Diagnosis and Treatment of Helicobacter pylori Infection.

The last 5 years have seen major shifts in defining whom to test and how to treat Helicobacter pylori infection. Peptic ulcer has changed from a chronic disease to a one-off condition, and countries with a high incidence of gastric cancer have begun implementing population-wide screening and treatment. A proactive approach to testing and treatment of H. pylori is now recommended, including outreach to family members of individuals diagnosed with active infection as well as high-risk local populations such as immigrants from high-risk countries. Increasing antimicrobial resistance has resulted in an overall decline in treatment success, causing a rethinking of the approach to development of treatment guidelines as well as the need to adopt the principles of antibiotic usage and antimicrobial stewardship. Required changes include abandoning empiric use of clarithromycin, metronidazole, and levofloxacin triple therapies. Here, we discuss these transformations and give guidance regarding testing and use of therapies that are effective when given empirically.

Prevalence and predictive factors of colorectal sessile serrated lesions in younger individuals.

BACKGROUND: Sessile serrated lesions (SSLs) are obscured lesions predominantly in the right-sided colon and associated with interval colorectal cancer; however, their prevalence and risk factors among younger individuals remain unclear. METHODS: This retrospective study enrolled individuals who underwent index colonoscopy. The primary outcome was the SSL prevalence in the younger (<50 years) and older (≥50 years) age groups, while the secondary outcomes included clinically significant serrated polyps (CSSPs). Multivariable logistic regression was employed to identify predictors. RESULTS: Of the 9854 eligible individuals, 4712 (47.8%) were categorized into the younger age group. Individuals in the younger age group exhibited lower prevalences of adenomas (22.6% vs. 46.2%; P<0.001) and right-sided adenomas (11.2% vs. 27.2%; P<0.001) compared with their older counterparts. However, both groups exhibited a similar prevalence of SSLs (7.2% vs. 6.5%; P=0.16) and CSSPs (10.3% vs. 10.3%;P=0.96). Multivariable analysis revealed that age 40-49 years (odds ratio [OR] 1.81, 95%CI 1.01-3.23), longer withdrawal time (OR 1.17, 95%CI 1.14-1.20, per minute increment), and endoscopist performance (OR 3.35, 95%CI 2.44-4.58) were independent predictors of SSL detection in the younger age group. No significant correlation was observed between adenoma and SSL detection rates among endoscopists. CONCLUSION: SSLs are not uncommon among younger individuals. Moreover, diligent effort and expertise are of paramount importance in SSL detection. Future studies should explore the clinical significance of SSLs in individuals of younger age.

Prevalence of functional esophageal disorders and associated clinical characteristics in patients with proton-pump-inhibitor-unresponsive reflux symptoms.

BACKGROUND AND AIM: Patients with proton-pump-inhibitor (PPI)-unresponsive reflux symptoms, often caused by functional esophageal disorders (FED), are frequently encountered in clinical practice. We aimed to investigate the prevalence of FED and its associated clinical characteristics in patients with PPI-unresponsive reflux symptoms. METHODS: We retrospectively identified patients who were evaluated for persistent typical reflux symptoms, despite ≥8 weeks of PPI treatment, at the National Taiwan University Hospital from 2014 to 2023. All patients underwent a comprehensive evaluation comprising validated gastroesophageal reflux disease (GERD) symptom questionnaires, 5-item Brief Symptom Rating Scale (BSRS-5), Pittsburgh Sleep Quality Index (PSQI), esophagogastroduodenoscopy, high-resolution impedance manometry, and 24-h impedance-pH monitoring off PPI therapy. Diagnosis of FED and non-erosive reflux disease (NERD) was based on the Rome IV criteria. RESULTS: We analyzed 190 patients [46.8% male, median age 52 (interquartile range, 42-61) years], of whom 32 (16.8%) had NERD and 158 (83.2%) had FED (57.9% with functional heartburn and 25.3% with reflux hypersensitivity). Patients with FED had a lower body mass index than those with NERD and a higher prevalence of psychological comorbidities and poor sleep quality than healthy volunteers. The severity of reflux symptoms among FED patients was significantly associated with the severity of psychological comorbidities and sleep quality. CONCLUSIONS: A notably high prevalence (83.2%) of FED was observed among patients experiencing PPI-unresponsive reflux symptoms. Patients with FED had a higher level of psychological distress and diminished sleep quality, both of which were associated with reflux symptom severity.

