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.

Clarithromycin Versus Metronidazole in First-Line Helicobacter Pylori Triple Eradication Therapy Based on Resistance to Antimicrobial Agents: Meta-Analysis.

BACKGROUND: International treatment guidelines for Helicobacter pylori infection recommend a proton pump inhibitor (PPI)/amoxicillin/clarithromycin (CAM) regimen (PAC) or PPI/amoxicillin/metronidazole (MNZ) regimen (PAM) as first-line therapy based on culture and sensitivity testing. As incidence rates of antimicrobial agent-resistant strains are changing year by year, it is important to reevaluate the efficacy of eradication regimens. We performed a meta-analysis to evaluate the efficacy and safety of PAC and PAM based on different locations categorized by the reported incidence of CAM- and MNZ-resistant strains. METHODS: Randomized control trials (RCTs) comparing eradication rates between PAC and PAM first-line treatment up to December 2018 were included. We divided RCTs into four groups based on resistance to CAM (< 15% or ≥ 15%) and MNZ (< 15% or ≥ 15%). RESULTS: A total of 27 studies (4825 patients) were included. Overall eradication rates between PAC and PAM were similar (74.8% and 72.5%, relative risk (RR): 1.13, 95% confidence interval (CI): 0.91-1.39, P = 0.27) in the intention-to-treat analysis. In areas with low MNZ- and high CAM-resistance rates, PAM had a significantly higher eradication rate than PAC (92.5% vs. 70.8%, RR: 0.29, 95% CI: 0.13-0.68). In areas with high MNZ- and low CAM-resistance rates, the eradication rate with PAC was only 72.9%. CONCLUSIONS: Overall eradication rates with PAC and PAM were equivalent worldwide. In low MNZ-resistance areas, PAM may be recommended as first-line therapy. However, the efficacy of PAC may be insufficient, irrespective of susceptibility to CAM.

Guidelines for the management of Helicobacter pylori infection in Japan: 2016 Revised Edition.

BACKGROUND: Since "Helicobacter pylori (H. pylori) infection" was set as the indication in the Japanese Society for Helicobacter Research (JSHR) Guidelines 2009, eradication treatment for H. pylori gastritis is covered under insurance since 2013 in Japan, and the number of H. pylori eradication has rapidly increased. Under such circumstances, JSHR has made the third revision to the "Guidelines for diagnosis and treatment of H. pylori infection" for the first time in 7 years. METHODS: The Guideline Committee held 10 meetings. Articles published between the establishment of the 2009 Guidelines and March 2016 were reviewed and classified according to the evidence level; the statements were revised on the basis of this review. After inviting public comments, the revised statements were finalized using the Delphi method. RESULTS: There was no change in the basic policy that H. pylori infectious disease is an indication for eradication. Other diseases presumed to be associated with H. pylori infection were added as indications. Serum pepsinogen level, endoscopic examination, and X-ray examination were added to the diagnostic methods. The effects of 1-week triple therapy consisting of potassium-competitive acid blocker (P-CAB), amoxicillin, and clarithromycin have improved, and high eradication rates can also be expected with proton pump inhibitors (PPI) or P-CAB combined with amoxicillin and metronidazole. If the susceptibility test is not performed, the triple PPI or P-CAB/amoxicillin/metronidazole therapy should be chosen, because the PPI/amoxicillin/metronidazole combination demonstrated a significantly higher eradication rate than PPI/amoxicillin/clarithromycin. In the proposal for gastric cancer prevention, we divided gastric cancer prevention measures by age from adolescent to elderly, who are at an increased gastric cancer risk, and presented measures for gastric cancer prevention primarily based on H. pylori eradication. CONCLUSION: We expect the revised guidelines to facilitate appropriate interventions for patients with H. pylori infection and accomplish its eradication and prevention of gastric cancer.

Vonoprazan-based triple therapy is non-inferior to susceptibility-guided proton pump inhibitor-based triple therapy for Helicobacter pylori eradication.

