Effects of anti-thrombotic drugs on all-cause mortality after upper gastrointestinal bleeding in Japan: A multicenter study with 2205 cases.

OBJECTS: Although anti-thrombotic use is recognized as a risk factor for upper gastrointestinal bleeding (UGIB), there has been no clear evidence that it worsens the outcomes after the bleeding. The aim of this study is to investigate the effects of anti-thrombotic agents on in-hospital mortality following UGIB. METHODS: Information on clinical parameters, including usage of anti-thrombotic agents, was retrospectively collected from consecutive patients with UGIB at 12 high-volume centers in Japan between 2011 and 2018. The all-cause in-hospital mortality rate was evaluated according to the usage of anti-thrombotic agents. RESULTS: Clinical data were collected from 2205 patients with endoscopically confirmed UGIB. Six hundred and forty-five (29.3%) patients used anti-thrombotic agents. The all-cause in-hospital mortality rate was 5.7% (125 deaths). After excluding 29 cases in which death occurred due to end-stage malignancy, 96 deaths (bleeding-related, n = 22 ; non-bleeding-related, n = 74) were considered "preventable." Overall, the "preventable" mortality rate in anti-thrombotic users was significantly higher than that in non-users (6.0% vs. 3.7%, P < 0.05). However, the "preventable" mortality of anti-thrombotic users showed a marked improvement over time; although the rate in users remained significantly higher than that in non-users until 2015 (7.3% vs. 4.2%, P < 0.05), after 2016, the difference was no longer statistically significant (4.8% vs. 3.5%). CONCLUSIONS: Although the usage of anti-thrombotic agents worsened the outcomes after UGIB, the situation has recently been improving. We speculate that the recent revision of the Japanese guidelines on the management of anti-thrombotic treatment after UGIB may have partly contributed to improving the survival of users of anti-thrombotic agents.

Nature and treatment outcomes of bleeding post-bulbar duodenal ulcers.

BACKGROUND: Although post-bulbar duodenal ulcers (PBDUs) could become a source of upper gastrointestinal bleeding, the whole picture of the disease is unknown. We compared the characteristic features and treatment outcomes after endoscopic hemostasis between PBDUs and bulbar duodenal ulcers (BDUs). METHODS: Data on duodenal ulcers with evidence of endoscopically-active bleeding were extracted from the data that were retrospectively collected from 12 institutes in Japan between 2011 and 2018. Rebleeding and in-hospital mortality were compared between patients with PBDUs and those with BDUs by logistic regression analyses. RESULTS: Among 468 consecutive patients with bleeding duodenal ulcers, 96 (20.5%) had endoscopically-confirmed PBDUs. PBDUs were more frequently observed in patients with a poor general condition in comparison to BDUs. The rates of rebleeding and in-hospital mortality in patients with PBDUs were approximately three times higher than those in patients with BDUs (PBDU vs. BDU: 29.2% vs. 10.2% [P < 0.0001] and 14.6% vs. 5.1% [P = 0.0029], respectively). Although the high in-hospital mortality in PBDUs could be explained, to a lesser extent, by the likelihood of rebleeding, and, to a greater extent, by the patients' poor general condition, the presence of a PBDU itself was largely responsible for the high rebleeding rates in PBDUs. CONCLUSION: This is the first study focusing on the nature and treatment outcomes of bleeding PBDUs. PBDUs were associated with much higher rebleeding and mortality rates in comparison to BDUs, and the likelihood of rebleeding may be derived from their unique anatomic location.

Long-term endoscopic surveillance for Barrett's esophagus in Japan: Multicenter prospective cohort study.

