Evolution of the Correa's cascade steps: A long-term endoscopic surveillance among non-ulcer dyspepsia and gastric ulcer after H. pylori eradication.

BACKGROUND: This study is aimed toward investigating the evolution of each Correa's step after Helicobacter pylori eradication in a long-term follow-up and exploring the factors correlated with a high-risk of gastric cancer. METHODS: A total of 1824 H. pylori-infected subjects were enrolled to receive screening endoscopy. Among them, 491 received surveillance endoscopy. The patients were divided into Correa's steps I to VI, from normal to gastric cancer. A group-based trajectory model was used to classify patients as persistent high-risk status or not. RESULTS: The prevalence rates of positive corpus-predominant gastritis index (CGI) were 20%-40% in all age groups and Correa's steps IV-V increased >35% after 50 years based on screening endoscopy. Successful eradication of H. pylori regressed CGI after the 1st year-and-thereafter (P < 0.05) and decreased Correa's step progression (Relative risk 0.66 [95% CI 0.49-0.89], P = 0.01); however, it did not regress OLGA and OLGIM. Not only in steps IV-V, but also in step III, the patients had a risk of developing gastric cancer (11.13-76.41 and 4.61 per 1000 person-years). Age (Hazard ratio 1.012 [1.003-1.020], P = 0.01), OLGA stages ≥ I (2.127 [1.558-2.903], P < 0.001), and OLGIM stages ≥ I (1.409 [1.119-1.774], P = 0.004) were correlated independently with a persistent high-risk status. CONCLUSION: The patients in Correa's steps III-V, but not I-II, were at risk of gastric cancer after H. pylori eradication. Age, OLGA stages ≥ I, and OLGIM stages ≥ I were independent factors correlated to a persistent high-risk of gastric cancer. The data may be useful when scheduling surveillance endoscopy for subjects in each Correa's step (NCT04527055).

Atrophic gastritis in Helicobacter pylori-infected children.

BACKGROUND: Helicobacter pylori infection is the leading cause of peptic ulcer and chronic gastritis and may initiate gastric carcinogenesis following the Correa cascade. Another lineage of metaplasia, spasmolytic peptide-expressing metaplasia (SPEM) has recently been found to be an alternative precursor to gastric cancer. To date, few reports have investigated gastric precancerous lesions among children with H. pylori infection. This study aimed to evaluate the histopathological pattern of H. pylori atrophic gastritis in children and the extent of precancerous lesions. MATERIALS AND METHODS: This study enrolled pediatric patients with H. pylori infection from 1998 to 2019. During esophagogastroduodenoscopy examinations, biopsy fragments were collected from the gastric antrum and corpus for rapid urease test, culture, and histology evaluation. The presence and degree of chronic inflammation, activity of gastritis, H. pylori density, atrophy, and intestinal metaplasia (IM) were assessed according to the modified Updated Sydney System. Trefoil factor 2 (TFF2) immunohistochemistry was also performed to assess SPEM in the gastric tissues collected from each case using rabbit anti-human TFF2 antibodies. RESULTS: A total of 92 children with H. pylori infection and adequate gastric mucosa biopsies were enrolled. Esophagogastroduodenoscopy showed that 39 (42.4%) had duodenal ulcers, 11 (12.0%) had gastric ulcers, 41 (44.6%) had gastritis, and 1 (1.1%) had negative findings. Mild-to-moderate IM was identified in 4 patients (4.3%). SPEM was found in 8 patients (8.7%) with a significantly higher incidence among female patients (15.8% vs. 8.7%, p = .031). Gastric glandular atrophy presented in 28 patients (30.4%), and high-grade atrophy was more common in female patients (3.2% vs. 1.9%, p = .031). CONCLUSIONS: The prevalence rates of atrophic gastritis in the children with H. pylori infection were 30.4% for gastric glandular atrophy, 4.3% for IM and 8.7% for SPEM. SPEM and high-grade atrophy were more common in female patients.

Optimizing the MIC breakpoints of amoxicillin and tetracycline for antibiotic selection in the rescue therapy of H. pylori with bismuth quadruple regimen.

