Atrophic Progression Induced by H. pylori Infection Is Correlated with a Changing Pepsinogen I Value and Associated with the Development of Gastric Cancer

It is well known that H. pylori infection induces gastric mucosal atrophy, and patients with gastric cancer, which is often complicated by H. pylori infection, possess gastric mucosal atrophy including intestinal metaplasia as a background. One hundred forty-seven patients with dyspeptic symptom and without gastric cancer diagnosed at first endoscopy have been prospectively studied to detect early gastric cancer every year by endoscopy for approximately 6 years. The status of H. pylori infection was detected by histology and ELISA, the value of pepsinogen I (PGI) determined by ELISA, and atrophic pattern determined by the histology of multiple specimens. After the follow-up period (mean, 6.1 years), 6 early gastric cancers had developed in the 49 H. pylori-positive patients with transformation of the atrophic pattern, and no cancer had developed in either the 48 H. pylori-positive patients without transformation of the atrophic pattern or the 50 H. pylori-negative patients. There is a significant relationship between the incidence of transformation of the atrophic pattern and that of the development of gastric cancer in the H. pylori-positive patients. PGI per year in the H. pylori-positive group with transformation of the atrophic pattern was significantly decreased compared with that in the other two groups. Gastric cancers have a background of progressive atrophy, and PGI per year can be a good marker to detect gastric cancer at early stages which is developing or has developed on the background of atrophic progression.     

Prevalence of Gastric Myoelectrical Abnormalities in Patients with Nonulcer Dyspepsia and H. pylori Infection

The aims of this study were to investigate the effects of H. pylori eradication on gastric myoelectrical activity and dyspeptic symptoms. Sixty-two subjects with H. pylori infection and no active peptic ulcer participated in this study, which involved three sessions. Anti-H. pylori therapy consisting of clarithromycin and omeprazole was given for two weeks. Gastric myoelectrical activity was measured using surface electrogastrography and dyspeptic symptoms were scored at each session. A [¹⁴C] urea breath test was performed at baseline and one month after treatment. In comparison with baseline, the percentage of normal slow waves was significantly increased and the mean total symptom score was significantly reduced one and three months after therapy (P < 0.05). Approximately 40% of patients with nonulcer dyspepsia symptoms and H. pylori infection have abnormal gastric myoelectrical activity, which may be normalized following the eradication of H. pylori infection. The normalization of gastric myoelectrical activity may be one explanation for the significant symptom improvement in this subset of the dyspepsia population after H. pylori eradication.     

Helicobacter pylori Seropositivity Is Associated with Gastric Cancer Regardless of Tumor Subtype in Korea

Background/Aims

To evaluate the association between Helicobacter pylori (H. pylori) infection and gastric cancer (GC) according to tumor subtype in Korea.

Methods

H. pylori status was determined serologically using the enzyme-linked immunosorbent assay. In total, 2,819 patients with GC and 562 healthy controls were studied. A logistic regression method was used after adjusting for possible confounders.

Results

The prevalence of H. pylori infection was significantly higher in the GC patients (84.7%) than in the controls (66.7%) (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.46-3.97). The adjusted OR was significantly higher in H. pylori-infected patients aged <60 years (OR, 4.69; 95% CI, 3.44-6.38) than in those aged ≥60 years (OR, 1.48; 95% CI, 0.88-2.46; p<0.001). Subgroup analyses revealed no differences in seroprevalence between early gastric cancer (84.8%; OR, 3.01; 95% CI, 2.27-4.01) and advanced gastric cancer (84.6%; OR, 2.94; 95% CI, 2.24-3.85), cardia cancer (83.8%; OR, 2.98; 95% CI, 2.16-4.02) and noncardia cancer (84.8%; OR, 3.17; 95% CI, 2.48-4.04), and differentiated carcinoma (82.7%; OR, 2.99; 95% CI, 2.21-4.04) and undifferentiated carcinoma (86.8%; OR, 3.05; 95% CI, 2.32-4.00).

