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Background and Objective: Two decades ago, an international initiative (GEMINI) was launched in a high-risk, low-resource region in Northeast Iran, aiming to investigate incidence, etiology, early detection, and treatment of esophageal squamous cell carcinoma (ESCC). An earlier report from this area, highlighted poor ESCC survival rates, with a 5-year survival probability of 3.3% and the median survival time of 7 months. Our study assesses whether ESCC survival has improved since the implementation of the GEMINI initiative in this region., Material and Methods: 490 adult patients with histologically-confirmed ESCC were recruited from the Atrak clinic, Golestan, Iran, between 2007 and 2018. At recruitment, information on demographics and various exposures were collected. Active (telephone surveys) and passive (linkage to Golestan population-based cancer and death registries) follow-up methods were used to determine patients' vital status though March 2019. Survival estimates were obtained by Kaplan-Meier method and Cox proportional hazards regression models., Results: Over the study period 340 deaths were recorded. Five-year ESCC survival probability was 23% (95% Confidence Interval: 19% to 28%), and the median survival time was 19 months. Five-year survival probability was higher among individuals who were younger (35% in <60-year-olds vs. 12% for >70-year-olds, p<0.001), educated (34% vs. 21% for no formal education, p = 0.027), never used opium (28% vs. 15%, p = 0.0016), and received cancer treatment (37% vs. 4%, p<0.001). In the adjusted models, a higher hazard of death was associated with older age [HR for each 10-year increase = 1.36 (95% CI = 1.22 to 1.51)], Turkman ethnicity [HR = 1.35 (95%CI: 1.07 to 1.70)], opium use [HR = 1.53 (95%CI: 1.20 to 1.94)],and receiving no cancer treatment [HR = 5.81 (95%CI: 3.97 to 8.52)]., Conclusion: Over the last two decades, ESCC survival in this population has significantly improved, highlighting the potential of enhancing healthcare infrastructure and ensuring access to affordable medical care in resource-limited, high-risk regions. Older age at diagnosis, Turkman ethnicity, opium use, and untreated cases (indicative of advanced disease at diagnosis) were identified as the main ESCC prognostic factors in this population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nemati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Esophageal squamous cell carcinoma (ESCC) is the second most common cancer in Malawi. Risk factors for this cancer in Malawi are poorly understood. Poor oral health has previously been linked to increased ESCC risk in other high-incidence regions, including parts of Eastern and Southern Africa. We assessed the relationship between oral health and ESCC risk in a sex, age and location frequency-matched case-control study based at two hospitals in Lilongwe, Malawi from 2017 to 2020. Trained interviewers used a structured questionnaire and direct observation to collect data on demographics; behaviors; oral hygiene habits; the sum of decayed, missing or filled teeth (DMFT score); oral mucosa status; lip depigmentation and dental fluorosis via a visual scale. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI), adjusted for known and suspected ESCC risk factors. During the study period, 300 cases and 300 controls were enrolled. Subjects in the highest tertile of DMFT score (≥7) had an increased risk of ESCC with an adjusted OR of 1.96 (95% CI: 1.16-3.36) compared to those with a DMFT score of 0. Severe dental fluorosis was associated with a statistically nonsignificant increased risk of ESCC (adjusted OR = 2.24, 95% CI: 0.97-5.49) compared to individuals with no fluorosis. Associations with oral mucosa status, lip depigmentation and toothbrushing method and frequency were mostly null or uncertain. Poor oral health, indicated by a higher DMFT score, was associated with increased ESCC risk in Malawi. Dental fluorosis is another possible risk factor in this population, but further evaluation is necessary to clarify any effects of fluorosis on ESCC risk., (© 2024 UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Somatic copy number variations (SCNVs) in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma. However, whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia (ESCdys) is unknown. This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate (m/M) ESCdys., Methods: This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China (Ci County, Hebei Province; Yanting, Sichuan Province; Linzhou, Henan Province; Yangzhong, Jiangsu Province; and Feicheng, Shandong Province) from 2005 to 2019. Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients, and a quantitative polymerase chain reaction assay, P16-Light, was used to detect CDKN2A copy number. The cumulative regression and progression rates of ESCdys were evaluated using competing risk models., Results: A total of 205 patients with baseline m/M ESCdys were enrolled. The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts (18.8% [13/69] vs. 35.0% [28/80] vs. 51.8% [29/56], P  <0.001). In the univariable competing risk analysis, the cumulative regression rate was statistically significantly lower ( P = 0.008), while the cumulative progression rate was higher ( P = 0.017) in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion. CDKN2A deletion was also an independent predictor of prognosis in ESCdys ( P = 0.004) in the multivariable analysis., Conclusion: The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Studying carcinogens in tobacco and nontobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer., Methods: The Golestan Cohort Study has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma. For this nested study, the cases comprised of all incident cases by January 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for associations between the 90th vs the 10th percentiles of the biomarker concentrations and incident esophageal squamous cell carcinoma., Results: Among individuals who did not currently use tobacco (148 cases and 163 controls), 2 acrolein metabolites, 2 acrylonitrile metabolites, 1 propylene oxide metabolite, and one 1,3-butadiene metabolite were significantly associated with incident esophageal squamous cell carcinoma (adjusted odds ratios between 1.8 and 4.3). Among tobacco users (57 cases and 63 controls), metabolites of 2 other volatile organic compounds (styrene and xylene) were associated with esophageal squamous cell carcinoma (OR = 6.2 and 9.0, respectively). In tobacco users, 2 tobacco-specific nitrosamines (NNN and N'-Nitrosoanatabine) were also associated with esophageal squamous cell carcinoma. Suggestive associations were seen with some polycyclic aromatic hydrocarbons (especially 2-hydroxynaphthalene) in nonusers of tobacco products and other tobacco-specific nitrosamines in tobacco users., Conclusion: These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications., (Published by Oxford University Press 2023.)

