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Introduction Gastroesophageal reflux disease is a common condition, and proton pump inhibitors (PPIs) are the mainstays of treatment. However, concerns have been raised about the safety of PPIs. A potassium‐competitive acid blocker (P‐CAB), vonoprazan (VPZ), was recently introduced, which may provide clinical benefits. This study was performed to investigate the cost‐effectiveness of alternative long‐term strategies including continuous and discontinuous treatment with VPZ for the management of reflux esophagitis in Japan. Methods A health state transition model was developed to capture the long‐term management of reflux esophagitis. Four different strategies were compared: (a) intermittent PPI using lansoprazole (LPZ); (b) intermittent P‐CAB; (c) maintenance PPI using LPZ; and (d) maintenance P‐CAB. Results Intermittent P‐CAB was the most cost‐effective, and the number of days for which medication was required with this strategy was fewest. Maintenance PPI was more efficacious, but more costly than intermittent P‐CAB. Maintenance P‐CAB was more efficacious, but more costly than maintenance PPI. Co‐payments were higher for maintenance PPI than for intermittent P‐CAB, and for maintenance P‐CAB than for maintenance PPI, which were considered reasonable for the majority of patients to improve symptoms. Conclusions Intermittent P‐CAB appears to be the strategy of choice for the majority of reflux esophagitis patients in clinical practice. If a patient is not satisfied with the symptom control of the current strategy, switching to a more effective strategy appears to be a reasonable option for the majority of patients., A decision analysis was conducted to investigate the cost‐effectiveness of alternative long‐term strategies for the management of reflux esophagitis in Japan. Intermittent treatment with a potassium‐competitive acid blocker, vonoprazan, appears to be the strategy of choice for the majority of reflux esophagitis patients in clinical practice. If a patient is not satisfied with the symptom control of the current strategy, switching to a more effective strategy appears to be a reasonable option for the majority of patients.

Objective Gastroesophageal reflux disease (GERD) is a highly prevalent disorder that negatively affects patients' quality of life and reduces their work productivity. The medical expenses associated with the treatment of GERD are the highest among all digestive diseases. Current guidelines recommend the administration of a standard dose of proton pump inhibitor (PPI) for eight weeks as an initial GERD treatment. However, there is growing concern regarding the safety of PPI treatment. Recently, a novel potassium-competitive acid blocker (P-CAB), vonoprazan (VPZ), was approved for the treatment of reflux esophagitis in Japan and may provide clinical benefits in GERD treatment. This study was conducted to evaluate the cost-effectiveness of a P-CAB, VPZ vs. a PPI, lansoprazole (LPZ), for the acute medical treatment of reflux esophagitis. Methods A clinical decision analysis was performed using a Markov chain approach to compare VPZ to LPZ in the acute treatment of reflux esophagitis in Japan. Results The P-CAB strategy was superior to the PPI strategy in terms of cost-effectiveness (direct cost per patient to achieve clinical success) and the number of days for which medication was required. Sensitivity analyses revealed that this superiority was robust within the plausible range of probabilities. This remained true even when the healing rates in cases of mild esophagitis were applied. Conclusion The P-CAB strategy was consistently superior to the conventional PPI strategy using the original LPZ in terms of cost-effectiveness and the number of days for which medication was required. Thus, VPZ appears to be the drug of choice for the acute medical treatment of reflux esophagitis.