Vascular endothelial dysfunction induced by 3-bromofluoranthene via MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

Eradicating Helicobacter pylori via 13C-urea breath screening to prevent gastric cancer in indigenous communities: a population-based study and development of a family index-case method.

OBJECTIVE: Screening and eradication of Helicobacter pylori help reduce disparities in the incidence of gastric cancer. We aimed to evaluate its acceptability and feasibility in the indigenous communities and develop a family index-case method to roll out this programme. DESIGN: We enrolled residents aged 20-60 years from Taiwanese indigenous communities to receive a course of test, treat, retest and re-treat initial treatment failures with the 13C-urea breath tests and four-drug antibiotic treatments. We also invited the family members of a participant (constituting an index case) to join the programme and evaluated whether the infection rate would be higher in the positive index cases. RESULTS: Between 24 September 2018 and 31 December 2021, 15 057 participants (8852 indigenous and 6205 non-indigenous) were enrolled, with a participation rate of 80.0% (15 057 of 18 821 invitees). The positivity rate was 44.1% (95% CI 43.3% to 44.9%). In the proof-of-concept study with 72 indigenous families (258 participants), family members of a positive index case had 1.98 times (95% CI 1.03 to 3.80) higher prevalence of H. pylori than those of a negative index case. The results were replicated in the mass screening setting (1.95 times, 95% CI 1.61 to 2.36) when 1115 indigenous and 555 non-indigenous families were included (4157 participants). Of the 6643 testing positive, 5493 (82.6%) received treatment. According to intention-to-treat and per-protocol analyses, the eradication rates were 91.7% (89.1% to 94.3%) and 92.1% (89.2% to 95.0%), respectively, after one to two courses of treatment. The rate of adverse effects leading to treatment discontinuation was low at 1.2% (0.9% to 1.5%). CONCLUSION: A high participation rate, a high eradication rate of H. pylori and an efficient rollout method indicate that a primary prevention strategy is acceptable and feasible in indigenous communities. TRIAL REGISTRATION NUMBER: NCT03900910.

Double-contrast barium enema is no longer justified as a backup examination for colonoscopy in the population screening program: Population study in an organized fecal immunochemical test-based screening program.

BACKGROUND AND AIM: Currently, some countries still acknowledge double-contrast barium enema (DCBE) as a backup confirmatory examination when colonoscopy is not feasible or incomplete in colorectal cancer (CRC) screening programs. This study aims to compare the performance of colonoscopy and DCBE in terms of the risk of incident CRC after negative results in the fecal immunochemical test (FIT)-based Taiwan Colorectal Cancer Screening Program. METHODS: Subjects who had positive FITs and received confirmatory exams, either colonoscopy or DCBE, without the findings of neoplastic lesions from 2004 to 2013 in the screening program comprised the study cohort. Both the colonoscopy and DCBE subcohorts were followed until the end of 2018 and linked to the Taiwan Cancer Registry to identify incident CRC cases. Multivariate analysis was conducted to compare the risk of incident CRC in both subcohorts after controlling for potential confounders. RESULTS: A total of 102 761 colonoscopies and 5885 DCBEs were performed after positive FITs without neoplastic findings during the study period. By the end of 2018, 2113 CRCs (2.7 per 1000 person-years) and 368 CRCs (7.6 per 1000 person-years) occurred in the colonoscopy and DCBE subcohorts, respectively. After adjusting for major confounders, DCBE had a significantly higher risk of incident CRC than colonoscopy, with an adjusted HR of 2.81 (95% CI = 2.51-3.14). CONCLUSIONS: In the FIT screening program, using DCBE as a backup examination was associated with a nearly threefold risk of incident CRC compared with colonoscopy, demonstrating that it is no longer justified as a backup examination for incomplete colonoscopy.

