Population-based Study of Gastric Cancer Survival and Associations in Rural Western Honduras.

BACKGROUND: Two-thirds of global cancer occur in low/middle income countries (LMICs). Northern Central America is the largest LMIC region in the western hemisphere, and lack cancer registries to guide cancer control. We conducted a gastric cancer (GC) survival study in rural western Honduras, characterized as having among the highest GC incidence rates in Latin America. METHODS: The cohort of incident GC diagnosed between 2002-2015 was studied with active follow-up, with household visits. The regional gastric cancer registry was primary for case identification, with completeness examination with hospital data and national death certificates. Cox regression models were used for survival calculations. RESULTS: Survival follow-up was achieved in 741/774 patients (95.7%). Household interviews were conducted in 74.1% (n=549). 65.7% were male, median age at diagnosis was 64 years, 24.5% were <55. 43.9% of tumors had pyloric obstruction. 45.2%, 43.2%, and 7.3% of histology was intestinal, diffuse, and mixed, respectively. 24.7% patients received treatment. 5-year survival rates were 9.9% for both males and females, 7.7% for age <45, and 7.9% for diffuse GC. Median survival time was 4.8 months (95%CI,4.2-5.6). In the final Cox regression model including age, sex, Lauren subtype, and poverty index, only treatment was significantly associated with survival (HR 2.43, 95%CI,1.8-3.2). CONCLUSIONS: Markedly low gastric cancer 5-year survival rates are observed in rural Central America. The majority of patients present with advanced disease, and a minority have access to therapy. IMPACT: The findings have implications for cancer control in the Central America LMICs and for U.S. Latino populations.

High Incidence of Gastric Cancer in El Salvador: A National Multisectorial Study 2000-2014.

BACKGROUND: Gastric adenocarcinoma (GC) is the fourth leading cause of global cancer mortality, and leading infection-associated cancer. GC has significant geographic variability, with a high incidence in East Asia and mountainous regions of Latin America. In the U.S., GC represents a marked disparity with incidence rates that are 2-3 times higher in Hispanics compared to non-Hispanic whites. METHODS: We conducted a national retrospective study of incident GC in El Salvador from to 2000-2014 to estimate the age-standardized incidence rate (ASIR) by using a combination of pathology and endoscopy databases. A unique multisectorial coalition was formed between the Ministry of Health (MINSAL) and ES Gastroenterology Society (AGEDES), representing public hospitals (n=5), governmental employee hospitals (ISSS, n=5), and private facilities (n=6), accounting for >95% of national endoscopy capacity. HER2 and EBV tumor status was ascertained in a representative sample during 2014-2016. RESULTS: 10,039 unique cases of GC were identified, 45.5% female, and mean age of 65. 21% and 9.4% were <55 and <45 years old, respectively. ASIRs (M, F) were 18.9 (95%CI;14.4-20.7) and 12.2 per 100,000 persons (95%CI;10.9-13.5), respectively, in the period 2010-2014 with all centers operational. Intestinal GC was 2.8 times more common than diffuse GC. 23.2% had partial or complete pyloric obstruction. The HER2 2+/3+ status was 16.7% and EBER positivity was 10.2%. CONCLUSIONS: A high incidence of gastric cancer was confirmed in El Salvador, and nearly half of patients were female. IMPACT: The findings have implications for cancer control in the Central America LMICs and for U.S. Latino populations.

Wood cookstove use is associated with gastric cancer in Central America and mediated by host genetics.

Biomass cookstove food preparation is linked to aero-digestive cancers, mediated by ingested and inhaled carcinogens (e.g., heterocyclic amines, and polycyclic aromatic hydrocarbons). We investigated the association between gastric adenocarcinoma, wood cookstove use, H. pylori CagA infection and risk modification by variants in genes that metabolize and affect the internal dose of carcinogens. We conducted a population-based, case-control study (814 incident cases, 1049 controls) in rural Honduras, a high-incidence region with a homogeneous diet and endemic H. pylori infection, primarily with the high-risk CagA genotype. We investigated factors including wood cookstove use, H. pylori CagA serostatus, and 15 variants from 7 metabolizing genes, and the interactions between wood stove use and the genetic variants. Male sex (OR 2.0, 1.6-2.6), age (OR 1.04, 1.03-1.05), wood cookstove use (OR 2.3, 1.6-3.3), and CagA serostatus (OR 3.5, 2.4-5.1) and two SNPs in CYP1B1 (rs1800440 and rs1056836) were independently associated with gastric cancer in multivariate analysis. In the final multivariate model, a highly significant interaction (OR 3.1, 1.2-7.8) was noted between wood cookstove use and the rs1800440 metabolizing genotype, highlighting an important gene-environment interaction. Lifetime wood cookstove use associates with gastric cancer risk in the high-incidence regions of Central America, and the association is dependent on the rs1800440 genotype in CYP1B1. H. pylori CagA infection, wood cookstove use and the rs1800440 genotype, all of which are highly prevalent, informs who is at greatest risk from biomass cookstove use.

