Antimicrobial-resistant Helicobacter pylori in Japan: Report of nationwide surveillance for 2018-2020.

BACKGROUND: Antimicrobial therapy is necessary to eradicate Helicobacter pylori infection. The emergence of antimicrobial-resistant bacteria poses a threat to continued treatment with antimicrobial agents. For those who prescribe antimicrobial therapy, it is necessary to constantly monitor the emergence of antimicrobial-resistant bacteria. METHOD: H. pylori clinical isolates were collected in Japan from August 2018 to December 2020 for antimicrobial susceptibility testing. The agar dilution method was used for the determination of the minimum inhibitory concentration (MIC) of clarithromycin (CLR), amoxicillin (AMX), metronidazole (MNZ), and sitafloxacin (STX). RESULTS: MICs for 938 H. pylori isolates were examined. The primary resistance rates of H. pylori clinical isolates for CLR, AMX, MNZ, and STX in Japan were 35.5%, 2.7%, 4.2%, and 27.6%, respectively. The primary resistance rates for CLR, AMX, and MNZ were significantly higher than those of the 2002-2005 isolates. The resistance rate for CLR was significantly higher in females (males: 30.7%, females: 41.5%, p < 0.001) and higher in the ≤29 years age group (54.8%) than in the other age groups, although there were no significant differences (p = 0.104). The MNZ resistance rate was significantly higher in the ≤29 years age group than in the other age groups (p = 0.004). The resistance rate for STX increased with age, but a significant difference was only seen between the 30-49 years age group and the ≥70 years age group (p < 0.001), and the resistance rate was significantly higher in strains isolated in the Kyushu region than in the other regions (p < 0.001). CONCLUSIONS: The primary resistance rates for CLR, AMX, and MNZ of H. pylori clinical isolates in Japan were higher than those of the 2002-2005 isolates. Continuous surveillance is needed to monitor the trends in antimicrobial-resistant H. pylori.

Efficacy of the Castor Oil-Filled Capsule Method as Preparation for Colon Capsule Endoscopy.

BACKGROUND: Colon capsule endoscopy (CCE) is useful as an alternative examination for patients in whom colonoscopy is difficult. The Japanese Association for Capsule Endoscopy has published a recommended regimen for CCE using castor oil, which is becoming a standard examination method for CCE in Japan. However, castor oil has an unpleasant flavor. Therefore, patient acceptance is not good. OBJECTIVES: The aims were to develop a castor oil-filled capsule and evaluate its feasibility and patient acceptance in a retrospective, comparative study. METHOD: A dissolution study of pig-derived gelatin capsules filled with castor oil was performed using artificial gastric juice. The CCE excretion rates within battery lifetime, CCE examination times, endoscopic colonic cleansing levels, and patient acceptability between CCE boosters with a castor oil-filled capsule and without castor oil were retrospectively compared using medical information, clinical data, and endoscopic findings at Takada Chuo Hospital from September 2016 to August 2019. RESULTS: The castor oil-filled capsules were completely disintegrated at approximately 1-3 min in artificial gastric juice. Bowel preparation with oil-filled capsules and without castor oil was performed in 27 and 24 patients, respectively. CCE excretion rates within battery life were 100% and 91.7% (p = 0.217), small bowel transit times were 115 min and 143 min (p = 0.046), colon transit times were 168 min and 148 min (p = 0.733), and adequate colonic cleansing rates were 85.2% and 86.3% (p = 1.000) in patients using bowel preparation with and without oil-filled capsules, respectively. Regarding acceptance, the taste was not problematic in 85.2%, and tolerability for the next CCE was 96.3%. CONCLUSIONS: CCE using a castor oil-filled capsule method achieved high examination performance and sufficient patient tolerability.

Differences in clinical features and morphology between differentiated and undifferentiated gastric cancer after Helicobacter pylori eradication.