Conclusions

The seroprevalence of H. pylori was higher in GC patients than in healthy controls, especially in younger patients. H. pylori infection is associated with GC, regardless of the tumor location, stage, or differentiation.     

Helicobacter pylori Infection Is Not Associated with Subclinical Hepatic Encephalopathy in Stable Cirrhotic Patients

The importance of ammonia-producing Helicobacter pylori infection as a cause of subclinical encephalopathy in cirrhosis was investigated. In addition, a single psychometric test that can reliably detect subclinical hepatic encephalopathy was sought. Out-patients with cirrhosis and no overt encephalopathy underwent [¹⁴C]urea breath testing once and psychometric testing on two separate occasions, with an intervening course of clarithromycin/omeprazole if they had subclinical encephalopathy (two of four psychometric tests abnormal). Subclinical encephalopathy was present in 27 of 69 patients (39%), and Helicobacter pylori infection in 14 of 69 (20%). There was no association between the two conditions (P = 0.769). Subclinical encephalopathy resolved in 75% of treated Helicobacter pylori-positive patients and 37.5% of treated Helicobacter pylori-negative patients (P = 0.285). Number connection test-B had high reproducibility among untreated patients (R = 0.655) and high correlation (P 0.01) with three surrogate gold standards. In stable cirrhotic patients, subclinical hepatic encephalopathy was found to: (1) have a high prevalence, (2) not be associated with Helicobacter pylori infection, and (3) be readily detected with the number connection test-B alone.     

A Functional Polymorphism in the Interleukin-1 Receptor-1 Gene Is Associated with Increased Risk of Helicobacter pylori Infection but Not with Gastric Cancer

The proinflammatory cytokine interleukin-1 has been implicated in host susceptibility to Helicobacter pylori-associated disease. Recent studies suggest that this susceptibility may be under genetic control. It remains to be determined whether the relationship between IL-1 gene polymorphism and gastrointestinal disease in patients with H. pylori infection is due to the role of IL-1 in determining susceptibility to H. pylori infection per se or to the development of distinct pathological lesions. The aim of this study was to prospectively investigate the relationship between selected polymorphisms in three of the major IL-1 gene family members, seeking associations with H. pylori infection and/or gastric cancer. A total of 559 individuals were studied: 191 patients attending for gastroscopy, 98 with current or previous H. pylori, an additional 79 patients with gastric cancer, and 289 healthy controls. The major novel finding of the study was a marked difference in the genotype frequencies for the IL1R1 Hinfl SNP in those with current or previous evidence of H. pylori compared to those without. (GG, 53 vs 75%; GA, 40 vs 19%; AA, 7 vs 6%; P = 0.0079). The association indicates an increased risk of H. pylori infection or persistence in those with the IL1R1 Hinfl A allele (0.27 vs 0.156; P = 0.009; OR = 2.01). Our results suggest that the relationship among IL-1 gene polymorphism, H. pylori, and disease is more complex than initially proposed. More detailed studies of the IL-1 gene cluster are needed.     

Helicobacter pylori Infection Is Not Associated with Delayed Gastric Emptying or Upper Gastrointestinal Symptoms in Diabetes Mellitus

This study evaluated the relationship between gastric emptying and upper gastrointestinal symptoms with H. pylori status in patients with diabetes mellitus. Sixty-three outpatients (44 type 1, 19 type 2, age 45 ± 1.5 years) underwent measurements of gastric emptying of a mixed solid and liquid meal, gastrointestinal symptoms (gastric and esophageal), glycemic control (HbA_lc), and autonomic nerve function. Anti-H. pylori IgG antibodies were quantified using a validated kit. Gastric emptying of solid and/or liquid was delayed in 47 (75%) patients, and 31 (49%) had autonomic neuropathy. Fifteen (24%) of the patients were H. pylori positive. There were no differences in gastric emptying (solid retention at 100 min: 67.5 ± 5.7% vs 63.2 ± 3.6%; P = 0.63, liquid T50: 35.5 ± 2.9 min vs 42.5 ± 3.4 min; P = 0.42), upper gastrointestinal symptoms (gastric 3.9 ± 0.7 vs 4.0 ± 0.4; P = 0.94 or esophageal 1.7 ± 0.5 vs 1.3 ± 0.2; P = 0.42) or HbA_lc (8.8 ± 0.4% vs 8.6 ± 0.2%; P = 0.89) between H. pylori-positive and -negative patients. We conclude that H. pylori infection is not associated with delayed gastric emptying or upper gastrointestinal symptoms in diabetes.     

