Role of non-Helicobacter pylori gastric Helicobacters in helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma

Marginal zone lymphomas rank as the third most prevalent form of non-Hodgkin B-cell lymphoma,trailing behind diffuse large B-cell lymphoma and follicular lymphoma.Gastric mucosa-associated lymphoid tissue lymphoma(GML)is a low-grade B-cell neoplasia frequently correlated with Helicobacter pylori(H.pylori)-induced chronic gastritis.On the other hand,a specific subset of individuals diagnosed with GML does not exhibit H.pylori infection.In contrast to its H.pylori-positive counterpart,it was previously believed that H.pylori-negative GML was less likely to respond to antimicrobial therapy.Despite this,surprisingly,increasing evidence supports that a considerable proportion of patients with H.pylori-negative GML show complete histopathological remission after bacterial eradication therapy.Nonetheless,the precise mechanisms underlying this treatment responsiveness are not yet fully comprehended.In recent years,there has been growing interest in investigating the role of non-H.pylori gastric helicobacters(NHPHs)in the pathogenesis of H.pylori-negative GML.However,additional research is required to establish the causal relationship between NHPHs and GML.In this minireview,we examined the current understanding and proposed prospects on the involvement of NHPHs in H.pylori-negative GML,as well as their potential response to bacterial eradication therapy.

Association between Helicobacter pylori infection,mismatch repair,HER2 and tumor-infiltrating lymphocytes in gastric cancer

BACKGROUND The influence of Helicobacter-pylori(H.pylori)infection and the characteristics of gastric cancer(GC)on tumor-infiltrating lymphocyte(TIL)levels has not been extensively studied.Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.AIM To determine the rates of deficient mismatch-repair(dMMR),HER2-status and H.pylori infection and their association with TIL levels in GC.METHODS Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral(IT),stromal(ST)and invasive-border(IB)compartments.The density of CD3,CD8 and CD163 immune cells,and dMMR and HER2-status were determined by immunohistochemistry(IHC).H.pylori infection was evaluated by routine histology and quantitative PCR(qPCR)in a subset of samples.RESULTS dMMR was found in 34.4%,HER2+in 5%and H.pylori-positive in 55.7%of samples.High IT-TIL was associated with grade-3(P=0.038),while ST-TIL with grade-1(P<0.001),intestinal-histology(P<0.001)and no-recurrence(P=0.003).dMMR was associated with high TIL levels in the ST(P=0.019)and IB(P=0.01)compartments,and STCD3(P=0.049)and ST-CD8(P=0.05)densities.HER2-was associated with high IT-CD8(P=0.009).H.pylorinegative was associated with high IT-TIL levels(P=0.009)when assessed by routine-histology,and with high TIL levels in the 3 compartments(P=0.002-0.047)and CD8 density in the IT and ST compartments(P=0.001)when assessed by qPCR.A longer overall survival was associated with low IT-CD163(P=0.003)and CD8/CD3(P=0.001 in IT and P=0.002 in ST)and high IT-CD3(P=0.021),ST-CD3(P=0.003)and CD3/CD163(P=0.002).CONCLUSION TIL levels were related to dMMR and H.pylori-negativity.Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Non-improvement of atrophic gastritis in cases of gastric cancer after successful Helicobacter pylori eradication therapy