Risk of colonoscopy-related complications in a fecal immunochemical test-based population colorectal cancer screening program.

BACKGROUND: The likelihood of advanced or synchronous neoplasms is significantly higher in fecal immunochemical test (FIT)-positive individuals than in the general population. The magnitude of the colonoscopy-related complication rate in FIT-positive individuals remains unknown. This study aimed to elucidate the colonoscopy-related complication rate after a positive FIT result and compare it with the rate when colonoscopy was performed for other purposes. METHODS: Information regarding colonoscopy-related severe complications after a positive FIT result (FIT-colonoscopy) and ordinary colonoscopy during 2010-2014 was collected from the Taiwanese Colorectal Cancer Screening Program Database and National Health Insurance Research Database. Severe complications included significant bleeding, perforation, and cardiopulmonary events ≤ 14 days after colonoscopy. The number of events per 1000 procedures was used to quantify complication rates. Multivariate analysis was conducted to assess the association of various factors with severe complications associated with FIT-colonoscopy compared with ordinary colonoscopy. RESULTS: 319 114 FIT-colonoscopies (214 955 patients) were identified, 51 242 (16.1 %) of which included biopsy and 94 172 (29.5 %) included polypectomy. Overall, 2125 significant bleedings (6.7 ‰) and 277 perforations (0.9 ‰) occurred ≤ 14 days after FIT-colonoscopy. Polypectomy, antiplatelet use, and anticoagulant use were associated with higher risk of complications (adjusted odds ratio [aOR] 4.41, 95 % confidence interval [CI] 4.05-4.81); aOR 1.35, 95 %CI 1.12-1.53; aOR 1.88, 95 %CI 0.61-5.84, respectively). Compared with ordinary colonoscopy, FIT-colonoscopy involved significantly higher risk of significant bleeding (aOR 3.10, 95 %CI 2.90-3.32). CONCLUSIONS: FIT-colonoscopy was associated with a more than two-fold risk of significant bleeding, especially when polypectomy was performed.

Declining trends of prevalence of Helicobacter pylori infection and incidence of gastric cancer in Taiwan: An updated cross-sectional survey and meta-analysis.

BACKGROUND: We aimed to assess the latest prevalence and secular trend of Helicobacter pylori infection and its association with the incidence and mortality of gastric cancer in Taiwan. MATERIALS AND METHODS: Adults naive to H. pylori eradication received 13 C-urea breath test (13 C-UBT), H. pylori stool antigen test, and serology test during 2019-2020 in this prospective screening program. Children and adolescent aged between 7 and 19 years received 13 C-UBT for H. pylori screening. We also conducted a systematic review and meta-analysis to assess the secular trend of prevalence of H. pylori from 1990 to 2020 in Taiwan. The secular trends of age-standardized incidence and mortality of gastric cancer were obtained from the Taiwan Cancer Registry. RESULTS: A total of 1494 participants were enrolled, including 294 children or adolescents and 1200 adults. The overall prevalence of active H. pylori infection by 13 C-UBT was 26.6% (397/1494), which was 30.8% in adults and 9.5% in adolescents/children. The age-standardized prevalence of active H. pylori infection was 32.3% in adults after adjustment of the population structure in Taiwan. Of the 29 studies including 38,597 subjects eligible for the meta-analysis, the pooled prevalence of H. pylori infection decreased from 63.8% (95% CI: 55.9%-71%) in 1990-2000 to 28.2% (95% CI:21.8%-35.6%) in 2016-2020. The age-standardized incidence and mortality of gastric cancer have also declined from 15.2 to 10.75 per 100,000, respectively, in 1999 to 9.29 and 5.4 per 100,000, respectively, in 2019. CONCLUSIONS: The prevalence of H. pylori infection has declined in Taiwan, which correlates with the declining trends of age-standardized incidence and mortality of gastric cancer in Taiwan.

Brand interchangeability of pepsinogen tests in the real-world setting after eradication of Helicobacter pylori: a community-based study.