Purpose: Esophageal cancer (EC) is the second most common cancer in Malawi, with esophageal squamous cell carcinoma (ESCC) representing >90% of all ECs. Despite significant morbidity and mortality, little is known about disease outcomes. In this study, we assess survival after ESCC diagnosis in Malawi., Methods: We report on ESCC cases enrolled in a case-control study at Kamuzu Central Hospital in Lilongwe from August 2017 to April 2020. Suspected cases completed a questionnaire interview; provided blood, urine, and saliva specimens; and underwent a tumor biopsy for histologic confirmation. Cases were followed up by phone biweekly from enrollment to the study end date (December 31, 2020), date of death, or loss to follow-up. Survival was assessed using Kaplan-Meier analysis with the log-rank test. We also examined associations between treatment and ESCC mortality using Cox regression models., Results: There were 300 patients with ESCC enrolled in this study, of whom 290 (97%) had known vital status at the end of follow-up and 10 (3%) were lost to follow-up. Among the 290 patients, 282 (97%) died during follow-up. The median age at enrollment was 55 years (IQR, 48-66), and the median time to death was 106 days (95% CI, 92 to 127). The 1-year, 2-year, and 3-year survival rates were 11% (95% CI, 8 to 15), 3% (95% CI, 1 to 6), and 0.9% (95% CI, 0.8 to 4), respectively. Palliative chemotherapy significantly improved the overall survival of patients with ESCC ( P log-rank = .038) and was significantly associated with reduced mortality (adjusted hazard ratio, 0.71 [95% CI, 0.51 to 0.99]). No significant association was observed between tobacco use, alcohol consumption, or HIV status and mortality., Conclusion: Survival after diagnosis of ESCC was poor in Malawi. Although palliative chemotherapy was associated with improved survival, prevention and earlier detection remain key priorities to improve ESCC mortality at a population level.

Background: Recent evidence suggests overall diet quality, as assessed by dietary scores, may play a role in the development of upper gastrointestinal (UGI) cancers. However, the existing dietary scores are derived from high-income countries with different dietary habits than regions with the highest burden of UGI cancers, where limited data is available. This study aimed to investigate the association between overall diet quality and risk of esophageal and stomach cancers in a high-risk region for UGI cancers., Methods: We recruited 50045 individuals aged 40-75 between 2004-2008 from northeastern Iran and followed them annually through July 2020. Data on demographics, diet, and various exposures were collected using validated questionnaires. Diet quality was assessed by calculating the Healthy Eating Index (HEI), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (AMED), Dietary Approaches to Stop Hypertension (DASH), and World Cancer Research Fund-American Institute for Cancer Research (WCRF-AICR) scores., Results: During an average 12 years of follow-up, 359 participants developed esophageal cancer and 358 developed stomach cancer. After adjustments, each standard deviation increase in baseline dietary scores was associated with up to 12% reduction in esophageal cancer risk and up to 17% reduction in stomach cancer risk. Esophageal cancer showed stronger inverse associations with adherence to AMED (HR Q4-vs-Q1 =0.69 (0.49-0.98), P -trend=0.038). Stomach cancer showed stronger inverse correlation with WCRF-AICR (HR Q4-vs-Q1 =0.58 (0.41-0.83), P -trend=0.004), and DASH (HR C4-vs-C1 =0.72 (0.54-0.96), P -trend=0.041). These associations were comparable across different population subgroups. We did not observe significant associations between HEI and AHEI scores and UGI cancers in this population., Conclusion: Despite the differences in consuming individual food groups, adherence to the available dietary recommendations (derived from high-income countries) was associated with lower risk for subsequent esophageal and gastric cancers in this high-risk population. Educating the public to have a healthy eating pattern might be an effective strategy towards prevention of UGI cancers in high-risk regions., (© 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Competing Interests: We declare no competing interests.

