Serodiagnosis and Bacterial Genome of Helicobacter pylori Infection.

The infection caused by Helicobacter pylori is associated with several diseases, including gastric cancer. Several methods for the diagnosis of H. pylori infection exist, including endoscopy, the urea breath test, and the fecal antigen test, which is the serum antibody titer test that is often used since it is a simple and highly sensitive test. In this context, this study aims to find the association between different antibody reactivities and the organization of bacterial genomes. Next-generation sequences were performed to determine the genome sequences of four strains of antigens with different reactivity. The search was performed on the common genes, with the homology analysis conducted using a genome ring and dot plot analysis. The two antigens of the highly reactive strains showed a high gene homology, and Western blots for CagA and VacA also showed high expression levels of proteins. In the poorly responsive antigen strains, it was found that the inversion occurred around the vacA gene in the genome. The structure of bacterial genomes might contribute to the poor reactivity exhibited by the antibodies of patients. In the future, an accurate serodiagnosis could be performed by using a strain with few gene mutations of the antigen used for the antibody titer test of H. pylori.

Risk of gastric cancer in the second decade of follow-up after Helicobacter pylori eradication.

BACKGROUND AND AIMS: Eradication of Helicobacter pylori reduces the risk of gastric cancer. In this study, we investigated the risk beyond 10 years after eradication of H. pylori. METHODS: We conducted a retrospective cohort study of 2737 patients who had yearly endoscopic follow-up after cure of H. pylori infection. For comparison of gastric cancer risk in the second decade of follow-up with that in the first decade, we calculated standardized incidence ratios (SIRs) by dividing the number of observed cases of gastric cancer in the second decade of follow-up by that of expected cases which was estimated using the incidence rate ratio of age in the first decade. RESULTS: During the follow-up for as long as 21.4 years (mean 7.1 years), gastric cancer developed in 68 patients (0.35% per year). The SIRs for diffuse-type gastric cancer was infinity (0 expected case and 4 observed cases) in patients with mild gastric mucosal atrophy and 10.9 (95% confidence interval 4.53-26.1) with moderate atrophy, whereas no significant increase of SIRs was observed in intestinal-type cancer regardless of the grade of baseline gastric atrophy or in diffuse-type cancer in patients with severe atrophy even though who had the highest risk. CONCLUSIONS: The longer the follow-up, the greater the risk of developing diffuse-type gastric cancer becomes in patients with mild-to-moderate gastric atrophy at baseline. Endoscopic surveillance should be continued beyond 10 years after cure of H. pylori irrespective of the severity of gastric atrophy.

Correction to: Risk of gastric cancer in the second decade of follow-up after Helicobacter pylori eradication.

In the original publication of the article, the figure 3 was published with errors. The corrected figure 3 should appear as in this correction.

DEC205 mediates local and systemic immune responses to Helicobacter pylori infection in humans.

Helicobacter pylori infections cause gastritis and affect systemic immune responses; however, no direct association between immune cells and stomach bacteria has yet been reported. The present study investigated DEC205-mediated phagocytosis of H. pylori and the role of DEC205-positive macrophages in the human gastric mucosa. DEC205 mediated phagocytosis of H. pylori was detected immunocytochemically in PMA-stimulated macrophages differentiated from NOMO1 cells. Expression of DEC205 mRNA in peripheral blood mononuclear cells (PBMCs) from H. pylori-infected patients was analyzed following stimulation with H. pylori cell lysate. We found that anti-DEC205 antibodies inhibited phagocytosis of H. pylori. The number of cells double-positive for DEC205 and CD14 in human gastric mucosa was higher in H. pylori-infected patients. DEC205-positive macrophages invaded the extracellular space between epithelial cells within gastric pits. In addition, DEC205 mRNA expression was upregulated in human PBMCs stimulated with H. pylori lysate. These findings suggest DEC205-expressing macrophages are important for recognition of H. pylori in human gastric mucosa, which affects systemic immunity.

