ObjectiveGastrointestinal microbiota may be involved in Helicobacter pylori-associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from H. pylori infection.DesignDeep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment, relative to 49 H.pylori negative subjects.ResultsIn H. pylori positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in H. pylori positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between Helicobacter and Fusobacterium, Neisseria, Prevotella, Veillonella, Rothia were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased Bifidobacterium after successful H. pylori eradication and more upregulated drug-resistant functional orthologs after failed treatment.ConclusionH. pylori infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful H. pylori eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
Background Probe-based confocal laser endomicroscopy (pCLE) allows real-time detection of neoplastic Barrett’s esophagus (BE) tissue. However, the accuracy of pCLE in real time has not yet been extensively evaluated. Objective To compare the sensitivity and specificity of pCLE in addition to high-definition white-light endoscopy (HD-WLE) with HD-WLE alone for the detection of high-grade dysplasia (HGD) and early carcinoma (EC) in BE. Design International, prospective, multicenter, randomized, controlled trial. Setting Five tertiary referral centers. Patients A total of 101 consecutive BE patients presenting for surveillance or endoscopic treatment of HGD/EC. Interventions All patients were examined by HD-WLE, narrow-band imaging (NBI), and pCLE, and the findings were recorded before biopsy samples were obtained. The order of HD-WLE and NBI was randomized and performed by 2 independent, blinded endoscopists. All suspicious lesions on HD-WLE or NBI and 4-quadrant random locations were documented. These locations were examined by pCLE, and a presumptive diagnosis of benign or neoplastic (HGD/EC) tissue was made in real time. Finally, biopsies were taken from all locations and were reviewed by a central pathologist, blinded to endoscopic and pCLE data. Main Outcome Measurements Diagnostic characteristics of pCLE. Results The sensitivity and specificity for HD-WLE were 34.2% and 92.7%, respectively, compared with 68.3% and 87.8%, respectively, for HD-WLE or pCLE (P = .002 and P < .001, respectively). The sensitivity and specificity for HD-WLE or NBI were 45.0% and 88.2%, respectively, compared with 75.8% and 84.2%, respectively, for HD-WLE, NBI, or pCLE (P = .01 and P = .02, respectively). Use of pCLE in conjunction with HD-WLE and NBI enabled the identification of 2 and 1 additional HGD/EC patients compared with HD-WLE and HD-WLE or NBI, respectively, resulting in detection of all HGD/EC patients, although not statistically significant. Limitations Academic centers with enriched population. Conclusions pCLE combined with HD-WLE significantly improved the ability to detect neoplasia in BE patients compared with HD-WLE. This may allow better informed decisions to be made for the management and subsequent treatment of BE patients.
ObjectiveTo investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE).DesignAdults with active EoE (n=76) randomly received 14 days’ treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm2 hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation.ResultsHistological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients.ConclusionsBET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation.ClinicalTrials.gov numberNCT02280616; EudraCT number, 2009-016692-29.
Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. We demonstrate that intestinal epithelial cell specific expression of oncogenic K-ras(G12D) in mice induces serrated hyperplasia, which is characterized by p16(ink4a) overexpression and induction of senescence. Deletion of Ink4a/Arf in K-ras(G12D) expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras represents a key player during an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development.
BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given offlabel. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n ¼ 59) or placebo (n ¼ 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity 2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label Gastroenterology 2019;157:74-86 CLINICAL AT treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.
Additional capnographic monitoring of ventilatory activity reduces the incidence of oxygen desaturation and hypoxemia during propofol sedation for colonoscopy.
Objective To clarify the full range of benefits and adverse consequences of Helicobacter pylori eradication as a strategy for gastric cancer prevention, the community-based intervention trial was launched in Linqu County, China. Design A total of 184 786 residents aged 25-54 years were enrolled in this trial and received 13 C-urea breath test. H. pylori positive participants were assigned into two groups, either receiving a 10-day quadruple anti-H. pylori treatment or lookalike placebos together with a single dosage of omeprazole and bismuth. Results The prevalence of H. pylori in trial participants was 57.6%. A total of 94 101 subjects completed the treatment. The overall H. pylori eradication rate was 72.9% in the active group. Gender, body mass index, history of stomach disease, baseline delta over baselinevalue of 13 C-urea breath test, missed medication doses, smoking and drinking were independent predictors of eradication failure. The missed doses and high baseline delta over baseline-value were important contributors in men and women (all P trend <0.001). However, a doseresponse relationship between failure rate and smoking or drinking index was found in men (all P trend <0.001), while high body mass index (P trend <0.001) and history of stomach disease were significant predictors in women. The treatment failure rate increased up to 48.8% (OR 2.87, 95% CI 2.24 to 3.68) in men and 39.4% (OR 2.67, 95% CI 1.61 to 4.42) in women with multiple factors combined. Conclusions This large community-based intervention trial to eradicate H. pylori is feasible and acceptable. The findings of this trial lead to a distinct evaluation of factors influencing eradication that should be generally considered for future eradication therapies. Trial registration number ChiCTR-TRC-10000979 in accordance with WHO ICTRP requirements. INTRODUCTIONHelicobacter pylori (H. pylori) is a recognised cause of chronic gastritis and peptic ulcer disease, and may play an important role in the etiology of Significance of this studyWhat is already known on this subject?▸ Gastric cancer is a global public health burden, nearly one million new cases are diagnosed each year worldwide, of which 42% cases occur in China. ▸ Helicobacter pylori infection is the main risk factor for gastric cancer, and it was classified as a class I carcinogen for gastric cancer by International Agency for Research on Cancer in 1994. ▸ The Shandong Intervention Trial launched in Linqu in 1995 yielded a 39% reduction in gastric cancer incidence rate after 15 years follow-up. ▸ Benefits and adverse consequences of strategy for gastric cancer prevention by eradication of H. pylori are still in concern in the community setting.What are the new findings?▸ The large community-based intervention trial to eradicate H. pylori is feasible and acceptable in a high-risk area of gastric cancer in China. It gained an elimination of 72.9% of H. pylori in such community intervention trial without severe side effects among all the subjects during the entire 30-month trial pe...
Eradication of Helicobacter pylori has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and H. pylori-related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were Bacteroidetes, Firmicutes, and Proteobacteria with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current H. pylori infection compared with negative subjects. As for the differential bacteria, the average relative abundance of Bacteroidetes was found to significantly decrease from H. pylori negative (66.16%) to past infection group (33.01%, p = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, p = 0.027). For Firmicutes and Proteobacteria, the average relative abundances showed elevated trends in the past H. pylori infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, p = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, p = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both p < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of Bacteroidetes, Firmicutes and Proteobacteria, may be involved in the process of H. pylori-related gastric lesion progression and provide hints for future evaluation of microbial changes after H. pylori eradication.
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