Prior studies have conflicting findings regarding the association between gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). We examined this relationship in a prospective cohort in a region of high ESCC incidence. Baseline exposure data were collected from 50 045 individuals using in-person interviews at the time of cohort entry. Participants were followed until they developed cancer, died, or were lost to follow up. Participants with GERD symptoms were categorized into any GERD (heartburn or regurgitation), mixed symptoms, or heartburn alone. Multivariable Cox regression was used to assess the relationship between GERD symptom group and histologically confirmed ESCC. The model was adjusted for known risk factors for GERD and ESCC. 49 559 individuals were included in this study, of which 9005 had GERD symptoms. Over 13.0 years of median follow up, 290 individuals were diagnosed with ESCC. We found no association between any GERD and risk of ESCC (aHR 0.90, 95% CI: 0.66-1.24, P = .54). Similar findings were observed for the GERD symptom subtypes. Significant interactions between any GERD and sex (P = .013) as well as tobacco smoking (P = .028) were observed. In post-hoc analyses, GERD was associated with a decreased risk of ESCC in men (aHR 0.51, 95% CI: 0.27-0.98 P = .04) and in smokers (aHR 0.26, 95% CI: 0.08-0.83 P = .02). While there was little evidence for an overall association between GERD symptoms and ESCC risk, significant interactions with sex and smoking were observed. Men and smokers with GERD symptoms had a lower risk of ESCC development., (© 2022 UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: The epidemiological evidence regarding the carcinogenicity of nitrate and sodium in drinking water is limited, partly because measuring the exposure at the individual level is complex. Most studies have used nitrate in water supplies as a proxy for individual exposure, but dietary intakes and other factors may contribute to the exposure. The present study investigates the factors associated with urinary nitrate and sodium in a high-risk area for esophageal and gastric cancers., Methods: For this cross-sectional study, we used data and samples collected in 2004-2008 during the enrollment phase of the Golestan Cohort Study from a random sample of 349 participants (300 individuals from 24 rural villages and 49 from the city of Gonbad), stratified by average water nitrate in their district, the source of drinking water, and the usual dietary intake of nitrate and sodium. Nitrate, sodium, and creatinine were measured in a spot urine sample collected at the time of interview. We used the provincial cancer registry data to calculate the cumulative incidence rates of esophageal and gastric cancers for each location through June 1, 2020, and used weighted partial Pearson correlation to compare the incidence rates with median urinary nitrate and sodium in each village or the city., Results: Among 349 participants (mean age±SD: 50.7 ± 8.6 years), about half (n = 170) used groundwater for drinking, and the use of groundwater was significantly more common in high-elevation locations (75.8%). The geometric mean of the creatinine-corrected urinary nitrate concentration was 68.3 mg/g cr (95%CI: 64.6,72.3), and the corresponding geometric mean for urinary sodium was 150.0 mmoL/g cr (95%CI: 139.6,161.1). After adjusting for confounders, urinary nitrate was associated with being a woman, drinking groundwater, and living in high-elevation locations, but not with estimated dietary intake. Urinary sodium concentration was significantly associated with monthly precipitation at the time of sampling but not with elevation or drinking water source. There were significant positive correlations between both median urinary nitrate and sodium in each location and esophageal cancer incidence rates adjusted for sex and age (r = 0.65 and r = 0.58, respectively, p < 0.01), but not with gastric cancer incidence., Conclusion: In a rural population at high risk for esophageal and gastric cancers, nitrate excretion was associated with living at a higher elevation and using groundwater for drinking. The associations between nitrate and sodium excretion with esophageal cancer incidence warrant future investigation., (Published by Elsevier Inc.)

Red meat and processed meat are associated with some gastrointestinal cancers. Our study aims to investigate the association of different meat types with esophageal and gastric cancer (EC, GC) in a high-risk population. The Golestan Cohort Study (GCS) is a population-based cohort of 50 045 individuals aged 40 to 75 from northeast Iran. Detailed data on different exposures were collected using validated questionnaires. We considered quintiles of meat consumption, using grams and density (g/1000 kcal/day). We calculated intake of red, processed, organ and white meat, as well as total red meat, including the first three. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between meat types and cancer. During 12 years of follow-up, out of 49 585 participants (57.4% women), 369 developed EC (48.2% women) and 368 developed GC (27.5% women), including 309 esophageal squamous cell, 20 esophageal adenocarcinomas, 216 cardia and 95 non-cardia GC. No association was found for EC except for red meat among females (HR for one quintile increase 1.13, 95% CI = 1.00-1.27). The risk of GC increased for intake of total red meat (HR 1.08, 95% CI = 1.00-1.17) and red meat separately (HR 1.09, 95% CI = 1.00-1.18). The HR for red meat and non-cardia GC was 1.23 (95% CI = 1.02-1.48). No associations were observed for other types of meat. In conclusion, in this high-risk population red meat intake is associated with GC, but not EC, suggesting a substantial role of this modifiable factor in determining the burden of GC., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The objective of this study was to update the association between multivitamin supplementation and total or cause-specific mortality in a population with a high prevalence of undernutrition in China., Methods: The Linxian Dysplasia Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial in which 3318 persons aged 40-69 years with esophageal squamous dysplasia were assigned to receive daily multivitamin supplementation or a placebo for 6 years and were followed for 29 years. The primary outcome was esophageal/gastric cardia cancer mortality. The data were analyzed with Cox proportional hazards regression models. Subgroup analyses were performed by common characteristics such as age and gender., Results: The cumulative total mortality was 83.5%. Multivitamin supplementation did not affect total or cause-specific mortality in the participants as a whole (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03). Subgroup analyses showed that no association between multivitamin supplementation and all-cause mortality was observed in men (HR, 0.90; 95% CI, 0.81-1.01), women (HR, 1.01; 95% CI, 0.91-1.12), younger participants (HR, 0.97; 95% CI, 0.87-1.08), or older participants (HR, 0.94; 95% CI, 0.85-1.04). Significant reductions in heart disease mortality (HR, 0.64; 95% CI, 0.47-0.87) and cerebrovascular disease mortality (HR, 0.74; 95% CI, 0.56-1.00) were seen in older men. In a subgroup of younger men and a subgroup of moderate or severe dysplasia, subjects receiving multivitamin supplementation had a lower risk of esophageal/cardia cancer mortality (HR for younger men, 0.76; 95% CI, 0.58-0.99; HR for moderate or severe dysplasia, 0.76; 95% CI, 0.58-1.00). No association between multivitamin supplementation and any cause-specific mortality was observed in a mild dysplasia population., Conclusions: Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial. In light of this and previous trials, multivitamin supplements should be used thoughtfully to improve health status of populations with esophageal squamous dysplasia., Lay Summary: Multivitamin supplementation is common, yet its effect on mortality is unclear. The aim of this study was to update the long-term effects of multivitamin supplementation on total and cause-specific mortality during nearly 35 years of follow-up in the Linxian Dysplasia Nutrition Intervention Trial in China. Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial, and this indicates that multivitamin supplements should be used thoughtfully to improve health status., (© 2022 American Cancer Society.)