BACKGROUND Helicobacter pylori(H.pylori)infection is closely related to the development of gastric cancer(GC).However,GC can develop even after H.pylori eradication.Therefore,it would be extremely useful if GC could be predicted after eradication.The Kyoto classification score for gastritis(GA)is closely related to cancer risk.However,how the score for GC changes after eradication before onset is not well understood.AIM To investigate the characteristics of the progression of Kyoto classification scores for GC after H.pylori eradication.METHODS Eradication of H.pylori was confirmed in all patients using either the urea breath test or the stool antigen test.The Kyoto classification score of GC patients was evaluated by endoscopy at the time of event onset and three years earlier.In ad-dition,the modified atrophy score was evaluated and compared between the GC group and the control GA group.RESULTS In total,30 cases of early GC and 30 cases of chronic GA were evaluated.The pathology of the cancer cases was differentiated adenocarcinoma,except for one case of undifferentiated adenocarcinoma.The total score of the Kyoto classifi-cation was significantly higher in the GC group both at the time of cancer onset and three years earlier(4.97 vs 3.73,P=0.0034;4.2 vs 3.1,P=0.0035,respectively).The modified atrophy score was significantly higher in the GC group both at the time of cancer onset and three years earlier and was significantly improved only in the GA group(5.3 vs 5.3,P=0.5;3.73 vs 3.1,P=0.0475,respectively).CONCLUSION The course of the modified atrophy score is useful for predicting the onset of GC after eradication.Patients with severe atrophy after H.pylori eradication require careful monitoring.

Effects of Helicobacter pylori and Moluodan on the Wnt/β-catenin signaling pathway in mice with precancerous gastric cancer lesions

BACKGROUND Helicobacter pylori(H.pylori)is the primary risk factor for gastric cancer(GC),the Wnt/β-Catenin signaling pathway is closely linked to tumourigenesis.GC has a high mortality rate and treatment cost,and there are no drugs to prevent the progression of gastric precancerous lesions to GC.Therefore,it is necessary to find a novel drug that is inexpensive and preventive to against GC.AIM To explore the effects of H.pylori and Moluodan on the Wnt/β-Catenin signaling pathway and precancerous lesions of GC(PLGC).METHODS Mice were divided into the control,N-methyl-N-nitrosourea(MNU),H.pylori+MNU,and Moluodan groups.We first created an H.pylori infection model in the H.pylori+MNU and Moluodan groups.A PLGC model was created in the remaining three groups except for the control group.Moluodan was fed to mice in the Moloudan group ad libitum.The general condition of mice were observed during the whole experiment period.Gastric tissues of mice were grossly and microscopically examined.Through quantitative real-time PCR(qRT-PCR)and Western blotting analysis,the expression of relevant genes were detected.RESULTS Mice in the H.pylori+MNU group showed the worst performance in general condition,gastric tissue visual and microscopic observation,followed by the MNU group,Moluodan group and the control group.QRT-PCR and Western blotting analysis were used to detect the expression of relevant genes,the results showed that the H.pylori+MNU group had the highest expression,followed by the MNU group,Moluodan group and the control group.CONCLUSION H.pylori can activate the Wnt/β-catenin signaling pathway,thereby facilitating the development and progression of PLGC.Moluodan suppressed the activation of the Wnt/β-catenin signaling pathway,thereby decreasing the progression of PLGC.

Effectiveness of Helicobacter pylori eradication in the treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma:An up-to-date meta-analysis

BACKGROUND Gastric mucosa-associated lymphoid tissue(MALT)lymphoma(GML)is usually a low-grade B-cell neoplasia strongly associated with Helicobacter pylori(H.pylori)-induced chronic gastritis.Clinical practice guidelines currently recommend H.pylori eradication as the preferred initial treatment for early-stage GML.To determine the practical effect of bacterial eradication as the sole initial therapy for early-stage GML,an updated analysis and review of available evidence is imperative.AIM To perform a meta-analysis to assess the rate of complete remission(CR)of H.pylori-positive early-stage GML following bacterial eradication.METHODS We performed independent,computer-assisted literature searches using the PubMed/MEDLINE,Embase,and Cochrane Central databases through September 2022.Prospective and retrospective observational studies evaluating the CR of early-stage GML following bacterial eradication in H.pylori-positive patients.The risk of bias was assessed using Joanna Briggs Institute(JBI)Critical Appraisal Tools.The pooled estimate of the complete histopathological remission rate and respective confidence intervals(95%CI)were calculated following the random-effects model.Heterogeneity and inconsistency were assessed using Cochran’s Q test and I2 statistic,and heterogeneity was defined as P<0.01 and I²>50%,respectively.Subgroup and meta-regression analyses were conducted to explore potential sources of heterogeneity.RESULTS The titles and abstracts of 1576 studies were screened;96 articles were retrieved and selected for full-text reading.Finally,61 studies were included in the proportional meta-analysis(P-MA).Forty-six were prospective and fifteen were retrospective uncontrolled,single-arm,observational studies.The overall risk of bias was low to moderate in all but a single report,with an average critical appraisal score across all studies of 79.02%.A total of 2936 H.pylori-positive early-stage GML patients,in whom H.pylori was successfully eradicated,were included in the analysis.The pooled CR of H.pylori-positive early-stage GML after bacterial eradication was 75.18%(95%CI:70.45%-79.91%).P-MA indicated the substantial heterogeneity in CR reported across studies(I2=92%;P<0.01).Meta-regression analysis identified statistically significant effect modifiers,including the proportion of patients with t(11;18)(q21;q21)-positive GML and the risk of bias in each study.CONCLUSION Comprehensive synthesis of available evidence suggests that H.pylori eradication is effective as the sole initial therapy for early-stage GML.Although the substantial heterogeneity observed across studies limits the interpretation of the pooled overall CR,the present study is a relevant to informing clinical practice.

