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.

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.

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.

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.

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.

Epidemiology of Helicobacter pylori infection in six Latin American countries (SWOG Trial S0701).

OBJECTIVE: To investigate the potential determinants of Helicobacter pylori infection between adults 21-65 years old. METHODS: Data are from the initial screening visit of a randomized clinical trial of three antibiotic regimens to eradicate H. pylori, conducted in seven sites (Santiago-Chile, Túquerres-Colombia, Guanacaste-Costa Rica, Copán-Honduras, Obregón and Tapachula-México, León-Nicaragua). Thousand eight hundred and fifty-nine adults from the general population were screened for H. pylori infection using an urea breath test (UBT) and were interviewed to assess socioeconomic-, demographic-, and symptom-related characteristics. Logistic regression was used to assess the relationship between these characteristics and H. pylori positivity at enrollment. RESULTS: Among the 1,852 eligible participants for whom a conclusive UBT result was obtained, H. pylori prevalence was 79.4 %, ranging from 70.1 to 84.7 % among the seven centers. Prevalence did not differ by sex (female: 78.4, male: 80.9; p = 0.20) or age (p = 0.08). H. pylori positivity increased with increasing number of siblings (p trend <0.0001). Participants with education beyond 12 years were less likely to be UBT-positive (OR 0.4: 0.3-0.6, compared to participants with 0-6 years of schooling) as were those employed outside the home (OR 0.7: 0.6-1.0). Odds of H. pylori infection increased with the presence of certain living conditions during childhood including having lived in a household with an earth floor (OR 1.8: 1.4-2.4), lack of indoor plumbing (OR 1.3: 1.0-1.8) and crowding (OR 1.4: 1.0-1.8, for having more than two persons per bedroom). Regarding current household conditions, living with more than 3 children in the household (OR 1.7: 1.2-2.5) and crowding (OR 1.8: 1.3-2.3) were associated with H. pylori infection. CONCLUSIONS: The prevalence of H. pylori in adults was high and differed significantly among the six Latin American countries studied (p < 0.001). Our findings confirm the strong link between poor socioeconomic conditions and H. pylori infection.

Gastric cancer and the high combination prevalence of host cytokine genotypes and Helicobacter pylori in Honduras.

BACKGROUND & AIMS: Inflammatory cytokine polymorphisms are associated with gastric adenocarcinoma in Helicobacter pylori-infected patients in Europe and Asia. We investigated the cytokine profile in the Latino population, specifically Honduras, a high-incidence region, and the use of the combination prevalence of H pylori and genotypes in identifying high-risk populations. METHODS: A population-based case-control study identified 170 incident gastric cancer cases and 162 healthy village controls. Interleukin (IL)-Ibeta-511, IL-1RN, IL-10-1082, and tumor necrosis factor-alpha-308 genotypes were determined. We define the combination prevalence index (CPI) as the product of H pylori and IL-1beta-511T+ genotype prevalence in healthy subjects. Medline identified gastric cancer studies to facilitate country-specific CPI calculations. RESULTS: In healthy, population-based Honduran controls, IL-1beta-511T+ prevalence was 81% (95% confidence interval, 75%-87%; CT, 57%; TT, 25%), which was among the highest reported. IL-10-1082A+ prevalence was 93% (95% confidence interval, 88%-97%), mirroring Asian populations. Seventeen percent were homozygous for both proinflammatory cytokines (TT/AA), with increased risk among cases (odds ratio, 2.6; 95% confidence intervals, 1.0-6.8). Tumor necrosis factor-alpha polymorphisms were nearly absent. Endemic H pylori infection (85%) was confirmed. Importantly, the CPI association with country incidence is highly significant (P = .0057), based on 16 global populations and Honduras. Sensitivity analysis confirms a robust CPI. CONCLUSIONS: The CPI, based on IL-1beta genotypes, has a strong association with country-specific gastric cancer incidence. The CPI correlation supports the chronic inflammation carcinogenesis model, and may explain the geographic variation. We report a novel cytokine profile in Honduras that mirrors Asian populations and explains the high incidence rates. This may have dyspepsia management and screening implications for the growing US Latino population.