BACKGROUND/AIMS: Although undifferentiated gastric cancer (UGC) diagnosed after Helicobacter pylori eradication (HPE) carries a poor prognosis, characteristics of post-HPE UGC have not been evaluated in detail because of its low incidence. Therefore, we compared the clinicopathologic characteristics of UGC and differentiated gastric cancers (DGC) diagnosed after successful HPE. METHODS: GC lesions from patients who had successfully completed HPE and who had undergone upper gastrointestinal endoscopy between January 2004 and March 2016 were analyzed. Tumors were divided into DGC and UGC groups. Clinicopathologic factors of background and tumor characteristics were compared using univariate and multiple logistic analyses. RESULTS: A total of 129 tumors from 115 patients were evaluated; 113 tumors were in the DGC group and 16 in the UGC group. Depressed-type tumors (P = 0.024) and sub-submucosal invasion (P<0.001) were significantly higher in the UGC group. The UGC group had larger tumor diameters (25.9±7.3 mm) than the DGC group (13.2±10.2 mm) (P<0.001). Multivariate analysis showed that female sex (odds ratio [OR] 3.24, 95%CI:1.02-10.37; P = 0.047) and absent follow-up (OR 4.99, 95%CI:1.60-15.57; P = 0.006) were significant independent risk factors for UGC. The DGC group showed a gradually decreasing temporal trend by trend test (P = 0.015), while the UGC group showed a relatively constant incidence over time, although the number of cases was small. CONCLUSION: UGC was diagnosed even after long time spans following HPE, although the number of cases was small. Female sex, and especially absent follow-up, were risks for post-HPE UGC, suggesting that diligent long-term follow-up after HPE is essential.

Efficient Establishment of Bile-Derived Organoids From Biliary Cancer Patients.

Patient-derived tumor organoids have considerable potential as an in vitro diagnostic tool for drug susceptibility testing. In the present study, we investigated whether bile collected for diagnostic purposes could be a potential source for the establishment of biliary cancer organoids. Among 68 cases of biliary cancer, we successfully generated 60 bile-derived organoids (BDOs) from individual patients. Consistent with previous reports that described biliary cancer organoids from surgical tissues, the BDOs showed diverse morphologies such as simple cysts, multiloculated cysts, thick capsulated cysts, and solid masses. They also harbored mutations in KRAS and TP53 at frequencies of 15% and 55%, respectively. To enrich the cancer organoids by removing contaminated noncancerous components of BDOs, we attempted to verify the effectiveness of 3 different procedures, including repeat passage, xenografting, and selection with an MDM2 inhibitor for TP53 mutation-harboring BDOs. By monitoring the sequence and expression of mutated TP53, we found that all these procedures successfully enriched the cancer organoids. Our data suggest that BDOs can be established with minimal invasiveness from almost all patients with biliary cancers, including inoperable cases. Thus, despite some limitations with respect to the characterization of BDOs and methods for the enrichment of cancer cell-derived organoids, our data suggest that BDOs could have potential applications in personalized medicine.

Comparison of the improvement in gastric mucosal tissue after Helicobacter pylori eradication between young and elderly people.

BACKGROUND AND STUDY AIMS: Helicobacter pylori (H. pylori) infection has been clearly shown to be a cause of gastric cancer, and the incidence of gastric cancer has been shown to decrease with eradication. However, few reports have described the utility of eradication therapy in elderly people. Thus, an investigation focusing on how much actual histological improvement is obtained with eradication therapy in elderly people was conducted. PATIENTS AND METHODS: This was a retrospective study conducted using medical information of patients diagnosed with H. pylori-associated gastritis and who underwent eradication therapy. The histological improvement was assessed based on changes in the atrophy and intestinal metaplasia scores of the Updated Sydney system from before to after eradication. We investigated the rates of histological improvement in atrophy and intestinal metaplasia one year after and long term more than five years after H. pylori eradication in an elderly group and a younger group. RESULTS: This study included 221 patients (elderly group 123, younger group 98). In histological atrophy, higher rates of improvement were seen in the corpus than in the antrum, and the rates of cure in the antrum were lower in elderly group than in younger group (p = 0.0282). With regard to intestinal metaplasia, the rates of improvement in the antrum were lower in elderly group than in younger. In long term observation, although the rates of cure in the antrum were lower in elderly, improvements were seen in atrophy scores in most of the patients and intestinal metaplasia scores in about half of patients. CONCLUSION: Though there is more obvious improvement in the gastric mucosa when H. pylori eradication therapy is performed at a young age, some mucosal improvement can be expected in about half of patients after eradication, even in elderly people.