PURPOSE: H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. METHODS: We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. RESULTS: The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025). CONCLUSION: Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.

H. pylori isolates with amino acid sequence polymorphisms as presence of both HtrA-L171 & CagL-Y58/E59 increase the risk of gastric cancer.

BACKGROUND: H. pylori CagL-Y58/E59 increase gastric cancer risk by stronger binding with integrin to faciliate type IV secretory system (T4SS). H. pylori can secrete high temperature requirement A (HtrA) to mediate E-Cadherin cleavage for gastric epithelial junction disruption, so H. pylori CagL can adhere to integrin located on basolateral side of epithelium. The study test whether H. pylori HtrA amino acid polymorphisms can increase gastric cancer risk synergistically with CagL-Y58/E59. METHODS: One-hundred and sixty-four H. pylori-positive patients, including 71 with non-ulcer dyspepsia (NUD), 63 with peptic ulcers (PU), and 30 with gastric cancers (GC), were enrolled to receive upper gastrointestinal endoscopy to obtain gastric biopsies for H. pylori culture and histology by the updated Sydney system. Each isolate was screened for htrA & cagL genotype by polymerase chain reaction and HtrA & CagL-Y58/E59 amino acid sequence polymorphisms by sequencing. RESULTS: The prevalence rates of htrA & cagL gene were both 100%. The HtrA amino acid sequence polymorphisms were not different between NUD and PU. The H. pylori isolates of GC had higher rates of HtrA residue 171 as leucine than those of NUD (73.3% vs. 50.7%, P = 0.036, OR[95%CI] = 2.7[1.1-6.8]). The risk of the H. pylori-infected subjects to get gastric cancer was increased up to 15.4-fold, if the infected isolates had presence of both HtrA-L171 and CagL-Y58/E59 (P < 0.001). CONCLUSIONS: The H. pylori isolates of gastric cancer subjects had a higher rate of HtrA-L171. H. pylori isolates with presence of both HtrA-171 & CagL-Y58/E59 can synergistically increase the risk of gastric cancer.

Spasmolytic polypeptide-expressing metaplasia associated with higher expressions of miR-21, 155, and 223 can be regressed by Helicobacter pylori eradication in the gastric cancer familial relatives.

BACKGROUND AND AIMS: Spasmolytic polypeptide-expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori-infected first-degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR-21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication. METHODS: We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR-21, 155, and 223 before and after eradication. RESULTS: GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P < 0.01) than controls. The tissue miR-21, 155, and 223 in antrum were higher in cases with SPEM than in those without SPEM (P <= 0.05). There was similar SPEM reversibility after H pylori eradication between GCF subjects and controls (72% vs 69%, P = 0.852). In the SPEM regressed cases, tissue miR-21, 155, and 223 decreased after H pylori eradication (P < 0.05). CONCLUSION: The H pylori-infected GCF subjects were prone to have SPEM with higher tissues miR-21, 155, and 223 expressions. H pylori eradication can result in a 70% SPEM regression, accompanied by a decline in miR-21, 155, and 233 expression levels.

Male non-insulin users with type 2 diabetes mellitus are predisposed to gastric corpus-predominant inflammation after H. pylori infection.