Health economic evaluation on population-based Helicobacter pylori eradication and endoscopic screening for gastric cancer prevention

Gastric cancer is a global public health burden, nearly one million new cases are diagnosed per year worldwide, of which 44% of cases occur in China. The prognosis of gastric cancer varies remarkably by the stage of cancer, and most of the patients in China are diagnosed at advanced stages, resulting in poor prognoses. Effective strategies to reduce the burden of gastric cancer include primary prevention through testing and treatment of Helicobacter pylori(H. pylori) and secondary prevention by screening and early detection. Although many countries have issued management guidelines and consensus reports concerning these strategies, the limited availability of healthcare resources often precludes their widespread implementation. Therefore, assessing the costs, benefits, and harms of population-based intervention measures through health economic evaluation is necessary for informed health policy decisions. Accordingly, we synthesize management approaches from different countries on H. pylori eradication and endoscopic screening, and also summarize recent advancements in health economic evaluations on population-based preventive strategies. The goal of the review is to provide empirical evidence supporting optimal resource allocation, maximizing benefits for the population, and ultimately reducing the burden of gastric cancer.

Intraprocedural gastric juice analysis as compared to rapid urease test for real-time detection of Helicobacter pylori

BACKGROUND Endofaster is an innovative technology that can be combined with upper gastrointestinal endoscopy(UGE)to perform gastric juice analysis and real-time detection of Helicobacter pylori(H.pylori).AIM To assess the diagnostic performance of this technology and its impact on the management of H.pylori in the real-life clinical setting.METHODS Patients undergoing routine UGE were prospectively recruited.Biopsies were taken to assess gastric histology according to the updated Sydney system and for rapid urease test(RUT).Gastric juice sampling and analysis was performed using the Endofaster,and the diagnosis of H.pylori was based on real-time ammonium measurements.Histological detection of H.pylori served as the diagnostic gold standard for comparing Endofaster-based H.pylori diagnosis with RUT-based H.pylori detection.RESULTS A total of 198 patients were prospectively enrolled in an H.pylori diagnostic study by Endofasterbased gastric juice analysis(EGJA)during the UGE.Biopsies for RUT and histological assessment were performed on 161 patients(82 men and 79 women,mean age 54.8±19.2 years).H.pylori infection was detected by histology in 47(29.2%)patients.Overall,the sensitivity,specificity,accuracy,positive predictive value,and negative predictive value(NPV)for H.pylori diagnosis by EGJA were 91.5%,93.0%,92.6%,84.3%,and 96.4%,respectively.In patients on treatment with proton pump inhibitors,diagnostic sensitivity was reduced by 27.3%,while specificity and NPV were unaffected.EGJA and RUT were comparable in diagnostic performance and highly concordant in H.pylori detection(κ-value=0.85).CONCLUSION Endofaster allows for rapid and highly accurate detection of H.pylori during gastroscopy.This may guide taking additional biopsies for antibiotic susceptibility testing during the same procedure and then selecting an individually tailored eradication regimen.

Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia

Heliobacter pylori(H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer.Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia(IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia(SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals.There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H.pylori infection.

Helicobacter pylori eradication treatment for primary gastric diffuse large B-cell lymphoma:A single-center analysis

BACKGROUND Unlike the already established effect of Helicobacter pylori(H.pylori)eradication on gastric mucosa-associated lymphoid tissue(MALT)lymphoma,its therapeutic effect on primary gastric diffuse large B-cell lymphoma(DLBCL)is still unclear.AIM To clarify the efficacy of H.pylori eradication treatment for primary gastric DLBCL.METHODS We reported on 3 new cases,and added them to 3 previously reported cases.We analyzed the usefulness of H.pylori eradication treatment for gastric DLBCL for a total of 6 cases at our center.RESULTS Of the 6 patients(27-90 years old,3 males and 3 females),all 3 patients with single lesions(one transformed from MALT lymphoma)achieved complete remission(CR)after H.pylori eradication.Regarding the 2 newly reported cases,CR was maintained for more than 6 years with eradication treatment alone.In contrast,none of the 3 patients with 2 lesions achieved CR.In 1 newly reported case,endoscopic CR was achieved in one lesion,while stable disease was obtained in the other lesion.Two patients with progressive disease responded to standard chemo therapy±radiation and remained in CR for more than 6 years.CONCLUSION We believe it is worthwhile to attempt H.pylori eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden.

Risk factor profiles for gastric cancer prediction with respect to Helicobacter pylori:A study of a tertiary care hospital in Pakistan

BACKGROUND Gastric cancer(GC)is the fourth leading cause of cancer-related deaths worldwide.Diagnosis relies on histopathology and the number of endoscopies is increasing.Helicobacter pylori(H.pylori)infection is a major risk factor.AIM To develop an in-silico GC prediction model to reduce the number of diagnostic surgical procedures.The meta-data of patients with gastroduodenal symptoms,risk factors associated with GC,and H.pylori infection status from Holy Family Hospital Rawalpindi,Pakistan,were used with machine learning.METHODS A cohort of 341 patients was divided into three groups[normal gastric mucosa(NGM),gastroduodenal diseases(GDD),and GC].Information associated with socioeconomic and demographic conditions and GC risk factors was collected using a questionnaire.H.pylori infection status was determined based on urea breath test.The association of these factors and histopathological grades was assessed statistically.K-Nearest Neighbors and Random Forest(RF)machine learning models were tested.RESULTS This study reported an overall frequency of 64.2%(219/341)of H.pylori infection among enrolled subjects.It was higher in GC(74.2%,23/31)as compared to NGM and GDD and higher in males(54.3%,119/219)as compared to females.More abdominal pain(72.4%,247/341)was observed than other clinical symptoms including vomiting,bloating,acid reflux and heartburn.The majority of the GC patients experienced symptoms of vomiting(91%,20/22)with abdominal pain(100%,22/22).The multinomial logistic regression model was statistically significant and correctly classified 80%of the GDD/GC cases.Age,income level,vomiting,bloating and medication had significant association with GDD and GC.A dynamic RF GC-predictive model was developed,which achieved>80%test accuracy.CONCLUSION GC risk factors were incorporated into a computer model to predict the likelihood of developing GC with high sensitivity and specificity.The model is dynamic and will be further improved and validated by including new data in future research studies.Its use may reduce unnecessary endoscopic procedures.It is freely available.