Slow progression of gastric adenocarcinoma of fundic gland type: a case report.

Here we report the case of a 73-year-old male who had undergone esophagogastroduodenoscopy (EGD) at a nearby hospital or at our hospital every year since 2006. In 2013, EGD results revealed a discolored lesion, measuring 6mm in diameter, on the anterior side of the upper body in the stomach. Helicobacter pylori (HP) was eradicated in 2010, and the background mucosa around the lesion was endoscopically diagnosed as non-atrophic. We performed endoscopic biopsy of the lesion. Histological examination of the specimen confirmed gastric adenocarcinoma of the fundic gland type. Based on the findings of EGD, ultrasonic endoscopy, and upper gastrointestinal series, we diagnosed that the infiltration of the adenocarcinoma was limited to the mucosa. Hence, we performed endoscopic submucosal dissection (ESD). After ESD, the resected cancer was located in the mucosa and no invasive lesion was detected at any vessels. Therefore, complete resection was performed through ESD. Retrospectively, the lesion could be detected in the endoscopic images taken in 2006. The shape and diameter of the lesion did not seem to have significantly changed from 2006 to 2013. In this case, slow tumor progression was observed. In 2015, no new lesions in the stomach or metastatic area were detected. Here we report a rare case of gastric adenocarcinoma of the fundic gland type that showed very slow progression.

[A Study to Determine the Optimum Antigens for the Serodiagnosis of Helicobacter Pylori Infection in Japanese Patients and the Association with IgG Subclass and Gastric Cancer].

Atrophic gastritis is caused by Helicobacter pylori infection, and is involved in gastric cancer. In this study, we investigated the association with total IgG and IgG subclass antibodies using several strains isolated from Japanese in H. pylori positive and negative individuals, and gastric atrophy using measuring pepsinogen I and II levels. We found that total IgG antibody measurement using typical Japanese genotype as an antigen was available for diagnosis of H. pylori infection, whereas IgG1 and IgG2 antibodies were not for diagnosis. Furthermore, the IgG1/G2 ratio was elevated in a patient with gastric cancer. The accuracy of serodiagnosis of H. pylori infection may increase when the optimal antigens are used, and measurement IgG subclass may provide additional prediction of gastric cancer.

Seventeen-year effects of eradicating Helicobacter pylori on the prevention of gastric cancer in patients with peptic ulcer; a prospective cohort study.

BACKGROUND: We previously reported that eradication of Helicobacter pylori in our cohort of patients with peptic ulcer disease reduced their risk of developing gastric cancer to approximately one-third after a mean follow-up period of 3.4 years (up to 8.6 years). We have now followed these patients for a longer period. METHODS: A total of 1,222 consecutive patients with peptic ulcer diseases who completed more than 1-year follow-up after receiving H. pylori eradication therapy were followed with annual endoscopic surveillance for a mean of 9.9 years (as long as 17.4 years). RESULTS: H. pylori infection was judged cured in 1,030 patients (eradication-success group) but persisted in 192 (eradication-failure group) after initial eradication therapy. In the eradication-failure group, 114 patients received re-treatment at a mean of 4.4 years after the start of follow-up, and 105 of these were cured of infection. Gastric cancer developed in 21 of the 1,030 patients in the eradication-success group and in nine of the 192 in the failure group (p = 0.04). The risk of developing gastric cancer in the eradication-success group (0.21 %/year) was significantly lower than that in the failure group (0.45 %, p = 0.049). The longest interval between the initial H. pylori eradication and the occurrence of gastric cancer was 14.5 years in the eradication-success group and 13.7 years in the eradication-failure group. CONCLUSIONS: A prophylactic effect for gastric cancer persists for more than 10 years after H. pylori eradication therapy, but we should be aware that cancer can develop even after that interval.

The genetic diversity of Helicobacter pylori virulence genes is not associated with gastric atrophy progression.

