Prevention of gastric cancer by Helicobacter pylori eradication

The evidence supporting the important role of Helicobacter pylori causing gastric cancer is getting stronger. The mechanisms by which H. pylori can influence the progression to severe changes in the gastric mucosa are under investigation. An increased gastric epithelial cell proliferation has been observed in individuals infected with H. pylori. This lifelong increased cell turnover is deemed to be a major risk factor for increased mutational changes and may lead to the development of gastric cancer. Successful eradication of H. pylori infection induces the healing of the gastritis and a significant decrease in gastric epithelial cell proliferation. Nevertheless, it is right now unknown at which time the point of no return, meaning at which time an eradication therapy leads to a benefit for the individual to prevent gastric cancer, has been reached. Therefore the major question that arises is to whom an eradication therapy should be offered to prevent gastric cancer. A general elimination of the infection might be worthwhile, but seems to be unrealistic now because of the high prevalence of the infection and the missing of a vaccine. This review reflects possible mechanisms of gastric cancer development induced by chronic H. pylori infection and recent investigational trials for prevention of gastric cancer by H. pylori eradication therapy will be discussed.     

Treatment of Helicobacter pylori and prevention of gastric cancer

Gastric cancer is the second commonest fatal malignancy in the world with a high incidence in China. Helicobacter pylori infection is an important factor in the pathogenesis of gastric cancer. Epidemiological studies have shown a strong causal relationship between H. pylori infection and gastric cancer. Animal studies also show that eradication of H. pylori infection, especially at the early stage, is effective in preventing H. pylori-related gastric carcinogenesis. H. pylori eradication leads to regression and prevents the progression of gastric precancerous lesions, but only in a minority of cases. H. pylori eradication appears to be the most promising approach in gastric cancer prevention. The current available data in human studies showed that H. pylori eradication can reduce the risk of developing gastric cancer and this strategy is more useful in patients without atrophic gastritis or intestinal metaplasia. A longer follow-up and additional studies are needed for better understanding this issue.     

Eradication of H pylori for the prevention of gastric cancer

Infection with H pylori is the most important known etiological factor associated with gastric cancer. While colonization of the gastric mucosa with H pylori results in active and chronic gastritis in virtually all individuals infected, the likelihood of developing gastric cancer depends on environmental, bacterial virulence and host specific factors. The majority of all gastric cancer cases are attributable to H pylori infection and therefore theoretically preventable. There is evidence from animal models that eradication of H pylori at an early time point can prevent gastric cancer development. However, randomized clinical trials exploring the prophylactic effect of H pylori eradication on the incidence of gastric cancer in humans remain sparse and have yielded conflicting results. Better markers for the identification of patients at risk for H pylori induced gastric malignancy are needed to allow the development of a more efficient public eradication strategy. Meanwhile, screening and treatment of H pylori in first-degree relatives of gastric cancer patients as well as certain high-risk populations might be beneficial.     

Helicobacter pylori in Gastric Malignancies

Helicobacter pylori infection remains common worldwide and is significantly associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT)lymphoma. This article reviews recent developments in the field of H. pylori with an emphasis on mechanisms of carcinogenesis, and the bacterial, environmental and host factors that may alter risk of developing gastric cancer or gastric MALT lymphoma. The topic of eradication of H. pylori to prevent the development of malignancy and the possibility of a vaccine against H. pylori are also explored.     

Can gastric cancer be prevented by Helicobacter pylori eradication?

Helicobacter pylori infection always causes chronic gastritis and triggers several gastroduodenal pathologies ranging from peptic ulcer disease to gastric cancer. It is well established that H. pylori eradication decreases the incidence of gastroduodenal ulcer and its recurrence. However, despite being accepted as the critical risk factor for gastric cancer, there is no conclusive evidence that H. pylori eradication decreases the incidence of gastric cancer. Bacterial virulence characteristics, as well as genetic predisposition of the host in conjunction with certain environmental conditions, are the major factors which influence the development of gastric cancer. Preclinical and clinical data suggest that reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) is possible in some patients after H. pylori eradication. Since neoplastic lesions do not progress - or even regress in some cases - after H. pylori eradication, eradication therapy should be considered even in patients with precancerous lesions. Nonetheless, progression of atrophic gastritis and intestinal metaplasia into cancer has been also demonstrated in patients after H. pylori eradication, suggesting that there might be a point of no return where genetic changes have already happened and are irreversible despite elimination of the triggering carcinogen (H. pylori). At the present time the clinical decision to treat a patient is based on established risk profiles. A general screen-and-treat policy, although desirable, currently awaits a less complex treatment regimen.     

Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer in Japan

This article describes the characteristics of H. pylori infection dynamics in early gastric cancer cases in Japan and the reduced likelihood of metachronous cancer development and growth inhibition by H. pylori eradication based on healing of background gastric mucosa. In the future, these clinical studies and experimental studies in Mongolian gerbils and mice should elucidate the role of H. pylori infection in the development of gastric carcinogenesis to clinical cancer on the genetic level so that gastric cancer prevention by H. pylori eradication is established.     

Diet, Hpylori infection and gastric cancer： Evidence and controversies

Despite decreasing incidence and mortality rates, gastric cancer (GC) still remains the fourth most common cancer and the second most common cause of cancer-related deaths worldwide. Due to the limited treatment options, at present, prevention is likely to be the only effective means of controlling this disease. The success of a prevention strategy depends upon the understanding of etiological and pathogenic mechanisms underlying gastric carcinogenesis. The etiology of GC is multi-factorial, however, in the recent years, mounting evidence suggests that environmental factors play a key role. The most important environmental factors implicated in the pathogenesis of GC are diet and H pylori infection. Thus, modifications in lifestyle and dietary habit associated with eradication of H pylori infection could hypothetically represent the most promising potential targets for GC prevention. In this review we will address the evidence and the controversies on the role of these agents in noncardia GC by focusing on retrospective and prospective observational studies and interventional trials.     

根除幽门螺杆菌在预防胃癌中的作用

胃癌在全球恶性肿瘤致死亡的原因中位居第二位,幽门螺杆菌（H．pylori）感染是胃癌发生的重要病因。动物研究显示根除H.pylori,特别是在早期阶段,能有效预防胃癌的发生。部分病例通过根除npylori可阻止胃癌前病变的发展并可能使其逆转。最新研究表明根除H．pylori可降低胃癌发生的风险,对无萎缩或肠化生者可能尤其有效。本文就根除H．p）tori在预防胃癌中作用的研究进展作一综述。     

Causal role of Helicobacter pylori infection and eradication therapy in gastric carcinogenesis

Many epidemiological reports indicate that Helicobacterpylori(H pylori)infection plays an important role ingastric carcinogenesis.Several genetic and epigeneticalterations contribute to the initiation,promotion,andprogression of the cancer cells in a multi-step manner.H pylori is known to induce chronic inflammation in thegastric mucosa.Its products,including superoxides,participate in the DNA damage followed by initiation,andthe inflammation-derived cytokines and growth factorscontribute to the promotion of gastric carcinogenesis.By eradicating H pylori,gastric inflammation can becured; the therapy diminishes the levels not onlyof inflammatory cell infiltration,but also atrophy/intestinal metaplasia in part.A randomized controlledtrial revealed that the eradication therapy diminishedthe gastric cancer prevalence in cases without pre-cancerous conditions.In addition,recent epidemiologicalstudies from Japanese groups demonstrated thatthe development of gastric cancer,especially of theintestinal type,was decreased by successful eradicationtherapy,although these were designed in a non-randomized manner.However,it should be mentionedthat endoscopic detection is the only way to evaluate thedegree of gastric carcinogenesis.We have reported thatthe endoscopic and histological morphologies could bemodified by eradication therapy and it might contributeto the prevalence of gastric cancer development.Considering the biological nature of cancer cellproliferation,it is considered that a sufficiently long-termfollow-up would be essential to discuss the anticancereffect of eradication therapy.     

Is screening for and surveillance of atrophic gastritis advisable?

