Helicobacter pylori Infection following Endoscopic Resection of Early Gastric Cancer

The role of Helicobacter pylori (H. pylori) infection in patients following endoscopic resection of early gastric cancer (EGC) remains unclear. This article presents a review of literature published in the past 15 years. H. pylori‐mediated persistent methylation levels are associated with the development of metachronous gastric cancer. The methylation of certain specific genes can be used to identify patients with a high risk of metachronous gastric cancer even after H. pylori eradication. H. pylori eradication after endoscopic resection should be performed as early as possible for eradication success and prevention of metachronous precancerous lesions. Although whether the eradication of H. pylori could prevent the development of metachronous cancer after endoscopic resection is controversial, several meta‐analyses concluded that H. pylori eradication could reduce the incidence of metachronous gastric cancer significantly. In addition, H. pylori eradication in gastric cancer survivors after endoscopic resection could reduce healthcare cost and save lives in a cost‐effective way. Taken together, H. pylori eradication after endoscopic resection of EGC is recommended as prevention for metachronous precancerous lesions and metachronous gastric cancer.


Introduction
In recent years, endoscopic resection including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) has been widely used in the treatment of early gastric cancer (EGC) [1]. e risk of the development of metachronous gastric cancer in patients who underwent endoscopic resection of EGC is higher than that in gastrectomized patients. Endoscopic resection is minimally invasive and preserves the whole stomach, which could increase the risk of metachronous cancers on unresected parts of the stomach compared to surgical resection [2, 3]. Helicobacter pylori (H. pylori) is the major cause of gastric carcinogenesis, and its infection leads to chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and subsequently to gastric adenocarcinoma [4,5]. e role of H. pylori infection in patients following endoscopic resection of EGC remains unclear due to different results from various studies. It is still controversial whether the eradication of H. pylori can reduce the likelihood of metachronous gastric cancer. In the present study, we will review the literature on the relationship between H. pylori infection and metachronous gastric lesion a er endoscopic resection. e purpose of the present study is to explore the role of H. pylori infection and H. pylori eradication in the patients a er endoscopic resection of EGC.

Prevalence of H. pylori Infection after Endoscopic Resection of Early Gastric Cancer
Endoscopic therapy is a minimally invasive treatment that allows the patient to preserve the entire stomach. e anatomy of the stomach has no significant change a er endoscopic resection for EGC, but few studies have examined whether the microbiological profile in the stomach has changed. Prevalence of H. pylori infection a er endoscopic resection for EGC has seldom been reported. Hwang -14]. e reasons for these are as follows: Eradication therapy promotes the healing process of peptic ulcers by improving microcirculation. However, muscular contraction might be a major factor in the healing process of artificial ulcers, while improvement of microcirculation is only a secondary factor. In addition, the pathogenesis of artificial ulcers is completely mechanical rather than H. pylori-induced apoptosis or gastric juiceinduced degradation. Further follow-up prospective studies will help to clarify the effect of H. pylori on ulcers developing a er endoscopic resection of EGC.

Molecular Pathogenesis of H. pylori-Related
Metachronous Gastric Cancer e current studies found that the mechanisms by which H. pylori infection might eventually lead to gastric cancer included H. pylori-induced atrophic gastritis and intestinal metaplasia, aberrant DNA methylation, epithelial-mesenchymal transition, and gastric cancer stem cells (Figure 1) [15]. Chronic active H. pylori infection leads to the recruitment of immune cells, increasing secretion of interleukin-1 , tumor necrosis factor-, and reactive oxygen species, which together cause the activation of DNA methyltransferase 1, mediating abnormal DNA methylation in the gastric mucosa [16]. e methylation level in gastric mucosa is partially reversible by H. pylori eradication in a gene-specific manner [17][18][19], but the methylation of some molecules in stem cells can last for a long time [20]. us, it is likely that the methylation level a er H. pylori eradication could reflect the epigenomic damage of stem cells [20,21]. It was reported that the methylation of MOS and miR-124a-3 could predict the risk of metachronous gastric cancer [20,22]. e methylation level of MOS in patients with metachronous gastric cancer was significantly higher than that in patients without metachronous gastric cancer [22]. Likewise, high miR-124a-3 methylation level was correlated with an increased risk of developing metachronous gastric cancers [20]. erefore, H. pylori-mediated persistent methylation levels are associated with the development of metachronous gastric cancer. e methylation of certain specific genes can be used to identify patients with a high risk of metachronous gastric cancer even a er H. pylori eradication.

