Korean Red Ginseng Extract Inhibits IL-8 Expression via Nrf2 Activation in Helicobacter pylori-Infected Gastric Epithelial Cells.

Helicobacter pylori (H. pylori) causes gastric diseases by increasing reactive oxygen species (ROS) and interleukin (IL)-8 expression in gastric epithelial cells. ROS and inflammatory responses are regulated by the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of Nrf2 target genes, superoxide dismutase (SOD) and heme oxygenase-1 (HO-1). We previously demonstrated that Korean red ginseng extract (RGE) decreases H. pylori-induced increases in ROS and monocyte chemoattractant protein 1 in gastric epithelial cells. We determined whether RGE suppresses the expression of IL-8 via Nrf2 activation and the expression of SOD and HO-1 in H. pylori-infected gastric epithelial AGS cells. H. pylori-infected cells were treated with RGE with or without ML385, an Nrf2 inhibitor, or zinc protoporphyrin (ZnPP), a HO-1 inhibitor. Levels of ROS and IL-8 expression; abundance of Keap1, HO-1, and SOD; levels of total, nuclear, and phosphorylated Nrf2; indices of mitochondrial dysfunction (reduction in mitochondrial membrane potential and ATP level); and SOD activity were determined. As a result, RGE disturbed Nrf2-Keap1 interactions and increased nuclear Nrf2 levels in uninfected cells. H. pylori infection decreased the protein levels of SOD-1 and HO-1, as well as SOD activity, which was reversed by RGE treatment. RGE reduced H. pylori-induced increases in ROS and IL-8 levels as well as mitochondrial dysfunction. ML385 or ZnPP reversed the inhibitory effect of RGE on the alterations caused by H. pylori. In conclusion, RGE suppressed IL-8 expression and mitochondrial dysfunction via Nrf2 activation, induction of SOD-1 and HO-1, and reduction of ROS in H. pylori-infected cells.

Helicobacter pylori and Epstein-Barr Virus Coinfection Stimulates Aggressiveness in Gastric Cancer through the Regulation of Gankyrin.

Persistent coinfection with Helicobacter pylori and Epstein-Barr virus (EBV) promotes aggressive gastric carcinoma (GC). The molecular mechanisms underlying the aggressiveness in H. pylori and EBV-mediated GC are not well characterized. We investigated the molecular mechanism involved in H. pylori- and EBV-driven proliferation of gastric epithelial cells. Results showed that the coinfection is significantly more advantageous to the pathogens as coinfection creates a microenvironment favorable to higher pathogen-associated gene expression. The EBV latent genes ebna1 and ebna3c are highly expressed in the coinfection compared to lone EBV infection at 12 and 24 h. The H. pylori-associated genes 16S rRNA, cagA, and babA were also highly expressed during coinfection compared to H. pylori alone. In addition, upregulation of gankyrin, which is a small oncoprotein, modulates various cell signaling pathways, leading to oncogenesis. Notably, the knockdown of gankyrin decreased the cancer properties of gastric epithelial cells. Gankyrin showed a similar expression pattern as that of ebna3c at both transcript and protein levels, suggesting a possible correlation. Further, EBV and H. pylori created a microenvironment that induced cell transformation and oncogenesis through dysregulation of the cell cycle regulatory (ccnd1, dapk3, pcna, and akt), GC marker (abl1, tff-2, and cdx2), cell migration (mmp3 and mmp7), DNA response (pRB, pten, and p53), and antiapoptotic (bcl2) genes in infected gastric epithelial cells through gankyrin. Our study provides a new insight into the interplay of two oncogenic agents (H. pylori and EBV) that leads to an enhanced carcinogenic activity in gastric epithelial cells through overexpression of gankyrin. IMPORTANCE In the present study, we evaluated the synergistic effects of EBV and H. pylori infection on gastric epithelial cells in various coinfection models. These coinfection models were among the first to depict the exposures of gastric epithelial cells to EBV followed by H. pylori; however, coinfection models exist that narrated the scenario upon exposure to H. pylori followed by that to EBV. We determined that a coinfection by EBV and H. pylori enhanced the expression of oncogenic protein gankyrin. The interplay between EBV and H. pylori promoted the oncogenic properties of AGS cells like elevated focus formation, cell migration, and cell proliferation through gankyrin. EBV and H. pylori mediated an enhanced expression of gankyrin, which further dysregulated cancer-associated genes such as cell migratory, tumor suppressor, DNA damage response, and proapoptotic genes.