Gastric Cancer: Emerging Trends in Prevention, Diagnosis, and Treatment.

Gastric adenocarcinoma (GC) is the fourth leading cause of global cancer mortality, and the leading infection-associated cancer. Helicobacter pylori is the dominant risk factor for GC and classified as an IARC class I carcinogen. Surveillance of gastric premalignant conditions is now indicated in high-risk patients. Upper endoscopy is the gold standard for GC diagnosis, and image-enhanced endoscopy increases the detection of gastric premalignant conditions and early gastric cancer (EGC). Clinical staging is crucial for treatment approach, defining early gastric cancer, operable locoregional disease, and advanced GC. Endoscopic submucosal dissection is the treatment of choice for most EGC. Targeted therapies are rapidly evolving, based on biomarkers including MSI/dMMR, HER2, and PD-L1. These advancements in surveillance, diagnostic and therapeutic strategies are expected to improve GC survival rates in the near term.

Western Honduras Copán Population-Based Cancer Registry: Initial Estimates and a Model for Rural Central America.

PURPOSE: Population-based cancer registries (PBCRs) are critical for national cancer control planning, yet few low- and middle-income countries (LMICs) have quality PBCRs. The Central America Four region represents the principal LMIC region in the Western hemisphere. We describe the establishment of a PBCR in rural Western Honduras with first estimates for the 2013-2017 period. METHODS: The Western Honduras PBCR was established through a collaboration of academic institutions and the Honduras Ministry of Health for collection of incident cancer data from public and private health services. Data were recorded using the Research Electronic Data Capture (REDCap) web-based platform with data monitoring and quality checks. Crude and age-standardized rates (ASRs) were calculated at the regional level, following WHO methodology. RESULTS: The web-based platform for data collection, available ancillary data services (eg, endoscopy), and technical support from international centers (United States and Colombia) were instrumental for quality control. Crude cancer incidence rates were 112.2, 69.8, and 154.6 per 100,000 habitants overall, males, and females, respectively (excluding nonmelanoma skin cancer). The adjusted ASRs were 84.2, 49.6, and 118.9 per 100,000 overall habitants, males, and females, respectively. The most common sites among men were stomach (ASR 26.0, 52.4%), colorectal (ASR 5.11, 10.15%), and prostate (ASR 2.7, 5.4%). The most common sites in women were cervix (ASR 34.2, 36.7%), breast (ASR 11.2, 12.3%), and stomach (ASR 10.8, 11.7%). CONCLUSION: The Copán-PBCR represents a successful model to develop cancer monitoring in rural LMICs. Innovations included the use of the REDCap platform and leverage of Health Ministry resources. This provides the first PBCR data for Honduras and the Central America Four and confirms that infection-driven cancers, such as gastric and cervical, should be priority targets for cancer control initiatives.

Ornithine decarboxylase (ODC1) gene variant (rs2302615) is associated with gastric cancer independently of Helicobacter pylori CagA serostatus.

