Serum pepsinogen levels in gastric cancer patients and their relationship with Helicobacter pylori infection: a prospective study.

BACKGROUND: Our aim was to study the serum pepsinogen levels in gastric cancer patients in our population in relation to histology and the presence of Helicobacter pylori. METHODS: Forty-six patients with gastric cancer and 70 controls were studied prospectively in a 1-year period. Serum levels of pepsinogen I (PG I), pepsinogen II (PG II), and gastrin were measured by radioimmunoassay. RESULTS: The mean PG I levels for cancer patients and controls were 83.5 microg/l and 60.9 microg/l, respectively (P = 0.03), the mean PG II levels were 27.2 microg/l and 12.1 microg/l respectively (P < 0.0001). The PG I/II ratio was significantly lower in cancer patients (P = 0.04) and in those with Helicobacter infection. Serum pepsinogen levels were not affected by any pathological characteristics. Histology showed that the prevalence of chronic gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%, respectively. CONCLUSION: The prevalence of gastric atrophy is low in our population, and serum pepsinogen measurement is not useful as a screening tool for gastric cancer in this population.     

Trends in the incidence of gastric cancer in Japan and their associations with Helicobacter pylori infection and gastric mucosal atrophy

Background Although age-adjusted mortality from gastric cancer has been decreasing in Japan, the crude incidence of gastric cancer shows a slight increase.Methods We have observed trends in the incidence of gastric cancer by sex and 20-year age groups over the past two decades (1976–1996). Source data were obtained from the cancer statistics materials provided by the Research Group for Population-Based Cancer Registration in Japan. Simultaneously, we observed changes in the prevalence of Helicobacter pylori infection and in serological atrophy of the gastric mucosa, and compared the results with those involving changes in the incidence of gastric cancer.Results A slight decline was observed in all age groups over 40 years old, in both men and women, between 1986 and 1996. However, a marked decline in incidence was observed for those aged 20–39 years. The prevalence of H. pylori infection declined in both sexes between 1989 and 1998. The frequency of serological atrophy of the gastric mucosa significantly declined in all age groups between 1989 and 1996, with young age groups experiencing a more marked decrease.Conclusion The marked decline in gastric cancer incidence observed in the young population will also begin to occur in the elderly population in the future.     

Helicobacter pylori,gastric microbiota and gastric cancer relationship: Unrolling the tangle

Helicobacter pylori infection (Hp-I) represents a typical microbial agent intervening in the complex mechanisms of gastric homeostasis by disturbing the balance between the host gastric microbiota and mucosa-related factors, leading to inflammatory changes, dysbiosis and eventually gastric cancer. The normal gastric microbiota shows diversity, with Proteobacteria [Helicobacter pylori (H. pylori) belongs to this family], Firmicutes, Actinobacteria, Bacteroides and Fusobacteria being the most abundant phyla. Most studies indicate that H. pylori has inhibitory effects on the colonization of other bacteria, harboring a lower diversity of them in the stomach. When comparing the healthy with the diseased stomach, there is a change in the composition of the gastric microbiome with increasing abundance of H. pylori (where present) in the gastritis stage, while as the gastric carcinogenesis cascade progresses to gastric cancer, the oral and intestinal-type pathogenic microbial strains predominate. Hp-I creates a premalignant environment of atrophy and intestinal metaplasia and the subsequent alteration in gastric microbiota seems to play a crucial role in gastric tumorigenesis itself. Successful H. pylori eradication is suggested to restore gastric microbiota, at least in primary stages. It is more than clear that Hp-I, gastric microbiota and gastric cancer constitute a challenging tangle and the strong interaction between them makes it difficult to unroll. Future studies are considered of crucial importance to test the complex interaction on the modulation of the gastric microbiota by H. pylori as well as on the relationships between the gastric microbiota and gastric carcinogenesis.     

幽门螺杆菌感染与胃癌及癌前病变中P21蛋白的表达

 用LSAB免疫组化法，对20例谓癌、22例异型增生、30例肠化生及13例正常组织进行了P21蛋白表达的检测。结果发现，胃癌、异型增生和肠化生的P21阳性者分别为13例（65.0%）,12例（60.0%）,11例（36.6%）,正常组织全部阴性；三种组织中，HP阳性病人的P21阳性率为41.6%（30/72）,明显高于HP阴性病人的8.3%（6/72）,有显着差别（P<0.01）.说明HP感染与P21过度表达存在着明显的相关性。提示HP感染可能通过ras癌基因的突变而参予致癌作用。     

Susceptibility to allitridi of Helicobacter pylori with different genotypes in gastric diseases

Objective:To investigate the difference in susceptibilities to allitridi of Helicobacter pylori(H.pylori)strains in different gastric diseases and the associations with different genotypes.Methods:H.pylori strains were isolated from gastric antral biopsy specimens and identified.DNA was isolated from H.pylori strains.Different genotypes were determined by polymerase chain reaction(PCR),and the allitridi MICs were determined by agar dilution methods.MIC_(50) was calculated. Results:The susceptibilities of...     