MicroRNA Changes in Gastric Carcinogenesis: Differential Dysregulation during Helicobacter pylori and EBV Infection.

Despite medical advances, gastric-cancer (GC) mortality remains high in Europe. Bacterial infection with Helicobacter pylori (H. pylori) and viral infection with the Epstein-Barr virus (EBV) are associated with the development of both distal and proximal gastric cancer. Therefore, the detection of these infections and the prediction of further cancer development could be clinically significant. To this end, microRNAs (miRNAs) could serve as promising new tools. MiRNAs are highly conserved noncoding RNAs that play an important role in gene silencing, mainly acting via translational repression and the degradation of mRNA targets. Recent reports demonstrate the downregulation of numerous miRNAs in GC, especially miR-22, miR-145, miR-206, miR-375, and miR-490, and these changes seem to promote cancer-cell invasion and tumor spreading. The dysregulation of miR-106b, miR-146a, miR-155, and the Let-7b/c complex seems to be of particular importance during H. pylori infection or gastric carcinogenesis. In contrast, many reports describe changes in host miRNA expression and outline the effects of bamHI-A region rightward transcript (BART) miRNA in EBV-infected tissue. The differential regulation of these miRNA, acting alone or in close interaction when both infections coexist, may therefore enable us to detect cancer earlier. In this review, we focus on the two different etiologies of gastric cancer and outline the molecular pathways through which H. pylori- or EBV-induced changes might synergistically act via miR-155 dysregulation to potentiate cancer risk. The three markers, namely, H. pylori presence, EBV infection, and miR-155 expression, may be checked in routine biopsies to evaluate the risk of developing gastric cancer.

Metformin attenuates synergic effect of diabetes mellitus and Helicobacter pylori infection on gastric cancer cells proliferation by suppressing PTEN expression.

It has been reported that CagA of Helicobacter pylori reduced PTEN expression by enhancing its promoter methylation. Furthermore, diabetes mellitus (DM) may also promote the methylation status of PTEN, a tumour suppressor gene in gastric cancer (GC). It is intriguing to explore whether DM may strengthen the tumorigenic effect of H pylori (HP) by promoting the methylation of PTEN promoter and whether the administration of metformin may reduce the risk of GC by suppressing the methylation of PTEN promoter. In this study, we enrolled 107 GC patients and grouped them as HP(-)DM(-) group, HP(+)DM(-) group and HP(+)DM(+) group. Bisulphite sequencing PCR evaluated methylation of PTEN promoter. Quantitative real-time PCR, immunohistochemistry and Western blot, immunofluorescence, flow cytometry and MTT assay were performed accordingly. DNA methylation of PTEN promoter was synergistically enhanced in HP(+)DM(+) patients, and the expression of PTEN was suppressed in HP(+)DM(+) patients. Cell apoptosis was decreased in HP(+)DM(+) group. Metformin showed an apparent effect on restoring CagA-induced elevation of PTEN promoter methylation, thus attenuating the PTEN expression. The reduced PTEN level led to increased proliferation and inhibited apoptosis of HGC-27 cells. In this study, we collected GC tumour tissues from GC patients with or without DM/HP to compare their PTEN methylation and expression while testing the effect of metformin on the methylation of PTEN promoter. In summary, our study suggested that DM could strengthen the tumorigenic effect of HP by promoting the PTEN promoter methylation, while metformin reduces GC risk by suppressing PTEN promoter methylation.

Status of kinases in Epstein-Barr virus and Helicobacter pylori Coinfection in gastric Cancer cells.