Predictive model using four ferroptosis-related genes accurately predicts gastric cancer prognosis

BACKGROUND Gastric cancer(GC)is a common malignancy of the digestive system.According to global 2018 cancer data,GC has the fifth-highest incidence and the thirdhighest fatality rate among malignant tumors.More than 60%of GC are linked to infection with Helicobacter pylori(H.pylori),a gram-negative,active,microaerophilic,and helical bacterium.This parasite induces GC by producing toxic factors,such as cytotoxin-related gene A,vacuolar cytotoxin A,and outer membrane proteins.Ferroptosis,or iron-dependent programmed cell death,has been linked to GC,although there has been little research on the link between H.pylori infection-related GC and ferroptosis.AIM To identify coregulated differentially expressed genes among ferroptosis-related genes(FRGs)in GC patients and develop a ferroptosis-related prognostic model with discrimination ability.METHODS Gene expression profiles of GC patients and those with H.pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus(GEO)databases.The FRGs were acquired from the FerrDb database.A ferroptosis-related gene prognostic index(FRGPI)was created using least absolute shrinkage and selection operator–Cox regression.The predictive ability of the FRGPI was validated in the GEO cohort.Finally,we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues.RESULTS Four hub genes were identified(NOX4,MTCH1,GABARAPL2,and SLC2A3)and shown to accurately predict GC and H.pylori-associated GC.The FRGPI based on the hub genes could independently predict GC patient survival;GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group.The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression.Moreover,the gene expression levels of common immune checkpoint proteins dramatically increased in the highrisk subgroup of the FRGPI cohort.The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane.The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner.CONCLUSION In this study,we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.

Retrospective analysis of discordant results between histology and other clinical diagnostic tests on helicobacter pylori infection

BACKGROUND A reliable test is essential for diagnosing Helicobacter pylori(H.pylori)infection,and crucial for managing H.pylori-related diseases.Serving as an excellent method for detecting H.pylori infection,histologic examination is a test that clinicians heavily rely on,especially when complemented with immunohistochemistry(IHC).Additionally,other diagnostic tests for H.pylori,such as the rapid urease test(CLO test)and stool antigen test(SA),are also highly sensitive and specific.Typically,the results of histology and other tests align with each other.However,on rare occasions,discrepancy between histopathology and other H.pylori diagnostic tests occurs.AIM To investigate the discordance between histology and other H.pylori tests,the underlying causes,and the impact on clinical management.METHODS Pathology reports of gastric biopsies were retrieved spanning August 2013 and July 2018.Reports were included in the study only if there were other H.pylori tests within seven days of the biopsy.These additional tests include CLO test,SA,and H.pylori culture.Concordance between histopathology and other tests was determined based on the consistency of results.In instances where histology results were negative while other tests were positive,the slides were retrieved for re-assessment,and the clinical chart was reviewed.RESULTS Of 1396 pathology reports were identified,each accompanied by one additional H.pylori test.The concordance rates in detecting H.pylori infection between biopsy and other tests did not exhibit significant differences based on the number of biopsy fragments.117 discrepant cases were identified.Only 20 cases(9 with CLO test and 11 with SA)had negative biopsy but positive results in other tests.Four cases initially stained with Warthin-Starry turned out to be positive for H.pylori with subsequent IHC staining.Among the remaining 16 true discrepant cases,10 patients were on proton pump inhibitors before the biopsy and/or other tests.Most patients underwent treatment,except for two who were untreated,and two patients who were lost to follow-up.CONCLUSION There are rare discrepant cases with negative biopsy but positive in SA or CLO test.Various factors may contribute to this inconsistency.Most patients in such cases had undergone treatment.

Tumor infiltrating lymphocytes in gastric cancer:Unraveling complex interactions for precision medicine

This editorial will focus on tumor immunity and the factors that alter the tumor immune micro-environment.The role of tumor infiltrating lymphocytes(TILs)will also be discussed in detail,including the types,mechanism of action,and role.Gastric cancer(GC)often presents in the advanced stage and has various factors predicting the outcomes.The interplay of these factors and their correlation with the TILs is discussed.A literature review revealed high intratumoral TILs associated with higher grade,HER2-,and Helicobacter pylori negativity.Moreover,stromal(ST)TILs correlated with lower grade and lesser recurrence risk in GC.High TILs in ST and invasive border also correlated with mismatch repair deficiency status.Further characterization of the CD3+,CD8+,and other cells is also warranted.In the future,this complex correlation of cancer cells with the immune system can be explored for therapeutic avenues.