OBJECTS: Although a recent study showed the cancer incidence of Barrett's esophagus (BE) to be 1.2%/year in 251 patient-years in Japan, the long-term outcomes remain unclear. The present study estimated the cancer risk of BE in Japan using our original prospective multicenter cohort. METHODS: A total of 98 patients with BE of maximum length of ≥2 cm were enrolled during the period of 2010-2012 and received at least one follow-up endoscopy over 5 years thereafter. Cancer incidence rates with 95% confidence interval for occurrence of esophageal adenocarcinoma (EAC) were calculated as the number of events divided by patient-years of follow-up and were expressed as %/year. RESULTS: Overall, the median endoscopic follow-up period was 59.9 (first and third quartiles, 48.5-60.8) months, constituting a total of 427 patient-years of observation. Since two EAC cases developed, the cancer incidence was 0.47% (0.01%-1.81%)/year. The cancer incidence was 0.39% (-0.16% to 2.44%) in 232 patient-years and 0.31% (-0.13% to 1.95%)/year in 318 patient-years for 55 cases with specialized intestinal metaplasia and 70 with BE ≥3 cm (maximum), respectively. At the end of follow-up, 12 of 92 patients (13.0%) died, but none died from EAC. CONCLUSION: This is the largest prospective follow-up study with endoscopy to investigate the incidence of EAC in unequivocal BE with the maximum length of ≥2 cm in Japan. Although a further large-scale study will be required to validate our results, the cancer risk of BE in Japan would be lower than previously reported (0.47% vs 1.2%/year).

A Chronological Increase in Gastric Acid Secretion from 1995 to 2014 in Young Japanese Healthy Volunteers under the Age of 40 Years Old.

Gastric acid secretion levels are an important determinant of the manifestation of acid-related upper GI diseases such as gastroesophageal reflux disease. We recently reported that gastric acid secretion levels did not change from the 1990s to 2010s in H. pylori-negative asymptomatic Japanese outpatients with a mean age of 63 years old. However, because young people have a quite different lifestyle, including dietary pattern, from elderly people in Japan, it is worth investigating any chronologic changes in gastric acid secretion in younger generations. The aim of this analysis is to investigate the potential changes in gastric acid secretion from 1995 to 2014 in young Japanese healthy volunteers. Eighty-eight young Japanese healthy volunteers under the age of 40 with a mean age of 26 were extracted from a database accumulated from 1995 to 2014 for the present analysis. Their gastrin-stimulated gastric acid level was determined with the endoscopic gastrin test. In 76 H. pylori-negative subjects, gastric acid secretion levels showed a significant positive correlation with the calendar year when the test was performed (r = 0.27, p < 0.01). A similar trend was observed in 12 H. pylori-positive subjects. A chronological 5-year time period showed a significant positive association with gastric acid secretion in univariate and multivariate analyses (p < 0.01 and p = 0.01, respectively). Gastric acid secretion levels have been increasing in young Japanese healthy volunteers during the last 20 years. We need to monitor future trends in the prevalence of acid-related diseases such as gastro-esophageal reflux disease in Japan.

Clinicopathological features of gastric adenocarcinoma of the fundic gland (chief cell predominant type) by retrospective and prospective analyses of endoscopic findings.

BACKGROUND AND AIM: Gastric adenocarcinoma of the fundic gland type (chief cell predominant type) (GA-FG-CCP) is a variant of gastric adenocarcinoma with chief cell differentiation. GA-FG-CCP is rare and not well understood. The present study aimed to investigate the clinicopathological features of GA-FG-CCP using retrospective and prospective analyses of endoscopic findings. METHODS: A total of 20 patients including nine cases treated with endoscopic submucosal dissection (ESD) were diagnosed with GA-FG-CCP. Morphological changes were analyzed by retrospectively retracing past endoscopic records and following up after definitive diagnoses, including the status of Helicobacter pylori (H. pylori) infection. RESULTS: GA-FG-CCP were small and whitish lesions accompanied by atypical vascular growth and their macroscopic types were classified as 0-IIa (60%), 0-IIb (25%), and 0-IIc (15%), respectively. The lesions were found in the non-atrophic gastric mucosa of the upper (70%) or middle portion (30%), although gastric mucosal atrophy associated with current or past H. pylori infection was identified in 75% of cases. In the nine cases treated with ESD, submucosal invasion was identified in 80% of the resected lesions, but no lymphovenous infiltration was detected. Ki-67 labeling index of GA-FG-CCP was low at 3.2% and visible morphological changes were rarely detected during long-term endoscopic observation for 58.9 ± 13.1 months. CONCLUSIONS: These data indicate that GA-FG-CCP, even when submucosal invasion occurs easily, might be of low-grade malignancy as long as it is the chief cell predominant type without other epithelial abnormalities. In addition, GA-FG-CCP might develop despite H. pylori infection or gastric mucosal atrophy.

[Eosinophilic esophagitis].