BACKGROUND: Helicobacter pylori (H. pylori) and Epstein - Barr virus (EBV) plays a significant role in aggressive gastric cancer (GC). The investigation of genes associated with these pathogens and host kinases may be essential to understand the early and dynamic progression of GC. AIM: The study aimed to demonstrate the coinfection of EBV and H. pylori in the AGS cells through morphological changes, expression of the kinase and the probable apoptotic pathways. METHODS: Genomic DNA isolation of H. pylori and its characterization from clinical samples were performed. RT-qPCR of kinases was applied to scrutinize the gene expression of kinases in co-infected GC in a direct and indirect (separated through insert size 0.45 µm) H. pylori infection set up. Morphological changes in co-infected GC were quantified by measuring the tapering ends of gastric epithelial cells. Gene expression profiling of apoptotic genes was assessed through RT-qPCR. RESULTS: An interleukin-2-inducible T-cell kinase (ITK) showed significant upregulation with indirect H. pylori infection. Moreover, Ephrin type-B receptor six precursors (EPHB6) and Tyrosine-protein kinase Fyn (FYN) showed significant upregulation with direct coinfection. The tapering ends in AGS cells were found to be extended after 12 h. A total of 24 kinase genes were selected, out of which EPHB6, ITK, FYN, and TYK2 showed high expression as early as 12 h. These kinases may lead to rapid morphological changes in co-infected gastric cells. Likewise, apoptotic gene expression such as APAF-1 and Bcl2 family genes such as BAD, BID, BIK, BIM, BAX, AND BAK were significantly down-regulated in co-infected AGS cells. CONCLUSION: All the experiments were performed with novel isolates of H. pylori isolated from central India, for the functional assessment of GC. The effect of coinfection with EBV was more profoundly observed on morphological changes in AGS cells at 12 h as quantified by measuring the tapering of ends. This study also identifies the kinase and apoptotic genes modulated in co-infected cells, through direct and indirect approaches. We report that ITK, EPHB6, TYK2, FYN kinase are enhanced, whereas apoptotic genes such as APAF-1, BIK, FASL, BAX are significantly down-regulated in AGS cells coinfected with EBV and H. pylori.

How do international gastric cancer prevention guidelines influence clinical practice globally?

Clinical guidelines recommend particular approaches, including 'screen-and-treat' strategy for Helicobacter pylori, to prevent gastric cancer. However, little of this is implemented in clinical practice. The aim of the study was to identify barriers to implementation of international guidelines. A web-based questionnaire distributed globally to specialists in the field. Altogether 886 responses from 75 countries were received. Of the responders, 570 (64%) were men of mean age 47 years. There were 606 gastroenterologists and 65 epidemiologists among the responders. Altogether, 79.8% of the responders disagreed that the burden of gastric cancer is a diminishing problem. 'Screen-and-treat' strategy for H. pylori in the responder's country was considered appropriate by 44.4%, inappropriate by 24.3%, with 31.3% being uncertain. Population-based screening for gastric cancer was considered appropriate in the respective home-country by 62.2%, in other areas - but not the home country - by 27.6%, and inappropriate by 10.2%. As a screening tool, upper endoscopy was acceptable by 35.6%, upper X-ray series by 55.3%, pepsinogens by 26.2% and breath-tests by 23.4%; accuracy, cost-effectiveness and feasibility among the tests varied widely. The attitude towards H. pylori vaccination was that 4.6% of the responders were eager to start vaccination immediately, 55.9% were supporting vaccination but considered that more data are required 12% were negative, and 27.6% did not have an opinion. In general, the attitude of the specialists was in line with guidelines, but was not always translated into clinical practice, particularly in the case of 'screen-and-treat' strategy.

Associations of the -238(G/A) and -308(G/A) TNF-α Promoter Polymorphisms and TNF-α Serum Levels with the Susceptibility to Gastric Precancerous Lesions and Gastric Cancer Related to Helicobacter pylori Infection in a Moroccan Population.