The primary cause of gastric cancer is chronic infection with Helicobacter pylori (H. pylori), particularly the high-risk genotype cagA, and risk modification by human genetic variants. We studied 94 variants in 54 genes for association with gastric cancer, including rs2302615 in ornithine decarboxylase (ODC1), which may affect response to chemoprevention with the ODC inhibitor, eflornithine (difluoromethylornithine; DFMO). Our population-based, case-control study included 1366 individuals (664 gastric cancer cases and 702 controls) from Western Honduras, a high incidence region of Latin America. CagA seropositivity was strongly associated with cancer (OR = 3.6; 95% CI: 2.6, 5.1). The ODC1 variant rs2302615 was associated with gastric cancer (OR = 1.36; p = 0.018) in a model adjusted for age, sex, and CagA serostatus. Two additional single nucleotide polymorphisms (SNPs) in CASP1 (rs530537) and TLR4 (rs1927914) genes were also associated with gastric cancer in univariate models as well as models adjusted for age, sex, and CagA serostatus. The ODC1 SNP association with gastric cancer was stronger in individuals who carried the TT genotype at the associating TLR4 polymorphism, rs1927914 (OR = 1.77; p = 1.85 × 10-3). In conclusion, the ODC1 variant, rs2302615, is associated with gastric cancer and supports chemoprevention trials with DFMO, particularly in individuals homozygous for the T allele at rs1927914.

Prevalence and Associated Dietary Factors of Rome IV Functional Gastrointestinal Disorders in Rural Western Honduras.

BACKGROUND: The literature is limited regarding the prevalence of functional gastrointestinal disorders (FGIDs) in Central America, and the role of dietary factors. METHODS: The Rome IV diagnostic questionnaire and National Cancer Institute Diet History questionnaire were administered in one-on-one interviews to a distributed cross section of the general adult population of Western Honduras. Our aim was to estimate prevalence of common FGIDs and symptoms and their relationships to dietary habits. RESULTS: In total, 815 subjects were interviewed, of whom 151 fulfilled criteria for an FGID (18.5%). Gastroduodenal FGIDs were noted in 9.4%, with epigastric pain syndrome (EPS) more common than postprandial distress syndrome, 8.5% versus 1.6%. Among bowel disorders, functional abdominal bloating (FAB) was most prevalent (6.3%), followed by irritable bowel syndrome (3.6%), functional diarrhea (FDr; 3.4%), and functional constipation (1.1%). A significant inverse association was noted between regular bean intake and any FGID (OR 0.41, 95% CI 0.27-0.63), driven by IBS and FDr. Vegetable consumption was associated with lower prevalence of functional diarrhea (OR 0.12; 95% CI 0.04-0.35) and any diarrheal disorder (OR 0.11; 95% CI 0.04-0.31). Subjects with a median daily intake of ≥ 4 corn tortillas had 1.75 (95% CI 1.22-2.50) times the odds of having any FGID. CONCLUSIONS: FGIDs were common in this rural low-resource setting in Central America, with an intriguing distribution of specific FGIDs. EPS and FAB were common, but IBS was not. Local dietary factors were associated with specific FGIDs, suggesting that diet may play a role in global variations of FGIDs.

Traumatic injuries in rural Honduras: A two month pilot study.

OBJECTIVES: Trauma is a leading cause of morbidity and mortality worldwide, with a disproportionate burden of illness in low- and middle- income countries. This study sought to provide a proof-of-concept pilot study to evaluate the feasibility of a trauma registry in the Western Honduras Hospital. METHODS: A cross-sectional, observation study was performed that included all admitted, transferred, or deceased trauma patients presenting to the Western Honduras Hospital from February 4, 2019 until April 4, 2019. Descriptive statistics were utilized to describe patient demographics and injury characteristics. RESULTS: 268 patients were enrolled. The average age was 27.5 years (SD ±21.3). 10% of injuries were due to interpersonal violence. The most common mechanisms of injury were falls (33.6%) and motor vehicle collisions (MVCs) (22.4%). The mean Modified Kampala Trauma Score (M-KTS) was 12 (SD ±1.4). The mortality rate was 1.1% (N = 3). 94.5% of data points were complete. CONCLUSIONS: A continuous injury surveillance system in the Western Honduras Hospital is feasible and provides valuable information. The data completeness was suboptimal, but the current data collection system may be improved via modifying and utilizing the registry form as both a clinical and data collection instrument.

Circulating Antibodies against Epstein-Barr Virus (EBV) and p53 in EBV-Positive and -Negative Gastric Cancer.

BACKGROUND: Epstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serologic profiles may inform viral contribution to carcinogenesis. METHODS: We compared humoral responses of EBV-positive (n = 67) and EBV-negative (n = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer. RESULTS: Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, P < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, P = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, P = 0.021). Anti-p53 prevalence from the literature was 15%. CONCLUSIONS: These serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype. IMPACT: Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies.