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

Background and Aim To examine the differences in esophageal histopathology between non-erosive reflux disease (NERD) and reflux esophagitis (RE), and to investigate whether baseline esophageal histopathology can predict the therapeutic response to proton pump inhibitors (PPIs). Method The subjects comprised 94 patients with NERD (n = 71) or mild RE (n = 23). Tissue was biopsied from 5 cm above the squamo-columnar junction (SCJ), and the degree or presence of nine histopathological markers was assessed. The patients were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. If complete heartburn relief was not achieved, RPZ was increased to 10 mg twice daily for another 2 weeks, and then to 20 mg twice daily for another 2 weeks if heartburn remained. Results Features of esophageal histopathology 5 cm above the SCJ differed between NERD and RE patients. The esophageal histopathology in patients unresponsive to RPZ was characterized by Protein Gene Product (PGP) 9.5 negativity in those with NERD, and intraepithelial bleeding in those with RE. In addition, the combination of dilated intercellular spaces (DIS) (+)/PGP 9.5 (−) was indicative of strong resistance to PPI therapy in NERD patients. Conclusion The therapeutic efficacy of PPI can be predicted from the features of biopsied esophageal tissue. Factors predictive of resistance to treatment with PPI are negativity for PGP 9.5 in NERD patients and intraepithelial bleeding in RE patients.

Background: Nighttime acid reflux that influences refractory symptoms is strongly associated with sleep disturbances. The aim of this study was to examine the associations between sleep disturbances and refractory gastroesophageal reflux disease (GERD) symptoms in patients receiving once daily proton pump inhibitors (PPI) and the efficacy of twice-daily rabeprazole treatment. Method: In a multicenter survey, 433 GERD patients receiving once-daily PPI treatment completed a self-report questionnaire that included the Frequency Scale for the Symptoms of GERD (FSSG) and questions about sleep disturbances. Study cases were defined as patients with an FSSG score ≥8. Of the 222 study cases, 106 individuals received rabeprazole 10 mg twice daily for 4-8 weeks. Results: Of the 433 subjects, 222 patients revealed FSSG scores of ≥8. Use of a half dose of PPI was associated with such cases. PPI-refractory symptoms were found in 46% of patients with standard-dose PPI treatment. Nighttime symptoms (OR = 2.56), daytime sleepiness (OR = 1.64), and poorer sleep quality (OR = 1.67) were significantly associated with refractory GERD symptoms. Twice-daily rabeprazole treatment significantly improved FSSG scores and sleep disturbances. Conclusion: About half of the GERD patients receiving once-daily standard-dose PPI treatment had refractory GERD symptoms. Sleep disturbances were significantly associated with refractory GERD symptoms. Twice-daily rabeprazole treatment was effective in such cases.

Though gastric cancer screening by X-ray examination has been confirmed to be effective for reducing gastric cancer mortality, decreases in efficiency have been pointed out. Establishment of an effective screening system, focusing on high-risk status such as Helicobacter pylori infection and atrophic gastritis, is desirable. To date, combined use of serum anti-Helicobacter pylori antibodies and pepsinogen measurement has been assessed prospectively in participants in opportunistic and workplace health check-ups; however, there are no reports of population-based cohort study. To clarify the population-based risk of Helicobacter pylori infection and atrophic gastritis for gastric cancer, a cohort study was conducted in rural towns in Kyoto Prefecture. Subjects were 1,011 males and 1,848 females recruited in a health check-up in 1987. Their serum was examined for anti-Helicobacter pylori antibodies and pepsinogen I and II. Gastric cancer cases were assessed from the cancer registry of those towns. Up to the end of 1996, 33 males and 28 females developed gastric cancer. A sex- and age-adjusted hazard ratio was calculated by Cox’s proportional model. Helicobacter pylori infection increased the risk of gastric cancer even when the subjects had no atrophy (hazard ratio = 4.20; 95% confidence interval, 0.96–18.40). The risk increased further when they had both Helicobacter pylori infection and atrophy (hazard ratio = 11.23; 95% confidence interval, 2.71–46.51). Subjects with atrophy but negative for anti-Helicobacter pylori antibodies had the highest risk (hazard ratio = 14.81; 95% confidence interval, 2.47–88.80). A high-risk group for gastric cancer can be selected by serological prescreening.