OBJECTIVE: Helicobacter pylori (H. pylori) induces the production of tumor necrosis factor-alpha (TNF-α), which is closely related to a gastric epithelial injury. TNF-α gene polymorphism and TNF-α serum levels are associated with various malignant conditions. Identification of the ideal marker for gastric cancer (GC) is still the leading aim of several trials. Physio-pathological considerations of GC led us to investigate the association of two TNF-α promoter polymorphisms (-308G>A and -238G>A), and TNF-α serum levels with the susceptibility to gastric precancerous (PL) and GC. METHODS: Patients suffering from gastric lesions (65 chronic gastritis, 50 PL, 40 GC) related to H. pylori infection , and 63 healthy controls (HC) were involved in this study. Individuals are genotyped by TNF-α gene promoter sequencing and TNF-α serum levels are measured by ELISA quantitative method. RESULTS: Regarding TNF-α-308 G/A locus, we noticed higher risk for GC (OR=4.3, CI 1.5-11.9, p-value=0.005)  and PL (OR=3.4, CI 1.2-9.2, p-value=0.01) for individuals with AA/GA genotypes compared to GG genotype. Concerning TNF-α-238 G/A locus, we noticed higher  risk for GC (OR=5.9, CI 1.2-27.5, p-value=0.01) and PL (OR=4.8, CI 1.3-18, p-value=0.01) for individuals with GG genotype compared to AA/GA genotypes. We noticed that TNF-α serum levels have been increased together with gastric lesions severity. Moreover, TNF-α-308 and TNF-α-238 A alleles seemed to, respectively, upregulate and downregulate TNF-α serum levels. CONCLUSION: The TNF-α -308 A allele has a promotive effect for GC progression, whereas the TNF-α -238 A allele has a protective function against GC progression. High levels of TNF-α seemed to be associated with the aggressiveness of gastric lesions. TNF-α gene polymorphisms and TNF-α serum levels might be helpful to select those patients who are at high risk for GC.

Involvement of Helicobacter Pylori in Ocular Adnexa Lymphoma.

Helicobacter pylori has been proposed as a possible etiologic factor of ocular adnexa lymphoma (OAL), although with conflicting results. To assess the involvement of H. pylori in OAL, as (1) H. pylori DNA positivity on OAL specimens, and (2) prevalence of H. pylori gastric infection in patients with OAL. A systematic review of studies assessing H. pylori in patients with OAL was conducted by searching electronic databases from their inception to May 2019. Pooled positivity for H. pylori in OAL specimens detected by polymerase chain reaction, and pooled prevalence of H. pylori gastric infection, were calculated with 95% confidence interval (CI). Eleven studies with 308 patients were included. Pooled positivity for H. pylori was 16.8% in all OALs and 22.7% in MALT OAL, with high heterogeneity among studies. Pooled prevalence of H. pylori gastric infection in patients with OAL was 34.7%, with low statistical heterogeneity. In conclusion, H. pylori seems to be involved in a subset of OAL, but the heterogeneity found needs to be investigated in further studies. The prevalence of H. pylori gastric infection in patients with OAL does not seem to differ from that of the general population.

Prevalence and Antibiotic Resistance Patterns of Helicobacter pylori Infection in Koh Kong, Cambodia.