BACKGROUND: Serum pepsinogen (PG) is recommended as a screening test for premalignant gastric lesions. However, real-world evidence demonstrating its applicability and equivalence between different test brands is limited. METHODS: Mass screening began in 2018 in a high-risk Taiwanese population after eradication of Helicobacter pylori, with the first stage of two PG tests (GastroPanel®, Helsinki, Finland and LZ-Test®, Tokyo, Japan) and the second stage of endoscopy. A positive test was defined as PG-I < 30 ng/mL or PG-I/II ratio < 3 for GastroPanel® and PG-I ≤ 70 ng/mL and PG-I/II ratio ≤ 3 for LZ-Test®. Index lesions included atrophic gastritis and intestinal metaplasia. Test performance was evaluated based on the participation rate, positivity rate, referral rate, positive predictive value (PPV), and the detection rate. RESULTS: Among 7616 eligible participants, 5117 (67.2%) received PG tests and 284 (5.6%) tested positive. Of those who tested positive, 105 (37.0%) underwent endoscopy. Overall PPVs for atrophic gastritis and intestinal metaplasia were 12.4% and 18.9%, respectively, with detection rates of 2.5 and 3.9 per 1000, respectively. Correlations of numerical measures between tests were high and the agreements of test results were substantial. The PPVs (16.3% vs. 16.3% and 23.8% vs. 21.3%, P = 1.00 and 0.71, respectively), detection rates (2.5 vs. 2.5 and 3.7 vs. 3.3 per 1000, P = 1.00 and 0.27, respectively), and the stage distributions of gastritis were all comparable, which were confirmed by multiple regression analyses. CONCLUSIONS: PG testing is effective for mass screening after eradication of H. pylori. Tests from different manufacturers, even using different analytical methods and cutoff criteria, can perform equivalently.

Mass screening and eradication of Helicobacter pylori as the policy recommendations for gastric cancer prevention.

Gastric cancer is an inflammation-related cancer triggered by Helicobacter pylori infection. Understanding of the natural disease course has prompted the hypothesis that gastric cancer can be prevented by administering a short-course antibiotic treatment to eradicate the H. pylori infection and interrupt this carcinogenic cascade. Results from randomized controlled trials and cohort studies have repeatedly confirmed this concept, which has moved attention from individual management of H. pylori infection to population-wide implementation of screening programs. Such a paradigm shift follows a three-tier architecture. First, healthcare policy-makers determine the most feasible and applicable eligibility, invitation, testing, referral, treatment, and evaluation methods for an organized screening program to maximize the population benefits and cost-effectiveness. Second, provision of knowledge and effective feedback to frontline general practitioners, including choice of diagnostic tests, selection of eradication regimens, and the indication of endoscopic examination, ensures the quality of care and increases the likelihood of desired treatment responses. Third, initiatives to raise population awareness are designed regarding the impact of H. pylori infection and risky lifestyle habits on the stomach health. These programs, with increased accessibility and geographic coverage in progress, will accelerate the decline in morbidity, mortality, and associated costs of this preventable malignancy.

Quality assurance of integrative big data for medical research within a multihospital system.

BACKGROUND: The need is growing to create medical big data based on the electronic health records collected from different hospitals. Errors for sure occur and how to correct them should be explored. METHODS: Electronic health records of 9,197,817 patients and 53,081,148 visits, totaling about 500 million records for 2006-2016, were transmitted from eight hospitals into an integrated database. We randomly selected 10% of patients, accumulated the primary keys for their tabulated data, and compared the key numbers in the transmitted data with those of the raw data. Errors were identified based on statistical testing and clinical reasoning. RESULTS: Data were recorded in 1573 tables. Among these, 58 (3.7%) had different key numbers, with the maximum of 16.34/1000. Statistical differences (P < 0.05) were found in 34 (58.6%), of which 15 were caused by changes in diagnostic codes, wrong accounts, or modified orders. For the rest, the differences were related to accumulation of hospital visits over time. In the remaining 24 tables (41.4%) without significant differences, three were revised because of incorrect computer programming or wrong accounts. For the rest, the programming was correct and absolute differences were negligible. The applicability was confirmed using the data of 2,730,883 patients and 15,647,468 patient-visits transmitted during 2017-2018, in which 10 (3.5%) tables were corrected. CONCLUSION: Significant magnitude of inconsistent data does exist during the transmission of big data from diverse sources. Systematic validation is essential. Comparing the number of data tabulated using the primary keys allow us to rapidly identify and correct these scattered errors.