Summary Background Few studies have compared the efficacy of proton pump inhibitors in resolving the symptoms of non-erosive reflux disease (NERD) and of erosive gastro-oesophageal reflux disease (GERD) in Japan. Aim To investigate and compare the efficacy of 4-week course of rabeprazole 10 mg/day on symptom resolution in NERD and erosive GERD in Japan. Methods The modified Los Angeles classification was used to grade endoscopically GERD in patients with heartburn (Grades N and M: NERD, Grades A and B: mild reflux oesophagitis (RO), and Grades C and D: severe RO). Rabeprazole 10 mg/day was administered for 4 weeks to 180 patients who kept symptom diaries. Results Complete relief of the symptoms was achieved in 35.8% of the NERD group and 55.4% of the erosive GERD group (mild RO: 51.1% and severe RO: 77.8%). Rabeprazole was significantly more effective in erosive GERD than in NERD patients. Among the NERD subgroups (Grades N and M), no difference in symptom improvement was observed. Conclusions Four-week, rabeprazole 10 mg/day acid suppression therapy was effective in resolving symptoms in Japanese GERD patients. This therapy was more effective in erosive GERD than in NERD patients, and in those with severe RO than in those with mild RO.

Fibrovascular polyps are very rare benign tumors almost originating from the cervical esophagus. We present the case of a 50-year-old man with a history of dizziness and dyspnea on effort for two weeks. The barium esophagogram showed a smooth and rounded polypoid tumor at EG junction. Endoscopy revealed the smooth and white polypoid tumor at EG junction, which arose from the lower esophagus, and the head of the tumor was herniated into the stomach. Because the potentially malignant tumor was suspected by endoscopic biopsy, and the tumor was small in size, we performed endoscopic resection. The final diagnosis was the fibrovascular polyp of the esophagus. This is a very rare case, because this polyp was not only small but also arose from lower esophagus.

To evaluate the socio-economic effects of Helicobacter pylori eradication in the treatment of duodenal ulcer disease in Japan, a clinical decision analysis was performed to assess H. pylori eradication therapy compared with the conventional strategy of maintenance with histamine-2 receptor antagonists. A decision tree-based state transition model (Markov chain approach) implemented to simulate a 5 year period of follow up was constructed. The H. pylori eradication strategy was found to be superior to the conventional maintenance strategy with regard to clinical effectiveness and other dimensions of a patient's outcome. Furthermore, in a long-term perspective, the eradication strategy was less costly than the maintenance strategy. Helicobacter pylori eradication should be recommended as the first choice treatment of H. pylori-positive duodenal ulcer patients. The clinical implication of H. pylori eradication entails an improvement in clinical effectiveness and other dimensions of a patient's outcome and a significant reduction in the costs of duodenal ulcer treatment. The long-term total costs do not depend on the initial drug cost of an eradication regimen. Pursuing a high eradication rate of H. pylori is essential in improving the patient's outcome and the cost-effectiveness of treatment.

Gastric cancer manifesting as a submucosal tumor (SMT) is not common. A gastric barium meal and endoscopic studies performed on a 49-year-old male with epigastric pain, revealed an elevated lesion with bridging folds and central depression on the posterior wall of the lower body. An endoscopic ultrasonography (EUS) revealed a hypoechoic mass lesion within the submucosal layer. Due to an increase in the size of the tumor and its central depression during the subsequent year and a half, the patient was admitted for closer examination. Endoscopic biopsy material from the deeper layer, obtained by mucosal resection, revealed a poorly differentiated adenocarcinoma. Microscopic examination of the resected stomach showed a poorly differentiated adenocarcinoma within the submucosal layer, with considerable lymphocyte infiltration. Immunohistological examination disclosed marked T cell infiltration adjacent to the cancer cells. We suggest that considerable lymphocyte infiltration, particularly T cells, may have some role in the protective reaction against cancer cells. Our case was diagnosed as being cancer 18 months after the first endoscopic study. The biopsy material taken from the depression at the time of the first examination showed benign findings and a EUS revealed typical SMT. In the case of SMT shown by EUS to be a hypoechoic mass lesion in the submucosal layer, it is recommended that biopsy material be obtained from the deeper layer using methods available such as artificial ulcer formation.

