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).

The Risk Factors for Metastasis in Non-Ampullary Duodenal Neuroendocrine Tumors Measuring 20 mm or Less in Diameter.

BACKGROUND/AIMS: The treatment strategy for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤20 mm in diameter has not been established. In this study, we aimed to evaluate the detailed characteristics of NAD-NETs ≤20 mm in diameter to clarify the risk factors of subsequent metastasis. METHODS: The patients with NAD-NETs ≤20 mm in diameter who had been treated at 12 institutions between 1992 and 2013 were enrolled. Clinical records were retrieved, and histopathological findings of all cases were centrally reviewed by 2 pathologists. RESULTS: We studied 49 patients with a mean follow-up period of 66.5 months. Thirty-five patients were initially treated with endoscopic resection (ER), and 14 with surgery. A univariate analysis revealed the ORs and 95% CIs of the risk factors for metastasis were lymphovascular invasion (12.5 [2.01-77.9]), multiple tumors (9.75 [1.46-65.4]), a tumor size of 11-20 mm (6.67 [1.21-36.6]), and World Health Organization grade G2 (7.13 [1.16-43.9]). Five-year overall and disease-specific survival rates were 86.1 and 97.2%, respectively. CONCLUSION: This is the first study to demonstrate the risk factors of metastasis in NAD-NETs ≤20 mm in diameter. These findings may be helpful for determining the appropriate therapeutic approach and the clinical strategy of treatment following ER.

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.

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.

[A case of undifferentiated pleomorphic sarcoma of the stomach showing rapid growth].

We report an extremely rare case of undifferentiated pleomorphic sarcoma of the stomach. A 74-year-old woman was admitted for abdominal discomfort. A 13-cm gastric submucosal tumor and multiple liver and bone metastases were detected by computed tomography. The tumor had not been detected 8 months earlier. We performed EUS-FNAB for a suspected mesenchymal tumor, but the immunohistochemical test (c-kit, CD34, desmin, SMA, S-100) findings were negative. The tumor was confirmed as wild type for c-kit and PDGFRα. It grew rapidly and the patient died 2 months after admission. Pathological analysis of the EUS-FNAB specimens and autopsy revealed an undifferentiated pleomorphic sarcoma.

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.

Tongue-like Barrett's esophagus is associated with gastroesophageal reflux disease.

AIM: To test this hypothesis of barrett esophagus (BE) classified into two types and to further determine if there was any correlation between the shape of endoscopically suspected esophageal metaplasia (ESEM), prevalence of reflux esophagitis (RE) and heartburn. METHODS: A total of 6504 Japanese who underwent endoscopy for their annual stomach check-up were enrolled in this study. BE was detected without histological confirmation that is ESEM. We originally classified cases of ESEM into 3 types based on its shape: Tongue-like (T type), Dome-like (D type) and Wave-like (W type) ESEM. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a one-month period. RESULTS: ESEM was observed in 10.3% of 6504 subjects (ESEM < 1 cm, 9.4%; 1 cm < or = ESEM < 3 cm, 1.7%; ESEM > or = 3 cm, 0.5%). The frequency of ESEM was significantly higher in males compared with female subjects. Statistical analysis showed that the prevalence of heartburn and RE were significantly higher in the T type ESEM than in the W type ESEM (P < 0.05). CONCLUSION: The T type ESEM was strongly asso-ciated with reflux symptoms and RE whereas the W type ESEM was not associated with GERD.

Incidence of reflux esophagitis and H pylori infection in diabetic patients.

AIM: To investigate the incidence of reflux esophagitis (RE) and H pylori infection in the diabetic patient. METHODS: The incidence of RE and H pylori infection were investigated in 85 patients with diabetes mellitus and the results were compared with controls. RESULTS: The incidence of RE in diabetic patients was 17.6%. Although this tended to be higher in diabetic patients, there were no statistically significant differences between diabetic patients and controls. The incidence of H pylori infection in diabetic patients was 53.7% but no statistically significant difference was seen between diabetic patients and controls in the incidence of H pylori infection. CONCLUSION: No significant differences could be seen between diabetic patients and controls in the incidence of RE and H pylori infection.

Prevalence of gastroesophageal reflux symptoms in a large unselected general population in Japan.