Background: Esophageal squamous cell carcinoma (ESCC) and its asymptomatic precursor lesion, esophageal squamous dysplasia (ESD), are common in East Africa. It is unknown whether family history of esophageal cancer is a risk factor for both ESD and ESCC in Africa, and whether family members of affected persons should be screened., Methods: We recruited 296 asymptomatic adult first-degree relatives of ESCC patients residing in southwestern Kenya. Participants completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy to determine the prevalence of ESD. Prevalence comparisons were made with a prior population-based cohort from the same catchment area who also underwent Lugol's chromoendoscopy., Results: Mean age was 40.7 years, compared to 62.7 years in the prior population study. The overall prevalence of ESD/ESCC among first-degree relatives was 14.7%, comparable to the background population prevalence of 14.4%, and this comparability remained even after adjusting for the different age distributions of the studies. Post-primary education was the only measured variable that was associated with a decreased risk of ESD/ESCC (adjusted OR=0.31, 95% CI: 0.11, 0.83). There was heterogeneity in the ESD prevalence across families, even after adjustments for varying age and other measured factors., Conclusions: The prevalence of esophageal squamous dysplasia among first-degree relatives of persons with ESCC was similar to that of the background population of southwestern Kenya; however, there was heterogeneity in ESD prevalence between families, suggesting other genetic or environmental factors may influence family prevalence. Further study of families with a high prevalence of ESD or ESCC is justified., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tooth loss and periodontal disease have been associated with several cancers, and poor oral health may be an important risk factor for upper gastrointestinal (UGI, i.e., esophageal and gastric) cancers. We assessed the relationship between oral health and UGI cancers using a large prospective study of over 50,000 adults living in Golestan Province, Iran, a high-incidence area for these cancers. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated for the association between three different measures of oral health [frequency of tooth brushing; number of missing teeth; and the sum of decayed, missing, and filled teeth (DMFT)] and UGI cancers. During a median follow-up duration of 13 years, there were 794 incident UGI cancers (396 esophageal and 398 gastric cancers). Daily tooth brushing was associated with a decreased risk of developing both esophageal (HR = 0.670; 95% CI: 0.486-0.924) and gastric (HR = 0.741; 95% CI: 0.544-1.01) cancers (combined UGI cancer HR = 0.697; 95% CI: 0.558-0.871) compared with never brushing. Tooth loss in excess of the loess smoothed, age- and sex-specific median number of teeth lost was significantly associated with esophageal (HR = 1.64; 95% CI: 1.08-2.47) and gastric cancers (HR = 1.58; 95% CI: 1.05-2.38). There were some adverse associations between DMFT and UGI cancers but most were not statistically significant. These results suggest increased risk of developing UGI cancers among individuals with poor oral health, and those who do not perform regular oral hygiene. PREVENTION RELEVANCE: Poor oral health is associated with the risk of upper gastrointestinal cancers, and oral hygiene practices may help prevent these cancers., (©2021 American Association for Cancer Research.)

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) is a risk factor for esophageal squamous cell carcinoma (ESCC) in high-incidence areas of China, Iran and Brazil, but PAH assessments have not been conducted in East Africa, another ESCC hot spot., Objective: To evaluate demographic or lifestyle factors associated with the PAH biomarker concentrations in the study population, and whether PAH metabolite concentrations showed any associations with esophageal precancerous lesions., Methods: We recruited a community-based sample of 289 asymptomatic adults from a rural area of Kenya and performed Lugol's chromoendoscopy to detect esophageal squamous dysplasia (ESD); participants completed a questionnaire and provided a spot urine specimen. We analyzed urine for seven hydroxylated metabolites of naphthalene, fluorene, phenanthrene, and pyrene at the U.S. National Center for Environmental Health, and compared creatinine-corrected PAH metabolite concentrations with questionnaire data and the presence of ESD., Results: PAH metabolite concentrations among never tobacco users in these rural Kenya residents were 2.4-28.1 times higher than those reported from never tobacco users in Iran, Brazil and the USA. Female sex, cooking indoors, having no post-primary education, and age <50, but not tobacco use, were positively and significantly associated with PAH metabolite concentrations. Almost all participants used wood as cooking fuel. Nine participants had advanced ESD. Adjusted logistic regression showed a significant association between 2-hydroxynaphthalene (OR = 4.19, 95%CI: 1.01-17.47) and advanced ESD. All other PAH metabolites had positive but non-significant associations with advanced ESD., Conclusions: Urinary PAH metabolite concentrations among never tobacco users are markedly higher in this group from Kenya than in other populations and are associated with indoor cooking with wood on open, unvented stoves. These metabolite concentrations were also associated with the presence of advanced esophageal dysplasia. Our findings underline the importance of assessing alternative cooking conditions to reduce PAH exposure in this population., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC)., Methods: We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer., Results: Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07-1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P < 0.001) with risk significantly elevated in type A (1.37, 1.14-1.65) and AB (1.44, 1.10-1.89) compared to type O. Blood type was not associated with gastric cardia adenocarcinoma (P = 0.13)., Conclusions: This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.