BACKGROUND: Gastric cancer, which is the leading cause of cancer mortality in Cambodia, can be prevented by Helicobacter pylori (H. pylori) eradication. There is limited data about H. pylori strains in Cambodia. This study aimed to evaluate H. pylori prevalence and antibiotic resistance in Koh Kong, Cambodia. METHODS: 118 Cambodian dyspeptic patients were scheduled to enter this study and 58 were enrolled between July and September 2019. All patients underwent upper GI endoscopy. 3 gastric biopsies were obtained for rapid urease test, H. pylori culture with E-test and GenoType® HelicoDr (Hain Lifescience factory, Germany). 3-mL blood sample was collected for CYP2C19 genotyping. RESULTS: 58 subjects were enrolled (40 females, 18 males, mean age 43.8 years). Overall H. pylori prevalence was 31.0%. Antibiotic resistance rates were 78.6% for metronidazole, 50.0% for fluoroquinolones, and 27.8% for clarithromycin. There was no amoxicillin and tetracycline resistance. More than half of H. pylori strains (57.1%) were multidrug-resistant. Most (35.7%) were resistant to metronidazole and quinolone. Poor, intermediate and rapid metabolizers were 5.5%, 38.9% and 55.6%, respectively. CONCLUSIONS: H. pylori infection remains common infection in Cambodia. High prevalence of clarithromycin, metronidazole, levofloxacin and multidrug-resistant H. pylori is still major problems in Cambodia. Treatment regimens without clarithromycin and quinolone such as 14-day bismuth-based quadruple therapy might be an appropriate choice for H. pylori eradication in this particular area.

Contrasting serum biomarker profiles in two Colombian populations with different risks for progression of premalignant gastric lesions during chronic Helicobacter pylori infection.

BACKGROUND: Colombians in coastal Tumaco have a lower incidence of Helicobacter pylori-associated gastric cancer compared to individuals from Tuquerres in the high Andes. This is despite nearly universal prevalence of H. pylori infection and chronic gastritis. METHODS: H. pylori infection was confirmed by Steiner stain and serology using African and European-origin strains. Gastric histology and serum inflammatory biomarkers in dyspeptic Tumaco or Tuquerres patients were evaluated to predict progression of gastric lesions. RESULTS: H. pylori infection was nearly universal by Steiner stain and serology. IgG response to European-origin H. pylori strains were greater than African-origin. High gastric cancer-risk Tuquerres patients, compared to low-risk Tumaco, had significant odds ratios for lesion progression associated with serum IL-5, trefoil factor 3 (TFF3), and low pepsinogen I/II ratio. Sensitivity and specificity for these parameters was 63.8% and 67.9%, respectively, with correctly classifying patients at 66.7%. Most odds ratios for 26 other biomarkers were significant for the town of residency, indicating an environmental impact on Tumaco patients associated with decreased lesion progression. CONCLUSION: An IL-5 association with progression of gastric lesions is novel and could be evaluated in addition to TFF3 and pepsinogen I/II ratio as a non-invasive prognostic screen. Results suggest Tumaco patients were exposed to infectious diseases beyond H. pylori such as the documented high incidence of helminthiasis and toxoplasmosis. IMPACT: Results support a prior recommendation to evaluate TFF3 and pepsinogen I/II together to predict aggressive gastric histology. Our data indicate IL-5 should be further evaluated as prognostic parameter.

Association of Helicobacter pylori babA2 gene and gastric cancer risk: a meta-analysis.

BACKGROUND: The association of Helicobacter pylori (H. pylori) babA2 gene with gastric cancer (GC) was reported by several studies, but results were inconsistent. This meta-analysis was performed to investigate the relationship between H. pylori babA2 gene and GC risk. METHODS: Case-control studies involving the association between H. pylori babA2 gene and GC risk were systematically identified from PubMed databases. A meta-analysis was used to pool studies and to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of H. pylori babA2 gene associated with GC risk. RESULTS: Twenty studies were identified with a total of 1289 GC cases and 1081 controls. H. pylori babA2 gene was associated with an increased risk of GC by 2.05 fold (95% CI, 1.30-3.24, P = 0.002). In subgroup analysis, we found that H. pylori babA2 gene was significantly associated with GC risk in Asian population (OR = 2.63, 95% CI: 1.36-5.09 P = 0.004) but not in South American population (OR = 1.35, 95% CI: 0.69-2.64, P = 0.379). CONCLUSIONS: This meta-analysis indicates that H. pylori babA2 gene may be associated with increased risk of GC, especially in Asian population.

Gastric cancer: genome damaged by bugs.

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. Epstein-Barr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression. In this review, we summarized the related reports about the colonized microorganism in the stomach and discussed their specific roles in gastric tumorigenesis. Meanwhile, we highlighted the therapeutic significance of eradicating the microorganisms in GC treatment.