Geospatial analyses identify regional hot spots of diffuse gastric cancer in rural Central America.

BACKGROUND: Geospatial technology has facilitated the discovery of disease distributions and etiology and helped target prevention programs. Globally, gastric cancer is the leading infection-associated cancer, and third leading cause of cancer mortality worldwide, with marked geographic variation. Central and South America have a significant burden, particularly in the mountainous regions. In the context of an ongoing population-based case-control study in Central America, our aim was to examine the spatial epidemiology of gastric cancer subtypes and H. pylori virulence factors. METHODS: Patients diagnosed with gastric cancer from 2002 to 2013 in western Honduras were identified in the prospective gastric cancer registry at the principal district hospital. Diagnosis was based on endoscopy and confirmatory histopathology. Geospatial methods were applied using the ArcGIS v10.3.1 and SaTScan v9.4.2 platforms to examine regional distributions of the gastric cancer histologic subtypes (Lauren classification), and the H. pylori CagA virulence factor. Getis-Ord-Gi hot spot and Discrete Poisson SaTScan statistics, respectively, were used to explore spatial clustering at the village level (30-50 rural households), with standardization by each village's population. H. pylori and CagA serologic status was determined using the novel H. pylori multiplex assay (DKFZ, Germany). RESULTS: Three hundred seventy-eight incident cases met the inclusion criteria (mean age 63.7, male 66.3%). Areas of higher gastric cancer incidence were identified. Significant spatial clustering of diffuse histology adenocarcinoma was revealed both by the Getis-Ord-GI* hot spot analysis (P-value < 0.0015; range 0.00003-0.0014; 99%CI), and by the SaTScan statistic (P-value < 0.006; range 0.0026-0.0054). The intestinal subtype was randomly distributed. H. pylori CagA had significant spatial clustering only in association with the diffuse histology cancer hot spot (Getis-Ord-Gi* P value ≤0.001; range 0.0001-0.0010; SaTScan statistic P value 0.0085). In the diffuse gastric cancer hot spot, the lowest age quartile range was 21-46 years, significantly lower than the intestinal cancers (P = 0.024). CONCLUSIONS: Geospatial methods have identified a significant cluster of incident diffuse type adenocarcinoma cases in rural Central America, suggest of a germline genetic association. Further genomic and geospatial analyses to identify potential spatial patterns of genetic, bacterial, and environmental risk factors may be informative.

Hydrogen Metabolism in Helicobacter pylori Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation.

UNLABELLED: A known virulence factor of Helicobacter pylori that augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhyd mutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhyd strain showed a decreased frequency of DNA transformation, suggesting that H. pylori hydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhyd strain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhyd strain. By examining the hydrogenase activities from well-defined clinical H. pylori isolates, we observed that strains isolated from cancer patients (n = 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n = 6), further supporting an association between H. pylori hydrogenase activity and gastric carcinogenesis in humans. IMPORTANCE: Hydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen's (H. pylori) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H2-utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H2 oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.

Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns.

MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, -200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non-cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa-miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non-cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics.

Anti-Helicobacter pylori Antibody Profiles in Epstein-Barr virus (EBV)-Positive and EBV-Negative Gastric Cancer.

BACKGROUND: Helicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis. METHODS: We compared H. pylori serologic profiles of EBV-positive (n = 58) and EBV-negative (n = 111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by in situ hybridization. Serum levels of 15 antibodies to immunogenic proteins of H. pylori (Cad, CagA, Cagδ, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis. RESULTS: Seropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR = 3.15, p = .0024, Bonferroni corrected p = .036). Distributions of other antibodies did not vary by tumor EBV status. CONCLUSION: Similarity of host-response indicates the essential etiological role of H. pylori in EBV-positive gastric cancer.

The descriptive epidemiology of gastric cancer in Central America and comparison with United States Hispanic populations.