BACKGROUND: Both H. pylori infection and diabetes increase the risk of gastric cancer. This study investigated whether patients with type 2 diabetes mellitus (T2DM) and H. pylori infection had more severe corpus gastric inflammation and higher prevalence of precancerous lesions than non-diabetic controls. METHODS: A total of 797 patients with type 2 diabetes mellitus were screened for H. pylori, of whom 264 had H. pylori infection. Of these patients, 129 received esophagogastroduodenoscopy to obtain topographic gastric specimens for gastric histology according to the modified Updated Sydney System, corpus-predominant gastritis index (CGI), Operative Link on Gastritis Assessment, and Operative Link on Gastric Intestinal Metaplasia Assessment. Non-diabetic dyspeptic patients who had H. pylori infection confirmed by esophagogastroduodenoscopy were enrolled as controls. RESULTS: The male as well as total T2DM patients had higher acute/chronic inflammatory and lymphoid follicle scores in the corpus than non-diabetic controls (p < 0.05). In contrast, the female T2DM patients had higher chronic inflammatory scores in the antrum than the controls (p < 0.05). In T2DM patients, the males had significantly higher rates of CGI than the females (p < 0.05). Multivariate logistic regression analysis showed that male patients (odds ratio: 2.28, 95% confidence interval: 1.11-4.69, p = 0.025) and non-insulin users (odds ratio: 0.33, 95% confidence interval: 0.15-0.74, p = 0.007) were independent factors for the presence of CGI in the H. pylori-infected patients with type 2 diabetes mellitus. CONCLUSIONS: Patients with type 2 diabetes mellitus and H. pylori infection had more severe corpus gastric inflammation than non-diabetic controls. Moreover, male gender and non-insulin users of T2DM patients were predisposed to have corpus-predominant gastritis after H. pylori infection. TRIAL REGISTRATION: ClinicalTrial: NCT02466919 , retrospectively registered may 17, 2015.

Serum Level of Trefoil Factor 2 can Predict the Extent of Gastric Spasmolytic Polypeptide-Expressing Metaplasia in the H. pylori-Infected Gastric Cancer Relatives.

BACKGROUND & AIMS: Gastric cancer has familial clustering in incidence, and the familial relatives of gastric cancer sufferers are prone to have spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM) after H. pylori infection. This study tested whether serum pepsinogen I/II and trefoil factor family (TFF) proteins can predict SPEM or IM in the H. pylori-infected relatives of patients with gastric cancer. METHODS: We prospectively enrolled 119 H. pylori-infected relatives of gastric cancer patients of noncardiac gastric cancer patients, who then received panendoscopy to obtain gastric biopsy to define the presence of corpus gastritis index (CGI), SPEM, and IM. The advanced SPEM in histology was defined by TFF2 immunohistochemistry. Each patient also had checkups of serum TFF2, TFF3, and pepsinogen I/II by enzyme-linked immunosorbent assay (ELISA). RESULTS: The 119 H. pylori-infected relatives included 61 with SPEM, and 34 with IM. The presence of either IM or SPEM was not related to the serum TFF2, TFF3, and pepsinogen I/II levels (p > .05). Serum TFF2 levels were higher in relatives with CGI who also had advanced SPEM (p = .032). For relatives without CGI, the elevated serum TFF2 levels correlated with higher H. pylori density and more severe gastritis in antrum (p = .001). CONCLUSION: The serum TFF2 level cannot predict SPEM or IM in H. pylori-infected relatives of patients with gastric cancer. For H. pylori-infected relatives with CGI, serum TFF2 levels may predict the advanced severity of SPEM. Elevated serum TFF2 levels may indicate severe H. pylori-related inflammation, at risk of development or progression of SPEM in relatives without CGI.

The corpus-predominant gastritis index can be an early and reversible marker to identify the gastric cancer risk of Helicobacter pylori-infected nonulcer dyspepsia.

BACKGROUND: Corpus-predominant gastritis index (CGI) is an early histological marker to identify Helicobacter pylori-infected gastric cancer relatives at risk of cancer. This study validated whether CGI is more prevalent in H. pylori-infected nonulcer dyspepsia (NUD) subjects than in duodenal ulcer (DU) controls and whether it is reversible after H. pylori eradication or is correlated with noninvasive biomarkers. MATERIALS AND METHODS: In this longitudinal cohort study, 573 H. pylori-infected subjects were enrolled, including 349 NUD and 224 DU. Gastric specimens were provided to assess CGI, spasmolyic polypeptide-expressing metaplasia (SPEM), and Operative Link on Gastric Intestinal Metaplasia assessment (OLGIM). Serum pepsinogen I and II levels were assessed using enzyme-linked immunosorbent assay. CGI subjected were followed up at least 1 year after H. pylori eradication. RESULTS: NUD subjects had higher prevalence rates of CGI (47.0% vs 29.9%, P<.001) and OLGIM stages III-IV (24.1% vs 15.2%, P=.01) than controls. CGI was highly prevalent in NUD subjects after the age of 40, which was 10 years earlier than atrophic gastritis and intestinal metaplasia. NUD subjects with CGI had higher risk of SPEM (OR 2.86, P<.001) and lower serum pepsinogen I/II ratios (P<.001) than those without CGI. Serum pepsinogen I/II ratios <9 could predict CGI modestly (AUROC 0.69, 95% CI: 0.63-0.74). CGI was regressed after eradication (P<.001). CONCLUSIONS: CGI was more prevalent in H. pylori-infected NUD subjects than in controls, was correlated with SPEM, and may serve as a marker earlier than OLGIM to indicate risk of gastric cancer. Moreover, CGI could be regressed after eradication.