血清miR-30a-3p联合H.pylori抗体检测对老年人群早期胃癌的诊断价值

目的探究血清微小RNA-30a-3p(miR-30a-3p)联合幽门螺杆菌(H.pylori)抗体检测对老年人群早期胃癌的诊断价值。方法选取2020年5月至2022年12月进行胃镜检查的87例老年人群胃部疾病患者作为研究对象,根据病理学检查结果将患者分为慢性萎缩性胃炎(CAG)组(n=39)、早期胃癌组(n=27)和进展期胃癌组(n=21);同期选取33例健康体检者作为正常对照组。采用荧光定量PCR法(qRT-PCR)和化学发光法分别检测血清miR-30a-3p表达水平和H.pylori抗体;比较4组血清miR-30a-3p水平及H.pylori抗体阳性率;比较H.pylori抗体阳性与阴性者血清miR-30a-3p水平;Logistic回归分析影响老年人群早期胃癌的相关因素;受试者工作特征(ROC)曲线分析血清miR-30a-3p、H.pylori抗体对老年人群早期胃癌的诊断价值。结果早期胃癌组和进展期胃癌组血清miR-30a-3p表达水平均显著低于CAG组、对照组,早期胃癌组、进展期胃癌组和CAG组H.pylori抗体阳性率均显著高于对照组(P<0.05);纳入的87例胃部疾病患者和33例健康体检者中,H.pylori抗体阳性者血清miR-30a-3p显著低于H.pylori抗体阴性者(P<0.05);行Logistic回归分析结果显示,血清miR-30a-3p、H.pylori抗体阳性为影响老年人群发生早期胃癌的相关因素(P<0.05);血清miR-30a-3p联合H.pylori抗体诊断老年人群早期胃癌的曲线下面积(AUC)为0.957,优于血清miR-30a-3p、H.pylori抗体各自单独诊断(Z二者联合-miR-30a-3P=2.680、Z二者联合-H.pylori抗体=4.577,P=0.007、P<0.001),联合诊断的灵敏度和特异度分别为85.19%、96.67%。结论血清miR-30a-3p在老年人群早期胃癌患者中呈低表达,H.pylori抗体阳性率较高,二者联合检测对老年人群早期胃癌具有较高的诊断价值。

Helicobacter pylori associated chronic gastritis,clinical syndromes,precancerous lesions,and pathogenesis of gastric cancer development

Helicobacter pylori(H.pylori)infection is well known to be associated with the development of precancerous lesions such as chronic atrophic gastritis(AG),or gastric intestinal metaplasia(GIM),and cancer.Various molecular alterations are identified not only in gastric cancer(GC)but also in precancerous lesions.H.pylori treatment seems to improve AG and GIM,but still remains controversial.In contrast,many studies,including meta-analysis,show that H.pylori eradication reduces GC.Molecular markers detected by genetic and epigenetic alterations related to carcinogenesis reverse following H.pylori eradication.This indicates that these changes may be an important factor in the identification of high risk patients for cancer development.Patients who underwent endoscopic treatment of GC are at high risk for development of metachronous GC.A randomized controlled trial from Japan concluded that prophylactic eradication of H.pylori after endoscopic resection should be used to prevent the development of metachronous GC,but recent retrospective studies did not show the tendency.Patients with precancerous lesions(molecular alterations)that do not reverse after H.pylori treatment,represent the"point of no return"and may be at high risk for the development of GC.Therefore,earlier H.pylori eradication should be considered for preventing GC development prior to the appearance of precancerous lesions.

Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis

The sequence of events associated with the development of gastric cancer has been described as "the gastric precancerous cascade". This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori(H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the mostrelevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and mi RNAs in this context.