BACKGROUND: All Helicobacter pylori-infected patients are recommended for eradication with an appropriate regimen in each geographic area. The choice of the therapy is somewhat dependent on the antimicrobial susceptibility. The rate of clarithromycin resistance has been increasing and is associated with failure; thus, susceptibility testing is recommended before triple therapy with clarithromycin. However, antimicrobial susceptibility testing is not yet clinically available and an alternative newly developed acid inhibitor vonoprazan is used for triple therapy in Japan. The aim of this study was to determine whether vonoprazan-based triple therapy is plausible treatment in H. pylori eradication. METHODS: A retrospective observational study of H. pylori eradication was conducted in a single institute. The patients who requested antimicrobial susceptibility testing were treated with susceptibility-guided proton pump inhibitor-based triple therapy in International University of Health and Welfare Hospital from 2013 to 2016. Other patients were treated with empirical treatment with a proton pump inhibitor. From 2015 to 2016, vonoprazan-based triple treatment (vonoprazan, 20 mg; amoxicillin, 750 mg; and clarithromycin, 200 or 400 mg, b.i.d.) was conducted, and its effectiveness was compared with susceptibility-guided proton pump inhibitor-based triple therapy. We also investigated the improvement in eradication rate when antimicrobial susceptibility testing was performed, and compared the outcomes of vonoprazan-based and proton pump inhibitor-based empirical therapy. RESULTS: A total of 1355 patients who received first-line eradication treatment were enrolled in the present study. The eradication rates of the empirical proton pump inhibitor-based therapy and the vonoprazan-based therapy group in a per-protocol analysis were 86.3% (95% CI 83.8-88.8) and 97.4% (95% CI 95.7-99.1), respectively. In 212 patients who received antimicrobial susceptibility testing, the rate of clarithromycin resistant was 23.5% and the eradication rate in susceptibility-guided treatment was 95.7% (95% CI 92.9-98.4). The difference between susceptibility-guided and vonoprazan-based therapy was - 1.7% (95% CI - 4.9 to 1.5%), and the non-inferiority of vonoprazan-based triple therapy was confirmed. CONCLUSIONS: Vonoprazan-based triple therapy was effective as susceptibility-guided triple therapy for H. pylori eradication. An empirical triple therapy with vonoprazan is preferable even in area with high rates of clarithromycin-resistance. Trial registration The study was retrospectively registered in University Hospital Medical Information Network (UMIN000032351).

Evidence-based clinical practice guidelines for peptic ulcer disease 2015.

The Japanese Society of Gastroenterology (JSGE) revised the evidence-based clinical practice guidelines for peptic ulcer disease in 2014 and has created an English version. The revised guidelines consist of seven items: bleeding gastric and duodenal ulcers, Helicobacter pylori (H. pylori) eradication therapy, non-eradication therapy, drug-induced ulcer, non-H. pylori, non-nonsteroidal anti-inflammatory drug (NSAID) ulcer, surgical treatment, and conservative therapy for perforation and stenosis. Ninety clinical questions (CQs) were developed, and a literature search was performed for the CQs using the Medline, Cochrane, and Igaku Chuo Zasshi databases between 1983 and June 2012. The guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Therapy is initially provided for ulcer complications. Perforation or stenosis is treated with surgery or conservatively. Ulcer bleeding is first treated by endoscopic hemostasis. If it fails, surgery or interventional radiology is chosen. Second, medical therapy is provided. In cases of NSAID-related ulcers, use of NSAIDs is stopped, and anti-ulcer therapy is provided. If NSAID use must continue, the ulcer is treated with a proton pump inhibitor (PPI) or prostaglandin analog. In cases with no NSAID use, H. pylori-positive patients receive eradication and anti-ulcer therapy. If first-line eradication therapy fails, second-line therapy is given. In cases of non-H. pylori, non-NSAID ulcers or H. pylori-positive patients with no indication for eradication therapy, non-eradication therapy is provided. The first choice is PPI therapy, and the second choice is histamine 2-receptor antagonist therapy. After initial therapy, maintenance therapy is provided to prevent ulcer relapse.

[Diagnosis and treatment of aspirin--and NSAID-induced peptic ulcers].