Osteopontin polymorphism increases gastric precancerous intestinal metaplasia susceptibility in Helicobacter pylori infected male.

AIM: Whether genetic polymorphisms of osteopontin (OPN) coding gene, SPP1, determine the risk of gastric precancerous intestinal metaplasia (IM) in Helicobacter pylori infected patients. PATIENTS & METHODS: Helicobacter pylori infected patients (100 with and 210 without IM) were recruited to evaluate the associations of SPP1 promoter polymorphisms with gastric IM and adjusted for age, sex and smoking. Gastric OPN expression and inflammation were evaluated by immunohistochemistry, and haemotoxylin and eosin stain. RESULTS: Only in males, but not females, carriage of both GG genotype at rs11730059 and C-G-C haplotype at rs6833161-rs2853744-rs11730582 significantly increased the IM risk (OR: 4.92; 95% CI: 1.65-14.65; p = 0.004). Nearly 87.5% of males with IM carried risky genotype or haplotype. Carriers of the risky genotype or haplotype also had increased gastric OPN expression (p = 0.038) and inflammation (p = 0.007). CONCLUSION: SPP1 polymorphisms predispose to IM development in H. pylori infected males.

Genomic single nucleotide polymorphisms in the offspring of gastric cancer patients predispose to spasmolytic polypeptide-expressing metaplasia after H. pylori infection.

BACKGROUND: Gastric cancer exhibits familial clustering, and gastric cancer familial relatives (GCF) tend to present with corpus-predominant gastritis and precancerous lesions as SPEM or IM after H. pylori infection. The study determined whether the children of gastric cancer patients (GCA) had genomic single nucleotide polymorphisms (SNPs) predisposed to the gastric precancerous lesions as spasmolytic polypeptide-expressing metaplasia (SPEM) or intestinal metaplasia (IM). RESULTS: There were 389 family relatives of 193 non-cardiac GCA and 173 duodenal ulcer patients (DU), received blood sampling for DNA collection. The differences of the risk alleles of SNPs in the ITGA5, ITGB1, IL-10, COX-2, RUNX3, and TFF2 genes were compared between 195 children of GCA and 143 DU. The children of GCA had higher allele frequencies of ITGA5-1160 T-carrier (P = 0.006, OR[95% CI] = 2.2[1.2-4]), ITGB1-1949 A-carrier (P = 0.047; OR[95% CI] = 2.8[1.4-5.3]), ITGB1 + 31804 C-carrier (P = 0.013; OR[95% CI] = 4.7[1.7-13.0]), IL-10-592 AA (P = 0.014; OR[95% CI] = 2.3[1.4-4.0]) and COX-2-1195 G-carrier (P = 0.019; OR[95% CI] = 1.7[0.9-3.2]) than DU. The combined genotype with ITGA5-1160/ITGB1-1949/ITGB1 + 31804 as T/A/C carriers and COX-2-1195/IL-10-592 as G-carrier/AA was more prevalent in the children of GCA than in DU (P < 1×10(-4)), and predisposed with a 5.3-fold risk of getting SPEM in the H. pylori-infected children of GCA (P = 0.016). Such risk of getting SPEM increased to 112 folds, if combined with RUNX3 + 492/TFF2-308 as A-carrier/CC in this limited study scale (P = 1×10(-4)). CONCLUSIONS: The SNPs of ITGA5-1160/ITGB1-1949/ ITGB1 + 31804 as T/A/C carriers and COX-2-1195/IL-10-592 as G-carrier/AA, or more specific to combine RUNX3 + 492/TFF2-308 as A-carrier/CC shall be host factor predisposing to gastric cancer during H. pylori infection, and serve as marker to identify high-risk subjects for H. pylori eradication.