Role of Helicobacter pylori CagA + Infection in Determining Oxidative DNA Damage in Gastric Mucosa

Background: Although Helicobacter pylori is a risk factor for gastric cancer, the role of the bacterium in the development of this malignancy is not defined precisely. Reactive oxygen species (ROS) could play an important role in carcinogenesis by inducing DNA damage. The aims of the present study were: 1) to assess the production of ROS and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA injury, in gastric mucosa, according to H. pylori status and cytotoxic associated gene product A (CagA); 2) to determine the relationship between ROS generation and amount of 8-OHdG. Methods: Gastric biopsy specimens were obtained from 60 consecutive patients. ROS generation was measured by luminol enhanced chemiluminescence. 8-OHdG detection was performed by an immunoperoxidase method, using a specific anti 8-OHdG monoclonal antibody. Results: 40/60 patients (67%) were H. pylori -positive. ROS generation was significantly higher in patients positive for H. pylori infection as compared to negative. 8-OHdG detection was performed in 30 patients in which CagA presence was also investigated. High expression of 8-OHdG was detected in 14/20 (70%) H. pylori positive patients (13 CagA + and 1 CagA - ) and in 2/10 (20%) H. pylori -negative patients. A significant correlation was found between ROS production and 8-OHdG content. Conclusion: H. pylori infection by a CagA + strain is associated with the highest production of ROS to which a severe oxidative DNA damage corresponds. This sequence of events could support the hypothesis that the oxygen-free radicalsmediated damage due to H. pylori cytotoxic strains could be a driving force that leads from chronic gastritis to gastric carcinoma.     

幽门螺杆菌感染能促进胃粘膜上皮细胞的增殖

用免疫组织化学染色方法,对30例幽门螺杆菌(Hp)相关性慢性胃炎和15例Hp阴性胃粘膜基本正常者胃粘膜中增殖细胞核抗原(PCNA)标记指数(LI％)和表皮生长因子受体(EGF-R)的表达进行了检测。结果表明,Hp阳性患者PCNA LI％为13.94±1.64,Hp阴性对照组为7.71±O.92.有显著差异(P0.05)。提示,Hp感染能引起胃粘膜上皮细胞过度增殖。这为阐明Hp感染在胃癌发病中作用的机理提供了线索。     

早期胃癌和进展期胃癌患者幽门螺杆菌感染与胃黏膜组织学特点的关系

背景幽门螺杆菌(H.pylori)感染已被确认为慢性胃炎的主要病因,由慢性非萎缩性胃炎、慢性萎缩性胃炎至肠化生,经过数十年最终可能导致胃癌发生。目的评价H.pylori感染与胃镜检查正常者、慢性胃炎、早期胃癌和进展期胃癌患者胃黏膜组织学特点的关系。方法在受检者胃窦大弯侧、胃体大弯侧和胃角处各取一块黏膜活检标本,以Giemsa染色和免疫组化染色检测H.pylori感染情况;以HE染色评价胃黏膜炎症、活动性、萎缩和肠化生情况。结果慢性胃炎、早期胃癌和进展期胃癌患者的总体H.pylori感染率均显著高于胃镜检查正常者(52.4%、52.4%和81.2%对44.9%,P<0.05),慢性胃炎与早期胃癌患者的感染率无显著差异,但均显著低于进展期胃癌患者(P<0.05)。胃镜检查正常和慢性胃炎组H.pylori感染者的胃黏膜炎症、活动性、萎缩和肠化生检出率均显著高于无感染者(P<0.05);早期胃癌和进展期胃癌组H.pylori感染者的炎症活动性检出率显著高于无感染者(P<0.05),而炎症、萎缩和肠化生检出率与无感染者无显著差异。结论由H.pylori感染引起的胃黏膜慢性炎症、萎缩和肠化生可能在胃癌的发生、发展过程中起直接或间接作用。     