幽门螺杆菌与残胃癌

残胃癌发病与幽门螺杆菌感染密切相关,幽门螺杆菌能促进残胃黏膜上皮细胞增殖,促进胃液中亚硝基化合物的产生及人体某些基因异常表达,最终促使残胃癌发生.根除幽门螺杆菌感染有望减少残胃癌的发生.     

Prevalence of Helicobacter pylori infection in gastric remnant after distal gastrectomy for primary gastric cancer

Background. The development of a second primary cancer in the gastric remnant after gastrectomy for early gastric carcinoma is a problem, and eradication of Helicobacter pylori after the operation has been recommended. However, to date, practical indications for H. pylori eradication after gastric cancer surgery have not yet been reported. Methods. We examined H. pylori infection in the gastric remnant after distal gastrectomy for primary gastric cancer. One hundred and nine patients who had had a gastrectomy were studied. Endoscopic findings and results from the urease test, bacteriologic assessment, serological test, and histopathological examination were analyzed. Results. Seventy-one patients (65.1%) were judged to be positive for H. pylori infection. The prevalence of H. pylori infection was found to be significantly decreased in older patients, patients in whom the operation had been performed a long time before examination, patients with symptoms, and patients with severe reflux gastritis. On the other hand, histologically, chronic and acute gastritis correlated significantly with H. pylori infection. H. pylori prevalence was highest in mildly atrophic mucosa and decreased with more extensive atrophic changes of the mucosa. Conclusions. The persistence of H. pylori -related active gastritis in the gastric remnant after gastric cancer surgery was suggested in younger patients with mild atrophic gastritis and without reflux gastritis. These patients may be the best candidates for H. pylori eradication therapy. Received: April 13, 2001 / Accepted: June 18, 2001     

Serological response to Helicobacter pylori infection among Latin American populations with contrasting risks of gastric cancer

Gastric cancer is a rare outcome of chronic Helicobacter pylori infection. Serologic profiles may reveal bacterial, environmental and/or host factors associated with cancer risk. We therefore compared specific anti‐H. pylori antibodies among populations with at least twofold differences in gastric cancer mortality from Mexico, Colombia and Chile. Our study included 1,776 adults (mean age 42 years) from three nationally representative surveys, equally divided between residents of high‐ and low‐risk areas. Antibodies to 15 immunogenic H. pylori antigens were measured by fluorescent bead‐based multiplex assays; results were summarized to identify overall H. pylori seropositivity. We used logistic regression to model associations between antibody seroreactivity and regional cancer risk (high vs. low), adjusting for country, age and sex. Both risk areas had similar H. pylori seroprevalence. Residents in high‐ and low‐risk areas were seroreactive to a similar number of antigens (means 8.2 vs. 7.9, respectively; adjusted odds ratio, OR: 1.02, p = 0.05). Seroreactivities to Catalase and the known virulence proteins CagA and VacA were each significantly (p < 0.05) associated with residence in high‐risk areas, but ORs were moderate (1.26, 1.42 and 1.41, respectively) and their discriminatory power was low (area under the curve < 0.6). The association of Catalase was independent from effects of either CagA or VacA. Sensitivity analyses for antibody associations restricted to H. pylori‐seropositive individuals generally replicated significant associations. Our findings suggest that humoral responses to H. pylori are insufficient to distinguish high and low gastric cancer risk in Latin America. Factors determining population variation of gastric cancer burden remain to be identified.     

幽门螺杆菌感染与不同胃粘膜病变中PCNA、bcl-2表达的关系

 目的　研究不同胃粘膜病变中幽门螺杆菌 (Hp)感染与细胞增生、凋亡的关系。 方法　采用SP免疫组化染色及图像分析方法 ,对 312例慢性萎缩性胃炎 (CAG)、肠上皮化生 (IM )、胃上皮不典型增生 (GED)及胃癌 (GC)中Hp感染与PCNA、bcl 2表达和DNA含量及倍体进行检测。 结果　在Hp感染组 ,从CAG→IM→GED→GC ,PCNA和bcl 2阳性表达率和高表达率均逐渐增高。尤其在IMIII、GEDII III和肠型GC中 ,PCNA高表达率分别明显或显著高于IMI II、GEDI和IMIII、GEDII III(P <0 .0 5 ,P <0 .0 1)。其DNA含量和倍体分析与PCNA的表达一致。Hp未感染组不同病变中各指标均不显示Hp感染组的变化特点。结论　Hp感染可引起胃上皮细胞增生水平显著增高 ,凋亡水平明显降低     