Intracellular Osteopontin Induced by CagA-positive Helicobacter pylori Promotes Beta-catenin Accumulation and Interleukin-8 Secretion in Gastric Epithelial cells.

BACKGROUND: Osteopontin, an important immune modulator and oncogenic promoter, is upregulated in H. pylori-infected gastric mucosa. However, the underlying mechanisms and biological significance are poorly understood. We investigated whether osteopontin was upregulated in gastric epithelial cells by H. pylori and the virulence factors involved. Moreover, cellular component changes caused by osteopontin were also investigated. MATERIALS AND METHODS: The gastric epithelial cell line MKN45 was cocultured with wild-type and mutant H. pylori to analyze osteopontin expression. Beta-catenin levels in cell lysate and interleukin-8 levels in supernatant were analyzed. The difference in osteopontin expression levels in both gastric epithelium and plasma was compared between H. pylori-infected patients and uninfected controls. RESULTS: H. pylori induced intracellular, but not secretory, osteopontin expression in MKN45 cells. Accordingly, osteopontin expression intensity in gastric epithelium was higher in H. pylori-infected patients than in controls, but osteopontin levels in plasma were similar between both patient groups. H. pylori virulence factor CagA delivered via the type IV secretion system was essential for intracellular osteopontin upregulation. H. pylori induced ß-catenin accumulation and interleukin-8 secretion, whereas osteopontin knockdown completely abrogated these effects, in MKN45 cells. TLR2 antagonist abolished iOPN expression induced by H. pylori gastritis strain, but not by H. pylori cancer strain. CONCLUSIONS: H. pylori is dependent on CagA translocation via the type IV secretion system to induce intracellular osteopontin expression in gastric epithelial cells. Upregulated intracellular osteopontin may promote gastric carcinogenesis via increased ß-catenin accumulation and interleukin-8 secretion.

Response evaluation with endoscopic ultrasound and computed tomography in esophageal squamous cell carcinoma treated by definitive chemoradiotherapy.

BACKGROUND AND AIM: We assessed the feasibility of combined endoscopic ultrasound and computed tomography on response evaluation in patients with esophageal squamous cell carcinoma treated by definitive chemoradiotherapy, and the impact of response on prognosis. METHODS: Sixty patients treated by definitive chemoradiotherapy were followed by miniprobe endoscopic ultrasound and computed tomography. The post-treatment esophageal wall thickness was measured by miniprobe endoscopic ultrasound. Metastatic tumors were evaluated by computed tomography. The correlation between post-treatment image findings and prognosis was evaluated. RESULTS: Twenty-four patients (40%) had esophageal stricture after chemoradiotherapy, which limited complete evaluation by endoscopy. Miniprobe successfully penetrated all strictures to measure post-treatment esophageal wall thickness. Both post-treatment esophageal wall thickness < 8 mm measured by endoscopic ultrasound and no enlargement of metastatic tumor foci on computed tomography predicted good prognosis (P = 0.001). Combined evaluation with these two modalities improved survival prediction (P < 0.001). Patients who met the above two criteria after chemoradiotherapy had the longest survival compared with those who met only one or none of the criteria. The corresponding median survivals were > 30 months, 16.8 months and 7.1 months, respectively (P < 0.001). On multivariate analysis, treatment response is the strongest independent prognostic factor (hazard ratio 3.65, P = 0.006) regardless of baseline tumor-node-metastasis staging and chemoradiation regimen. CONCLUSIONS: Response evaluation by miniprobe endoscopic ultrasound and computed tomography can predict the prognosis of esophageal squamous cell carcinoma patients treated by definitive chemoradiotherapy. Those who were judged as poor responder should receive additional treatment to improve outcome.