Helicobacter pylori Infection Is a Major Risk Factor for Gastric Carcinoma in Young Patients

Background: Helicobacter pylori has been established as a risk factor for gastric carcinoma (GCa). Since before the discovery of H. pylori, atrophic gastritis and intestinal metaplasia have been linked to GCa, especially the intestinal-type tumor. The prevalence of H. pylori infection and atrophic gastritis increase with age. Thus, analysis of H. pylori infection in young patients with GCa could help clarify the role of this bacterium in the development of GCa. Accordingly, we investigated the relationship between H. pylori infection, GCa, and histologic gastritis in patients less than 30 years old. Methods: Fifty GCa patients less than 30 years (mean, 26.4 years) and 100 sex- and age-matched controls (mean, 26.8 years) were examined for the presence of H. pylori infection and histologic gastritis. Results: The prevalence of H. pylori infection was significantly higher in GCa patients than in controls (94% versus 40%, P &lt; 0.01). Its prevalence was not associated with tumor location, tumor stage, or histologic type. Gastritis, atrophy, and intestinal metaplasia significantly increased the risk of GCa. By means of multiple logistic regression analysis, the odds ratio for the risk of GCa in H. pylori-positive subjects was found to be 23.5 (95% confidence interval, 6.84-80.7). Conclusions: We confirmed a strong association between H. pylori infection and GCa in young patients. Along with H. pylori infection, histologic gastritis might play an important role in the pathogenesis of GCa in these patients.     

MYO5B Is Epigenetically Silenced and Associated with MET Signaling in Human Gastric Cancer

Background

Our previous study has shown that MYO5B is downregulated in gastric cancer. However, the mechanism by which the expression of MYO5B was inhibited remains unknown.

Methods

Inspection of the human MYO5B locus uncovered a large and dense CpG island within the 5′ region of this gene. Methylation-specific PCR (MSP) and bisulfite sequencing (BSP) were used for determination of MYO5B promoter methylation in gastric cancer cell lines and gastric cancer samples. Involvement of histone H3 methylation in those cell lines were examined by ChIP assay.

Results

The densely methylated MYO5B promoter region was confirmed by MSP and BSP. Enhanced gene expression was detected when the cells were treated with the DNA-demethylating agent 5-aza-2′-deoxycytidine (DAC) and trichostatin A (TSA), a histone deacetylase inhibitor. Knockdown of MYO5B expression in gastric cancer cells expressing endogenous MYO5B inhibits HGF-stimulated MET degradation, concomitant with sustained c-MET levels and signaling.

Conclusion

The results of our study showed for the first time that MYO5B is epigenetically silenced in gastric cancer cells by aberrant DNA methylation and histone modification. Inactivation of MYO5B expression in gastric cancer cells expressing endogenous MYO5B inhibits HGF-stimulated MET degradation, concomitant with sustained c-MET levels and signaling.     

Pretreatment Gastric Histology Is Helpful to Predict the Symptomatic Response After H. pylori Eradication in Patients with Nonulcer Dyspepsia

