Lisette Capelle

The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis.

BACKGROUND The OLGA (operative link on gastritis assessment) staging system is based on severity of atrophic gastritis (AG). AG remains a difficult histopathologic diagnosis with low interobserver agreement, whereas intestinal metaplasia (IM) is associated with high interobserver agreement. OBJECTIVE The aim of this study was to evaluate whether a staging system based on IM is preferable to estimate gastric cancer risk. DESIGN AND SETTING Prospective multicenter study. PATIENTS A total of 125 patients previously diagnosed with gastric IM or dysplasia. INTERVENTIONS Surveillance endoscopy with extensive biopsy sampling. MAIN OUTCOME MEASUREMENTS Three pathologists graded biopsy specimens according to the Sydney classification. Interobserver agreement was analyzed by kappa statistics. In the OLGA, AG was replaced by IM, creating the OLGIM. RESULTS Interobserver agreement was fair for dysplasia (kappa = 0.4), substantial for AG (kappa = 0.6), almost perfect for IM (kappa = 0.9), and improved for all stages of OLGIM compared with OLGA. Overall, 84 (67%) and 79 (63%) patients were classified as stage I-IV according to OLGA and OLGIM, respectively. Of the dysplasia patients, 5 (71%) and 6 (86%) clustered in stage III-IV of OLGA and OLGIM, respectively. LIMITATION Prospective studies should confirm the correlation between gastric cancer risk and OLGIM stages. CONCLUSION Replacement of AG by IM in the staging of gastritis considerably increases interobserver agreement. The correlation with the severity of gastritis remains at least as strong. Therefore, the OLGIM may be preferred over the OLGA for the prediction of gastric cancer risk in patients with premalignant lesions.

Risk and Epidemiological Time Trends of Gastric Cancer in Lynch Syndrome Carriers in The Netherlands

BACKGROUND & AIMS Although gastric cancer forms part of the Lynch syndrome tumor spectrum, the risk of developing gastric cancer in Lynch syndrome families is unknown, resulting in a lack of clear guidelines for surveillance. The aim of this study was to evaluate incidence trends and risk of developing gastric cancer among Lynch syndrome mutation carriers in a Western population. METHODS Lynch syndrome mutation carriers were selected from the Dutch Hereditary Cancer Registry. The gastric cancer incidence in Lynch syndrome mutation carriers was compared to the gastric cancer incidence in the Dutch population between 1970 and 2003. Standardized incidence ratios were calculated by a Poisson model. Cumulative risks were calculated by Kaplan-Meier analysis. RESULTS Overall, 2014 Lynch syndrome mutation carriers were identified. Gastric cancer was diagnosed in 32 (1.6%) subjects (male/female: 21/11), 22 (69%) of them had a negative family history of gastric cancer. The standardized incidence ratios of gastric cancer was 3.4 (95% confidence interval, 2.1-5.2) and showed a nonsignificant decline between 1970 and 2003 (P = .30). Absolute risk of developing gastric cancer also showed no significant change over time (P = .51). Lifetime risk of developing gastric cancer was 8.0% in males vs 5.3% in females (P = .02), and 4.8% and 9% for MLH1 and MSH2 carriers, respectively. None of the 378 MSH6 carriers developed gastric cancer (P = .002 vs MLH1 and MSH2 combined lifetime risk). CONCLUSIONS Lynch syndrome mutation carriers have a substantial risk for gastric cancer, in particular patients with an MLH1 or MSH2 mutation. Family history for gastric cancer is a poor indicator for individual risk. Surveillance gastroscopy for Lynch syndrome patients carrying an MLH1 or MSH2 mutation should therefore be considered.

Identification of genetic loci associated with Helicobacter pylori serologic status.

IMPORTANCE Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H. pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H. pylori susceptibility. OBJECTIVE To identify genetic loci associated with H. pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling. DESIGN, SETTING, AND PARTICIPANTS Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H. pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H. pylori antigen in SHIP-TREND (n = 961). MAIN OUTCOMES AND MEASURES H. pylori seroprevalence. RESULTS Of 10,938 participants, 6160 (56.3%) were seropositive for H. pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single-nucleotide polymorphism (SNP), rs10004195; P = 1.4 × 10(-18); odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 × 10(-8); odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H. pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (β = -0.23 [95% CI, -0.34 to -0.11]; P = 2.1 × 10(-4)). Individuals with high fecal H. pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by χ2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP. CONCLUSIONS AND RELEVANCE GWAS meta-analysis identified an association between TLR1 and H. pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H. pylori infection.