Atrophy of the gastric mucosa is a precursor of intestinal-type gastric cancer, and Helicobacter pylori infection causes atrophic gastritis. The aim of this study was to determine whether the genetic diversity of H. pylori virulence genes is associated with the development and progression of gastric atrophy in humans. We isolated and cultured H. pylori strains from patients with gastric ulcer and duodenal ulcer accompanied by atrophic gastritis in background mucosa. H. pylori strains were stored at －80℃ prior to the experiments being carried out. We analyzed iceA, babA, vacA, cagA, and cagE genes by PCR. The cagA gene was analyzed through sequencing of the C-terminal region containing the EPIYA motif, which is related to tyrosine phosphorylation. Severe atrophy was observed in patients with gastric ulcer. The major phenotype of the vacA gene was s1c/m1 (93%). The cagA gene was detected in all strains. The cagE gene was not detected in 2 and 5 strains from the mild cases and severe cases, respectively. The major cagA EPIYA motif, which is amino acids repeat in the C terminus, was the A-B-D type (44 of 58 strains). The virulence genes were not statistically associated with the severity of atrophy in the background gastric mucosa in humans. Not only identification of bacterial virulence factors but also studies of the host response will be necessary to investigate the progression of gastric atrophy and subsequent cancer development in humans.

Multi-center randomized controlled study to establish the standard third-line regimen for Helicobacter pylori eradication in Japan.

BACKGROUNDS: The present study sought to establish a standard third-line eradication regimen for Helicobacter pylori in Japan. METHODS: Subjects were 204 patients with H. pylori infection in whom the standard Japanese first- and second-line eradication therapies had proven unsuccessful. Patients were randomly assigned to one of the following third-line eradication therapy groups: (1) LA group: lansoprazole (LPZ) 30 mg 4 times a day (qid) + amoxicillin (AMPC) 500 mg qid for two weeks; (2) LAL group: LPZ 30 mg twice a day (bid) + AMPC 750 mg bid + levofloxacin (LVFX) 300 mg bid for one week; (3) LAS group: LPZ 30 mg bid + AMPC 750 mg bid + sitafloxacin (STFX) 100 mg bid for one week. Patients for whom these therapies failed underwent a crossover fourth-line eradication regimen. Drug sensitivity was also tested for AMPC, clarithromycin (CAM), MNZ, LVFX, and STFX. RESULTS: Drug resistance rates prior to third-line eradication therapy were 86.4 % for CAM, 71.3 % for MNZ, 57.0 % for LVFX, 8.2 % for AMPC, and 7.7 % for STFX. Intention-to-treat analysis of third-line eradication therapy eradication rates showed a significantly higher rate in the LAS group (70.0 %) compared with the LA group (54.3 %; p < 0.05) and the LAL group (43.1 %; p < 0.001). The significantly lower rate in the LAL group than the LAS group was caused by bacterial resistance to LVFX. CONCLUSIONS: The findings suggest that triple therapy with PPI, AMPC, and STFX for one week would be an effective standard third-line eradication regimen for H. pylori in Japan.

Reinfection rate of Helicobacter pylori after eradication treatment: a long-term prospective study in Japan.

BACKGROUND: We previously reported that the reinfection rate with Helicobacter pylori in Japan was low despite a high prevalence of infection. In the present study, we extended our previous work to more accurately determine the reinfection rate. METHODS: We enrolled 1625 patients (219 women and 1406 men, mean age 50.8 years) who had received H. pylori eradication therapy. After documentation of eradication, bacterial culture and urea breath test were carried out yearly. H. pylori strains were analyzed by using random amplification of polymorphic DNA fingerprinting. RESULTS: A total of 1609 patients were followed for up to 12.5 years (mean 4.7 years); H. pylori became re-positive in 26 patients. In 13 of the 26 patients, H. pylori became positive at the first-year follow up. Stored H. pylori isolates were available for analysis from ten of the 13 patients; four of the isolates were genetically different from the initial strain, but the other six were identical to the initial strain. In the other 13 patients, H. pylori became positive at later follow up (mean 4.8 years; range 1.8-8.0 years). In all of the four of these patients whose isolates could be analyzed, the H. pylori strains were different from the initial strain. Assuming that reinfection occurred in the four patients positive for different strains of H. pylori at the first-year follow up and in the 13 positive at later follow up, the reinfection rate was 0.22% per year. CONCLUSIONS: When probable recrudescence (H. pylori positivity with identical strains) was excluded, the reinfection rate of H. pylori in this Japanese population was very low, but we note that reinfection can occur over many years.