From Helicobacter pylori infection to gastric cancer: Current evidence on the immune response

Gastric cancer (GC) is the result of a multifactorial process whose main components are infection by Helicobacter pylori (H. pylori), bacterial virulence factors, host immune response and environmental factors. The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes, which results in deregulation of cell signaling pathways and apoptosis process. This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H. pylori.     

Helicobacter pylori IgA and IgG antibodies, serum pepsinogen I and the risk of gastric cancer: changes in the risk with extended follow-up period

The prediction of Helicobacter pylori antibodies immunoglobulin A (IgA) and immunoglobulin G (IgG) and serum pepsinogen I (PG I) on gastric cancer occurrence was studied in a nested case-control study, based on 225 incident cancer cases and 435 matched controls from a Finnish cohort followed from 1966-1991. The odds ratio of noncardia gastric cancer between infected and noninfected persons was 3.12 (95% confidence interval (CI)=1.97-4.95) for elevated IgA and 2.88 (CI: 1.63-5.07) for elevated IgG antibodies. The odds ratio between low and high PG I was 2.24 (CI: 1.43-3.49). The strength of association was significant for IgA antibodies during the total follow-up, but for IgG antibodies this was only true for follow-up periods of 15 years or more. IgA antibodies were significantly associated with all registered histological subtypes apart from intestinal type adenocarcinoma. The highest gastric cancer risk was found among individuals with simultaneously elevated IgA and IgG antibodies and low PG I with an odds ratio of 10.9 (CI: 4.31-27.7) in comparison with those who were negative for both antibodies and had normal PG I. Elevated IgA and IgG antibodies and low PG I were not associated with cancers of the gastric cardia. The findings support the hypothesis that H. pylori infection is a cause of noncardia gastric cancer. Although elevated H. pylori IgA and IgG antibodies and low PG I independently could predict the occurrence of noncardia gastric cancer, their power to do so varied with the stage and length of the follow-up period and it increased when they were applied in combination.     

Helicobacter pylori infection and gastric carcinoma: Not all the strains and patients are alike

Gastric carcinoma (GC) develops in only 1%-3% of Helicobacter pylori (H. pylori) infected people. The role in GC formation of the bacterial genotypes, gene polymorphisms and host’s factors may therefore be important. The risk of GC is enhanced when individuals are infected by strains expressing the oncoprotein CagA, in particular if CagA has a high number of repeats containing the EPIYA sequence in its C’-terminal variable region or particular amino acid sequences flank the EPIYA motifs. H. pylori infection triggers an inflammatory response characterised by an increased secretion of some chemokines by immunocytes and colonised gastric epithelial cells; these molecules are especially constituted by proteins composing the interleukin-1beta (IL-1β) group and tumour necrosis factor-alpha (TNF-α). Polymorphisms in the promoter regions of genes encoding these molecules, could account for high concentrations of IL-1β and TNF-α in the gastric mucosa, which may cause hypochlorhydria and eventually GC. Inconsistent results have been attained with other haplotypes of inflammatory and anti-inflammatory cytokines. Genomic mechanisms of GC development are mainly based on chromosomal or microsatellite instability (MSI) and deregulation of signalling transduction pathways. H. pylori infection may induce DNA instability and breaks of double-strand DNA in gastric mucocytes. Different H. pylori strains seem to differently increase the risk of cancer development run by the host. Certain H. pylori genotypes (such as the cagA positive) induce high degrees of chronic inflammation and determine an increase of mutagenesis rate, oxidative-stress, mismatch repair mechanisms, down-regulation of base excision and genetic instability, as well as generation of reactive oxygen species that modulate apoptosis; these phenomena may end to trigger or concur to GC development.     