Serum pepsinogen (PG) measurement has been used for gastric cancer screening since the 1990s. However, there are no reports comparing the screening validity of the PG test method with that of conventional X-ray examination directly in the same population, using a follow-up study.From April 2000 to March 2001, 12 120 residents of Osaka Prefecture, who underwent opportunistic screening at a medical checkup organization in Osaka city (hereafter, "the organization"), were enrolled. They received both a barium meal examination and PG test simultaneously. All the participants were followed up for a 1-year period after the screening. For the participants advised to undergo endoscopic examination, the results of those who were examined at the organization were tallied. The other participants were checked using the Osaka Cancer Registry (hereafter, "the registry").Of the 12 120 participants, 493 (4.1%) were positive with the PG method and 728 (6.0%) were positive with the X-ray method. Fifty-four (0.4%) were positive for both methods. Thirteen gastric cancer cases were diagnosed by successive esophagogastroduodenoscopies at the organization. Six additional gastric cancer cases were identified by record linkage with the registry. The sensitivity, specificity, and positive predictive values of the PG method with a PGI cutoff level ofor=30 ng/ml and PGI/PGII ratio ofor=2.0 were 36.8%, 96.0%, and 1.4%, respectively. These values for the direct X-ray examination were 68.4%, 94.1%, and 1.8%, respectively.The PG test method alone with a PGI cutoff level ofor=30 ng/ml and PGI/PGIIor= 2.0 is not appropriate for gastric cancer screening.

Non-erosive reflux disease(NERD) is a common condition and acid-suppressing agents are the mainstay of treatment. A cost-effectiveness analysis comparing a PPI, lansoprazole (LPZ) and a H2RA, ranitidine (RAN) for the treatment of NERD in Japan was performed using a decision analysis. The time period studied was one month and payer or patient' s perspective was considered. Efficacy data were estimated from a randomized clinical trial. Expected days without symptom (healthy days) were 20 for LPZ 15 mg/day and 16 for RAN 300 mg/day. Direct costs were 4,750 yen for LPZ and 4,358 yen for RAN. Cost-effectiveness ratio (direct costs/healthy days) was 238 yen for LPZ and 272 yen for RAN. Considering the results from a large-scale survey of GERD patients in Japan, the slightly higher price of LPZ was outweighed by its greater efficacy, also from the patient's willingness to pay perspective. Lansoprazole was superior to ranitidine with regard to both efficacy and cost-effectiveness and therefore is the preferred therapeutic agent for treatment of NERD.

Gastroesophageal reflux disease (GERD) is a common condition, and acid-suppressing agents are the mainstays of treatment. For the acute medical management of GERD, two different strategies can be proposed: either the most effective therapy, i.e., proton-pump inhibitors (PPIs), can be given first, or histamine H2-receptor antagonists (H2RAs) can be attempted first (the “step-up” approach). A clinical decision analysis comparing the PPI-first strategy and the H2RA-first “step-up” strategy for the acute treatment of reflux esophagitis in Japan was performed, using a Markov chain approach. The PPI-first strategy was consistently superior to the step-up strategy with regard to clinical outcomes for the patient and with regard to cost-effectiveness (direct cost per patient to achieve clinical success). This superiority was robust within the plausible range of probabilities according to the sensitivity analyses. The PPI-first strategy is superior to the H2RA-first “step-up” strategy with regard to both efficacy and cost-effectiveness and therefore, the PPI-first strategy is the preferred therapeutic approach for the acute medical treatment of reflux esophagitis.

GERD is a common condition and acid-suppressing agents are the mainstay of treatment. A cost-effectiveness analysis comparing a PPI, lansoprazole (LPZ) and a H2RA, famotidine (FAM) for the maintenance treatment of reflux esophagitis in Japan was performed using a Markov chain approach. The time period studied was 6 months and payer perspective was chosen. Transition probabilities were estimated from meta-analyses. Expected days without esophagitis (healthy days) were 166 for LPZ 30 mg/day, 161 for LPZ 15 mg/day and 143 for FAM 40 mg/day. Direct costs were 55,624 yen for LPZ 30 mg/day, 42,078 yen for LPZ 15 mg/day and 67,969 yen for FAM 40 mg/day. Cost-effectiveness ratio (direct costs/healthy days) was 335 yen for LPZ 30 mg/day, 262 yen for LPZ 15 mg/day and 477 yen for FAM 40 mg/day. Lansoprazole was superior to famotidine with regard to both efficacy and cost-effectiveness and therefore is the preferred therapeutic agent for the maintenance treatment of GERD.