Gastric MALT lymphoma: Epidemiology and high adenocarcinoma risk in a nation-wide study

BACKGROUND Gastric marginal zone non-Hodgkin lymphomas MALT type (gMALT) and gastric adenocarcinomas (GC) are long-term complications of chronic Helicobacter pylori gastritis, however, the incidence of gMALT and the GC risk in these patients is unclear. OBJECTIVE To evaluate epidemiological time trends of gMALT in the Netherlands and to estimate GC risk. METHODS Patients with a first diagnosis of gMALT between 1991 and 2006 were identified in the Dutch nation-wide histopathology registry (PALGA). Age-standardised incidence rates were calculated. The incidences of GC in patients with gMALT and in the Dutch population were compared. Relative risks were calculated by a Poisson Model. RESULTS In total, 1419 patients were newly diagnosed with gMALT, compatible with an incidence of 0.41/100,000/year. GC was diagnosed in 34 (2.4%) patients of the cohort. Patients with gMALT had a sixfold increased risk for GC in comparison with the general population (p<0.001). This risk was 16.6 times higher in gMALT patients aged between 45 and 59 years than in the Dutch population (p<0.001). CONCLUSIONS GC risk in patients with gMALT is six times higher than in the Dutch population and warrants accurate re-evaluation after diagnosis and treatment for gMALT.

Precancerous lesions in the stomach: From biology to clinical patient management

Gastric cancer is the final step in a multi-stage cascade triggered by long-standing inflammatory conditions (particularly Helicobacter pylori infection) resulting in atrophic gastritis and intestinal metaplasia: these lesions represent the cancerization field in which (intestinal-type) gastric cancer develops. Intraepithelial neoplasia is consistently recognized as the phenotypic bridge between atrophic/metaplastic lesions and invasive cancer. This paper addresses the epidemiology, pathology, molecular profiling, and clinical management of advanced precancerous gastric lesions.

Follow-up of premalignant lesions in patients at risk for progression to gastric cancer

BACKGROUND AND STUDY AIMS A recent international guideline recommends surveillance of premalignant gastric lesions for patients at risk of progression to gastric cancer. The aim of this study was to identify the role of the distribution and severity of premalignant lesions in risk categorization. PATIENTS AND METHODS Patients with a previous diagnosis of atrophic gastritis, intestinal metaplasia, or low grade dysplasia were invited for surveillance endoscopy with non-targeted biopsy sampling. Biopsy specimens were evaluated by pathologists (four general and one expert) using the Sydney and the operative link for gastric intestinal metaplasia (OLGIM) systems, and scores were compared using kappa statistics. RESULTS 140 patients were included. In 37 % (95 % confidence interval [CI] 29 % - 45 %) the severity of premalignant lesions was less than at baseline, while 6 % (95 %CI 2 % - 10 %) showed progression to more severe lesions. Intestinal metaplasia in the corpus was most likely to progress to more than one location (57 %; 95 %CI 36 % - 76 %). The proportion of patients with multilocated premalignant lesions increased from 24 % at baseline to 31 % at surveillance (P = 0.014). Intestinal metaplasia was the premalignant lesion most frequently identified in subsequent endoscopies. Intestinal metaplasia regressed in 27 % compared with 44 % for atrophic gastritis and 100 % for low grade dysplasia. Interobserver agreement was excellent for intestinal metaplasia (k = 0.81), moderate for dysplasia (k = 0.42), and poor for atrophic gastritis (k < 0). CONCLUSIONS Premalignant gastric lesions found in the corpus have the highest risk of progression, especially intestinal metaplasia, which has excellent interobserver agreement. This supports the importance of intestinal metaplasia as marker for follow-up in patients with premalignant gastric lesions.