CD44v6在胃癌中的表达及其与幽门螺杆菌感染的关系

背景与目的:目前认为CD44v6在胃癌组织中有较高的表达率,并公认幽门螺杆菌(Helicobactor pylori,HP)感染为Ⅰ类胃癌致癌原,但迄今未见CD44v6与HP关系的文献报道。本文旨在探讨CD44v6在胃癌中的表达及其与HP感染的关系。方法:选取胃癌组织56例、癌旁非癌组织56例、非典型增生胃粘膜32例。CD44v6检测采用RT-PCR与Southern blot法;HP检测采用快速尿酶法与Warthin-Starry银染色;同时用ELISA测定56例胃癌患者血清中HP cagA抗体。结 果:胃粘膜HP阳性组中,转移性胃癌和非转移胃癌的CD44v6表达率分别达100％(12/12)和90.5％(19/21),明显高于癌旁非癌胃组织的48.6％(24/35)与非典型增生胃粘膜的23.6％(6/23);转移性胃癌与非转移胃癌的CD44v6表达率比较无显著差异(P>0.25),非典型增生胃粘膜与胃癌、癌旁非癌胃组织比较有非常显著性差异(P<0.005)。胃粘膜HP阴性组:在转移性胃癌、非转移胃癌、癌旁非癌组织和非典型增生CD44v6表达率分别是66.7％,51.4％,38.1％和18.1％,各组比较均无显著性差异。CD44v6表达与HP感染有密切关系(P<0.01)。肠型胃癌CD44v6表达与HP感染高于弥漫型胃癌(P>0.05)。胃癌患者血清HP cagA抗体阳性率高于胃癌组织HP感染率(P>0.05)。结论:CD44v6在胃癌中有较高的阳性率,与HP感染密切相关,可作为     

胃蛋白酶原C基因插入-缺失多态和幽门螺杆菌感染的交互作用与胃癌发病风险

目的 探讨胃癌发生发展过程中,胃蛋白酶原C(PGC)基因插入-缺失多态与幽门螺杆菌(Hp)及其不同基因亚型菌株感染的交互作用.方法 1:1频数配伍,选择基本正常(NOR)、胃糜烂溃疡(GU)、萎缩性胃炎(AG)和胃癌(Gc)各141例,分析PGE基因多态和Hp感染的交互作用.同时选择177例Hp感染阳性者,分析PGC基因多态与不同基因亚型Hp感染的交互作用.以聚合酶链反应(MR)检测PGC基因多态型及Hp基因亚型.以酶联免疫吸附实验(ELISA)检测血清Hp-IgG抗体.结果 PGG基因多态与Hp感染两因素交互作用,PGC等位基因1纯合型、Hp-IgG阳性者罹患GU、AG和GC的OR值分别为8.69、11.16和10.61(P值分别为0.049、0.02和0.03),交互作用指数分别为5.40、6.48和4.34,归因比分别为0.721、0.770和0.697.P02基因多态与不同基因亚型Hp感染对于AG和GC患病均无交互作用.结论 GC发生发展过程中,PGC基因多态与Hp感染存在正交互作用,而与不同基因亚型Hp菌株感染无交互作用.     

Helicobacter pylori infection and gastric carcinogenesis in animal models

The effects of Helicobacter pylori infection on gastric disorders have been proven by many epidemiological and experimental studies. To explore the relationships between H. pylori infection and gastric carcinogenesis, many factors, including host responses, environmental status, and the virulence factors of the bacteria should be taken into account. Mongolian gerbils ( Meriones unguiculatus ) can be easily infected with H. pylori , and provide an excellent in-vivo experimental model to clarify the role of H. pylori in active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. Studies have revealed that H. pylori infection markedly enhances all histological types of gastric cancers in gerbils treated with a chemical carcinogen. Eradication reduced the enhancing effect of H. pylori on gastric carcinogenesis, whereas a high-salt diet synergistically enhanced the effect of H. pylori . Various factors involving inflammation, cell proliferation, and cell differentiation could be examined with this experimental model to help elucidate this mechanisms of gastric carcinogenesis. Received: October 23, 2002 / Accepted: December 9, 2002 Acknowledgments We thank Dr. Toshiko Kumagai, Central Clinical Laboratories, Shinshu University Hospital; Dr. Atsushi Sugiyama, First Department of Surgery, Shinshu University; Professor Tsutomu Katsuyama, Department of Laboratory Medicine, Shinshu University School of Medicine; and Dr. Nobuyuki Shimizu and Professor Michio Kaminishi, Department of Gastrointestinal Surgery, Postgraduate School of Medicine, The University of Tokyo. Offprint requests to: M. Tatematsu     

Serum pepsinogen levels can quantify the risk of development of metachronous gastric cancer after endoscopic resection

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patient's request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (p = 0.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/II ≤ 3.0, which is one of the criteria of PG test‐positive, was significantly higher in patients with MGC (83 vs. 69%, p = 0.04). H. pylori eradication after ER did not affect MGC development (p = 0.2). On multivariate analysis, serum PG I/II ratio ≤ 3.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47–12.25, p = 0.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status.     