Effect of H. pylori on Metachronous Precancerous Lesions after Endoscopic Resection of Early Gastric Cancer
Many studies reported the results concerning the effect of H. pylori on gastric atrophy and intestinal metaplasia following endoscopic resection of EGC. Choi et al. [23] and Han et al. [24] reported that the grade of atrophy on corpus was significantly lower in the H. pylori-eradicated group than in the persistent group during a follow-up period longer than 5 years a er endoscopic treatment of EGC. Zhang et al. found that H. pylori infection was an independent risk factor for recurrence of gastric mucosal dysplasia a er endoscopic resection [25]. Similarly, the multivariate analysis by Chon et al. showed that eradication of H. pylori was related to reduce incidence of subsequent gastric dysplasia [26]. Of particular significance is the observation that failure of H. pylori eradication occurred more frequently in metachronous patients with gastric dysplasia than in those with carcinoma [27]. In other words, eradication failure was closely related to dysplasia, but not carcinoma, in the metachronous group. erefore, H. pylori infection could play a role in the development of metachronous precancerous lesions a er endoscopic resection of EGC. ere may be a 'point of no return, ' beyond which molecular changes are irreversible and H. pylori eradication could no longer prevent metachronous lesions. It is difficult to correctly define the point of no return because the molecular process cannot be determined precisely. On the basis of the above studies, H. pylori eradication a er endoscopic resection of EGC should be performed as early as possible for the prevention of metachronous precancerous lesions.

Effect of H. pylori Eradication on the Development of Metachronous Gastric Cancer
Although H. pylori is a well-known risk factor and plays an important role in the development of gastric cancer, the effect of H. pylori infection on the development of metachronous gastric cancer a er endoscopic resection of EGC still remains unclear [28]. e mucosa adjacent to H. pylori-infected gastric cancer is usually accompanied by atrophy and intestinal metaplasia, which is susceptible to develop metachronous gastric cancer. Endoscopic resection preserves the gastric mucosa to the greatest extent, so the incidence of metachronous gastric cancer in the abnormal background mucosa is significantly increased [2]. Previous studies illustrated that persistent H. pylori infection was associated with an increased risk of subsequent gastric dysplasia or cancer a er endoscopic resection of EGC, and H. pylori infection is an independent risk factors for metachronous gastric cancer a er ESD of EGC [29][30][31]. However, Lim et al. showed an inverse relationship between H. pylori infection and metachronous gastric cancer [32]. One possible reason is that H. pylorinegative patients may have previously been infected with H. pylori and previous long-term infection might have a greater effect on the development of metachronous gastric cancer than newly developed current infection.
It is still on debate whether the eradication of H. pylori could prevent the development of metachronous cancer a er endoscopic resection of EGC. Several long follow-up prospective studies reported that eradication of H. pylori in the patients treated with endoscopic resection of gastric dysplasia or EGC could reduce the risk of metachronous cancer [23,33,34]. However, a 3-year prospective study by Choi et al. reported that the cumulative incidence of metachronous gastric cancer was not different between patients with or without H. pylori eradication [35]. Other retrospective studies showed similarly controversial conclusions [26,27,31,[36][37][38][39][40]. e reasons for this discrepancy are as follows: First, the study designs were different among the studies. Some were prospective randomized trials, and others were retrospective cohort studies. Second, the timing of the H. pylori eradication was not consistent. Some persons received eradication treatment immediately a er endoscopic resection, and others received treatment several months a er endoscopic resection. ird, the follow-up time was not consistent among the studies and most studies had a follow-up period of less than 5 years. In addition, the methods for calculations of the observation period were different among the studies. Some started from eradication of H. pylori, and others started from the initial ESD.
Nevertheless, several meta-analyses concluded that H. pylori eradication could reduce the incidence of metachronous gastric cancer significantly, therefore preventing against metachronous gastric cancer in patients who have undergone endoscopic resection [41][42][43][44]. Although it is possible to develop metachronous gastric cancer a er successful eradication of H. pylori, H. pylori eradication a er endoscopic resection of EGC is still recommended in the Maastricht consensus report and the Guidelines of the Japanese Gastroenterological Society [45,46]. Further prospective studies with long-term follow-up could help clarify the effect of H. pylori eradication in preventing metachronous gastric cancer a er endoscopic resection of EGC.
Furthermore, Park et al. clarified that H. pylori infection or eradication did not affect the time interval between the initial ESD and the development of metachronous gastric cancer [47], which implied that H. pylori eradication might not halt the progression of precancerous lesions, especially when the neoplastic change has reached a certain degree. A possible reason is that metachronous gastric lesions might have already been in the stomach at the time of ESD for EGC as tiny or invisible lesions, and therefore, the time interval to occurrence of metachronous gastric cancer might not be affected by H. pylori eradication in patients with undetected early cancer or slowly growing latent cancer [48].