[Helicobacter pylori eradication therapy does not prevent gastric cancer development in all patients].

We previously reported that eradication of Helicobacter pylori reduced the risk of gastric cancer developing in patients with peptic ulcer diseases. In the present study, we followed up with our patient group to investigate the occurrences and clinical features of gastric cancers that developed after cure of the infection. Prospective post-eradication evaluations were conducted on 1, 674 consecutive patients who had received successful H. pylori eradication therapy. The patients underwent endoscopic examination before eradication therapy to test for peptic ulcers, background gastric mucosal atrophy, and H. pylori infection. After confirmation of the cure of infection, the annual follow-up endoscopy was performed. The patients were followed up to more than 10 years. During the follow-up, their risk of developing gastric cancer after the cure of infection was almost the same as we reported previously. There was still a risk of developing gastric cancer of both the intestinal and diffuse types. The grade of gastric mucosal atrophy present before receiving eradication therapy was closely related to the development of gastric cancer after eradication of H. pylori. The stage of most gastric cancer was at the early TNM stage, but advanced cancer was observed in patients who skipped regular endoscopic surveillance. H. pylori eradication therapy does not prevent gastric cancer development in all infected patients. Thus, it is important to inform patients about the risk of gastric cancer after eradication therapy and to offer them surveillance endoscopy.

The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori.

BACKGROUND: We previously reported that eradication of Helicobacter pylori reduced the risk of developing gastric cancer in patients with peptic ulcer diseases. In the present study, we further followed up our patient group to investigate the occurrence and clinical features of gastric cancers that developed after cure of the infection. METHODS: Prospective post-eradication evaluations were conducted on 1674 consecutive patients who had received successful H. pylori eradication therapy. The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers, background gastric mucosal atrophy, and H. pylori infection. After confirmation of cure of the infection, follow-up endoscopy was performed yearly. RESULTS: The patients were followed for up to 14.1 years (a mean of 5.6 years). During the follow-up, gastric cancer developed in 28 of the 1674 patients as long as 13.7 years after the cure of H. pylori infection. The risk of developing gastric cancer was 0.30% per year. Histologically, 16 of the gastric cancers were the intestinal type and 12 were the diffuse type; the risk of each cancer type was 0.17 and 0.13% per year, respectively. There was no significant inflammatory cell infiltration in the background gastric mucosa at the time the cancers were recognized. CONCLUSION: There is a risk of developing gastric cancer of both the intestinal and diffuse types even after the cure of H. pylori infection and extinction of gastric inflammation. It is important to inform patients about the risk of gastric cancer after eradication therapy and offer them surveillance endoscopy.

Helicobacter pylori eradication may induce de novo, but transient and mild, reflux esophagitis: Prospective endoscopic evaluation.