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. Because of elevated total IgE levels and high rates of concurrent allergic diseases compared with the general population, EoE appears to be an antigen-driven immunologic process that caused by allergens like food or aeroallergens. EoE is a disease that features dense intraepithelial infiltration by eosinophils which cause excessive mucosal immunologic reactions which cause several symptoms that mostly involve dysphagia. For establishment of the diagnosis, infiltration of eosinophils (≥ 20 eosinophils/HPF) should be identified in an esophageal mucosal biopsy specimen. In treatment of patients have a possibility of EoE, proton-pump inhibitors(PPIs) must be tried as first choice. Other proved therapeutic options include topical or systemic corticosteroids, chronic dietary elimination, and esophageal dilation, but local administration of glucocorticoids has recently been reported as useful therapy for EoE.

Association between the body mass index and the risk of Barrett's esophagus in Japan.

BACKGROUND: We investigated the association between long-segment Barrett's esophagus and obesity in the Japanese population in a multicenter case-control trial. METHODS: One hundred thirteen patients with endoscopically detected Barrett's esophagus with a length of more than 2 cm and the same number of sex- and age-matched controls were prospectively enrolled. Barrett's esophagus was diagnosed based on the Prague C and M criteria. The body mass index (BMI) of the subjects was categorized into the following groups: normal, BMI <22.9; overweight, BMI 23.0-24.9, and obese, BMI >25.0. To determine the association between BMI and the risk of Barrett's esophagus, multivariate logistic regression analyses were performed. RESULTS: The basically adjusted regression model adjusted for smoking and alcohol consumption revealed that overweight and obesity were significantly associated with an elevated risk of Barrett's esophagus (OR 2.4, 95% CI 1.2-4.7, and OR 2.5, 95% CI 1.3-4.6, respectively). The intensity of the association was not attenuated even after adjustment for gastroesophageal reflux disease-related parameters. CONCLUSIONS: An increased BMI was associated with an increased risk for Barrett's esophagus through a gastroesophageal reflux-independent mechanism in the Japanese population. Further, unlike in Caucasian populations, being even slightly overweight with a BMI of 23.0-24.9 was an independent risk factor in the Japanese population.

Calcium carbonate breath test for non-invasive estimation of gastric acid secretion.

Gastric acid measurement is useful in assessing the effectiveness of antisecretory drugs, however, the conventional tests involve invasive nasogastric intubation. Orally administered ¹³C-labeled calcium carbonate (Ca¹³CO3) reacts with gastric acid to produce ¹³C-labeled carbon dioxide (¹³CO2), which is then excreted in the breath. The objective of this study was to evaluate the suitability of Ca¹³CO3 breath test for estimating gastric acid secretion in human noninvasively. First, the Ca¹³CO3 breath test and the measurement of pooled gastric acid under a fasting condition were performed in 6 healthy volunteers to evaluate the correlation between the two parameters. Next, endoscopic gastric acid collection and the Ca¹³CO3 breath test were performed on different days after pentagastrin injection in 20 subjects to evaluate the correlation between the tests and the reproducibility. Finally, the same studies were repeated in 4 subjects before and after 1-week rabeprazole, a proton pump inhibitor, administration. The maximum CO2 concentration (Cmax) correlated very well with the amount of pooled gastric acid (r = 0.95), suggesting that Ca¹³CO3 breath test values well reflected the fasting intragastric acidity. The ¹³CO2 concentration after pentagastrin injection correlated well with pentagastrin-stimulated maximal acid output (r = 0.79 at 20 min). The reproducibility of the Ca¹³CO3 breath test under pentagastrin-stimulation was good (coefficient of variation = 0.11). Rabeprazole administration markedly reduced the values of the Ca¹³CO3 breath test, suggesting that it can sensitively assess the efficacy of rabeprazole. The Ca¹³CO3 breath test can potentially be a useful method for non-invasive estimation for gastric acid secretion in human.

Localized esophageal eosinophilia: Is it an early manifestation of eosinophilic esophagitis or a subtype of gastroesophageal reflux disease?