AIM: To examine the prevalence of gastroesophageal reflux disease (GERD) symptoms in a large unselected general population in Japan. METHODS: In Japan, mature adults are offered regular check-ups for the prevention of gastric cancer. A notice was sent by mail to all inhabitants aged>40 years. A total of 160983 Japanese (60774 male, 100209 female; mean age 61.9 years) who underwent a stomach check up were enrolled in this study. In addition, from these 160983 subjects, we randomly selected a total of 82894 (34275 male, 48619 female; mean age 62.4 years) to evaluate the prevalence of abdominal pain. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a 1 mo period. RESULTS: The respective prevalences of the symptoms in males and females were: heartburn, 15.8% vs 20.7%; dysphagia, 5.4% vs 7.8%; and abdominal pain, 6.6% vs 9.6%. Among these symptoms, heartburn was significantly high compared with the other symptoms, and the prevalence of heartburn was significantly more frequent in females than in males in the 60-89-year age group. Dysphagia was also significantly more frequent in female patients. CONCLUSION: The prevalence of typical GERD symptoms (heartburn) was high, at about 20% of the Japan population, and the frequency was especially high in females in the 60-89 year age group.

Effect of Helicobacter pylori status on intragastric pH during administration of lafutidine or famotidine.

BACKGROUND/AIMS: There has been no study attempting to compare the effects of lafutidine, a novel H2-receptor antagonist and other H2-receptor antagonists in the same subjects and relating them to H. pylori status. The first aim of this study was to investigate the effect of H. pylori status on intragastric pH in healthy volunteers receiving lafutidine or famotidine. The second aim was to compare the effects of the two antisecretory drugs. METHODOLOGY: The study was carried out in 11 healthy asymptomatic male volunteers. H. pylori infection was present in 5 subjects. Subjects were first examined by an ambulatory pH monitoring for 24 hours without medication. The second and third 24-hour pH monitoring study was performed on all subjects. Subjects took 10 mg lafutidine or 20mg famotidine at 9:00 and 21:00. RESULTS: During administration of lafutidine or famotidine, the percentage of period holding intragastric pH >4 was not significantly different between the H. pylori-negative and -positive subjects. Among the H. pylori negative subjects, the percentage of daytime period holding intragastric pH >4 was significantly greater with lafutidine than with famotidine (p < 0.05). CONCLUSIONS: The effect of lafutidine to increase intragastric pH was not affected by the H. pylori status. Among H. pylori-negative subjects, lafutidine was proven to be more effective than famotidine for acid control during the daytime in Japanese healthy volunteers.

Extensive gastric atrophy: an increased risk factor for superficial esophageal squamous cell carcinoma in Japan.

OBJECTIVES: A recent study in Sweden has reported that gastric atrophy is associated with an increased risk for esophageal squamous cell carcinoma. However, this finding needs to be confirmed in other ethnic groups due to the wide geographic variation of this cancer. OBJECTIVES: To investigate whether gastric atrophy is associated with a risk for esophageal squamous cell carcinoma using a case-control study in Japanese subjects, a population known to have a high prevalence of H. pylori infection and accompanying gastric atrophy. METHODS: Seventy-three patients who had undergone endoscopic mucosal resection for superficial esophageal squamous cell carcinoma, and 73 sex- and age-matched controls, were enrolled prospectively. Gastric fundic atrophy was evaluated by histology of biopsy specimens and serum pepsinogen I level (cutoff level 25 ng/mL). Conditional logistic regression model with adjustment for potential confounding factors was used to assess the associations. RESULTS: Gastric atrophy, defined histologically or serologically, was independently associated with an increased risk for esophageal squamous cell carcinoma and the risk seemed to increase with the progression of the atrophy. Multivariate odds ratio (95% confidence interval) for histological fundic atropy, fundic intestinal metaplasia, and serological atrophy are 4.2 (1.5-11.7), 10.7 (2.3-50.4), and 8.2 (2.2-30.4), respectively. CONCLUSIONS: Gastric atrophy, a newly recognized risk factor for esophageal squamous cell carcinoma in Sweden, is likely to be a risk factor in other areas. Further studies are warranted to explore the causal relationship.

Therapeutic effects of 10 mg/day rabeprazole administration on reflux esophagitis was not influenced by the CYP2C19 polymorphism.