Severe atrophic gastritis with Helicobacter pylori infection and gastric cancer

Background. We conducted a case-control study to evaluate whether patients with severe gastric atrophy (indicated by serum pepsinogen concentration) have a high risk of gastric cancer. Methods. At the time of diagnosis of gastric cancer, sera from 301 patients (cases) and 602 sex- and age-matched cancer-free individuals (controls) were tested for the presence of anti-Helicobacter pylori IgG antibody (HM-CAP enzyme-linked immunoassay [ELISA] kit; Kyowa Medix, Tokyo, Japan) and serum pepsinogen (PG) levels (PG I and II Riabead Kits; Dainabot, Tokyo, Japan). We defined positivity for pepsinogen a pepsinogen I concentration of less than 70 ng/mL and a PG I/II ratio of less than 3.0. We categorized the subjects according to serum pepsinogen levels and anti-Helicobacter pylori IgG antibody, creating four categories. Results. Of the 301 cancer cases, 177 had positive serum pepsinogen levels, and 172 were positive for anti-Helicobacter pylori IgG antibody. The category in which subjects had positive serum pepsinogen levels and were negative for anti-Helicobacter pylori IgG antibody had the highest proportion (76.9%) of individuals with gastric cancer and the highest odds ratio (4.20) of the four categories. The odds ratios were 2.55 (95% confidence interval; 1.92–3.88) for positive serum pepsinogen levels and 0.93 (95% confidence interval; 0.63–1.27) for positive anti-Helicobacter pylori IgG antibody. Conclusion. These results suggest that patients with positive serum pepsinogen levels who are negative for IgG antibody to Helicobacter pylori, constitute a high-risk group for gastric cancer. Helicobacter pylori infection is associated with the development of gastric cancer by providing a suitable environment i.e., severe gastric atrophy, for carcinogenesis of the gastric mucosa. Received for publication on Mar. 20, 1998; accepted on Aug. 20, 1998     

幽门螺杆菌感染及其相关因素与胃癌关系的研究进展

 胃癌是人类最常见的恶性肿瘤之一,目前研究认为幽门螺杆菌（HP）是胃癌发生发展进程的重要推动因素,现就目前国内外学者对HP在胃癌发生中致病的毒力因子及作用机制、宿主基因的易感性和环境因素三个方面进行综述。     

CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study

Helicobacter pylori (H. pylori), atrophic gastritis, dietary and life-style factors have been associated with gastric cancer (GC). These factors have been evaluated in a large case-control study nested in the European Prospective Investigation into Cancer and Nutrition carried out in 9 countries, including the Mediterranean area. Participants, enrolled in 1992-1998, provided life-style and dietary information and a blood sample (360,000; mean follow-up: 6.1 years). For 233 GC cases diagnosed after enrolment and their 910 controls individually-matched by center, gender, age and blood donation date H. pylori antibodies (antilysate and antiCagA) and plasma Pepsinogen A (PGA) were measured by ELISA methods. Severe chronic atrophic gastritis (SCAG) was defined as PGA circulating levels <22 microg/l. Overall, in a conditional logistic regression analysis adjusted for education, smoke, weight and consumption of total vegetables, fruit, red and preserved meat, H. pylori seropositivity was associated with GC risk. Subjects showing only antibodies anti-H. pylori lysate, however, were not at increased risk, while those with antiCagA antibodies had a 3.4-fold increased risk. Overall, the odds ratio associated with SCAG was 3.3 (95% CI 2.2-5.2). According to site, the risk of noncardia GC associated with CagA seropositivity showed a further increase (OR 6.5; 95% CI 3.3-12.6); on the other hand, a ten-fold increased risk of cardia GC was associated with SCAG (OR 11.0; 95% CI 3.0-40.9). These results support the causal relationship between H. pylori CagA+ strains infection, and GC in these European populations even after taking into account dietary habits. This association was limited to distal GC, while serologically defined SCAG was strongly associated with cardia GC, thus suggesting a divergent risk pattern for these 2 sites.     

Gastric cancer, Helicobacter pylori infection and other risk factors

Gastric cancer incidence is declining. However, it is too early to consider this neoplastic disease as rare and the worldwide mortality rate still remains high. Several risk factors have been identified for non-cardia gastric cancer and primary prevention is feasible since most of the risk factors can be removed. Helicobacter pylori eradication treatment reduces but does not abolish gastric cancer risk. Indeed, gastric cancer is a multifactorial disease and removing one factor does not therefore prevent all cases. Endoscopic surveillance is still needed, especially in subjects at higher risk. The definition of high-risk patients will be the future challenge as well as identifying the best surveillance strategy for such patients.