Background. Only a few reported studies focus on the natural history and course of advanced and severe chronic atrophic gastritis. Methods. In this study we followed 47 men (mean age 62 years) with advanced (moderate or severe) Helicobacter pylori-positive atrophic corpus gastritis. Duration of endoscopic follow-up was 6 years and follow-up based on serum levels of pepsinogen I and antibodies to H. pylori covered a period of 10 years. None of the patients was treated for H. pylori infection prior to end of follow-up. Results. The median H. pylori antibody titre declined (IgG from 4000 to 1300; IgA from 200 to 50) in the study population, and 11 men (23%) converted to seronegative (p=0.0005, Fisher's exact test). There was a small but significant (p=0.0004, Page's test) declining trend in mean atrophy score of the corpus during follow-up (from 2.5 to 2.2). However, no significant changes were observed in grade of atrophy or intestinal metaplasia of the antral mucosa or in grade of intestinal metaplasia in the corpus. The mean SPGI level remained at the initial low level during the entire follow-up. Conclusions. H. pylori antibodies disappear spontaneously within 10 years in almost one fourth of patients with advanced atrophic corpus gastritis. The disappearance of H. pylori antibodies is accompanied by no or more than a mild improvement of the gastric mucosa.

Purpose: Cyclooxygenase-2 (COX-2) promotes carcinogenesis and its expression associates with clinicopathologic characteristics in gastric cancer. HuR is an mRNA binding protein that controls the stability of certain transcripts including COX-2.We evaluated the prognostic significance of COX-2 and HuR expressions in gastric cancer and whether there exists a link between HuR and COX-2 expressions. Experimental Design: The study included 342 consecutive patients with histologically confirmed gastric adenocarcinoma, of whom 321patients had tissue specimens available for COX-2 and 316 for HuR immunohistochemistry. Specimens were stained by COX-2^and HuR-specific monoclonal antibodies and scored by two independent observers. Correlation to clinical data and survival was assessed. TMK-1 gastric adenocarcinoma cells were treated with small interfering RNA against HuR and expressions of HuR and COX-2 were detected by immunofluorescence andWestern blot analysis. Results: Patients with low COX-2 expression had a cumulative 5-year survival of 53% and those with high COX-2 expression had 16% (P < 0.0001). In multivariate analysis, COX-2 was an independent prognostic factor (P = 0.003). Cytoplasmic HuR expression was associated with high COX-2 expression (P < 0.0001) and with reduced survival (P = 0.004) whereas nuclear positivity for HuR was not. When TMK-1 cells were treated with HuR small interfering RNA, expressions of HuR and COX-2 were reduced. Conclusions: High COX-2 is an independent prognostic factor in gastric cancer. Cytoplasmic expression of HuR associates with high COX-2 expression and with reduced survival, and tissue culture experiments show that HuR can regulate expression of COX-2 in gastric cancer cells.

It has been estimated that at least one-half of the world's population is infected with Helicobacter pylori.1 Approximately 50% will develop atrophic gastritis of some topographic type or grade during their lifetime. 2±4Autoimmune mechanisms represent other aetiopathogenetic factors of atrophic gastritis, but it has been suggested that even this type of atrophic gastritis may be initiated by H. pylori infection.5, 6 H. pylori infection, atrophic gastritis and intestinal metaplasia are wellknown risk conditions for gastric carcinoma. 7±9 Studies have shown that H. pylori gastritis increases the risk of non-cardiac gastric cancer approximately six-fold. 10In patients with advanced H. pylori-associated atrophic gastritis, the natural course of the changes in the gastric mucosa is not well known. In follow-up studies of H. pylori gastritis, atrophy (loss of normal mucosal glands) and intestinal metaplasia have been reported to be stable or progressive.3, 11 H. pylori eradication SUMMARYBackground: There are few data on the natural course of Helicobacter pylori-related atrophic gastritis. Aim: To investigate the effect of H. pylori eradication on advanced atrophic gastritis in the corpus. Methods: Twenty-two elderly men with H. pylori infection and moderate or severe atrophic corpus gastritis formed the study population. These men were under endoscopic surveillance because of the presence of inde®nite or de®nite dysplastic gastric lesions in addition to atrophic corpus gastritis. The men were gastroscopically and bioptically examined four times before they received H. pylori eradication therapy (mean follow-up time, 7.5 years), and once again 2.5 years after eradication therapy. Serum levels of pepsinogen I and H. pylori antibodies were analysed at baseline, immediately before and 2.5 years after eradication therapy.

Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited condition characterized by gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation.

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We studied DNA copy number changes in gastric cancer (GC) using comparative genomic hybridization (CGH) analysis on 35 resected gastric carcinomas (22 of the intestinal type and 13 of the diffuse type). Eighty‐three percent of the cases showed DNA copy number changes. Gains were more common than losses (median of 3 and 1 in primary tumors of the intestinal and diffuse type, respectively). The most common gains were detected on 20q [46%; 12 intestinal type (55%) and four diffuse type (31%)], 8q [37%; 10 intestinal type (45%) and three diffuse type (23%)], and 17q12‐21 [29%; all but one intestinal type (41%)]. The most frequent losses were detected on 18q [26%; all intestinal type (41%)] and on 4q [23%; all intestinal type (32%)]. High‐level amplifications were observed in the intestinal type of tumors at 17q12‐21 (three tumors), 20q (three tumors), 2p (one tumor), and 18q (one tumor). In the diffuse type, high‐level amplification was detected once at 13q. Genes Chromosom. Cancer 20:38–43, 1997. © 1997 Wiley‐Liss, Inc.

Purpose: We have investigated the expression and regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in gastric cancer. Experimental Design: Clinical gastric adenocarcinoma samples were analyzed by immunohistochemistry and quantitative real-time PCR for protein and mRNA expression of 15-PGDH and for methylation status of 15-PGDH promoter. The effects of interleukin-1h (IL-1h) and epigenetic mechanisms on 15-PGDH regulation were assessed in gastric cancer cell lines. Results: In a gastric cancer cell line with a very low 15-PGDH expression (TMK-1), the15-PGDH promoter was methylated and treatment with a demethylating agent 5-aza-2 ¶-deoxycytidine restored 15-PGDH expression. In a cell line with a relatively high basal level of 15-PGDH (MKN-28), IL-1h repressed expression of 15-PGDH mRNA and protein. This effect of IL-1h was at least in part attributed to inhibition of 15-PGDH promoter activity. SiRNA-mediated knockdown of 15-PGDH resulted in strong increase of prostaglandin E 2 production in MKN-28 cells and increased cell growth of these cells by 31% in anchorage-independent conditions. In clinical gastric adenocarcinoma specimens, 15-PGDH mRNA levels were 5-fold lower in gastric cancer samples when compared with paired nonneoplastic tissues (n = 26) and 15-PGDH protein was lost in 65% of gastric adenocarcinomas (n = 210). Conclusions: 15-PGDH is down-regulated in gastric cancer, which could potentially lead to accelerated tumor progression. Importantly, our data indicate that a proinflammatory cytokine linked to gastric carcinogenesis, IL-1h, suppresses 15-PGDH expression at least partially by inhibiting promoter activity of the 15-PGDH gene.

To elucidate gene expression signatures associated with gastric carcinogenesis, we performed a genome-wide expression analysis of 46 Finnish and 20 Japanese gastric tissues. Comparative analysis between Finnish and Japanese datasets identified 58 common genes that were differentially expressed between cancerous and non-neoplastic gastric tissues. Twenty-six of these genes were up-regulated in cancer and 32 down-regulated. Of these genes, 64% were also differentially expressed in another unrelated publicly available dataset. The expression levels of four of the up-regulated genes, CXCL1, SPARC, SPP1 and SULF, were further analyzed in 82 gastric tissues using quantitative real-time RT-PCR. This analysis validated the results from the microarray analysis as the expression of these four genes was significantly higher in the cancerous tissue compared with the normal tissue (fold change 3.4-8.9). Over-expression of CXCL1 also positively correlated with improved survival. To conclude, irrespective of the microarray platform or patient population, a common gastric cancer gene expression signature of 58 genes, including CXCL1, SPARC, SPP1, and SULF, was identified. These genes represent potential biomarkers for gastric cancer.