Questionnaire data have linked contact with ruminants to the risk of esophageal squamous cell carcinoma (ESCC) in high-risk Asian populations. To better understand this observed association, we investigated exposure to two major zoonotic ruminant pathogens relative to ESCC risk. Using enzyme-linked immunosorbent assay, immunofluorescence assay, and Brucella microagglutination test assays, we measured immunoglobulin G anti- Coxiella burnetii and anti- Brucella spp. antibodies in patients with ESCC ( n  = 177) and population-based controls ( n  = 177) matched by age, gender, and residence area from the Golestan case-control study in Iran. We found a similarly high seroprevalence of C. burnetii in ESCC cases and controls (75% and 80%, respectively), and a similarly low seroprevalence of Brucella spp. (0% and 0.6%, respectively). While documenting a high exposure to one of two zoonotic ruminant infections, this exposure failed to explain the observed association of ruminant contact and ESCC risk in this high-risk population.

Purpose: The eastern corridor of Africa is affected by a high burden of esophageal cancer (EC), with > 90% of patients presenting with advanced disease. Self-expanding metal stents (SEMS) have been previously reported as safe and effective for palliation of malignant dysphagia in resource-limited settings; however, access is limited throughout Eastern Africa., Methods: In response to demand for palliative interventions for patients with dysphagia because of EC, the African Esophageal Cancer Consortium (AfrECC) partnered with the Clinton Health Access Initiative to improve access to SEMS in Eastern Africa. We undertook a stepwise implementation approach to (1) identify barriers to SEMS access, (2) conduct a market analysis, (3) select an industry partner, (4) establish regulatory and procurement processes, (5) develop endoscopic training resources, (6) create a medical device registry, and (7) establish principles of accountability., Results: Following an evaluation of market demand and potential SEMS manufacturers, Boston Scientific Corporation announced its commitment to launch an access program to provide esophageal SEMS to patients in Tanzania, Kenya, Malawi, and Zambia at a subsidized price. Parallel regulatory and procurement processes were established in each participating country. Endoscopy training courses were designed and conducted, using the Training-of-Trainers model. A device registry was created to centralize data for quality control and to monitor channels of SEMS distribution. Principles of accountability were developed to guide the sustainability of this endeavor., Conclusion: The AfrECC Stent Access Initiative is an example of a multisector partnership formed to provide an innovative solution to align regional needs with a supply chain for a high-priority medical device.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (p trend  < 0.05) with HRs per quantile 1.28-1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57-0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL-4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis., (© 2019 UICC.)

Introduction: Data on the associations between esophageal histological lesions and risk of esophageal squamous cell carcinoma (ESCC) in general populations are limited. We aimed to investigate these associations in a large Chinese general population to inform future Chinese ESCC screening guidelines., Methods: We performed endoscopic screening of 21,111 participants aged 40-69 years from 3 high-risk areas of China in 2005-2009, and followed the cohort through 2016. Cumulative incidence and mortality rates of ESCC were calculated by baseline histological diagnosis, and hazard ratios of ESCC, overall and by age and sex, were assessed using the Cox proportional hazards models., Results: We identified 143 new ESCC cases (0.68%) and 62 ESCC deaths (0.29%) during a median follow-up of 8.5 years. Increasing grades of squamous dysplasia were associated with the increasing risk of ESCC incidence and mortality. The cumulative ESCC incidence rates for severe dysplasia/carcinoma in situ, moderate dysplasia (MD), and mild dysplasia were 15.5%, 4.5%, and 1.4%, respectively. Older individuals (50-69 years) had 3.1 times higher ESCC incidence than younger individuals (40-49 years), and men had 2.4 times higher ESCC incidence than women., Discussion: This study confirmed that increasing grades of squamous dysplasia are associated with increasing risk of ESCC and that severe dysplasia and carcinoma in situ require clinical treatment. This study suggests that in high-risk areas of China, patients with endoscopically worrisome MD should also receive therapy, the first screening can be postponed to 50 years, and endoscopic surveillance intervals for unremarkable MD and mild dysplasia can be lengthened to 3 and 5 years, respectively.