A Japanese case-control study showed the odds ratio of upper gastrointestinal bleeding was 5.5 for aspirin and 6.1 for other NSAIDs. A Japanese cohort study showed that peptic ulcers were found in 6.5% of 1,454 patients receiving low-dose aspirin (LDA). Some endoscopic studies reported that NSAID users often had antral, multiple, and irregular ulcers, irrespective of Helicobacter pylori status. Proton-pump inhibitor (PPI) and misoprostol should be used for therapy for NSAID-ulcers. Maintenance therapy with PPI should be given for prevention of relapse of ulcers of NSAIDs and LDA users. PPI and histamine 2-recetor antagonist were effective for prevention of upper GI mucosal injury in patients receiving LDA.

[Therapy for prevention of upper gastrointestinal bleeding in patients receiving anti-thrombotic therapy].

Meta-analysis of randomized controlled studies and case-control studies showed that the risk of low-dose aspirin for upper gastrointestinal bleeding was 1.6-8.2. Some reports showed that the risk of upper gastrointestinal bleeding (UGIB) was high in patients receiving ticlopidine or clopidogrel. A meta-analysis study reported that data regarding the risk for GI bleeding of new direct oral anticoagulants (apixaban, dabigatran and rivaroxaban) were inconclusive. Proton-pump inhibitor and histamine 2-recetor antagonist were effective for prevention of upper GI mucosal injury in patients receiving low-dose aspirin. Some case-control studies showed that PPI use significantly reduced the risk of UGIB in patients with receiving clopidogrel, but not in those with receiving warfarin.

Clinical management of Helicobacter pylori--the Japanese perspective.

BACKGROUND: After the approval of health insurance coverage of eradication therapy for Helicobacter pylori-positive peptic ulcer disease (PUD) in 2000, comprehensive coverage for H. pylori infection itself was implemented in 2013. METHODS: We did a literature search using PubMed database on the management of H. pylori infection including indications, regimens, outcomes of current eradication therapies, trends of antibiotic resistance rates and proposed third-line rescue therapy in Japan. We also collected data on changes of eradication rates in our hospital by searching electronic medical records. RESULTS: After implementation of insurance coverage of eradication therapy for PUD, dramatic reduction of the number patients with PUD as well as spending on ulcer drug was documented. According to the current regulation, proton pump inhibitor (PPI)-based triple therapy with 2 antibiotics, amoxicillin (AMPC) plus clarithromycin, for 7 days is approved as the first-line therapy. After failure of the first-line therapy, PPI plus AMPC and metronidazole is authorized as the second line, which maintains an excellent eradication rate of over 90% in Japan. When these two therapies fail, a sitafloxacin-based therapy seems to be most promising among many rescue regimens. CONCLUSION: Comprehensive public health insurance coverage of H. pylori infection will promote eradication in Japanese people infected with H. pylori, whose risk of developing gastric cancer has been shown to be high. It also provides us a unique opportunity to study whether the broader indications can accelerate the reduction of gastric cancer in Japan in the same way we witnessed the reduction of PUD.

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.

Diagnosis of extent of early gastric cancer using flexible spectral imaging color enhancement.

The demarcation line between the cancerous lesion and the surrounding area could be easily recognized with flexible spectral imaging color enhancement (FICE) system compared with conventional white light images. The characteristic finding of depressed-type early gastric cancer (EGC) in most cases was revealed as reddish lesions distinct from the surrounding yellowish non-cancerous area without magnification. Conventional endoscopic images provide little information regarding depressed lesions located in the tangential line, but FICE produces higher color contrast of such cancers. Histological findings in depressed area with reddish color changes show a high density of glandular structure and an apparently irregular microvessel in intervening parts between crypts, resulting in the higher color contrast of FICE image between cancer and surrounding area. Some depressed cancers are shown as whitish lesion by conventional endoscopy. FICE also can produce higher color contrast between whitish cancerous lesions and surrounding atrophic mucosa. For nearly flat cancer, FICE can produce an irregular structural pattern of cancer distinct from that of the surrounding mucosa, leading to a clear demarcation. Most elevated-type EGCs are detected easily as yellowish lesions with clearly contrasting demarcation. In some cases, a partially reddish change is accompanied on the tumor surface similar to depressed type cancer. In addition, the FICE system is quite useful for the detection of minute gastric cancer, even without magnification. These new contrasting images with the FICE system may have the potential to increase the rate of detection of gastric cancers and screen for them more effectively as well as to determine the extent of EGC.