BACKGROUND AND AIM: We recently encountered patients with localized esophageal eosinophilia in a small area of the esophagus. However, this condition remains to be described in detail, and its clinical significance has not been established. We investigated the clinical, endoscopic and histological features of localized esophageal eosinophilia in comparison with diffuse esophageal eosinophilia. METHODS: We investigated 10 patients with localized esophageal eosinophilia, and compared them with 23 who had diffuse esophageal eosinophilia. Whether esophageal eosinophilia was localized or diffuse was determined on the basis of endoscopic findings. Localized esophageal eosinophilia was defined endoscopically as a focal area of esophageal eosinophilia, whereas diffuse esophageal eosinophilia was defined as a widespread area of esophageal eosinophilia involving more than one of three locations: the upper, middle and lower esophagus. Histological esophageal eosinophilia in the mucosa showing endoscopic abnormality was confirmed by biopsy with a peak of ≥ 15 eosinophils/high-power field. RESULTS: There were no significant differences in age, gender distribution, allergic conditions or peripheral eosinophilia between the two groups. In all cases but one, localized esophageal eosinophilia was observed in a small area above the esophagogastric junction. Esophageal symptoms such as dysphagia, heartburn or chest pain were present in 20% of the localized group and in 65% of the diffuse group, the difference being statistically significant (P<0.05). The maximum amounts of eosinophils infiltrating the esophageal mucosa did not differ between the groups. CONCLUSIONS: Esophageal eosinophilia can be localized in a small area, especially above the esophagogastric junction. Gastric acid reflux or contact may influence this condition in addition to its allergic pathogenesis.

Changes in endoscopic findings of gastritis after cure of H. pylori infection: multicenter prospective trial.

BACKGROUND AND AIM: Successful eradication of H. pylori changes pathological findings of gastritis dramatically. However, change of endoscopic mucosal findings is not fully understood. To clarify the short-term changes of endoscopic mucosal findings after cure of H. pylori infection, a multicenter prospective trial was conducted. METHODS: One hundred and forty-seven patients with H. pylori infection from 12 institutions were enrolled into this prospective cohort trial. Nineteen endoscopic findings using high-resolution white light electronic endoscopy were assessed before and 2-4 months after eradication treatment of H. pylori. H. pylori infection was diagnosed by pathology of three stomach sites using hematoxylin-eosin stain or H. pylori-specific immunostaining. Endoscopic features of the successful eradication group and the failed eradication group were compared. The change of severity of endoscopic features before and after H. pylori eradication were compared between successful eradication and failed eradication. RESULTS: One hundred and twenty-six patients were analyzed. Eradication rate was 81% (102/126). Non-transparency of gastric juice, diffuse redness of fundic mucosa, enlarged fold, spotty redness of fundic mucosa, flat erosion of stomach, and hemoglobin index of fundic mucosa were significantly different between the successful eradication group and the failed eradication group. Gastric flat erosion was of higher frequency in the successful eradication group. When eradication was successful, spotty redness of fundic gland improved significantly. CONCLUSION: Assessment of endoscopic findings of spotty redness after eradication treatment is useful in the diagnosis of H. pylori eradication.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021.

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.

Two distinct types of cancer of different origin may be mixed in gastroesophageal junction adenocarcinomas in Japan: evidence from direct evaluation of gastric acid secretion.

BACKGROUND AND AIMS: Barrett's esophageal cancer is usually included in gastroesophageal (GE) junction adenocarcinoma in Japanese people. No study on the pathogenesis of Barrett's esophageal cancer in comparison with GE junction adenocarcinoma other than Barrett's esophageal cancer has been reported in Japan. The aim of this study was to evaluate the clinical and pathological characteristics and gastric acid secretion of Barrett's esophageal cancer and GE junction adenocarcinoma other than Barrett's esophageal cancer in Japanese subjects. MATERIAL AND METHODS: Twenty-three patients with Barrett's esophageal cancer and 23 patients with GE junction adenocarcinoma other than Barrett's esophageal cancer were enrolled in this study. We evaluated and compared them by assessing the Helicobactor pylori (HP) infection status and gastric acid secretion using the endoscopic gastrin test (EGT). RESULTS: In the patients with Barrett's esophageal cancer, no significant difference was found in the mean EGT value between HP-positive and -negative patients, but in the patients with GE junction adenocarcinoma other than Barrett's esophageal cancer, the mean EGT value in HP-positive patients was significantly lower than that in HP-negative patients. CONCLUSION: Two distinct types of cancer of different origin may be mixed in GE junction adenocarcinomas. One is Barrett's esophageal cancer associated with high gastric acid secretion and reflux of gastric acid into the esophagus, the other is cancer resembling distal gastric cancer associated with gastric atrophy and low gastric acid secretion.

Magnifying endoscopic findings of the surface structure of non-cancerous mucosa surrounding differentiated and undifferentiated gastric carcinoma.