The prevalence of premalignant gastric lesions in asymptomatic patients: Predicting the future incidence of gastric cancer

BACKGROUND Helicobacter pylori is the main risk-factor for gastric cancer through a cascade from gastritis through atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia (DYS) to malignancy. The presence of these lesions in the general population predicts the gastric cancer incidence in the coming decades. Prevalence data are mostly obtained from serological studies and endoscopy data in symptomatic patients. AIM To investigate the prevalence of H. pylori infection and its related gastric changes in asymptomatic subjects. METHODS 383 Patients undergoing routine colonoscopy were included. All subjects underwent upper GI endoscopy and completed the Gastrointestinal Symptom Rating Scale (GSRS). Biopsies were taken from antrum and corpus. RESULTS H. pylori infection was present in 22%. Non-Caucasian subjects had a significantly higher H. pylori prevalence (p < 0.001). AG, IM and DYS were together found in 9.3% of subjects. Subjects with AG, IM or DYS were significantly older (p < 0.001). No differences were found with respect to gender, presence of GI symptoms as scored by GSRS, lifestyle and medication use. CONCLUSIONS The prevalence of premalignant gastric lesions is considerable in general Western population with increasing age as the main risk factor. One time screening for premalignant lesions at the age of 60 years is a reasonable strategy since the numbers found imply that gastric cancer will remain a prevalent disease.

Increased risk of esophageal squamous cell carcinoma in patients with gastric atrophy: Independent of the severity of atrophic changes

An association between gastric atrophy and esophageal squamous cell carcinomas (ESCC) has been described. However, the mechanism of this association is unknown. In this study, we aimed to examine this relationship in a cohort of patients with varying grades of gastric atrophy to increase the understanding about the causality of the association. Patients diagnosed with gastric atrophy between 1991 and 2005 were identified in the Dutch nationwide histopathology registry (PALGA). The incidence of ESCC and, presumably unrelated, small cell lung carcinomas (SCLC) observed in these patients was compared with that in the general Dutch population. Relative risks (RRs) and 95% confidence intervals were calculated by a Poisson model. At baseline histological examination, 97,728 patients were diagnosed with gastric atrophy, of whom 23,278 with atrophic gastritis, 65,934 with intestinal metaplasia and 8,516 with dysplasia. During follow‐up, 126 patients were diagnosed with ESCC and 263 with SCLC (overall rates 0.19, respectively 0.39/1,000 person‐years at risk). Compared with the general Dutch population, patients with gastric atrophy ran a RR of developing ESCC of 2.2 [95% CI 1.8–2.6] and of SCLC of 1.8 [95% CI 1.6–2.1]. The risk of ESCC did not increase with increasing severity of gastric atrophy (p = 0.90). In conclusion, this study found an association between gastric atrophy and both ESCC and SCLC, but the risk of ESCC did not increase with the severity of gastric atrophy. Therefore, a causal relationship seems unlikely. Confounding factors, such as smoking, may explain both associations.

Serum Levels of Leptin As Marker For Patients At High Risk of Gastric Cancer

Background:  Serological screening for gastric cancer (GC) may reduce mortality. However, optimal serum markers for advanced gastric precursor lesions are lacking.

Bovine antibody-based oral immunotherapy for reduction of intragastric Helicobacter pylori colonization: A randomized clinical trial

BACKGROUND Antibiotic-based regimens are frequently used for the treatment of Helicobacter pylori infection. These regimens fail to eradicate H pylori in 15% to 40% of patients, primarily due to antimicrobial resistance and insufficient patient compliance. Effective prevention and eradication of H pylori by passive immunization with orally administered bovine antibodies has been demonstrated in animal studies, and may serve as an alternative therapy in humans. OBJECTIVE To study the efficacy and safety of orally administered bovine anti-H pylori antibodies for the reduction of intragastric bacterial load and eradication of H pylori in humans. METHODS Dairy cows were immunized against H pylori. After confirmation of the presence of anti-H pylori antibodies in the milk, the milk was subsequently processed into a whey protein concentrate (WPC). In a prospective, double-blind, placebo-controlled randomized clinical trial, H pylori-infected subjects were randomly assigned to treatment with the WPC preparation or placebo. Study medication was continued for 28 days; subjects were followed-up for 56 days. RESULTS Of the 30 subjects included, 27 completed the protocol. Of these 27 evaluable subjects, 14 were treated with WPC and 13 with placebo. There was no significant difference in urea breath test decrease between the WPC- and placebo-treated group (P=0.75). H pylori-associated gastritis and density were not significantly reduced in either group after treatment (P>0.05 for all). CONCLUSION Bovine antibody-based oral immunotherapy appears to be safe, but does not significantly reduce intragastric density in humans. Further studies are needed to determine whether WPC treatment has additional value to conventional antibiotic treatment for H pylori.