Clinical and pathological correlates of severity classifications in trigger fingers based on computer-aided image analysis.

BACKGROUND: The treatment of trigger finger so far has heavily relied on clinicians' evaluations for the severity of patients' symptoms and the functionality of affected fingers. However, there is still a lack of pathological evidence supporting the criteria of clinical evaluations. This study's aim was to correlate clinical classification and pathological changes for trigger finger based on the tissue abnormality observed from microscopic images. METHODS: Tissue samples were acquired, and microscopic images were randomly selected and then graded by three pathologists and two physicians, respectively. Moreover, the acquired images were automatically analyzed to derive two quantitative parameters, the size ratio of the abnormal tissue region and the number ratio of the abnormal nuclei, which can reflect tissue abnormality caused by trigger finger. A self-developed image analysis system was used to avoid human subjectivity during the quantification process. Finally, correlations between the quantitative image parameters, pathological grading, and clinical severity classification were assessed. RESULTS: One-way ANOVA tests revealed significant correlations between the image quantification and pathological grading as well as between the image quantification and clinical severity classification. The Cohen's kappa coefficient test also depicted good consistency between pathological grading and clinical severity classification. CONCLUSIONS: The criteria of clinical classification were found to be highly associated with the pathological changes of affected tissues. The correlations serve as explicit evidence supporting clinicians in making a treatment strategy of trigger finger. In addition, our proposed computer-aided image analysis system was considered to be a promising and objective approach to determining trigger finger severity at the microscopic level.

Long-term celecoxib can prevent the progression of persistent gastric intestinal metaplasia After H. pylori eradication.

BACKGROUND AND AIM: Intestinal metaplasia (IM) has overexpressions of COX-2. Short-term 8-week celecoxib, a selective COX-2 inhibitor, exerts a preliminary hint to improve regression in part for persistent IM after Helicobacter pylori eradication. This study further validated whether or not a prolonged duration of celecoxib of up to 1 year can be safe and effective. METHODS: One hundred and forty patients, with persistent IM after H. pylori eradication for 1 year, were included with half of them receiving celecoxib 200 mg/day for 12 months and the other half serving as controls. Each patient received serial checkups of blood creatinine levels every 4 months. After the 1-year follow-up, panendoscopy was repeated to assess the IM regression. The serial gastric specimens, taken before and after celecoxib therapy, were immunochemically stained for COX-2. RESULTS: The intention-to-treat (ITT) and per-protocol (PP) analyses to the rates of IM regression were higher in the celecoxib group than in the controls (ITT: 44.3% [31/70] vs 14.3% [10/70], p < .001; and PP: 51.7% [31/60] vs 16.1% [10/62], p < .001). All enrolled patients had no renal impairment during follow-up. Even in the patients without IM regression, the mean IM scores and COX-2 expressions were significantly more decreased in the celecoxib group than in the controls (p < .005). CONCLUSION: One year 200-mg celecoxib daily be safely administered to improve the regression or prevent the progression of persistent IM after H. pylori eradication.

Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways.

BACKGROUND: H. pylori infection may trigger Smad7 and NFκB expression in the stomach, whereas probiotics promote gastrointestinal health and improve intestinal inflammation caused by pathogens. This study examines if probiotics can improve H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways. RESULTS: Challenge with H. pylori increased IL-8 and TNF-α expressions but not TGF-ß1 in MKN45 cells. The RNA levels of Smad7 in AGS cells increased after H. pylori infection in a dose-dependent manner. A higher dose (MOI 100) of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-ß1. Such anti-inflammatory effect was mediated via increased cytoplasmic IκBα and depletion of nuclear NFκB. L. acidophilus also inhibited H. pylori-induced Smad7 transcription by inactivating the Jak1 and Stat1 pathways, which might activate the TGF-ß1/Smad pathway. L. acidophilus pre-treatment ameliorated IFN-γ-induced Smad7 translation level and subsequently reduced nuclear NF-κB production, as detected by western blotting. CONCLUSIONS: H. pylori infection induces Smad7, NFκB, IL-8, and TNF-α production in vitro. Higher doses of L. acidophilus pre-treatment reduce H. pylori-induced inflammation through the inactivation of the Smad7 and NFκB pathways.