BACKGROUND: Several reports have described the usefulness of magnifying endoscopy in observing the surface structure in gastric neoplasia. The aim of the present study was to evaluate the characteristics of the surface structure of non-cancerous mucosa surrounding gastric cancer. METHODS: Sixty Japanese patients with early gastric cancer were enrolled in this study. We observed the non-cancerous gastric mucosa surrounding gastric carcinoma by magnifying endoscopy and classified the magnified view into four patterns: (A) dotted; (B) short-linear; (C) striped; and (D) granular, according to Sakaki's classification. RESULTS: All patients were diagnosed as having Helicobacter pylori infection, and histological evaluation revealed 46 types of differentiated and 14 types of undifferentiated-type gastric carcinomas. There were significant differences in the gender, age and endoscopic-atrophic-border scale between patients with these two types. In all, the surface structure at 240 points (4 points each in 60 patients) of non-cancerous mucosa was observed by magnifying endoscopy. The prevalences of the surface patterns of the mucosa surrounding differentiated carcinoma were: A, 1.1%; B, 8.1%; C, 28.3%; D, 62.5%, and those of the mucosa surrounding undifferentiated carcinoma were: A, 8.9%; B, 73.2%; C, 14.3%; D, 3.6%. There were significant differences in the surface structure of the non-cancerous mucosa surrounding differentiated and undifferentiated gastric carcinoma. CONCLUSION: The microsurface structure of the gastric mucosa surrounding gastric cancer lesions differed between patients with differentiated and undifferentiated gastric cancer. These findings are expected to be useful for the early detection of gastric carcinoma lesions or for the determination of extensions of carcinoma lesions.

A simple prediction score for in-hospital mortality in patients with nonvariceal upper gastrointestinal bleeding.

BACKGROUND: No prediction scores for the mortality of both inpatients and outpatients who developed nonvariceal upper gastrointestinal bleeding (UGIB) without endoscopic findings have been established. We aimed to derive and validate a novel prediction score for in-hospital mortality. METHODS: We conducted a three-stage, multicenter retrospective study. In the derivation stage, patients with nonvariceal UGIB at six institutions were enrolled to derive the prediction score by logistic regression analysis. External validation of the score was performed to analyze discrimination by patients at six other institutions. Then the performance of this score was compared with that of four existing scores. RESULTS: We enrolled 1380 and 825 patients in the derivation and validation cohorts, respectively. A prediction score (CHAMPS-R Score) comprising seven variables (Charlson Comorbidity Index ≥ 2, in-hospital onset, albumin < 2.5 g/dL, altered mental status, Eastern Cooperative Oncology Group performance status ≥ 2, steroids, and rebleeding) with equal-weight scores was established, with high discriminative ability in both derivation and validation cohorts (c statistic, 0.91 and 0.80, respectively). When rebeeding was excluded from the score (an onset model; CHAMPS Score), this score also achieved high discriminative ability (c statistic, 0.90 and 0.81, respectively). The prediction scores had significantly higher discriminative ability than the Glasgow Blatchford Score, AIMS65, ABC Score, and clinical Rockall Score in both cohorts (all, p < 0.05). CONCLUSIONS: We derived and externally validated prediction scores for in-hospital mortality in patients with nonvariceal UGIB. The CHAMPS Score might be optimal for managing such patients. Its mobile application is freely available ( https://apps.apple.com/app/id1565716902 for iOS and https://play.google.com/store/apps/details?id=hatta.CHAMPS for Android).

[Efficacy evaluation of lafutidine for mild reflux esophagitis in Japanese patients].

To evaluate the efficacy of lafutidine (20mg) , famotidine (40mg) and placebo in patients with mild reflux esophagitis (Grades A and B according to the Los Angeles classification) , a double-blind, multicenter, randomized clinical trial was performed for the first time in Japanese patients. In addition to each physician's evaluation, efficacy was evaluated by judging panels using images submitted by each physician. The healing rate after 8 weeks for lafutidine, famotidine and placebo were 67.7%, 56.6% and 41.2%, respectively. Lafutidine was significantly more effective than placebo (p=0.002, according to the judging panels) . Based on the evaluation of endoscopic images by the judging panels, 91 (27.1%) of 336 images submitted by each physician were judged to not be mucosal breaks. Judging panels are considered one of the ways to resolve the problem of the need to unify the criteria.