History of Helicobacter pylori,duodenal ulcer,gastric ulcer and gastric cancer

Helicobacter pylori(H.pylori)infection underlies gastric ulcer disease,gastric cancer and duodenal ulcer disease.The disease expression reflects the pattern and extent of gastritis/gastric atrophy(i.e.,duodenal ulcer with non-atrophic and gastric ulcer and gastric cancer with atrophic gastritis).Gastric and duodenal ulcers and gastric cancer have been known for thousands of years.Ulcers are generally non-fatal and until the 20th century were difficult to diagnose.However,the presence and pattern of gastritis in past civilizations can be deduced based on the diseases present.It has been suggested that gastric ulcer and duodenal ulcer both arose or became more frequent in Europe in the 19th century.Here,we show that gastric cancer and gastric ulcer were present throughout the 17th to 19th centuries consistent with atrophic gastritis being the predominant pattern,as it proved to be when it could be examined directly in the late 19th century.The environment before the 20th century favored acquisition of H.pylori infection and atrophic gastritis(e.g.,poor sanitation and standards of living,seasonal diets poor in fresh fruits and vegetables,especially in winter,vitamin deficiencies,and frequent febrile infections in childhood).The latter part of the 19th century saw improvements in standards of living,sanitation,and diets with a corresponding decrease in rate of development of atrophic gastritis allowing duodenal ulcers to become more prominent.In the early 20th century physician’s believed they could diagnose ulcers clinically and that the diagnosis required hospitalization for"surgical disease"or for"Sippy"diets.We show that while H.pylori remained common and virulent in Europe and the United States,environmental changes resulted in changes of the pattern of gastritis producing a change in the manifestations of H.pylori infections and subsequently to a rapid decline in transmission and a rapid decline in all H.pylori-related diseases.

Role of Helicobacter pylori infection in gastric carcinogenesis:Current knowledge and future directions

Helicobacter pylori(H. pylori) plays a role in the patho-genesis of gastric cancer. The outcome of the infection depends on environmental factors and bacterial and host characteristics. Gastric carcinogenesis is a multistep process that is reversible in the early phase of mucosal damage, but the exact point of no return has not been identified. Therefore, two main therapeutic strategies could reduce gastric cancer incidence:(1) eradication of the already present infection; and(2) immunization(prior to or during the course of the infection). The success of a gastric cancer prevention strategy depends on timing because the prevention strategy must be introduced before the point of no return in gastric carcinogenesis. Although the exact point of no return has not been identified, infection should be eradicated before severe atrophy of the gastric mucosa develops. Eradication therapy rates remain suboptimal due to increasing H. pylori resistance to antibiotics and patient noncompliance. Vaccination against H. pylori would reduce the cost of eradication therapies and lower gastric cancer incidence. A vaccine against H. pylori is still a research challenge. An effective vaccine should have an adequate route of delivery, appropriate bacterial antigens and effective and safe adjuvants. Future research should focus on the development of rescue eradication therapy protocols until an efficacious vaccine against the bacterium becomes available.

Apoptosis,proliferation and p53 gene expression of H.pylori associated gastric epithelial lesions