Diagnosis of depressed-type early gastric cancer using small-caliber endoscopy with flexible spectral imaging color enhancement.

BACKGROUND AND AIM: Small-caliber endoscopy has lower resolution than normal-caliber endoscopy, limiting its use in routine outpatient practice. Flexible spectral imaging color enhancement (FICE) strengthens the color contrast of depressed-type early gastric cancer without magnification. The aim of the present study was to evaluate the detection of depressed-type early gastric cancer using small-caliber endoscopy with the FICE system. METHODS: Eighty-two patients diagnosed with depressed-type early gastric cancer by standard endoscopy and biopsy were evaluated by small-caliber endoscopy. FICE images and conventional images were compared. Color differences in all 82 lesions were measured between malignant lesions and the surrounding mucosa using the Commission Internationale de L'Eclairage (CIE) 1976 color space. RESULTS: Most cancers were readily detected as reddish lesions on FICE images. Lines of demarcation between the malignant lesion and the surrounding mucosa were easily identified with FICE images, as such cancers could be clearly distinguished from the surrounding atrophic mucosa. Greater median color differences between malignant lesions and the surrounding mucosa were present in FICE images compared with conventional images, resulting in images with better contrast (27.2 vs 18.7, P<0.0001). CONCLUSIONS: Small-caliber endoscopy with the FICE system provides better color contrast of depressed-type early gastric cancers than conventional small-caliber endoscopy, and the FICE system may facilitate the diagnosis of this type of cancer as a new endoscopic modality.

Diagnosis of gastric antral vascular ectasia by transnasal flexible spectral imaging color enhancement.

The endoscopic appearance of gastric antral vascular ectasia (GAVE) can be easily misinterpreted as inflammatory changes of gastric mucosa. We report on a case of GAVE that had been missed by conventional transnasal endoscopy but was diagnosed by flexible spectral imaging color enhancement (FICE) with a transnasal endoscope. A 45-year-old woman with severe anemia presented with a 1-month history of increasing fatigue. She was previously diagnosed as having acute antral gastritis by conventional transnasal endoscopy (EG 530N2) because of the presence of reddish mucosal changes on the entire antral rugal fold. However, the FICE images produced using a combination of new processor system (VP4450) and new small-caliber endoscope (EG 530NW), did not show reddish mucosal changes on the entire rugal fold, but gave a clear image of dilated vessels associated with GAVE distinct from the surrounding normal mucosa on the same fold. These findings are useful to differentiate GAVE from ordinary gastritis. The lesions of GAVE were managed with a combination of focal pulse and spray-painting techniques to obliterate the bulk of the disease in two sessions of argon plasma coagulation therapy. Three months later, the patient recovered from iron deficiency anemia with an oral medication of iron tablets.

[The present state and problem of gastric ulcer caused by low-dose aspirin].

Upper gastrointestinal (GI) injuries induced by non-steroidal anti-inflammatory drugs (NSAID) and low-dose aspirin (LDA) have been increasing, because the number of patients who need to use NSAID, LDA, other anti-platelet drugs and anti-coagulants have been increasing. The aging is one of the most important risk factors of upper GI injuries induced by LDA, such as gastric ulcer. Since atypical symptoms often lead to a delay in diagnosis and treatment in the elderly patients, endoscopic examination should be considered especially in the elderly patients to detect upper GI lesions before using LDA.

[Treatment and prevention of gastric ulcers in elderly persons].

Treatment and prevention of gastric ulcers is not different between young and elderly patients. Eradication therapy for H. pylori infection should be made for elderly patients with H. pylori-gastric ulcers, because the incidence of adverse events is not higher than in young patients. NSAIDs are often given elderly persons, and aging is a risk factor of the development of NSAID-related ulcer. If elderly patients have some risk factors (high dose NSAID therapy, past history of uncomplicated ulcers or concurrent use of aspirin, corticosteroids or anticoagulants), prophylactic therapy for NSAID-ulcers should be made.

Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition.

BACKGROUND: Over the past few years, the profile of Helicobacter pylori infection has changed in Japan. In particular, the relationship between H. pylori and gastric cancer has been demonstrated more clearly. Accordingly, the committee of the Japanese Society for Helicobacter Research has revised the guidelines for diagnosis and treatment of H. pylori infection in Japan. MATERIALS AND METHODS: Four meetings of guidelines preparation committee were held from July 2007 to December 2008. In the new guidelines, recommendations for treatment have been classified into five grades according to the Minds Recommendation Grades, while the level of evidence has been classified into six grades. The Japanese national health insurance system was not taken into consideration when preparing these guidelines. RESULTS: Helicobacter pylori eradication therapy achieved a Grade A recommendation, being useful for the treatment of gastric or duodenal ulcer, for the treatment and prevention of H. pylori-associated diseases such as gastric cancer, and for inhibiting the spread of H. pylori infection. Levels of evidence were determined for each disease associated with H. pylori infection. For the diagnosis of H. pylori infection, measurement of H. pylori antigen in the feces was added to the tests not requiring biopsy. One week of proton-pump inhibitor-based triple therapy (including amoxicillin and metronidazole) was recommended as second-line therapy after failure of first-line eradication therapy. CONCLUSION: The revised Japanese guidelines for H. pylori are based on scientific evidence and avoid the administrative restraints that applied to earlier versions.

Diagnosis of small flat early gastric cancer by flexible spectral imaging color enhancement.

Current conventional endoscopy often misses flat early gastric cancers (0-IIb) because they are sometimes invisible. We experienced a case of small flat early gastric cancer that had been missed by normal-caliber conventional endoscopy. By small-caliber endoscope, conventional endoscopy showed a subtle reddish change of gastric mucosa, but the image with flexible spectral imaging color enhancement clearly showed a flat reddish lesion with 10 mm diameter, distinct from the surrounding mucosa. Flat early gastric cancer was suspected even though the lesion was not clearly described by conventional endoscopy. Histological examination of biopsy specimen revealed atypical glands. Endoscopic submucosal dissection of the lesion was performed. Pathological examination of the resected specimen confirmed well-differentiated adenocarcinoma localized in the mucosal layer without any depression or protrusion compared with the surrounding mucosa, consistent with the endoscopic finding. The small flat early gastric cancer became clearly visible with the new endoscopic technology.

Endoscopic submucosal dissection of esophageal lymphangioma: a case report with a review of the literature.

Esophageal lymphangioma is a very rare disease. We report a case of esophageal lymphangioma successfully treated with endoscopic submucosal dissection (ESD), which yielded definitive histological diagnosis and symptom relief. ESD offers a better option for definitive diagnosis as well as complete resection of large esophageal lymphangiomas with flat configuration.

[Second-line therapy for patients with Helicobacter pylori eradication failure].

Meta-analyses showed that quadruple therapy, ranitidine bismuth-based triple therapy and levofloxacin-based triple therapy were the most effective for the second-line H. pylori eradication therapy. In Japan, many studies showed that triple therapy with proton pump inhibitor (PPI), amoxicillin (AMPC) and metronidazole was effective after eradication failure using triple therapy with PPI, AMPC and clarithromycin. The intention-to-treat eradication rates were 81-97%, and the incidence rates of adverse events were 8-33%.

[Helicobacter pylori eradication therapy for peptic ulcer disease].

Meta-analyses showed that Helicobacter pylori eradication therapy was effective for healing and prevention of recurrence of peptic ulcers in H. pylori-positive patients and that treatment of H. pylori infection was more effective than antisecretory non-eradicating therapy (with or without long-term maintenance antisecretory therapy) in preventing recurrent bleeding from peptic ulcer. H. pylori eradication therapy is effective for prevention of development of NSAID-ulcers in NSAID-naïve patients. For prevention of recurrence of NSAID-ulcers, therapy with proton pump inhibitor is effective.