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case-cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case-control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4 ) for GNCA in NIT was 1.35 (95% CI: 0.89-2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02-2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001). In contrast, a lower risk of ESCC (NIT ESCC HR Q1:Q4 = 0.65, 95% CI: 0.45-0.92; p-trend = 0.02) was found in NIT. Low baseline ghrelin concentrations were associated with an increased risk for GNCA and GCA in the NIT and the SWHS. In contrast, low ghrelin concentrations at baseline were associated with a reduced risk of developing ESCC in the NIT. Ghrelin may be an early marker of future cancer risk for developing upper gastrointestinal cancer in regions of high incidence., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Previous studies have reported an association between hot tea drinking and risk of esophageal cancer, but no study has examined this association using prospectively and objectively measured tea drinking temperature. We examined the association of tea drinking temperature, measured both objectively and subjectively at study baseline, with future risk of esophageal squamous cell carcinoma (ESCC) in a prospective study. We measured tea drinking temperature using validated methods and collected data on several other tea drinking habits and potential confounders of interest at baseline in the Golestan Cohort Study, a population-based prospective study of 50,045 individuals aged 40-75 years, established in 2004-2008 in northeastern Iran. Study participants were followed-up for a median duration of 10.1 years (505,865 person-years). During 2004-2017, 317 new cases of ESCC were identified. The objectively measured tea temperature (HR 1.41, 95% CI 1.10-1.81; for ≥60°C vs. <60°C), reported preference for very hot tea drinking (HR 2.41, 95% CI 1.27-4.56; for "very hot" vs. "cold/lukewarm"), and reported shorter time from pouring tea to drinking (HR 1.51, 95% CI 1.01-2.26; for <2 vs. ≥6 min) were all associated with ESCC risk. In analysis of the combined effects of measured temperature and amount, compared to those who drank less than 700 ml of tea/day at <60°C, drinking 700 mL/day or more at a higher-temperature (≥60°C) was consistently associated with an about 90% increase in ESCC risk. Our results substantially strengthen the existing evidence supporting an association between hot beverage drinking and ESCC., (© 2019 UICC.)

Background: Autoimmune gastritis is understudied and possibly associated with gastric noncardia adenocarcinoma (GNCA) and esophageal squamous cell carcinoma (ESCC) in Western populations when it presents as pernicious anemia., Methods: A nested case-control study within a Chinese cohort included 100 ESCC, 200 gastric cardia adenocarcinoma (GCA), and 200 GNCA cases diagnosed between 1986 and 2001 and 400 controls. Serostatus of antiparietal cell antibodies (APCA), Helicobacter pylori antibodies, and pepsinogens were measured using commercial kits and serum collected at baseline. We used logistic regression to calculate odds ratios (OR) and 95% confidence interval (CI) for associations between serologic biomarkers and cancer risk adjusted for numerous potential confounders., Results: There was an average interval of 8 years between baseline blood draw and cancer diagnosis. The baseline prevalence of APCA seropositivity was 10.0% and 14.5% in subjects who developed GCA and GNCA, respectively. APCA seropositivity was inversely associated with later development of GCA (OR = 0.42; 95% CI, 0.24-0.75), but not significantly associated with later development of GNCA (OR = 0.82; 95% CI, 0.50-1.36) or ESCC (OR = 1.05; 95% CI, 0.58-1.88). APCA seropositivity was significantly associated with low pepsinogen I/II ratios (OR = 3.69; 95% CI, 1.66-8.21), and individuals with low pepsinogen I/II ratios who were seronegative for APCA had the highest risk of both GCA and GNCA., Conclusions: APCA seropositivity measured years prior to diagnosis was associated with prevalent atrophic gastritis but inversely associated with incident GCA in this Chinese population., Impact: APCA may contribute to a growing list of serologic markers that can improve risk stratification for gastric cancer., (©2019 American Association for Cancer Research.)

Background and Aims: Esophageal squamous cell neoplasia (ESCN) has a significant risk for progression to cancer. Current treatment options, endoscopic mucosal resection (EMR) or submucosal dissection (ESD), have their limitations. The cryoballoon focal ablation system (CbFAS) is a novel endoscopic ablation therapy device. We aimed to assess the safety, tolerability, and efficacy of CbFAS for eradication of ESCN., Methods: In this single-center prospective trial in China, patients with 1 flat unstained lesion (USL) on Lugol chromoendoscopy that contained moderate- or high-grade intraepithelial neoplasia (MGIN or HGIN, respectively) were enrolled. CbFAS was performed using side-by-side applications of 10 seconds, treatment was repeated at 3-month intervals until a complete response (CR) was established. The response at 12 months was the primary trial endpoint. Safety phone calls were performed at 2, 7, and 30 days after the initial CbFAS., Results: We enrolled 80 patients (59 MGIN, 21 HGIN) with a median USL length of 3 cm (interquartile range [IQR], 3-4). Seventy-nine received treatment, with a median of 5 side-by-side applications (IQR, 4-7) per patient over a median of 8 minutes (IQR, 5-10). After a single treatment, 70 of 78 patients (90%) exhibited CR, and 1 was lost to follow-up. The other 8 with persisting USLs were retreated, and all achieved CR after this second treatment. At 12 months after the initial CbFAS, 76 of 78 patients (97%) exhibited CR and 2 (3%) had recurrent MGIN. No strictures or serious adverse events occurred. Four patients developed self-limiting mucosal lacerations on balloon inflation. The postprocedure median pain score was 1 of 10 (IQR, 0-2) at day 2 and 0 (0-0) at days 7 and 30., Conclusions: The results suggest that the CbFAS is safe, well tolerated, and effective in inducing endoscopic and histologic remission in patients with ESCN of limited size. (Clinical trial registration number: NCT02605759.)., (Copyright © 2019. Published by Elsevier Inc.)