Gastric cancer remains a leading cause of cancer-related deaths in many parts of the world. At present, prevention seems to be the most effective means to reduce its the incidence and mortality rate. Gastric atrophy is considered the first relevant step in the histogenesis of gastric adenocarcinoma. However, whether screening for and surveillance of atrophic gastritis is advisable is debated. The prevalence and pattern of chronic atrophic gastritis varies greatly from country to country, being higher and mainly diffuse pangastritis or localized in those countries with a high gastric cancer incidence. The only method available to detect gastric atrophy is histopathological examination of endoscopic specimens, but there is no consensus about diagnosis. Serum gastric secretion may be a marker of gastric atrophy, although it has high specificity but low sensitivity. Gastric atrophy is mainly related to chronic Helicobacter pylori (H. pylori) infection. Thus, the only effective strategy for gastric cancer prevention is eradication of H. pylori infection to arrest atrophy progression in selected populations. In conclusion, there is insufficient evidence to suggest screening for and surveillance of atrophic gastritis in the general population; however, this strategy should be applied in countries with a high incidence of gastric cancer.     

Helicobacter pylori-infected animal models are extremely suitable for the investigation of gastric carcinogenesis

Although various animal models have been developed to clarify gastric carcinogenesis, apparent mechanism of gastric cancer was not clarified in recent years. Since the recognition of the pathogenicity of Helicobacter pylori (H pylori), several animal models with H pylori infection have been developed to confirm the association between H pylori and gastric cancer. Nonhuman primate and rodent models were suitable for this study. Japanese monkey model revealed atrophic gastritis and p53 mutation after long-term infection of H pylori. Mongolian gerbil model showed the development of gastric carcinoma with H pylori infection alone, as well as with combination of chemical carcinogens, such as N-methyl-N-nitrosourea and N-methyl-N-nitro-N-nitrosoguanidine. The histopathological changes of these animal models after H pylori inoculation are closely similar to those in human beings with H pylori infection. Eradication therapy attenuated the development of gastric cancer in Hpylori-infected Mongolian gerbil. Although several features of animal models differ from those seen in human beings, these experimental models provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of H pylori infection and assist the planning of eradication therapy to prevent gastric carcinoma.     

Causal role of Helicobacter pylori infection in gastric cancer

Gastric cancer is the second most frequent cancer in the world, accounting for a large proportion of all cancer cases in Asia, Latin America, and some countries in Europe. Helicobacter pylori(H pylori) is regarded as playing a specific role in the development of atrophic gastritis, which represents the most recognized pathway in multistep intestinal-type gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of H pylori infection. The seminal discovery of H pylori as the leading cause of gastric cancer should lead to effective eradication strategies. Prevention of gastric cancer requires better screening strategies to identify candidates for eradication.     

Vaccinating against Helicobacter pylori infection

Helicobacter pylori infection of the gastric mucosa remains a cause of significant morbidity and mortality almost 30 years after its discovery. H. pylori infection can lead to several gastric maladies, including gastric cancer, and although antimicrobial therapies for the infection exist, the cost of treatment for gastric cancer and the prognosis of individuals who present with this disease make vaccine development a cost effective alternative to bacterial eradication. Experimental mucosal and systemic H. pylori vaccines in mice significantly reduce bacterial load and sometimes provide sterilizing immunity. Clinical trials of oral vaccines consisting of H. pylori proteins with bacterial exotoxin adjuvants or live attenuated bacterial vectors expressing H. pylori proteins induce adaptive immune mechanisms but fail to consistently reduce bacterial load. Clinical trials and murine studies demonstrate that where H. pylori is killed, either spontaneously or following vaccination, the host demonstrated cellular immunity. Improved efficacy of vaccines may be achieved in new trials of vaccine formulations that include multiple antigens and use methods to optimize cellular immunity. Unfortunately, the industrial sponsors that served as the primary engine for much of the previous animal and human research have withdrawn their support. A renewed or expanded commitment from the biotechnology or pharmaceutical industry that could exploit recent advances in our understanding of the host immune response to H. pylori is necessary for the advancement of an H. pylori vaccine.     