BACKGROUNDS AND AIM: The effect on reflux esophagitis of eradicating Helicobacter pylori is variable and not fully defined. We previously reported that in patients who have reflux esophagitis associated with duodenal ulcer, a significant improvement in the pre-existing reflux esophagitis occurred after H. pylori was eradicated. In the present study, we asked whether H. pylori eradication leads to de novo development of reflux esophagitis in peptic ulcer patients. METHODS: Prospective post-eradication evaluations were conducted in 1195 H. pylori-positive patients with peptic ulcer diseases who were confirmed not to have reflux esophagitis by endoscopic examination before eradication therapy. After eradication therapy, endoscopy and a urea breath test were performed yearly. RESULTS: A total of 1187 patients were followed for up to 10.0 years (a mean of 3.6 years). Reflux esophagitis developed in 279 of 1000 patients cured of infection and in 26 of 187 patients who had persistent infection (P < 0.0001, Fisher's exact test). The esophagitis was mild (Los Angeles grade A) in most patients, transient in approximately one-half, and rarely necessitated long-term medication for the condition. Cure of infection, alcohol consumption, younger age, and high body mass index were identified as significant factors for the risk of developing non-transient reflux esophagitis. CONCLUSIONS: Cure of H. pylori infection may increase the risk of developing reflux esophagitis in patients with peptic ulcer, but the esophagitis is mostly mild and transient, and long-term medication is rarely required. Thus, H. pylori eradication therapy need not be withheld for fear of provoking reflux esophagitis.

A better cure rate with 800 mg than with 400 mg clarithromycin regimens in one-week triple therapy for Helicobacter pylori infection in cigarette-smoking peptic ulcer patients.

BACKGROUND/AIMS: In Helicobacter pylori eradication therapy, using a proton pump inhibitor plus amoxicillin and clarithromycin (PPI/AC regimen), the impact of the clarithromycin dose and smoking on efficacy is conflicting. Here, we compared the efficacy of 400 and 800 mg of clarithromycin in the regimen in relation to smoking in patients with peptic ulcer disease. METHODS: We studied 601 H. pylori-positive patients with peptic ulcer disease who had received amoxicillin 750 mg and clarithromycin 200 or 400 mg together with lansoprazole 30 mg b.i.d. RESULTS: 305 patients were treated with a regimen containing 400 mg of clarithromycin (C400 group), and 296 patients with a regimen containing 800 mg (C800 group). Overall cure rates between the two groups were not significantly different, but the cure rate in the C800 group was significantly better than that in the C400 group among patients infected with clarithromycin-sensitive strains (p = 0.03). This difference could be attributed to differences among smokers versus non-smokers: the cure rate among smokers in the C800 group (91.0%) was better than that in the C400 group (80.0%, p = 0.003). CONCLUSIONS: 800 mg of clarithromycin is recommended in the PPI/AC regimen for patients who smoke and are infected with clarithromycin-sensitive H. pylori.

Baseline gastric mucosal atrophy is a risk factor associated with the development of gastric cancer after Helicobacter pylori eradication therapy in patients with peptic ulcer diseases.

BACKGROUND: We previously reported that eradication of Helicobacter pylori could reduce the risk of developing gastric cancer in patients with peptic ulcer diseases. In the present study, we further followed up our patient groups to identify factors associated with the development of gastric cancer. METHODS: Prospective posteradication evaluations were conducted in 1342 consecutive patients (1191 men and 151 women; mean age, 50 years) with peptic ulcer disease who had received H. pylori eradication therapy. The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers, background gastric mucosa, and H. pylori infection. After confirmation of eradication, follow-up endoscopy was performed yearly. RESULTS: A total of 1131 patients were followed for up to 9.5 years (mean, 3.9 years). Gastric cancer developed in 9 of 953 patients cured of infection and in 4 of 178 who had persistent infection (P=0.04). The risk of developing gastric cancer after receiving H. pylori eradication therapy was increased according to the grade of baseline gastric mucosal atrophy (P=0.01). In patients with peptic ulcer diseases, persistent infection of H. pylori (hazard ratio, 3.9; P=0.03), the grade of baseline gastric mucosal atrophy (3.3, P=0.01) and age (2.0, P=0.04) were identified as significant risk factors for developing gastric cancer. CONCLUSIONS: The grade of gastric atrophy was closely related to the development of gastric cancer after receiving H. pylori eradication therapy. Thus, eradication of H. pylori before the significant expansion of atrophy is most beneficial to prevent gastric cancer.