PURPOSE: The aims of this study were to delineate the epidemiology of gastric adenocarcinoma in Central America and contrast it with Hispanic-Latino populations in the USA. METHODS: Published literature and Central America Ministry of Health databases were used as primary data sources, including national, population-based, and hospital-based registries. US data was obtained from the National Cancer Institute (NCI)-Epidemiology End Results Program (SEER) registry. Incident gastric adenocarcinoma cases were analyzed for available data between 1985 and 2011, including demographic variables and pathology information. RESULTS: In Central America, 19,741 incident gastric adenocarcinomas were identified. Two thirds of the cases were male, 20.5 % were under age 55, and 58.5 %were from rural areas. In the SEER database (n = 7871), 57.8 % were male and 28.9 % were under age 55. Among the US Hispanics born in Central America with gastric cancer (n = 1210), 50.3 % of cases were male and 38.1 % were under age 55. Non-cardia gastric cancer was more common in Central America (83.3 %), among US Hispanics (80.2 %), and Hispanics born in Central America (86.3 %). Cancers of the antrum were more common in Central America (73.6 %), whereas cancers of the corpus were slightly more common among US Hispanics (54.0 %). Adenocarcinoma of the diffuse subtype was relatively common, both in Central America (35.7 %) and US Hispanics (69.5 %), although Lauren classification was reported in only 50 % of cases. CONCLUSIONS: A significant burden of gastric adenocarcinoma is observed in Central America based upon limited available data. Differences are noted between Central America and US Hispanics. Strengthening population-based registries is needed for improved cancer control in Central America, which may have implications for the growing US Hispanic population.

Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.

Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.

Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage.

BACKGROUND & AIMS: The gastric cancer-causing pathogen Helicobacter pylori up-regulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOX(high) cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects. METHODS: SMOX, apoptosis, and DNA damage were measured in gastric epithelial cells from H. pylori-infected Egfr(wa5) mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. A phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsy specimens from Colombian and Honduran cohorts were analyzed by immunohistochemistry. RESULTS: SMOX expression and DNA damage were decreased, and apoptosis increased in H. pylori-infected Egfr(wa5) mice. H. pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damage(high) apoptosis(low) cells. Phosphoproteomic analysis showed increased EGFR and erythroblastic leukemia-associated viral oncogene B (ERBB)2 signaling. Immunoblot analysis showed the presence of a phosphorylated (p)EGFR-ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damage(high) apoptosis(low) cells. SMOX was increased in all stages of gastric disease, peaking in tissues with intestinal metaplasia, whereas pEGFR, pEGFR-ERBB2, and pERBB2 were increased predominantly in tissues showing gastritis or atrophic gastritis. Principal component analysis separated gastritis tissues from patients with cancer vs those without cancer. pEGFR, pEGFR-ERBB2, pERBB2, and SMOX were increased in gastric samples from patients whose disease progressed to intestinal metaplasia or dysplasia, compared with patients whose disease did not progress. CONCLUSIONS: In an analysis of gastric tissues from mice and patients, we identified a molecular signature (based on levels of pEGFR, pERBB2, and SMOX) for the initiation of gastric carcinogenesis.

Risk of recurrent Helicobacter pylori infection 1 year after initial eradication therapy in 7 Latin American communities.