Background: Esophageal squamous cell carcinoma (ESCC) is common in certain areas worldwide. One area, western Kenya, has a high risk of ESCC, including many young cases (<30 years old), but has limited prior study of potential risk factors. Thermal injury from hot food and beverages and exposure to polycyclic aromatic hydrocarbons (PAHs) have been proposed as important risk factors for ESCC in other settings. The beverage of choice in western Kenya is milky tea (chai)., Methods: Healthy individuals >18 years of age who were accompanying relatives to an endoscopy unit were recruited to participate. The preferred initial temperature of chai consumption in these adults was measured by questionnaire and digital thermometer. Comparisons of these results were assessed by kappa statistics. Concentrations of 26 selected PAHs were determined by gas chromatography/mass spectrometry in samples of 11 brands of commercial tea leaves commonly consumed in Kenya., Results: Kappa values demonstrated moderate agreement between questionnaire responses and measured temperatures. The mean preferred chai temperatures were 72.1 °C overall, 72.6 °C in men (n = 78), and 70.2 °C in women (n = 22; p < 0.05). Chai temperature did not significantly differ by age or ethnic group. The PAH levels in the commercial Kenyan tea leaves were uniformly low (total PAH < 300 ng/g of leaves)., Conclusions: Study participants drink chai at higher temperatures than previously reported in other high-risk ESCC regions. Chai is not, however, a source of significant PAH exposure. Very hot chai consumption should be further evaluated as a risk factor for ESCC in Kenya with the proposed questionnaire., (Copyright © 2019. Published by Elsevier Ltd.)

Background & Aims: Northeast Iran has one of the highest reported rates of esophageal squamous cell carcinoma (ESCC) worldwide. Decades of investigations in this region have identified some local habits and environmental exposures that increase risk. We analyzed data from the Golestan Cohort Study to determine the individual and combined effects of the major environmental risk factors of ESCC., Methods: We performed a population-based cohort of 50,045 individuals, 40 to 75 years old, from urban and rural areas across Northeast Iran. Detailed data on demographics, diet, lifestyle, socioeconomic status, temperature of drinking beverages, and different exposures were collected using validated methods, questionnaires, and physical examinations, from 2004 through 2008. Participants were followed from the date of enrollment to the date of first diagnosis of esophageal cancer, date of death from other causes, or date of last follow-up, through December 31, 2017. Proportional hazards regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between different exposures and ESCC., Results: During an average 10 years of follow-up, 317 participants developed ESCC. Opium smoking (HR 1.85; 95% CI 1.18-2.90), drinking hot tea (≥60°C) (HR 1.60; 95% CI 1.15-2.22), low intake of fruits (HR 1.48; 95% CI 1.07-2.05) and vegetables (HR 1.62; 95% CI 1.03-2.56), excessive tooth loss (HR 1.66; 95% CI 1.04-2.64), drinking unpiped water (HR 2.04; 95% CI 1.09-3.81), and exposure to indoor air pollution (HR 1.57; 95% CI 1.08-2.29) were significantly associated with increased risk of ESCC, in a dose-dependent manner. Combined exposure to these risk factors was associated with a stepwise increase in the risk of developing ESCC, reaching a more than 7-fold increase in risk in the highest category. Approximately 75% of the ESCC cases in this region can be attributed to a combination of the identified exposures., Conclusions: Analysis of data from the Golestan Cohort Study in Iran identified multiple risk factors for ESCC in this population. Our findings support the hypothesis that the high rates of ESCC are due to a combination of factors, including thermal injury (from hot tea), exposure to polycyclic aromatic hydrocarbons (from opium and indoor air pollution), and nutrient-deficient diets. We also associated ESCC risk with exposure to unpiped water and tooth loss., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) are characterized by a strong male predominance. Concentrations of sex steroid hormones have been hypothesized to explain this sex disparity. However, no prospective population-based study has examined sex steroid hormones in relation to EA/GCA risk. Thus, we investigated whether prediagnostic circulating sex steroid hormone concentrations were associated with EA/GCA in a nested case-control study drawn from participants in three prospective cohort studies., Methods: Using gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in serum from 259 EA/GCA male case participants and 259 matched male control participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study II Nutrition Cohort. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA/GCA risk. All statistical tests were two-sided., Results: Higher concentrations of dehydroepiandrosterone (DHEA) were associated with a 38% decreased risk of EA/GCA (OR per unit increase in log2 DHEA = 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). Higher estradiol concentrations were associated with a 34% reduced risk of EA/GCA (OR = 0.66, 95% CI = 0.45 to 0.98, Ptrend = .05), and the association with free estradiol was similar. No other associations between baseline hormone concentrations and future EA/GCA risk were observed., Conclusions: This study provides the first evidence that higher concentrations of circulating DHEA, estradiol, and free estradiol may be associated with lower risks of EA/GCA in men.