Second Asia–Pacific Consensus Guidelines for Helicobacter pylori infection

The Asia–Pacific Consensus Conference was convened to review and synthesize the most current information on Helicobacter pylori management so as to update the previously published regional guidelines. The group recognized that in addition to long-established indications, such as peptic ulcer disease, early mucosa-associated lymphoid tissue (MALT) type lymphoma and family history of gastric cancer, H. pylori eradication was also indicated for H. pylori infected patients with functional dyspepsia, in those receiving long-term maintenance proton pump inhibitor (PPI) for gastroesophageal reflux disease, and in cases of unexplained iron deficiency anemia or idiopathic thrombocytopenic purpura. In addition, a population 'test and treat' strategy for H. pylori infection in communities with high incidence of gastric cancer was considered to be an effective strategy for gastric cancer prevention. It was recommended that H. pylori infection should be tested for and eradicated prior to long-term aspirin or non-steroidal anti-inflammatory drug therapy in patients at high risk for ulcers and ulcer-related complications. In Asia, the currently recommended first-line therapy for H. pylori infection is PPI-based triple therapy with amoxicillin/metronidazole and clarithromycin for 7 days, while bismuth-based quadruple therapy is an effective alternative. There appears to be an increasing rate of resistance to clarithromycin and metronidazole in parts of Asia, leading to reduced efficacy of PPI-based triple therapy. There are insufficient data to recommend sequential therapy as an alternative first-line therapy in Asia. Salvage therapies that can be used include: (i) standard triple therapy that has not been previously used; (ii) bismuth-based quadruple therapy; (iii) levofloxacin-based triple therapy; and (iv) rifabutin-based triple therapy. Both CYP2C19 genetic polymorphisms and cigarette smoking can influence future H. pylori eradication rates.     

Helicobacter pylori therapy: Present and future

Helicobacter pylori(H.pylori) plays a crucial role in the pathogenesis of chronic active gastritis,peptic ulcer and gastric mucosa-associated lymphoid tissue-lymphoma,and is also involved in carcinogenesis of the stomach.H.pylori treatment still remains a challenge for physicians,since no current first-line therapy is able to cure the infection in all treated patients.Several factors may help in the eradication of therapy failure.We reviewed both bacterial and host factors involved in therapeutic management of the H.pylori infection.In addition,we evaluated data on the most successful therapy regimens-sequential and concomitant therapies-currently available for H.pylori eradication.     

Helicobacter pylori associated gastric intestinal metaplasia: Treatment and surveillance

Gastric cancer(GC) is one of the leading causes of cancer related death in the world, particularly in East Asia. According to the Correa's cancer cascade, noncardia GC is usually developed through a series of mucosal changes from non-atrophic gastritis to atrophic gastritis(AG), intestinal metaplasia(IM), dysplasia and adenocarcinoma. Atrophic gastritis and IM are therefore generally considered to be pre-neoplastic gastric lesions. Helicobacter pylori(H. pylori) infection is an important initiating and promoting step of this gastric carcinogenesis cascade. Emerging long-term data showed that eradication of H. pylori reduced the risk of subsequent cancer development. It however remains confusing whether eradication of the bacterium in individuals with pre-neoplastic gastric lesions could regress these changes as well as in preventing cancer. Whilst H. pylori eradication could likely regress AG, the presence of IM may be a point of no return in this cascade. Hence, surveillance by endoscopy may be indicated in those with extensive IM or those with incomplete IM, particularly in populations with high GC risk. The optimal interval and the best tool of surveillance endoscopy remains to be determined in future studies.     

Are all H. pylori "bad"?]

The infection by Helicobacter pylori arises a question of great interest: should the infection be considered a disease in all cases? or, on the contrary, is the microorganism harmful in only some circumstances? The response to these questions is followed by therapeutic implications of great importance, as it is followed by the decision of administering eradication therapy to every patient or only to some individuals. In this article the arguments supporting each of the aforementioned options are reviewed. Firstly, the aphorism recently stated suggests that all microorganisms are harmful and, therefore, generalized H. pylori eradication therapy should be administered to all infected subjects. Among the arguments supporting this attitude are the following: the H. pylori carrier status does not exist; a high risk of developing peptic ulcer exists in infected patients; H. pylori positive patients are at risk of suffering gastric adenocarcinoma and lymphoma; and, finally, the eradication of the microorganism would reduce the potential reservoir of the infection. On the other hand, the expression summarises a more conservative position, that suggests the existence of , H. pylori, advising the eradication of the microorganism in only some cases. Several arguments supporting this idea, and, therefore, against the generalized use of eradication therapy, have been proposed: H. pylori has colonized humans since immemorial time and, therefore, it can not be very harmful to the human; the bacterium will induce peptic ulcer or gastric cancer in only a minority of infected subjects; the beneficial effect of eradication has been definitively demonstrated in few entities as gastroduodenal ulcer and MALT lymphoma; some strains could be beneficial to the human; generalized administration of antibiotic therapy will cause problems; the H. pylori vaccine represents a more rational alternative; and, finally, the incidence of H. pylori infection is spontaneously decreasing in some regions. In summary, there are strong arguments supporting both of the strategies that are reviewed in the present article, and, therefore, the dilemma remains.     