IMPORTANCE: The long-term effectiveness of Helicobacter pylori eradication programs for preventing gastric cancer will depend on recurrence risk and individual and community factors. OBJECTIVE: To estimate risk of H. pylori recurrence and assess factors associated with successful eradication 1 year after treatment. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of 1463 randomized trial participants aged 21 to 65 years from 7 Latin American communities, who were treated for H. pylori and observed between September 2009 and July 2011. INTERVENTIONS: Randomization to 1 of 3 treatment groups: 14-day lansoprazole, amoxicillin, and clarithromycin (triple therapy); 5-day lansoprazole and amoxicillin followed by 5-day lansoprazole, clarithromycin, and metronidazole (sequential); or 5-day lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant). Participants with a positive (13)C-urea breath test (UBT) 6 to 8 weeks posttreatment were offered voluntary re-treatment with 14-day bismuth-based quadruple therapy. MEASUREMENTS: Recurrent infection after a negative posttreatment UBT and factors associated with successful eradication at 1-year follow-up. RESULTS: Among participants with UBT-negative results who had a 1-year follow-up UBT (n=1091), 125 tested UBT positive, a recurrence risk of 11.5% (95% CI, 9.6%-13.5%). Recurrence was significantly associated with study site (P = .03), nonadherence to initial therapy (adjusted odds ratio [AOR], 2.94; 95% CI, 1.31-6.13; P = .01), and children in the household (AOR, 1.17; 95% CI, 1.01-1.35 per child; P = .03). Of the 281 with positive posttreatment UBT results, 138 completed re-treatment, of whom 93 tested UBT negative at 1 year. Among the 1340 who had a 1-year UBT, 80.4% (95% CI, 76.4%-83.9%), 79.8% (95% CI, 75.8%-83.5%), and 77.8% (95% CI, 73.6%-81.6%) had UBT-negative results in the triple, sequential, and concomitant groups, respectively (P = .61), with 79.3% overall effectiveness (95% CI, 77.1%-81.5%). In a single-treatment course analysis that ignored the effects of re-treatment, the percentage of UBT-negative results at 1 year was 72.4% (95% CI, 69.9%-74.8%) and was significantly associated with study site (P < .001), adherence to initial therapy (AOR, 0.26; 95% CI, 0.15-0.42; P < .001), male sex (AOR, 1.63; 95% CI, 1.25-2.13; P < .001), and age (AOR, 1.14; 95% CI, 1.02-1.27 per decade; P = .02). One-year effectiveness among all 1463 enrolled participants, considering all missing UBT results as positive, was 72.7% (95% CI, 70.3%-74.9%). CONCLUSIONS AND RELEVANCE: One year after treatment for H. pylori infection, recurrence occurred in 11.5% of participants who had negative posttreatment UBT results. Recurrence determinants (ie, nonadherence and demographics) may be as important as specific antibiotic regimen in determining the long-term success of H. pylori eradication interventions. Study findings are relevant to the feasibility of programs for the primary prevention of gastric cancer in high-incidence regions of Latin America. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01061437.

Gastric cancer incidence estimation in a resource-limited nation: use of endoscopy registry methodology.

PURPOSE: Cancer epidemiology is challenging in developing nations, in the absence of reliable pathology-based cancer registries. Clinical experience suggests that the incidence of gastric cancer is high in Honduras, in contrast to the limited available national statistics at the time of study initiation (IARC GLOBOCAN 2002: males 15.2, females 10.8). We estimate the incidence of gastric cancer for Honduras using an endoscopy registry as a complimentary resource. METHODS: We conducted a retrospective analysis of incident noncardia gastric adenocarcinoma cases in western Honduras for the period 2000-2009. This region is well circumscribed geopolitically with a single district hospital and established referral patterns, to provide a unique epidemiological niche to facilitate estimation of incidence rates. A prospective, comprehensive database of all endoscopy procedures from this hospital was utilized at the primary data source. The catchment area for gastroenterology services for the at-risk population was validated by calculating the overall endoscopy utilization rates for each municipality in western Honduras. Incident cases of gastric adenocarcinoma were determined by the endoscopic diagnosis. Pathology services are not financed by the Ministry of Health, and histology data were incorporated when available. Population statistics were obtained from the Honduras National Statistics Institute (INE). Age-standardized incidence rates (ASIRs) were calculated using world standard population fractions. RESULTS: The catchment area for western Honduras was validated with the municipality threshold of 30 endoscopies per 10(6) person-years, with inclusion of a total of 40 municipalities. In the western Honduras catchment area, there were 670 incident cases (439 M, 231 F) of noncardia gastric adenocarcinoma during the study decade 2000-2009. Notably, 67 (10.0 %) and 165 (24.6 %) of cases were under the ages of 45 and 55, respectively. The case-finding rate was 5.1 endoscopies performed for each new diagnosis of gastric cancer. The ASIRs for the decade were 30.8 for males and 13.9 for females. Clinically, 60.3 % of gastric cancers were Borrmann type 3 (ulcerated mass), and evidence of advanced disease with pyloric obstruction was common (35.2 %). Subtypes by the Lauren classification were distributed among diffuse (56 %), intestinal (34 %), and indeterminate (9.9 %), in subjects with available pathology (526/670). CONCLUSIONS: The endoscopy procedure registry may serve as a complimentary data resource for gastric cancer incidence estimation in resource-limited nation settings wherein pathology services and cancer registries are absent. The results remain an underestimation in this setting due to the challenges of access to care and related factors. The methodology helps to more fully characterize the high incidence of gastric cancer in western Honduras and this region of Central America and demonstrate the need for additional epidemiology research, and interventions focused on prevention and treatment.