Long-term follow-up of Helicobacter pylori reinfection and its risk factors after initial eradication: a large-scale multicentre, prospective open cohort, observational study.

Helicobacter pylori (H. pylori) recurrence remains a significant public health concern. The study aimed to assess H. pylori reinfection rate and identify its risk factors in China. This prospective open cohort, observational study was performed at 18 hospitals across 15 provinces in China. Consecutive patients who received the successful initial eradication during 1 January 2012 and 31 December 2018 were eligible for enrolment. H. pylori recurrence was defined as reinfection that occurred at more than the 12-month interval after successful initial eradication. Surveyed risk factors that might be associated with reinfection were preliminarily estimated by log-rank test and further determined by Cox regression model to calculate the hazard ratio (HR) and 95% confidence interval (CI). A total of 5193 subjects enrolled in the study. The follow-up intervals varied from 6 to 84 months with a general follow-up rate of 67.9%. Annual reinfection rate was 1.5% (95% CI: 1.2-1.8) per person-year. H. pylori reinfection was independently associated with the following five risk factors: minority groups (HR = 4.7, 95% CI: 1.6-13.9), the education at lower levels (HR = 1.7, 95% CI: 1.1-2.6), a family history of gastric cancer (HR = 9.9, 95% CI: 6.6-14.7), and the residence located in Western China (HR = 5.5, 95% CI: 2.6-11.5) following by in Central China (HR = 4.9, 95% CI: 3-8.1) (all P < 0.05). Reinfection rate of H. pylori in China is relatively low. Patients with specific properties of ethnic groups, education level, family history, or residence location appear to be at higher risk for reinfection.

Screening, Monitoring, and Treatment of Precancerous Atrophic Gastritis in the Prospective Study for Seven Years.

AIM: Develop a program to identify, treat, and prevent severe atrophic gastritis to reduce gastric cancer incidence and mortality. MATERIALS AND METHODS: In total, 2,847 people aged > 40 years old underwent serological noninvasive screening for atrophic gastritis by identifying postprandial gastrin-17 and pepsinogen-1 in the fasting state. Anti-H pylori IgG was found in 2,134 patients. Seven years later, 2,220 patientswho had undergone serological noninvasive screening were asked to fill out a questionnaire survey (were interviewed). We could not find any information on 627 of 2,847 patients. Next, 75 patients with multifocal atrophic gastritis who underwent gastroscopy and biopsies (the Updated Sydney System (USS)) were selected. To study gastrin-17 production, morpho-functional correlation was studies in 75 patients with multifocal atrophic gastritis. RESULTS: During seven years, no reported case of gastric cancer was done among 2,220 persons who underwent serological screening and treatment. In the same population, 4.3 persons who did not receive screening during the same period, developed gastric cancer and died of it. In this study, we can say that 4.3 lives were saved out of 2,220 tested persons. The cost for screening this number of people amounted to €23,750. A comparison of the prevalence rate of the four stages of multifocal atrophic gastritis based on the data of the histopathology tests and noninvasive serologic screening in accordance with OLGA classification showed a strong correlation (the correlation coefficient is 0.812). This finding suggested that using this classification not only for histopathology tests for atrophic gastritis but also for serologic markers of antral mucosa and corpus ventriculi atrophy: gastrin-17 and pepsinogen-1. CONCLUSION: Complex pathogenetic treatment of atrophic gastritis significantly reduced gastric cancer risk and incidence for such patients.
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Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1-mediated DNA methylation mechanism.

Krüppel-like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5-hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA-TET1-KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

Changing trends in cancer incidence of upper aerodigestive tract and stomach in Japanese alcohol-dependent men (1993-2018).