Optimal Timing for H. pylori Eradication for Patients after Endoscopic Resection of Early Gastric Cancer
Few studies have explored the optimal timing to eradicate H. pylori a er endoscopic resection of EGC. Huh et al. assessed whether the eradication of H. pylori at different time points a er endoscopic resection affected the success rates of eradication therapy [49]. ey concluded that the early treatment group (≤2 weeks a er endoscopic resection) achieved a H. pylori eradication a er endoscopic resection of EGC is recommended as prevention for metachronous precancerous lesions and meta chronous gastric cancer. A large-scale, longterm research is needed to examine the role of H. pylori infection and H. pylori eradication in the patients following endoscopic resection of EGC.

Conflicts of Interest
e authors declare that there is no conflict of interest regarding the publication of this article.

References
[1] T. Nishizawa and N. Yahagi, "Long-term outcomes of using endoscopic submucosal dissection to treat early gastric cancer, " Gut and Liver, vol. 12, no. 2, pp. 119-124, 2018. significantly higher eradication rate than the intermediate group (2-8 weeks) or the late group (≥8 weeks). Multivariate analysis showed that early initiation of H. pylori eradication therapy was an independent significant predictor of eradication success. On the other hand, it was reported that H. pylori eradication in the patients who underwent ESD for EGC should be performed before the progression of gastric mucosal atrophy [36]. e presence of moderate-to-severe mucosal atrophy or intestinal metaplasia may be a 'point of no return' and does not appear to regress following H. pylori eradication [36,50]. ese results suggest that eradication of H. pylori as early as possible a er endoscopic surgery offers the greatest chance of eradication success.  [51]. erefore, eradication of H. pylori in gastric cancer survivors a er endoscopic resection could reduce healthcare costs while saving lives, and these findings have favorable implication in decision making about the most appropriate treatment option a er endoscopic resection of EGC. Large-scale studies are needed to clarify whether this strategy could be cost-effective in selective population with high risk of developing metachronous gastric cancer.

Conclusion
In this review, we summarized the studies addressing H. pylori infection a er endoscopic resection of EGC. Unfortunately, prevalence of H. pylori infection a er endoscopic resection of EGC has seldom been reported. e effect of H. pylori eradication on ulcers developing a er endoscopic resection is still on debate.
H. pylori-mediated persistent methylation levels are associated with the development of metachronous gastric cancer. e methylation of certain specific genes can be used to identify patients with a high risk of metachronous gastric cancer even a er H. pylori eradication. H. pylori eradication a er endoscopic resection should be performed as early as possible for eradication success and prevention of metachronous precancerous lesions. Although whether the eradication of H. pylori could prevent the development of metachronous cancer a er endoscopic resection is controversial, several meta-analyses concluded that H. pylori eradication could reduce the incidence of metachronous gastric cancer significantly. In addition, H. pylori eradication in gastric cancer survivors a er endoscopic resection could reduce health care cost and save lives in a cost-effective way. Taken together,