Helicobacter pylori induces gastric mucosal intestinal metaplasia through the inhibition of interleukin-4-mediated HMG box protein Sox2 expression.

Helicobacter pylori is a major cause of the transdifferentiation into intestinal metaplasia that may develop gastric cancer. However, the molecular pathogenesis of this transdifferentiation is poorly understood. A SRY-related HMG box protein Sox2 is an essential transcription factor of organ development in brain, lung, and stomach. Our aim of this study was to investigate the mechanism responsible for regulation of Sox2 in host Th1-dominant response to H. pylori. Sox2 protein was immunohistochemically expressed in both human oxyntic and pyloric glands with H. pylori infection, but not in intestinal metaplasia. Western immunoblotting of gastric epithelial cell lines showed that IL-4, a Th2-related cytokine, dose dependently enhanced Sox2 expression among H. pylori infection-mediated cytokines. Small changes of Sox2 expression were observed after each treatment with IFN-gamma, IL-1beta, or TNF-alpha. IL-4-mediated Sox2 induction was suppressed by the inhibition of STAT6 activation with STAT6 RNA interference, and electrophoretic mobility shift assay indicated that activation of the Sox2 promoter by IL-4 occurred through the action of STAT6. Furthermore, H. pylori and IFN-gamma inhibited the phosphorylation of STAT6, resulting in the suppression of IL-4-mediated Sox2 expression. Immunohistochemical analyses showed significantly the suppressed STAT6 activity in H. pylori-infected human gastric mucosa. Additionally, downregulation of Sox2 by knockdown experiments led to intestinal phenotype with expressions of Cdx2 and MUC2. These results suggest that H. pylori and IFN-gamma interfere with the differentiation into oxyntic and pyloric glands by the downregulation of Sox2 on IL-4/STAT6 signaling, which may contribute to the transdifferentiation into intestinal metaplasia.

Sustained epithelial proliferation in a functionally irreversible fundic mucosa after Helicobacter pylori eradication.

BACKGROUND: We recently reported the expansion of the acid-secreting mucosa following Helicobacter pylori eradication with Congo red chromoendoscopy for a short-term follow-up of up to 7 months. We aimed to extend the observation period and to clarify the characteristic features of acid-secreting and non-acid-secreting mucosa. METHODS: In 24 H. pylori-positive patients with fundic atrophy, Congo red chromoendoscopy was performed prior to, 1 month, 7 months, and finally more than 2 years after the eradication. The areas of the acid-secreting mucosa were evaluated semiquantitatively. Two gastric biopsy specimens were taken from the acid-secreting and non-acid-secreting areas at the final chromoendoscopy and were subjected to histologic evaluation and immunohistochemistry for Ki-67 as a proliferation index. RESULTS: After a gradual increase in acid-secreting areas for up to 7 months after eradication, they further increased in 79% subjects between 7 months and the final observation at a mean follow-up of 62 months. However, there still existed non-acid-secreting mucosa in the fundic area in all subjects, indicating that the expansion of acid-secreting mucosa remained partial. Compared with the neighboring acid-secreting area, the non-acid-secreting area was characterized histologically by higher degrees of residual inflammation, mucosal atrophy, and intestinal metaplasia, and by sustained hyperproliferation as well. CONCLUSIONS: Functionally irreversible (non-acid-secreting) gastric mucosa after eradication was associated with extensive intestinal metaplasia and sustained hyperproliferation, suggesting that such mucosa still possesses malignant potential. Congo red chromoendoscopy may be useful for estimating the risk of subsequent development of gastric cancer following successful H. pylori eradication by determining the distribution of functionally irreversible mucosa.

Alteration of correlation between serum pepsinogen concentrations and gastric acid secretion after H. pylori eradication.