BACKGROUND: Esophageal squamous cell carcinoma (ESCC), head and neck SCC (HNSCC), and gastric adenocarcinoma (GA) are frequently detected at an early stage using endoscopic screening in Japanese alcohol-dependent men. METHODS: We performed endoscopic screening with esophageal iodine staining and oropharyngolaryngeal inspection in 7582 Japanese alcohol-dependent men (40-79 years) during 1993-2018, and retrospectively investigated their initial screening results. RESULTS: The 2008-2018 screening showed lower detection rates for ESCC (2.6% vs 4.0%, P = .0009) and GA (0.5% vs 1.4%, P < .0001) for all age brackets, compared with the 1993-2007 screening. The HNSCC detection rate did not change (1.0% vs 1.1%). Multiple logistic regression analyses showed that the 2008-2018 screening had a reduced OR (95% CI) for ESCC (0.34 [0.25-0.47]) and GA (0.19 [0.10-0.35]), compared with the 1993-2007 screening. The reduction in H pylori infection is probably the main reason for the decrease in GA detection over time. Declining trends in pack-years and gastric atrophy and increasing trends in age and body mass index (BMI) were found over time. The presence of advanced gastric atrophy increased the risk for ESCC as well as GA. The inactive heterozygous aldehyde dehydrogenase-2*1/*2 genotype was a strong risk factor for ESCC, HNSCC, and GA. Fewer pack-years and a larger BMI decreased the ESCC risk. However, these confounders cannot fully explain why the incidence of ESCC has decreased markedly over the recent decade. CONCLUSIONS: The detection rates of ESCC and GA have markedly decreased during the past decade in the alcohol-dependent population. The enigmatic declining trend of ESCC warrants research on this topic.

The impact of race and socioeconomic status on the presentation, management and outcomes for gastric cancer patients: Analysis from a metropolitan area in the southeast United States.

BACKGROUND: Socioeconomic disparities in gastric cancer have been associated with differences in care and inferior outcomes. We evaluated the presentation, treatment, and survival for patients with gastric cancer (GC) in a metropolitan setting with a large African American population. METHODS: Retrospective cohort analysis of patients with GC (2003-2018) across a multi-hospital system was performed. Associations between socioeconomic and clinicopathologic data with the presentation, treatment, and survival were examined. RESULTS: Of 359 patients, 255 (71%) were African American and 104 (29%) Caucasian. African Americans were more likely to present at a younger age (64.0 vs 72.5, P < .001), have state-sponsored or no insurance (19.7% vs 6.9%, P = .02), reside within the lowest 2 quintiles for median income (67.4% vs 32.7%, P < .001), and have higher rates of Helicobacter pylori (14.9% vs 4.8%, P = .02). Receipt of multi-modality therapy was not impacted by race or insurance status. On multivariable analysis, only AJCC T class (HR 1.68) and node positivity (HR 2.43) remained significant predictors of disease-specific survival. CONCLUSION: Despite socioeconomic disparities, African Americans, and Caucasians with GC had similar treatment and outcomes. African Americans presented at a younger age with higher rates of H. pylori positivity, warranting further investigation into differences in risk factors and tumor biology.

Helicobacter pylori infection is associated with diabetes among Chinese adults.

AIMS/INTRODUCTION: Several epidemiological studies investigated the effect of Helicobacter pylori infection on diabetes, but the conclusions remained inconsistent. We aimed to explore the relationship between H. pylori infection and diabetes, as well as glycemic metabolism profiles. MATERIALS AND METHODS: A cross-sectional study including 58,482 Chinese adults was carried out between January 2016 and December 2017. H. pylori infection was diagnosed by the 13 C-urea breath test. Multivariate regression analyses were carried out to evaluate the association of H. pylori infection with diabetes. RESULTS: Of the 58,482 participants, 3,449 (5.9%) had diabetes. The H. pylori-positive participants had a higher rate of diabetes (7.3% vs 5.2%, P < 0.001), and higher levels of fasting plasma glucose (5.36 ± 1.12 mmol/L vs 5.28 ± 0.95 mmol/L, P < 0.001) and glycated hemoglobin A1c (5.63 ± 0.68% vs 5.57 ± 0.60%, P < 0.001) than the H. pylori negative group. Multivariate regression analyses showed that H. pylori infection was positively related to diabetes (odds ratio 1.25, 95% confidence interval 1.15-1.35). Among the H. pylori-positive participants, the elevated levels of fasting plasma glucose and glycated hemoglobin A1c were 0.033 mmol/L (95% confidence interval 0.016-0.049 mmol/L) and 0.024% (95% confidence interval 0.008-0.041%), respectively. Additionally, H. pylori infection was significantly related to diabetes in participants aged ≥44 years, but not in participants aged <44 years. CONCLUSIONS: The present study showed that H. pylori infection is associated with diabetes among Chinese adults. More attention should be paid to adults with H. pylori infection for effective prevention of diabetes.