Pancreatic cancer with pseudoaneurysm after duckbill-shaped anti-reflux metal stent placement: A case report.

A 74-year-old man was diagnosed with unresectable pancreatic cancer with obstructive jaundice. Chemotherapy with gemcitabine and nab-paclitaxel was initiated after placement of a duckbill-shaped anti-reflux metal stent (D-ARMS). A period of 1 month after D-ARMS placement, the patient developed hematemesis and entered severe shock following emergency admission for further evaluation. Contrast-enhanced computed tomography revealed a pseudoaneurysm in the gastroduodenal artery, coincident with the site of D-ARMS placement, and bleeding from the same site was diagnosed. Angiography was performed, and the pseudoaneurysm was successfully treated by transcatheter arterial embolization using coils. The patient was subsequently discharged from hospital and experienced no further bleeding until his death due to an aggravation of the pancreatic cancer after 2 months. We report a case of pancreatic cancer with pseudoaneurysm after D-ARMS placement.

Acute Cholecystitis Associated with Eosinophilic Granulomatosis with Polyangiitis That Responded to Glucocorticoid Therapy.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic disorder characterized by tissue eosinophilic infiltration and vasculitis. Although EGPA causes multiple organ damage, it causes cholecystitis less frequently. We herein report a case of acute cholecystitis associated with EGPA in which successful treatment with glucocorticoid therapy allowed surgery to be avoided. EGPA can present as acute cholecystitis. It is important not to overlook acute cholecystitis associated with EGPA in patients with abdominal pain with peripheral eosinophilia. Furthermore, in cases of mild cholecystitis associated with EGPA that are diagnosed preoperatively, cholecystectomy might be avoided with conservative glucocorticoid treatment.

Potential association of eEF1A dimethylation at lysine 55 in the basal area of Helicobacter pylori-eradicated gastric mucosa with the risk of gastric cancer: a retrospective observational study.

BACKGROUND: Although eradication therapy for chronic Helicobacter pylori (H. pylori) reduces the risk of gastric cancer (GC), its effectiveness is not complete. Therefore, it is also critically important to identifying those patients who remain at high risk after H. pylori eradication therapy. Accumulation of protein methylation is strongly implicated in cancer, and recent study showed that dimethylation of eEF1A lysine 55 (eEF1AK55me2) promotes carcinogenesis in vivo. We aimed to investigate the relationship between eEF1A dimethylation and H. pylori status, efficacy of eradication therapy, and GC risk in H. pylori-eradicated mucosa, and to reveal the potential downstream molecules of eEF1A dimethylation. METHODS: Records of 115 patients (11 H. pylori-negative, 29 H. pylori-positive, 75 post-eradication patients) who underwent upper gastrointestinal endoscopy were retrospectively reviewed. The eEF1A dimethyl level was evaluated in each functional cell type of gastric mucosa by immunofluorescent staining. We also investigated the relationship between eEF1AK55me2 downregulation by CRISPR/Cas9 mediated deletion of Mettl13, which is known as a dimethyltransferase of eEF1AK55me2. RESULTS: The level of eEF1A dimethylation significantly increased in the surface and basal areas of H. pylori-positive mucosa compared with the negative mucosa (surface, p = 0.0031; basal, p = 0.0036, respectively). The eEF1A dimethyl-levels in the surface area were significantly reduced by eradication therapy (p = 0.005), but those in the basal area were maintained even after eradication therapy. Multivariate analysis revealed that high dimethylation of eEF1A in the basal area of the mucosa was the independent factor related to GC incidence (odds ratio = 3.6611, 95% confidence interval = 1.0350-12.949, p = 0.0441). We also showed the relationship between eEF1A dimethylation and expressions of reprogramming factors, Oct4 and Nanog, by immunohistochemistry and in vitro genome editing experiments. CONCLUSIONS: The results indicated that H. pylori infection induced eEF1A dimethylation in gastric mucosa. The accumulation of dimethyl-eEF1A in the basal area of the mucosa might contribute to GC risk via regulation of reprograming factors in H. pylori eradicated-gastric mucosa.