BACKGROUND: The acid suppressive effects of omeprazole (OPZ) and lansoprazole (LPZ) are influenced by the CYP2C19 polymorphism. On the other hand, some investigators have reported that acid suppressive effect of rabeprazole (RPZ) was not significantly affected by CYP2C19. The present study was designed to investigate whether the CYP2C19 genotype is related to the healing of reflux esophagitis (RE) in treatment with RPZ 10 mg. METHODS: One hundred and three Japanese patients with RE were treated with daily oral administration of 10 mg RPZ. At 4 and 8 weeks after the start of treatment, healing of RE was evaluated endoscopically. The CYP2C19 genotype was investigated before the treatment. RESULTS: At 4 weeks after the start of treatment, the healing rates for homo-extensive metabolizer, hetero-extensive metabolizer, and poor metabolizer patients were 83.3% (15/18), 77.3% (17/22), and 88.9% (8/9) [corrected] respectively, and at 8 weeks after the start of treatment, the healing rates were 86.1% (31/36), 92.0% (46/50), and 82.4% (14/17), respectively. There were no significant differences in the healing rate of RE among the three genotypes at either 4 or 8 weeks after the start of treatment. CONCLUSIONS: The therapeutic effects of 10 mg/day RPZ administration on RE may be uninfluenced by the CYP2C19 polymorphism.

Preservation of gastric acid secretion may be important for the development of gastroesophageal junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status.

BACKGROUND: We have previously reported that Helicobacter pylori infection prevents reflux esophagitis (RE) and Barrett's esophagus (BE) by decreasing gastric acid secretion. Gastroesophageal (GE) junction adenocarcinoma, including Barrett's adenocarcinoma, has been thought to be a complication of gastroesophageal reflux disease (GERD). However, the relationship between H. pylori infection, gastric acid secretion, and GE junction adenocarcinoma has not yet been investigated in Japan. The aim of this study was to evaluate this relationship in the Japanese population. METHODS: A total of 168 Japanese patients (RE alone: 80, short-segment BE (SSBE): 16, long-segment BE (LSBE): 20, GE junction adenocarcinoma: 12, distal early gastric cancer (EGC): 40; male/female = 106/62; mean age 61.5 yr) and 80 Japanese control subjects who had no localized lesions in the upper gastrointestinal tract (male/female = 43/37, mean age 58.1 yr) were enrolled for this study. The prevalence of H. pylori infection was determined by biopsy, the rapid urease test, and measurement of the serum H. pylori IgG antibody. Gastric acid secretion was assessed by the endoscopic gastrin test (EGT). RE was diagnosed according to the Los Angeles classification. RESULTS: The prevalence of H. pylori infection in the patients with RE alone (30%) was significantly lower than that in control subjects (71.2%). There was also a tendency for the prevalence of H. pylori infection to be lower in patients with BE (SSBE, 18.7%; LSBE, 0%) when compared to that in patients with RE alone. On the other hand, while the prevalence of H. pylori infection in patients with GE junction adenocarcinoma (58.3%) was significantly lower than that in patients with EGC (87.5%), it tended to be higher than that in patients with RE alone or BE. The mean EGT value in patients with RE alone (3.74 mEq/10 min) was significantly higher than that in control subjects (1.83). The mean EGT value in patients with BE (SSBE, 4.74; LSBE, 4.76) tended to be even higher than that in patients with RE alone. The mean EGT value in patients with GE junction adenocarcinoma (3.94) was significantly higher than that in control subjects and patients with EGC (0.67), but it was comparable to that independent of the H. pylori infection status in patients with RE alone or BE. CONCLUSION: Preservation of gastric acid secretion may be important for the development of GE junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status.

[Reflux esophagitis after H. pylori eradication].

We have reported that prevalence of H. pylori infection and grade of atrophic gastritis were significantly lower, while acid secretion was significantly greater in the patients with reflux esophagitis than those without it. We have also reported that increased gastric acid secretion after H. pylori eradication may explain a reason for developing reflux esophagitis. Therefore, H. pylori is considered to be a protective factor for the development of reflux esophagitis via the induction of gastric hyposecretion. Conversely, according to recent large population-based studies, no evidence was obtained that supports the increased frequency of heartburn symptoms or reflux oesophagitis after the eradication of H. pylori. One reason for the discrepancy may be the difference in the evaluation of gastro-esophageal reflux, another reason may be the difference in acid secretion before the clearance of H. pylori in individual subjects, because the effects of H. pylori on acid secretion vary from patient to patient.