H. pylori clinical isolates have diverse babAB genotype distributions over different topographic sites of stomach with correlation to clinical disease outcomes.

BACKGROUND: Intragenomic recombination between babA and babB mediates antigenic variations and may help H. pylori colonization. This study determined whether variable genotypes of babA and babB correlate to different clinical disease outcomes, and can distribute over the different gastric niches. RESULTS: This study enrolled 92 clinical strains (45 from peptic ulcer, 27 from gastritis, and 20 from gastric cancer) to detect whether the babA and babB are at locus A or B by PCR reactions using the primers designed from the upstream and variable region of the babA and babB genes. Four genotypes of babA and babB (A B, AB B, A AB, AB AB) were found. The distribution of the 4 genotypes in 92 clinical strains was significantly different among patients with different gastric diseases (p < 0.05). The isolates from gastric cancer patients had a higher rate of AB AB genotype than those from non-cancer patients (40.0% vs. 9.7%, p < 0.05). The AB AB genotype was associated with a higher intensity of intestinal metaplasia (p < 0.05), but did not correlate with a higher inflammation and colonization density in gastric histology (p > 0.05). Besides, the study enrolled 19 patients to verify whether variable genotypes of babAB existed in the different gastric niches. Among the patients infected with more than one babAB genotypes over antrum and corpus, there were higher rate of genotypes as A B or AB AB in isolates from antrum than in those from corpus (75.0 % vs. 16.7%, p < 0.05). CONCLUSIONS: The H. pylori isolate with the AB AB genotype correlates with an increased gastric cancer risk, and colonize in an antrum predominant manner.

Higher motility enhances bacterial density and inflammatory response in dyspeptic patients infected with Helicobacter pylori.

BACKGROUND: Motility mediated by the flagella of Helicobacter pylori is important for the cells to move toward the gastric mucus in niches adjacent to the epithelium; then, H. pylori uses the adhesin SabA to interact with sialyl-Le(x) on inflammatory host cells for persistent infection. Here, we reveal the clinical association of bacterial motility, SabA expression, and pathological outcomes. METHODS: Ninety-six clinical isolates were screened for bacterial motility, and the expression of SabA of each isolate was confirmed by Western blotting. H. pylori-infected patients were assessed for their bacterial density, sialyl-Le(x) expression, inflammatory scores, and clinical diseases. RESULTS: The mean diameter in the motility assay was 17 mm, and eight (8.3%) of the strains had impaired motility, with a diameter <5 mm. H. pylori density in cardia, the acute inflammatory score in the body locus, and the prevalence rate of gastric atrophy were increased in patients infected with higher-motility strains (p = .023, <.001, or <.001, respectively). The total inflammatory scores (both acute and chronic) and bacterial density dramatically increased in patients expressing the sialyl-Le(x) antigen and infected with higher-motility, SabA-positive H. pylori (p = .016, .01, or .005, respectively). CONCLUSION: These results suggest that the higher motility of H. pylori enhances pathological outcomes, and the SabA-sialyl-Le(x) interaction has a synergistic effect on virulence of the higher-motility strains.

Gemifloxacin can partially overcome quinolone resistance of H. pylori with gyrA mutation in Taiwan.