Analysis of long-term serological and histological changes after eradication of Helicobacter pylori.

Stratification of gastric cancer risk by measuring serological biomarkers is useful for screening of gastric cancer. However, this method has problem such as overlooking past infected patients. We aimed to evaluate the association between Helicobacter pylori infection status and serological biomarkers. We divided 5,268 patients according to Helicobacter pylori infection status and past infected patients were divided into 12 groups according to time elapsed since eradication. We analyzed mean serum H. pylori immunoglobulin G antibody, pepsinogen titers, histological and endoscopic atrophy score of each group. Mean H. pylori immunoglobulin G antibody showed a decreasing tendency, there was no significant difference from the uninfected group at 11 years after eradication (p = 0.19). PGI, PGII decreased in short term after eradication. However, both PGI and PGII gradually increased as long-term changes after eradication, became comparable to those in the uninfected group (p = 0.41, p = 0.37, respectively). Histological atrophy improved gradually, became equivalent to uninfected group. Endoscopic atrophy score did not improve for long term after eradication. In conclusion, patients with long term after eradication reach the uninfected condition serologically, histologically. Endoscopic assessment of gastric mucosal atrophy may be useful for accurate assessment of gastric cancer risk.

Clinicopathological characteristics of pancreatic acinar cell metaplasia associated with Helicobacter pylori infection.

BACKGROUND: Pancreatic acinar cell metaplasia (PACM) has been rarely reported in the gastric mucosa. In the present study, we aimed to elucidate the clinical and pathological characteristics of PACM associated with Helicobacter pylori (H. pylori). METHOD: 5930 patients who underwent five- or two-point gastric biopsy according to the updated Sydney system (USS) by upper gastrointestinal endoscopy were enrolled. The patients were categorized into current H. pylori infection (CHI), post-H. pylori eradication (PHE), and non-H. pylori infection (NHI) groups according to the H. pylori infection status, and the frequency and location of PACM were compared. Additionally, a case-control study was performed to compare the USS scores between patients with CHI and PACM and those with CHI but not PACM. RESULT: The frequencies of PACM were 0.49% (10/2039), 0.75% (25/3332), and 0% (0/559) in the CHI, PHE, and NHI groups, respectively. PACM was found in the greater curvature of the antrum in 33 of the 35 patients with PACM. Among the patients with CHI, the inflammation scores in the greater curvature of the antrum and the greater curvature of the corpus were lower in patients with PACM than in those without PACM. CONCLUSION: Although rarely reported in the gastric mucosa, PACM was closely related to H. pylori infection, especially in the antrum, and was associated with relatively mild inflammation.

Changes in Gastric Mucosal Glycosylation Before and After Helicobacter pylori Eradication Using Lectin Microarray Analysis.

BACKGROUND: Glycosylation is a common post-translational modification, and it has been reported that alterations in the glycosylation patterns on cells are related to cell proliferation, differentiation, tissue adhesion, and carcinogenesis. This study aimed to investigate the relationship between Helicobacter pylori infection and gastric mucosal glycosylation using a lectin microarray system. METHODS: Gastric mucosal samples were obtained from 10 Helicobacter pylori-non-infected patients, 10 H. pylori-infected patients, and 10 after H. pylori-eradicated patients who underwent gastric mucosal biopsy by endoscopy in our institute. The gastric gland cells which were isolated from formalin-fixed, paraffin-embedded gastric mucosal biopsy samples using laser capture microdissection were used for lectin microarray to obtain lectin-glycan interaction values. RESULTS: Comparison of the lectin-glycan interaction values before and after eradication in the same patients showed significant increases for Ricinus communis agglutinin 120, Trichosanthes japonica agglutinin II, Euonymus europaeus lectin, jacalin, Amaranthus caudatus agglutinin, and Maclura pomifera agglutinin and significant decreases for Urtica dioica agglutinin, Lycopersicon esculentum lectin, Ulex europaeus agglutinin, Sambucus nigra agglutinin, Sambucus sieboldiana agglutinin, and Trichosanthes japonica agglutinin I. Furthermore, jacalin and MPA in the gastric antrum were significantly decreased with H. pylori infection compared with the without infection group and improved to the levels seen without infection as a result of eradication. Lycopersicon esculentum lectin, Sambucus nigra agglutinin, Sambucus sieboldiana agglutinin, and Trichosanthes japonica agglutinin I in the gastric body were significantly increased with H. pylori infection and improved to the level seen without infection as a result of eradication. CONCLUSION: H. pylori infection changes the lectin binding state which is related to various cancers on the gastric mucosal cell. Furthermore, those changes are reversible by H. pylori eradication.

Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates.

Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as Helicobacter pylori, which causes gastric cancer. We conducted a small-sample GWAS (125 gastric cancer cases and 115 controls) followed by prediction of gastric cancer and control (duodenal ulcer) H. pylori strains. We identified 11 single nucleotide polymorphisms (eight amino acid changes) and three DNA motifs that, combined, allowed effective disease discrimination. They were often informative of the underlying molecular mechanisms, such as electric charge alteration at the ligand-binding pocket, alteration in subunit interaction, and mode-switching of DNA methylation. We also identified three novel virulence factors/oncoprotein candidates. These results provide both defined targets for further informatic and experimental analyses to gain insights into gastric cancer pathogenesis and a basis for identifying a set of biomarkers for distinguishing these H. pylori-related diseases.

Immunohistochemical differences in gastric mucosal damage between nodular and non-nodular gastritis caused by Helicobacter pylori infection.

In this study, the level of cell damage were analyzed immuno-histochemically to clarify the association between nodular gastritis and undifferentiated gastric cancer. Thirty patients of nodular gastritis were enrolled as the nodular gastritis group. Thirty patients of non-nodular gastritis were enrolled as the control group. They were evaluated according to the updated Sydney system and used for immunohistochemical staining (p53, Ki-67, E-cadherin, and 8-OHdG). The scores based on the updated Sydney system were significantly higher in the nodular group than in the non-nodular group for histologically assessed inflammation and activity in the gastric corpus (1.91 ±â€„0.77 vs 1.58 ±â€„0.60, p = 0.049, 0.83 ±â€„0.81 vs 0.44 ±â€„0.64, p = 0.032). On immunostaining, the detection of E-cadherin was lower in the nodular group for both the antrum (1.0 ±â€„0.62 vs 1.47 ±â€„0.85, p = 0.047) and the corpus (1.16 ±â€„0.81 vs 1.48 ±â€„0.71, p = 0.043) and the p53 labeling index of the gastric corpus was higher in the nodular group than in the non-nodular group (3.06 ±â€„1.94 vs 2.03 ±â€„1.99, p = 0.015). Nodular gastritis showed significant severe inflammation and immunohistochemical cell damage compared with non-nodular gastritis. These findings may play an important role in the oncogenesis of undifferentiated gastric cancer in nodular gastritis.

Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells.

Mutations in RAS or BRAF are associated with poor prognosis and resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer (CRC). Despite their common ability to activate downstream genes such as MEK and ERK, the therapeutic benefit of MEK inhibitors for patients with RAS/BRAF mutant CRC is limited, highlighting the need for biomarkers to predict the efficacy of MEK inhibition. Previously, we reported that a change in phosphorylation of ribosomal protein S6 (pS6) after MEK inhibition was significantly associated with sensitivity to MEK inhibition in gastric cancer cells. Here, we investigated the value of the response in pS6 for predicting the efficacy of trametinib, a MEK inhibitor, in patients with RAS/BRAF mutant CRC using patient-derived CRC organoids. We found that a subset of CRC cell lines and organoids were sensitive to trametinib. The change in phosphorylated ERK, a downstream molecule of the RAS/RAF/MEK pathway, was not significantly associated with trametinib sensitivity. On the other hand, only those with sensitivity showed a reduction of pS6 levels in response to trametinib. The change in pS6 after trametinib treatment was detectable by Western blotting, immunohistochemistry or immunocytochemistry. We also demonstrated an impact of MEK inhibition on pS6 in vivo using a xenograft model. Our data suggest that, in combination with patient-derived organoids, immunostaining-based detection of pS6 could be useful for prediction of trametinib sensitivity.