Summary Aim : To investigate the effect of different proton pump inhibitors, S-mephenytoin 4′-hydroxylase (CYP2C19) genotype and antibiotic susceptibility on the eradication rate of Helicobacter pylori. Methods : One hundred and eighty-seven H. pylori-infected peptic ulcer patients were randomly treated with either rabeprazole (10 mg b.d.) or lansoprazole (30 mg b.d.) plus amoxicillin (750 mg b.d.) and clarithromycin (400 mg b.d.) for 1 week. The antibiotic susceptibility and CYP2C19 genotype (extensive or poor metabolizer) were investigated. Results : The eradication rates in the rabeprazole–amoxicillin–clarithromycin (RAC) and lansoprazole–amoxicillin–clarithromycin (LAC) groups were 75% and 69%, respectively, on an intention-to-treat basis, and 80% and 75%, respectively, on a per protocol basis. The eradication rate for clarithromycin-resistant strains was significantly lower than that for clarithromycin-sensitive strains (24% vs. 86%, P

Background In Japan, treatment guidelines are lacking for patients with upper gastrointestinal symptoms. We aimed to compare the efficacy of different drugs for the treatment of uninvestigated upper gastrointestinal symptoms. Methods This was a randomized, open-label, parallel-group multicenter study. Helicobacter pylori-negative, endoscopically uninvestigated patients ≥ 20 years of age with upper gastrointestinal symptoms of at least moderate severity (Global Overall Symptom score [GOS] ≥ 4 on a 7-point Likert scale) were randomized to treatment with omeprazole (10 mg once daily), famotidine (10 mg twice daily), mosapride (5 mg three times daily) or teprenone (50 mg three times daily). The primary endpoint was sufficient relief of upper gastrointestinal symptoms after 4 weeks of treatment (GOS ≤ 2). UMIN clinical trial registration number: UMIN000005399. Results Of 471 randomized patients, 454 were included in the full analysis set. After 4 weeks of treatment, sufficient symptom relief was achieved by 66.9% of patients in the omeprazole group, compared with 41.0%, 36.3% and 32.3% in the famotidine, mosapride and teprenone groups, respectively (all, p Conclusions The favorable efficacy and safety profiles of omeprazole in relieving uninvestigated upper gastrointestinal symptoms support its use as first-line treatment in this patient group in Japan. Patients who show no improvement in symptoms despite PPI use, and those with alarm symptoms (such as vomiting, GI bleeding or acute weight loss) should receive further investigation, including prompt referral for endoscopy. Trial registration UMIN000005399.

Recently, carboxyl terminal glycine extended progastrin (gastrin-G), the immediate biosynthetic precursor of amidated gastrin, was found in human gastric antral mucosa. To investigate in pathophysiological conditions, we examined gastrin and gastrin-G levels and their molecular forms in gastric antral mucosa of healthy controls and patients with gastric or duodenal ulcer and in gastrinomas. There were no significant differences between controls and gastric or duodenal ulcer patients in antral gastrin and gastrin-G levels, the ratio of gastrin-G to gastrin and the pattern of their molecular forms. In contrast, gastrin and gastrin-G levels and the ratio of gastrin-G to gastrin in gastrinomas were much higher than those in antral mucosa of controls or ulcer patients. The predominant molecular form of gastrin-G was different between two Zollinger-Ellison syndrome (ZES) cases. These results suggest that there are no significant differences between healthy controls and patients with gastric or duodenal ulcer in the nature of gastrin amidation, and that the nature of gastrin amination in gastrinomas is different from that in normal gastrointestinal tissues.