BACKGROUNDS: The levofloxacin resistance caused by gyrA gene mutation is rising rapidly to limit wide application for Helicobacter pylori eradication. We investigated whether gemifloxacin has a superior antimicrobial activity to levofloxacin against H. pylori. MATERIALS AND METHODS: Forty-four consecutive clinical H. pylori isolates with levofloxacin resistance and 80 randomly selected levofloxacin-sensitive controls were tested for gemifloxacin sensitivity by E-test. The resistance to levofloxacin or gemifloxacin was defined as minimal inhibitory concentration (MIC) > 1 mg/L. The clinical features and GyrA mutation patterns checked by direct sequencing were also analyzed to assess its association with the H. pylori gemifloxacin resistance. RESULTS: All levofloxacin-sensitive H. pylori isolates were sensitive to gemifloxacin. Eight strains (18.2%) resistant to levofloxacin could be still sensitive to gemifloxacin. Gemifloxacin achieved a 5-time lower in MIC levels against levofloxacin-resistant isolates. Nearly all levofloxacin-resistant isolates (97.7%, 43/44) had GyrA mutation at amino acid position 87 or 91. Double mutation sites may play dual roles in quinolone resistance, as N87K plus H57Y or D91N plus V77A mutations showed high-level resistance to both quinolones; whereas D91Y plus A97V or D91N plus A97V mutations showed low level levofloxacin resistance to become sensitive to gemifloxacin. In H. pylori isolates with single N87K, D91Y or D91N mutation, near 20% was gemifloxacin-sensitive and levofloxacin-resistant. The gemifloxacin-resistant rate of H. pylori was higher in patients with gastric ulcer than in those without (p <.05). CONCLUSION: Gemifloxacin is superior to levofloxacin in antimicrobial activity against clinical H. pylori isolates, and even overcome some levofloxacin resistance.

Expressions of MMPs and TIMP-1 in gastric ulcers may differentiate H. pylori-infected from NSAID-related ulcers.

BACKGROUND: Two major causes of gastric ulcers are Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) use. AIMS: This study aimed to determine if there were different expressions of matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) between H. pylori-infected and NSAID-related ulcers. METHODS: The 126 gastric ulcer patients (H. pylori infected n = 46; NSAID related n = 30; combined with two factors n = 50) provided ulcer and nonulcer tissues for assessment of MMP-3, -7, and -9 and TIMP-1 expression by immunohistochemical staining. RESULTS: Gastric ulcer tissues had significantly higher MMP-3, -7, and -9 and TIMP-1 expressions than nonulcer tissues (P < 0.05). H. pylori-infected gastric ulcers had even higher MMP-7, MMP-9, and TIMP-1 expressions in epithelial cells than NSAID-related gastric ulcers (P < 0.05). In patients with the two combined factors, gastric ulcers expressed similar proportions of antral ulcers and MMP-7 and MMP-9 intensities to NSAID-related gastric ulcers, but lower MMP-9 and TIMP-1 than H. pylori-infected gastric ulcers (P < 0.05). CONCLUSIONS: H. pylori-infected gastric ulcers express higher MMP-7, MMP-9, and TIMP-1 than NSAID-related ulcers. In patients with the two combined factors, ulcer location and MMP-7 and MMP-9 intensities are similar to NSAID use.

H. pylori cagL amino acid sequence polymorphism Y58E59 induces a corpus shift of gastric integrin α5ß1 related with gastric carcinogenesis.

We tested whether cagL amino acid sequence polymorphisms of Helicobacter pylori correlated to clinico-histological outcomes and gastric α5ß1 integrin expressions. One hundred forty five patients with H. pylori infection and 47 noninfected controls were enrolled to check gastric integrin α5ß1 intensities topographically. The collected isolates were screened for cagL-genotype by polymerase chain reaction (PCR), and assessed for amino acid sequence polymorphisms using sequence translation. Our H. pylori isolates were predominantly (98.6%) cagL-genopositive, 95.8% of which had the RGD motif in their amino acid sequences. The isolates from the gastric cancer (GCA) patients indicated a higher rate of amino acid sequence polymorphisms-Y58 and E59-than those of the non-GCA patients (P < 0.05). The polymorphisms as Y58E59 noted with increased risk of GCA up to 4.6-fold (95%CI: 1.8-11.9). H. pylori-infected patients had higher integrin α5ß1 than noninfected patients (P < 0.05). Furthermore, cagL-Y58E59 H. pylori infection predisposed an upward shift in integrin α5ß1 (P = 0.007) in the corpus, leading to more severe corpus chronic inflammation (P < 0.05). H. pylori CagL amino acid polymorphisms like Y58E59 correlate with a higher risk of GCA, and may regulate a corpus shift of gastric integrin α5ß1 to lead to severe corpus gastritis during gastric carcinogenesis.