Faecal immunochemical test after negative colonoscopy may reduce the risk of incident colorectal cancer in a population-based screening programme.

OBJECTIVE: Subjects with a positive faecal immunochemical test (FIT) have a much higher likelihood of advanced neoplasms than the general population. Whether FIT-positive subjects with negative colonoscopy should receive subsequent FIT screening remain unclear. DESIGN: Subjects with a negative colonoscopy after positive FIT in the first screening in the Taiwanese Colorectal Cancer (CRC) Screening Program 2004-2009 were followed until the end of 2014. CRC incidence was compared between those who did and did not receive subsequent FIT screening. Cox regression analysis was conducted, adjusting for major confounders to investigate whether subsequent FIT was associated with lower risk of incident CRC. RESULTS: The study cohort was comprised of 9179 subjects who had negative diagnostic colonoscopy after positive FIT in 2004-2009, of whom 6195 received subsequent FIT during the study period. The CRC incidence (per 1000 person years) was 1.34 in those who received subsequent FIT and 2.69 in those who did not, with corresponding adjusted HR (aHR) of 0.47 (95% CI 0.31 to 0.71). Lower adenoma detection rate of diagnostic colonoscopy was associated with higher risk of incident CRC but became non-significant in multivariable analysis after adjustment for subsequent FIT. Higher baseline faecal haemoglobin concentration (FHbC, µg haemoglobin/g faeces) was associated with increased risk of incident CRC (reference: FHbC=20-39; aHR=1.93 (1.04-3.56), 0.95 (0.45-2.00), 2.26 (1.16-4.43) and 2.44 (1.44-4.12) for FHbC=40-59, 60-99, 100-149 and ≥150, respectively). CONCLUSION: Subsequent FIT should be scheduled after negative colonoscopy to detect missed neoplasms and reduce the risk of incident CRC in a national FIT screening programme.

Long-term effectiveness of faecal immunochemical test screening for proximal and distal colorectal cancers.

OBJECTIVE: To measure the effects of faecal immunochemical test (FIT) for colorectal cancer (CRC) screening on overall and site-specific long-term effectiveness of population-based organised service screening. DESIGN: A prospective cohort study of Taiwanese nationwide biennial FIT screening was performed. A total of 5 417 699 eligible subjects were invited to attend screening from 2004 through 2009 and were followed up until 2014. We estimated the adjusted relative rates (aRRs) on the effectiveness of reducing advanced-stage CRC (stage II+) and CRC death by Bayesian Poisson regression models with the full adjustment for a cascade of self-selection factors (including the screening rate and the colonoscopy rate) and the completeness of colonoscopy together with demographic features. RESULTS: FIT screening (exposed vs unexposed) reduced the incidence of advanced-stage CRC (48.4 vs 75.7 per 100 000) and mortality (20.3 vs 41.3 per 100 000). Statistically significant reductions of both incidence of advanced-stage CRCs (aRR=0.66, 95% CI 0.63 to 0.70) and deaths from CRC (aRR=0.60, 95% CI 0.57 to 0.64) were noted. FIT screening was more effective in reducing distal advanced-stage CRCs (aRR=0.61, 95% CI 0.58 to 0.64) and CRC mortality (aRR=0.56, 95% CI 0.53 to 0.69) than proximal advanced CRCs (aRR=0.84, 95% CI 0.77 to 0.92) and CRC mortality (aRR=0.72, 95% CI 0.66 to 0.80). CONCLUSION: A large-scale population-based biennial FIT screening demonstrates 34% significant reduction of advanced-stage CRCs and 40% reduction of death from CRC with larger long-term effectiveness in the distal colon than the proximal colon. Our findings provide a strong and consistent evidence-based policy for supporting a sustainable population-based FIT organised service screening worldwide. The disparity of site-specific long-term effectiveness also provides an insight into the remedy for lower effectiveness of FIT screening in the proximal colon.

Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands.

OBJECTIVE: Although mass eradication of Helicobacter pylori has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear. DESIGN: Mass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test positives for the 13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively. RESULTS: After six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of H. pylori fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI -14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of H. pylori. CONCLUSION: Population-based eradication of H. pylori has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period. TRIAL REGISTRATION NUMBER: NCT00155389.

Bismuth salts with versus without acid suppression for Helicobacter pylori infection: A transmission electron microscope study.

BACKGROUND: Bismuth oxychloride produced by interaction of bismuth compounds with gastric acid is believed to damage Helicobacter pylori. The effect of bismuth salts on H. pylori in the presence of strong acid suppression is unknown. This randomized trial aimed to determine effects of bismuth subcitrate on H. pylori with and without acid suppression. METHODS: H. pylori -positive participants were allocated (1:1:1) to receive (a) no treatment (control), (b) colloidal bismuth subcitrate (CBS, 125 mg/tab), or (c) CBS plus high-dose proton-pump inhibitor (PPI), esomeprazole 40 mg q.i.d. for 3 days. In the treatment groups, CBS was given: 1 dose, 1 hour before endoscopy, 1 dose, 4 hours before endoscopy, or q.i.d. 24 hours before endoscopy. The study end-points were evaluated using transmission electron microscopy to observe the morphological changes of H. pylori in antral and corpus biopsies. RESULTS: Twenty-seven H. pylori carriers were enrolled in this trial with qualitative end-points. In the no treatment group, active budding and replication of H. pylori were observed. In the CBS group, cellular swelling, vacuolization, structural degradation, and cell wall eruption of H. pylori were observed, with no apparent association with when the CBS was given. Among those receiving high-dose PPI-plus CBS or CBS only, there were no differences in number of H. pylori present or severity of bacterial damage whether CBS was given 1, 4, or 24 hours before endoscopy. CONCLUSIONS: Based on direct morphological evaluation, the toxic effect of CBS treatment on H. pylori was demonstrated independent of acid suppression with PPI.

Risk stratification for gastric cancer after Helicobacter pylori eradication: A population-based study on Matsu Islands.

BACKGROUND AND AIM: The reliable method to stratify the gastric cancer risk after Helicobacter pylori eradication remains an elusive goal. METHODS: Mass eradication of H. pylori began in 2004 in a high-risk population. After eradication, a screening program involving first-stage serological tests (pepsinogen-I, pepsinogen-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018. Index lesions included gastric cancer or extensive premalignant lesions. We evaluated the performance of the serological tests to "rule in" and "rule out" the risk based on positive and negative likelihood ratios, respectively. The methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage. RESULTS: Among 6512 invited subjects, 3895 (59.6%) participated. Both gastrin-17 and pepsinogen tests were normal in 3560 (91.4%) subjects; 206 (5.3%) gastrin-17 and 129 (3.3%) pepsinogen tests were abnormal. Years after eradication, the severity of gastritis had fallen greatly, and extensive premalignant lesions or gastric cancer frequently occurred in newly non-atrophic-appearing mucosa. Pepsinogen testing could moderately predict atrophic gastritis (positive likelihood ratio: 4.11 [95% confidence interval: 2.92-5.77]; negative likelihood ratio: 0.14 [0.10-0.19]). Gastrin-17 was not useful (0.66 and 1.20, respectively). However, pepsinogen testing poorly predicted the index lesions (2.04 [1.21-3.42] and 0.57 [0.34-0.95]). DNA methylation levels in the post-eradication mucosa were more discriminative for predicting index lesions (3.89 [2.32-6.54] and 0.25 [0.15-0.42]). CONCLUSIONS: After eradication, pepsinogen false-negative results become more frequent because histology is improved but genetic damage may persist. Direct testing for genetic damage offers better discrimination.

Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.

Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulation of genetic alterations, estimated as a frequency of rare base substitution mutations, significantly increased according to cancer risk in esophageal mucosae, but not in gastric mucosae. The mutation patterns reflected the exposure to lifestyle risk factors. In contrast, the accumulation of epigenetic alterations, measured as DNA methylation levels of marker genes, significantly increased according to cancer risk in both tissues. Patients with cancer (high-risk individuals) were precisely discriminated from healthy individuals with exposure to risk factors (intermediate-risk individuals) by a combination of alterations in the esophagus (odds ratio, 18.2; 95% confidence interval, 3.69-89.9) and by only epigenetic alterations in the stomach (odds ratio, 7.67; 95% confidence interval, 2.52-23.3). The relative importance of epigenetic alterations upon genetic alterations was 1.04 in the esophagus and 2.31 in the stomach. The differential impacts among tissues will be critically important for effective cancer prevention and precision cancer risk diagnosis.

3-Bromofluoranthene-induced cardiotoxicity of zebrafish and apoptosis in the vascular endothelial cells via intrinsic and extrinsic caspase-dependent pathways.

Fluoranthene, a high-molecular-weight polycyclic aromatic hydrocarbon (PAH), is widely present in air pollutants, including fine inhalable particulate matter. 3-Bromofluoranthene (3-BrFlu), which is a brominated fluoranthene and halogenated PAH, is generated from waste combustion, metallurgical processes, cement production, e-waste dismantling, and photoreaction. Vascular endothelial cells have key functions in the homeostasis and the development of the cardiovascular system. The zebrafish model has been widely employed to study cardiotoxicity and embryotoxicity. However, no evidence has indicated that 3-BrFlu induces cytotoxicity in vascular endothelial cells, or cardiotoxicity and embryotoxicity in zebrafish. In this study, 3-BrFlu induced concentration-dependent changes in embryo- and cardiotoxicity. Cytotoxicity was also induced by 3-BrFlu in a concentration-dependent manner through apoptosis and necrosis in vascular endothelial cells, SVEC4-10 cells. The activities of caspase-3, -8, and -9 were induced by 3-BrFlu via an intrinsic pathway constituting Bcl-2 downregulation, Bad upregulation, and mitochondrial dysfunction; the extrinsic pathway included the expression of death receptors, including tumour necrosis factor α and Fas receptors. These results indicated that 3-BrFlu caused cardio- and embryotoxicity in zebrafish through vascular endothelial cells cytotoxicity resulting from caspase-dependent apoptosis through intrinsic and extrinsic pathways.

Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus.

OBJECTIVE: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC). METHODS: 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed. RESULTS: Consensus was reached in 26 statements. At an individual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of 'the point of no return'. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori. CONCLUSION: Evidence supports the proposal that eradication therapy should be offered to all individuals infected with H. pylori. Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC.

Treatment of Helicobacter pylori infection and its long-term impacts on gut microbiota.

The rising prevalence of antibiotic resistance and the long-term safety following eradication therapy are important issues in the management of Helicobacter pylori infection. The prevalence of clarithromycin, levofloxacin, and metronidazole resistance of H. pylori has increased to 21%, 27%, and 45%, respectively, in the Asia-Pacific region. Personalized treatment guided by susceptibility testing may provide a reliably excellent eradication rate in the first-line treatment but is costly and not widely available. Population-specific empirical therapy according to the local prevalence of antibiotic resistance may be an alternative strategy. Levofloxacin-based therapy and bismuth quadruple therapy are the recommended second-line rescue therapy. Susceptibility testing or genotypic resistance-guided therapy is the preferred treatment for refractory H. pylori infection, but empirical therapy may be an acceptable alternative. Eradication of H. pylori leads to short-term perturbation of gut microbiota. The diversity of gut microbiota can be restored months after eradication therapy, but the speed of recovery varies with regimens. The short-term increases of antibiotic resistance of Escherichia coli and Klebsiella pneumoniae may be restored to basal states months after H. pylori eradication. Future studies that apply in-depth sequencing, such as shotgun metagenomics sequencing, are needed to clarify whether the compositions of gut microbiota at the species level are fully restored.