PURPOSE: The measurement of serum pepsinogens is clinically useful to represent gastric acid secretion. Since both serum pepsinogens and gastric acid secretion are considerably altered by H. pylori eradication, the correlation between these two parameters could be different prior to and after eradication. In this study, we investigated the correlation between the two parameters prior to and after eradication. METHODS: One hundred eighteen H. pylori-positive patients with peptic ulcers or chronic gastritis were enrolled in this retrospective analysis. In all participants both the measurement of serum pepsinogens and the determination of gastric acid secretion were performed prior to and at 1 month after successful eradication. In 85 subjects, the same assessments were repeated at 7 months. Correlations between serum pepsinogens and gastric acid secretion were assessed using linear regression analysis. RESULTS: The pepsinogen I/II ratio (r = 0.56) was a better indicator of gastric acid secretion in H. pylori-infected subjects than pepsinogen I itself (r = 0.31). Eradication of H. pylori altered the association, causing pepsinogen I (r = 0.55) to become a better indicator of gastric acid secretion compared with the pepsinogen I/II ratio (r = 0.40) at 1 month after eradication, followed by similar tendencies at 7 months. CONCLUSION: Using different serum biomarkers (pepsinogen I/II ratio prior to eradication or pepsinogen I after eradication), the measurement of serum pepsinogens is useful for predicting the individual gastric acid secretion level not only in H. pylori-infected subjects, but also in subjects with histories of eradication of the infection.

Exogenous luminal nitric oxide exacerbates esophagus tissue damage in a reflux esophagitis model of rats.

OBJECTIVE: Cytotoxic concentrations of nitric oxide are generated luminally at the gastroesophageal junction through the entero-salivary recirculation of dietary nitrate in humans. The site of luminal nitric oxide generation shifts to the lower esophagus when gastric acid is refluxed into the esophagus. The aim of this study was to investigate the influence of persistent administration of exogenous nitric oxide on esophageal damage. MATERIAL AND METHODS: 0.1% sodium nitrite and/or 1% ascorbic acid was administered in an established rat acid-refluxed esophagitis model. Co-administration of both reactants in this model is thought to induce high concentrations of nitric oxide luminally in the esophagus by an acid-catalyzed chemical reaction when refluxed gastric acid is present. The tissue damage was evaluated by a macroscopic lesion index and myeloperoxidase activity. Nitrotyrosin was assessed immunohistochemically as a footprint of peroxynitrite formation. RESULTS: Co-administration of sodium nitrite and ascorbic acid induced a 4- to 5-fold increase in the esophageal damage compared with baseline reflux esophagitis, while the damage was unchanged when either of the reagents alone was given. Nitrotyrosine was strongly stained in the tissue from the co-administration. Treatment of superoxide scavengers efficiently prevented the exacerbation of esophageal damage by exogenous nitric oxide exposure, suggesting an essential role of superoxide in esophageal damage. CONCLUSIONS: Exogenous luminal nitric oxide greatly exacerbated the tissue damage of reflux esophagitis. Diffusion of the luminal nitric oxide into the adjacent superoxide-enriched inflamed tissue of the esophagus could lead to the production of the highly toxic agent peroxynitrite, thus causing exacerbation of the esophageal damage.

Barrett's esophagus is characterized by the absence of Helicobacter pylori infection and high levels of serum pepsinogen I concentration in Japan.

BACKGROUND AND AIM: It has been reported that patients with Barrett's esophagus (BE) may have gastric acid hypersecretion. Serological markers such as serum pepsinogen or gastrin have been used to estimate the gastric secretory function. The aim of this study was to compare the serum pepsinogen and gastrin concentrations in view of Helicobacter pylori infection status between BE patients and the controls. METHODS: Thirty-six patients with long-segment BE were enrolled in this study. Three age- and sex-matched controls were assigned to each patient. Serum pepsinogen and gastrin concentrations were measured by radioimmunoassay and H. pylori infection was determined by histology and serum IgG antibodies. RESULTS: Helicobacter pylori infection was present in 4 of 36 patients (11%) with BE and in 80 of 108 controls (74%), being less prevalent in BE patients than in the controls (P < 0.0001). When examined in the H. pylori-negative subjects, both the serum pepsinogen I and pepsinogen II concentrations in BE patients were significantly higher than those in the controls (mean pepsinogen I:BE 51.0 +/- 14.0 ng/mL vs control 38.9 +/- 13.5 ng/mL, P = 0.0012; mean pepsinogen II:BE 10.8 +/- 4.0 ng/mL vs control 7.9 +/- 2.0 ng/mL, P = 0.0097). There was no significant difference in the serum gastrin levels between BE patients and the controls irrespective of the H. pylori infection status. CONCLUSIONS: Most of the Japanese BE patients are characterized by the absence of H. pylori infection and high levels of serum pepsinogen. Determination of the serum pepsinogen level in combination with the H. pylori infection status could be a useful serological marker for BE screening.