Combination of Bismuth and Standard Triple Therapy Eradicates Helicobacter pylori Infection in More than 90% of Patients.

BACKGROUND & AIMS: Due to the poor eradication rates of standard triple therapy, the addition of bismuth salts has been proposed for first-line eradication of Helicobacter pylori. We assessed the effectiveness and safety of the combination of bismuth and the standard, clarithromycin-containing triple therapy in eradication of H pylori infection, using data from a large multi-center registry. METHODS: We performed an interim analysis of data from the European Registry on H pylori Management, a prospective trial registering clinical data and outcomes from infected patients from 27 countries in Europe since 2013. We extracted data on 1141 treatment-naïve patients who received first-line treatment with bismuth salts (240 mg) and a proton pump inhibitor (57% received esomeprazole, 18% received omeprazole, 11% received pantoprazole, and 14% received rabeprazole), amoxicillin (1 g), and clarithromycin (500 mg), all taken twice daily. RESULTS: Intention to treat and per-protocol rates of eradication were 88% and 94%, respectively. Intention to treat eradication increased to 93% in patients who received 14-day treatments. Adverse events occurred in 36% of patients; 76% of these events were mild, with a mean duration of 6 days. In multivariate analysis, eradication was associated with treatment compliance (odds ratio [OR], 13.0), a double dose (equivalent to 40 mg omeprazole) of proton pump inhibitor (OR, 4.7), and 14-day duration of treatment (OR, 2.0). CONCLUSIONS: In an analysis of data from a large multi-center registry, we found the addition of bismuth to 14-day standard triple therapy with clarithromycin and amoxicillin to eradicate H pylori infection in more than 90% of patients, based on intention to treat analysis, with an acceptable safety profile and level of adherence. ClinicalTrials.gov no: NCT02328131.

Development of a novel gene signature in patients without Helicobacter pylori infection gastric cancer.

Gastric cancer (GC) is one of the most fatal common cancers in worldwide. Helicobacter pylori (H. pylori) infection is closely related to the development of GC, although the mechanism is still unclear. In our study, we aim to develop a robust messenger RNA (mRNA) signature associated with H. pylori (-) GC that can sensitively and efficiently predict the prognostic. The RNA-seq expression profile and corresponding clinical data of 598 gastric cancer samples and 63 normal samples obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Using gene set enrichment analysis H. pylori (+) GC and H. pylori (-) GC patients and normal samples to select certain genes for further analysis. Using univariate and multivariate Cox regression model to establish a gene signature for predicting the overall survival (OS). Finally, we identified G2/M related seven-mRNA signature (TGFB1, EGF, MKI67, ILF3, INCENP, TNPO2, and CHAF1A) closely related to the prognosis of patients with H. pylori (-) GC. The seven-mRNA signature was identified to act as an independent prognostic biomarker by stratified analysis and multivariate Cox regression analysis. It was also validated on two test groups from TCGA and GSE15460 and shown that patients with high-risk scores based on the expression of the seven mRNAs had significantly shorter survival times compared to patients with low-risk scores (P < .0001). In this study, we developed a seven-mRNA signature related to G2/M checkpoint from H. pylori (-) GCs that as an independent biomarker potentially with a good performance in predicting OS and might be valuable for the clinical management for patients with GC.