This study aimed to test whether pretreatment gastric pathology in H. pylori-infected nonulcer dyspepsia (HpNUD) patients is relevant to and predictive of the symptomatic response after H. pylori eradication. Anti-H. pylori triple therapy was administered to 250 HpNUD patients, enrolled as the therapy group. In addition, 60 patients were enrolled as the control group, in which omeprazole was an alternatives to the triple therapy. Pretreatment gastric histology was evaluated thoroughly by the updated Sydney system. A [¹³C] urea breath test was also performed to evaluate the H. pylori eradication two months and 12 months later. For each patient, the baseline, month 2, and month 12 symptom scores were assessed for the month 2 or month 12 residual symptom ratio (RSR-2m or RSR-12m), calculated from: 100% × month 2 or month 12 score/baseline score. Based on either RSR-2m or RSR-12m, patients were categorized as good response (RSR < 50%), moderate response (50–70%), and poor response (>70%) subgroups in both therapy and control groups to define the short-term and long-term symptomatic responses. Patients with successful H. pylori eradication in the therapy group showed a higher incidence of good symptomatic response (RSR < 50%) than those from the control group (month 2: 30.3 vs 12%, P < 0.05; month 12: 34.7 vs 17.1%, P < 0.05). Univariate and multivariate analysis disclosed that patients with a higher acute inflammation score (AIS) and the lowest incidence of lymphoid follicles (LF) at pretreatment gastric histology are predisposed to having a good symptom response after H. pylori eradication (P < 0.05). For HpNUD patients who have an AIS of more than three and an absence of LF at gastric histology, more than 85% had good short-term (month 2) and long-term (month 12) symptomatic relief after H. pylori eradication. In conclusion, nearly 30% of HpNUD patients can obtain symptomatic relief following H. pylori eradication. The pretreatment gastric histology of HpNUD can be helpful to monitor the symptomatic response after H. pylori eradication.     

幽门螺杆菌相关性胃癌患者局部Th1/Th2细胞免疫应答变化

背景:幽门螺杆菌(Hp)感染与胃癌发生相关,免疫应答可能是其主要致病机制之一。目的:探讨Hp相关性胃癌患者黏膜局部Th1/Th2细胞免疫应答变化。方法:选取2011年1～6月27例胃癌患者和28例对照者,采用14C-尿素呼气试验、Hp抗体检测Hp感染,免疫组化法检测胃黏膜局部干扰素(IFN)-γ和白细胞介素(IL)-4表达情况。结果:Hp总体感染率为61.8%。Hp阳性患者中,胃癌组IFN-γ表达明显低于对照组(P<0.05),IL-4表达明显高于对照组(P<0.05);Hp阴性患者中,胃癌组IFN-γ、IL-4表达与对照组均无明显差异(P>0.05)。Hp阳性胃癌患者IL-4表达明显高于Hp阴性胃癌患者(P<0.05),Hp阳性对照组IFN-γ表达明显高于Hp阴性对照组(P<0.05)。结论:Hp阳性对照者以Th1细胞介导的免疫应答为主,Hp阳性胃癌患者以Th2细胞为主。黏膜局部Th1/Th2细胞免疫应答变化可能与Hp感染相关疾病的进展,特别是胃癌的发生密切相关。     

The Association Between cagA+ H. pylori Infection and Distal Gastric Cancer: A Proposed Model

Cytotoxin-associated gene A (cagA)+ infection is associated with an increased risk of distal gastric cancer. The aim was to determine the effect of Helicobacter pylori (HP) on gastric mucus thickness, hydrophobicity, and PGE2 and their relation to colonization density. Ninety-nine patients were recruited (69 HP- and 30 HP+: 10 cagA+, 18 cagA-, 2 undetermined) and six biopsies were obtained from each patient. Mucus thickness, hydrophobicity, PGE2, and colonization density were determined. HP status was assessed by histology and culture; cagA+ was determined by PCR. In age- and sex-matched patients, PGE2 was greater in PH+ than HP- (P = 0.04), with cagA+ having higher PGE2 than HP- patients (P = 0.031). No differences were observed in mucus thickness (P = 0.717) or hydrophobicity (P = 0.27) between HP+ and HP- patients. However, cagA+ showed a nonsignificant trend of increase in mucus thickness (P = 0.784) and hydrophobicity (P = 0.30) compared to cagA- and HP- patients. cagA+ colonization density was weakly correlated with increased thickness (r = 0.333, P = 0.381), whereas cagA- density was inversely correlated with thickness (r = -0.805, P = 0.0001). A model suggesting the possible changes induced by cagA+ infection is proposed which explains the high association of cagA+ with distal gastric cancer. If supported by large multicenter studies, this could form the basis for the development of new therapies directed at the mucous layer to eradicate HP and thus reduce the risk of gastric cancer.