A case of dengue fever that should be considered as imported infectious disease with digestive symptoms.

Patients with dengue fever usually present with fever and rash, but non-specific symptoms such as headache, myalgia, arthralgia, and digestive symptoms are sometimes seen. We report a case of dengue fever with digestive symptoms in a patient who traveled to Indonesia. A 35-year-old man presented with fever, diarrhea, headache, and arthralgia. He later developed generalized rash. Dengue fever was clinically suspected from the travel history and confirmed by laboratory tests. He tested positive for anti-dengue virus antibodies, so dengue fever was diagnosed. Dengue fever should be included in the differential diagnosis of patients with digestive symptoms after returning to Japan.

Gastric mucosal changes, and sex differences therein, after Helicobacter pylori eradication: A long-term prospective follow-up study.

BACKGROUND AND AIM: Improvement of atrophic gastritis and intestinal metaplasia (IM) is considered to reduce the gastric cancer risk, but whether it can be achieved by H. pylori eradication (HPE) remains controversial. To evaluate the effect of HPE, we observed the gastric mucosa for up to17 years after HPE and sex differences in gastric mucosa. METHODS: In total, 172 patients (94 males, 78 females) with HPE were enrolled. Annual histological evaluations were performed for up to 17 years. The grades of mononuclear cells, neutrophils, atrophy, IM in the antrum and corpus were evaluated using the updated Sydney system. RESULTS: Relative to the pre-HPE period, atrophy had improved significantly 1 year after HPE in the antrum (1.50 ± 0.75 vs. 1.21 ± 1.25, P < 0.01) and corpus (0.59 ± 0.75 vs. 0.18 ± 0.52, P < 0.05). IM showed no significant change during 17 years after HPE at either biopsy site. Atrophy scores did not differ significantly between males and females. IM scores were significantly higher in males than in females before eradication (antrum, 0.67 ± 0.94 vs. 0.44 ± 0.77, P = 0.003, corpus, 0.20 ± 0.62 vs. 0.047 ± 0.21, P = 0.0027) and at most observation timepoints. CONCLUSIONS: During 17 years after HPE, atrophy, but not IM, improved significantly at the greater curvatures of the antrum and corpus. IM was significantly more severe in males than in females. Careful follow-up after HPE based on sex differences in gastric mucosal characteristics is important.

Evidence-based clinical practice guidelines for peptic ulcer disease 2020.

The Japanese Society of Gastroenterology (JSGE) revised the third edition of evidence-based clinical practice guidelines for peptic ulcer disease in 2020 and created an English version. The revised guidelines consist of nine items: epidemiology, hemorrhagic gastric and duodenal ulcers, Helicobacter pylori (H. pylori) eradication therapy, non-eradication therapy, drug-induced ulcers, non-H. pylori, and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant gastric ulcers, surgical treatment, and conservative therapy for perforation and stenosis. Therapeutic algorithms for the treatment of peptic ulcers differ based on ulcer complications. In patients with NSAID-induced ulcers, NSAIDs are discontinued and anti-ulcer therapy is administered. If NSAIDs cannot be discontinued, the ulcer is treated with proton pump inhibitors (PPIs). Vonoprazan (VPZ) with antibiotics is recommended as the first-line treatment for H. pylori eradication, and PPIs or VPZ with antibiotics is recommended as a second-line therapy. Patients who do not use NSAIDs and are H. pylori negative are considered to have idiopathic peptic ulcers. Algorithms for the prevention of NSAID- and low-dose aspirin (LDA)-related ulcers are presented in this guideline. These algorithms differ based on the concomitant use of LDA or NSAIDs and ulcer history or hemorrhagic ulcer history. In patients with a history of ulcers receiving NSAID therapy, PPIs with or without celecoxib are recommended and the administration of VPZ is suggested for the prevention of ulcer recurrence. In patients with a history of ulcers receiving LDA therapy, PPIs or VPZ are recommended and the administration of a histamine 2-receptor antagonist is suggested for the prevention of ulcer recurrence.