitro ischemic conditions, oxygen-glucose deprivation (OGD). Because endoplasmic reticulum (ER) stress is induced by ischemia, we attempted to clarify how ER stress affects the expression of PAC1. Tunicamycin, which induces ER stress, significantly suppressed PAC1 gene expression, and salubrinal, a selective inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase signaling pathway of ER stress, blocked the suppression. In luciferase reporter assay, we found that two Sp1 sites were involved in suppression of PAC1 gene expression due to tunicamycin or OGD. Immunocytochemical staining demonstrated that OGD-induced transglutaminase 2 (TG2) expression was suppressed by salubrinal or cystamine, a TG activity inhibitor. Further, the OGD-induced accumulation of cross-linked Sp1 in nuclei was suppressed by cystamine or salubrinal. Together with cystamine, R283, TG2-specific inhibitor, and siRNA specific for TG2 also ameliorated OGD-induced attenuation of PAC1 gene expression. These results suggest that Sp1 cross-linking might be crucial in negative regulation of PAC1 gene expression due to TG2 in OGD-induced ER stress.

A case of nodular gastritis progression to autoimmune gastritis after 10 years of Helicobacter pylori eradication.

A 61-year-old female patient underwent upper gastrointestinal endoscopy, which confirmed the presence of Helicobacter pylori (H. pylori)-positive nodular gastritis (NG). Routine upper gastrointestinal endoscopy after H. pylori eradication revealed atrophic changes of the corpus, having gradually progressed over the 10 years after successful eradication. Serological and biopsy specimen examination showed hypergastrinemia (1200 pg/mL), positive anti-parietal cell antibody (with a titer of more 160), and endocrine cell micronests after 11 years of H. pylori eradication. The patient was diagnosed with autoimmune gastritis (AIG) based on endoscopic, serological, and histological findings. This is the first report of AIG diagnosed in a patient with NG over a long period of time after H. pylori eradication.

Characteristic endoscopic findings in early-stage autoimmune gastritis.

Background and study aims Until recently, autoimmune gastritis (AIG) was usually diagnosed at late stages based on typical endoscopic findings, including corpus-dominant advanced atrophy. Early-stage AIG prior to complete gastric atrophy had rarely been diagnosed due to a lack of knowledge about its endoscopic characteristics. The present study sought to identify the endoscopic characteristics of early-stage AIG, enabling its early diagnosis. Patients and methods The clinical and endoscopic findings of 12 patients diagnosed with early-stage AIG between 2016 and 2021 were retrospectively evaluated. Patients were included if they were: (1) positive for serum anti-parietal cell antibody; (2) diagnosed with histological early-stage AIG; and (3) endoscopically positive for folds on the greater curvature of the gastric corpus. Results Two characteristic endoscopic findings of early-stage AIG were identified: longitudinal alignment of pseudopolyps (i.e., a bamboo joint-like appearance) and swelling of gastric areas with erythema (i.e., a salmon roe-like appearance). Conclusions Endoscopic findings characteristic of early-stage AIG include a bamboo joint-like appearance and a salmon roe-like appearance. Studies in large numbers of patients with long-term follow-up are needed to confirm these findings.

Synthesis of large [2]rotaxanes. The relationship between the size of the blocking group and the stability of the rotaxane.

[2]Rotaxanes with large macrocyclic phenanthrolines were prepared by the template method, and the stability of the rotaxanes was examined. Compared to the tris(biphenyl)methyl group, the tris(4-cyclohexylbiphenyl)methyl group was a larger blocking group, and the rate of the dissociation of the components decreased significantly when the thermal stability of a rotaxane with a 41-memebered ring was examined. We also succeeded in the synthesis of larger rotaxanes by the oxidative dimerization of alkynes with these bulky blocking groups, utilizing the catalytic activity of the macrocyclic phenanthroline-Cu complex.

[Gastric cancer risk classification (ABC classification)].

Infection with Helicobacter pylori (Hp) is considered a prerequisite for gastric carcinogenesis and gastric mucosal atrophy that develops in association with the infection is a risk factor for gastric cancer. The gastric cancer risk can be diagnosed by the ABC classification consisted of a combination of serum Hp antibody and the pepsinogen (PG) method. The ABC classification may contribute to gastric cancer screening as well as to primary care of digestive organ practice. However, we should remember that we cannot diagnose the gastric cancer by only the ABC classification, and an imaging examination is required.

[European guideline for the management of precancerous conditions in the stomach and it's application to Japan].

Atrophic gastritis, intestinal metaplasia, and Helicobacter pylori (H. pylori) infection are commonly recognized as the risk factor of gastric cancer. In Japan mass screening by the X-ray examination or endoscopy has been performed for a long time in general population or in work place because of the high death rate and high incidence of gastric cancer. Periodic endoscopy has been recommended for the subjects with atrophic gastritis and/or intestinal metaplasia to detect gastric cancer in early stage. On the other hand, there was no guideline to manage premalignant conditions such as atrophic gastritis, intestinal metaplasia, and dysplasia in foreign countries. Recently the guideline for the management of precancerous conditions and lesions in the stomach (MAPS) has been published by the combined efforts of the European Society of Gastrointestinal Endoscopy, European Helicobacter Study Group, European Society of Pathology, and the Sociedade Portuguesa de Endoscopia Digestiva. In this article the main statements have been discussed on comparing the understandings as the premalignant conditions in Japan.

A Case of Early Barrett's Adenocarcinoma With Eosinophilic Esophagitis.

A 61-year-old man presented with epigastric pain and underwent upper gastrointestinal endoscopy. A strongly erythematous area was found in the short segment of the Barrett's esophagus, and a biopsy revealed well-differentiated adenocarcinoma. Linear furrows were observed in the lower esophagus, and a biopsy of the lesion revealed eosinophil infiltration of 30 eosinophils per high-power field. Therefore, a diagnosis of Barrett's adenocarcinoma with eosinophilic esophagitis was made. Although rare, the incidence of Barrett's adenocarcinoma and eosinophilic esophagitis has been increasing in Japan in recent years, and the number of cases may increase in the future.