AIM: To study the relationship between Helicobacter pylori (H. Pylori) and gastric carcinoma and its possible pathogenesis by H. Pylori.METHODS: DNEL technique and immunohistochemical technique were used to study the state of apoptosis,proliferation and p53 gene expression. A total of 100 gastric mucosal biopsy specimens, including 20 normal mucosa, 30H. Pylori-negative and 30 H. Pylorf-positive gastric precancerous lesions along with 20 gastric carcinomas were studied.RESULTS: There were several apoptotic cells in the superficial epithelium and a few proliferative cells within the neck of gastric glands, and no p53 protein expression in normal mucosa. In gastric carcinoma, there were few apoptotic cells, while there were a large number of proliferative cells, and expression of p53 protein significantly was increased. In the phase of metaplasia, the apoptotic index (Al, 4.36% ± 1.95%), proliferative index (PI, 19.11% ± 6.79%) and positivity of p53 expression (46.7%) in H. Pylori-positive group were higher than those in normal mucosa (P< 0.01). Al in H. Pylori-positive group was higher than that in H. Pylori-negative group (3.81% ±1.76%), PI in H. Pylori-positive group was higher than that in H. Pylori-negative group (12.25% ±5.63%, P<0.01 ). In the phase of dysplasia, Al (2.31% ± 1.10%) in H. Pylori-positive group was lower (3.05% ± 1.29%) than that in H. Pylori-negative group, but PI (33.89% ± 11.65%)wassignificantly higher(22.09± 8018%, P< 0.01). In phases of metaplasia, dysplasia and gastric cancer in the H. Pylori-positive group, Als had an evidently graduall decreasing trend (P < 0.01 ), while Pis had an evidently gradual increasing trend (P< 0.05 or P< 0.01), and there was also a trend of gradual increase in the expression of p53 gene.CONCLUSION: In the course of the formation of gastric carcinoma, proliferation of gastric mucosa can be greatly increased by H. Pylori, and H. Pylori can induce apoptosis in the phase of metaplasia but in the phase of dysplasia H.pylori can inhibit cellular apoptosis. And H. Pylori infection can strengthen the expression of mutated p53 gene.

Multiple genetic alterations and behavior of cellular biology in gastric cancer and other gastric mucosal lesions:H.pylori infection,histological types and staging

AIM To investigate the expression of multiplegenes and the behavior of cellular biology ingastric cancer（GC）and other gastric mucosallesions and their relations to Helicobacter pylori（H.pylori）infection,tumor staging andhistological subtypes.METHODS Three hundred and twenty-sevenspecimens of gastric mucosa obtained viaendoscopy or surgical resection,and ABCimmunohistochemical staining were used todetect the expression of p53,p16,Bcl-2 andCOX-2 proteins.H.pylori was determined byrapid urea test combined with pathologicalstaining or14C urea breath test.Cellular image analysis was performed in 66 patients withintestinal metaplasia（IM）and/or dysplasia（Dys）.In 30 of them,both cancer and theparacancerous tissues were obtained at the timeof surgery.Histological pattern,tumor staging,lymph node metastasis,grading ofdifferentiation and other clinical data werestudied in the medical records.RESULTS p16 expression of IM or Dys wassignificantly lower in positive H.pylori chronicatrophic gastritis（CAG）than those withnegative H.pylori（CAG:54.8% vs 88.0%,IM:34.4% vs 69.6%,Dys:23.8% vs 53.6%,allP【0.05）,Bcl-2 or COX-2 expression of IM orDys in positive H.pylori cases was significantlyhigher than that without H.pylori（Bcl-2:68.8%vs23.9%,90.5% vs 60.7%;COX-2:50.0% vs10.8%,61.8% vs 17.8%;all P【0.05）.Themean number of most parameters of cellularimage analysis in positive H.pylori group wassignificantly higher than that in negative H.pylori group（Ellipser:53±14,40±12μm,Area1:748±572,302±202 μm2,Area2:3050±1661,1681±1990 μm2,all P【0.05;Ellipseb:79±23,58±15 μm,Ratio1:22%±5%,13%±4%,Ratio2:79%±17%,53%±20%,all P【0.01）.There was significant correlation between Bcl-2and histologic pattern of gastric carcinoma,andbetween COX-2 and tumor staging or lymph nodemetastasis（Bcl-2:75.0% vs 16.7%;COX-2:76.0% vs 20.0%,79.2% vs 16.7%;allP【0.05）.CONCLUSION p1l6, Bcl-2, and COX-2 but not p53 gene may play a role in the early genesis/ progression of gastric carcinoma and are associated with H. pylori infection. p53 gene is relatively late event in gastric tumorigenesis and mainly relates to its progression. There is more cellular-biological behavior of malignant tumor in gastric mucosal lesions with H. pylori infection. Aberrant Bcl-2 protein expression appears to be preferentially associated with the intestinal type cancer. COX-2 seems to be related to tumor staging and lymph node metastasis.