Helicobacter pylori eradication to prevent gastric cancer： underlying molecular and cellular mechanisms

Numerous cellular and molecular events have been described in development of gastric cancer. In this article, we overviewed roles of Helicobacter pylori (H pylori) infection on some of the important events in gastric car-cinogenesis and discussed whether these cellular and molecular events are reversible after cure of the infection. There are several bacterial components affecting gastric epithelial kinetics and promotion of gastric carci-nogenesis. The bacterium also increases risks of genetic instability and mutations due to NO and other reactive oxygen species. Epigenetic silencing of tumor suppressor genes such as RUNX3 may alter the frequency of phe-notype change of gastric glands to those with intestinal metaplasia. Host factors such as increased expression of growth factors, cytokines and COX-2 have been also reported in non-cancerous tissue in H py/ori-positive subjects. It is noteworthy that most of the above phenomena are reversed after the cure of the infection. However, some of them including overexpression of COX-2 continue to exist and may increase risks for carcinogenesis in metaplastic or dysplastic mucosa even after successful H pylori eradication. Thus, H pylori eradication may not completely abolish the risk for gastric carcinogenesis. Efficiency of the cure of the infection in suppressing gastric cancer depends on the timing and the target population, and warrant further investigation.     

The effect of Helicobacter pylori eradication on reducing the incidence of gastric cancer

Epidemiologically, the association between chronic Helicobacter pylori infection and development of gastric cancer is well established. Although the possibility of preventing gastric cancer by eradicating H. pylori infection was recently investigated by several research groups, the results remain controversial. The aim of this study was to determine whether the eradication of H. pylori infection would reduce the incidence of gastric cancer. In total, 304 patients with persistent H. pylori infection and 404 patients with H. pylori infection eradicated were examined annually for gastric cancer by endoscopy. Over an average of 3.1 years for the first group and 3.2 years for the second group, 13 and 6 patients, respectively, were diagnosed as having new gastric cancer. The cumulative incidence of gastric cancer was statistically different between the groups (P=0.019; log-rank test). The hazard ratio of H. pylori eradication was 0.335 by Cox proportional hazards model (P=0.047). Differentiated gastric cancer was found in 11 patients in the persistent infection group and 3 patients in the eradicated group. The incidence of differentiated cancer was significantly different (P=0.017) between the groups, but not for undifferentiated cancer (P=0.847). The results of the current study suggest that the eradication of H. pylori infection reduces the incidence of gastric cancer.     

Vaccine against Helicobacter pylori : Inevitable approach

Over three decades have passed since the discovery of Helicobacter pylori(H. pylori), and yet many questions about its treatment remain unanswered. For example, there is no certainty regarding continued use of current antibiotic therapy against H. pylori. The bad news is that even combined regimens are also unable to eradicate bacterial colonization. The worst problem with H. pylori chemotherapy is that even if we identify the most successful regimen, it cannot eliminate the risk of re-infection. This problem is further complicated by the fact that clinicians have no information as to whether probiotics are useful or not. Moreover, to date, we have no large scale produced vaccine effective against H. pylori. Due to the relatively rapid and abundant dissemination of guidelines globally reported concerning management of gastric cancer prevention and therapeutic regimens, clinicians may choose a vaccine as better effective weapon against H. pylori. Therefore, a radical shift in adopted strategies is needed to guide ultimate decisions regarding H. pylori management. In light of failures in vaccine projects, we should identify better vaccine design targeting conserved/essential genes. The unique character and persistence of H. pylori pose obstacles to making an effective vaccine. Preferably, in developing countries, the best reasonable and logical approach is to recommend prophylactic H. pylori vaccine among children as an obligatory national program to limit primary colonization. Trying to produce a therapeutic vaccine would be postponed until later. In reality, we should not forget to prescribe narrow spectrum antibiotics. In the current review, I draw a route to define the best adopted strategy against this rogue bacterium.