Aim: To identify the clinicopathological characteristics of pT1N0 esophageal squamous cell carcinoma (ESCC) that are associated with tumor recurrence., Methods: We reviewed 216 pT1N0 thoracic ESCC cases who underwent esophagectomy and thoracoabdominal two-field lymphadenectomy without preoperative chemoradiotherapy. After excluding those cases with clinical follow-up recorded fewer than 3 mo and those who died within 3 mo of surgery, we included 199 cases in the current analysis. Overall survival and recurrence-free survival were assessed by the Kaplan-Meier method, and clinicopathological characteristics associated with any recurrence or distant recurrence were evaluated using univariate and multivariate Cox proportional hazards models. Early recurrence (≤ 24 mo) and correlated parameters were assessed using univariate and multivariate logistic regression models., Results: Forty-seven (24%) patients had a recurrence at 3 to 178 (median, 33) mo. The 5-year recurrence-free survival rate was 80.7%. None of 13 asymptomatic cases had a recurrence. Preoperative clinical symptoms, upper thoracic location, ulcerative or intraluminal mass macroscopic tumor type, tumor invasion depth level, basaloid histology, angiolymphatic invasion, tumor thickness, submucosal invasion thickness, diameter of the largest single tongue of invasion, and complete negative aberrant p53 expression were significantly related to tumor recurrence and/or recurrence-free survival. Upper thoracic tumor location, angiolymphatic invasion, and submucosal invasion thickness were independent predictors of tumor recurrence (Hazard ratios = 3.26, 3.42, and 2.06, P < 0.001, P < 0.001, and P = 0.002, respectively), and a nomogram for predicting recurrence-free survival with these three predictors was constructed. Upper thoracic tumor location and angiolymphatic invasion were independent predictors of distant recurrence. Upper thoracic tumor location, angiolymphatic invasion, submucosal invasion thickness, and diameter of the largest single tongue of invasion were independent predictors of early recurrence., Conclusion: These results should be useful for designing optimal individual follow-up and therapy for patients with T1N0 ESCC., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this article.

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of cancer-related death; however, worldwide incidence and mortality rates do not reflect the geographic variations in the occurrence of this disease. In recent years, increased attention has been focused on the high incidence of esophageal squamous cell carcinoma (ESCC) throughout the eastern corridor of Africa, extending from Ethiopia to South Africa. Nascent investigations are underway at a number of sites throughout the region in an effort to improve our understanding of the etiology behind the high incidence of ESCC in this region. In 2017, these sites established the African Esophageal Cancer Consortium. Here, we summarize the priorities of this newly established consortium: to implement coordinated multisite investigations into etiology and identify targets for primary prevention; to address the impact of the clinical burden of ESCC via capacity building and shared resources in treatment and palliative care; and to heighten awareness of ESCC among physicians, at-risk populations, policy makers, and funding agencies.

Background: Consumption of maté , an infusion of the herb Ilex paraguariensis (yerba maté) , is associated with increased risk of esophageal squamous cell carcinoma (ESCC), but the carcinogenic mechanism is unclear. Commercial brands of yerba maté contain high levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs), which are acquired during the traditional drying process. The purpose of this study was to characterize exposure to PAHs in maté drinkers over a wide range of maté consumption. Methods: We recruited 244 adults who answered a questionnaire and collected a fasting spot urine specimen. We quantified urinary concentrations of seven PAH metabolites and assessed associations between self-reported recent maté consumption and urinary PAH metabolites by multivariate regression. Results: Recent maté consumption showed a significant dose-response association with 6 of 7 PAH metabolites in unadjusted models ( P trend < 0.05). After adjustment for creatinine and potential confounders, concentrations of 2-naphthol, 1-hydroxyphenanthrene, and the sum of 2- and 3-hydroxyphenanthrene remained significantly associated with recent maté intake. The sum of the urinary concentrations of the phenanthrene metabolites was similar or higher among maté drinkers who did not smoke than among smokers who did not drink maté Conclusions: Urinary concentrations of PAH metabolites were significantly associated with self-reported amounts of recent maté intake, and drinking maté increased urinary concentrations of some PAH metabolites as much as smoking cigarettes. Impact: Drinking maté is a source of exposure to potentially carcinogenic PAHs, consistent with the hypothesis that the PAH content of maté may contribute to the increased risk of ESCC in maté drinkers. Cancer Epidemiol Biomarkers Prev; 27(3); 331-7. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Esophageal adenocarcinoma (EA) is characterized by a strong male predominance. Sex steroid hormones have been hypothesized to underlie this sex disparity, but no population-based study to date has examined this potential association., Methods: Using mass spectrometry and ELISA, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in plasma from males- 172 EA cases and 185 controls-within the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study, a case-control investigation conducted in Northern Ireland and Ireland. Multivariable adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA., Results: Higher androgen:estrogen ratio metrics were associated with increased odds of EA (e.g., testosterone:estradiol ratio ORQ4 v. Q1 = 2.58, 95%CI = 1.23-5.43; Ptrend = 0.009). All estrogens and androgens were associated with significant decreased odds of EA. When restricted to individuals with minimal to no decrease in body mass index, the size of association for the androgen:estrogen ratio was not greatly altered., Conclusions: This first study of sex steroid hormones and EA provides tentative evidence that androgen:estrogen balance may be a factor related to EA. Replication of these findings in prospective studies is needed to enhance confidence in the causality of this effect.

Background: Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya., Methods: 294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression., Results: The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05-8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06-14.19)., Conclusion: This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

Studies conducted in China linked selenium deficiency to higher risk of esophageal squamous cell carcinoma (ESCC), but this has not been widely tested outside that selenium-deficient region. The aim of this study was to investigate the association between selenium and other mineral concentrations in toenails and risk of ESCC in a region with high incidence rates. In this nested case-control study, we identified 222 cases of ESCC from the Golestan Cohort Study, Iran, which has followed up 50,045 participants since enrollment (2004-2008). We randomly selected one control for each case matched by age and sex, using incidence density sampling. We used toenail samples collected at baseline to measure the concentration of selenium, zinc, chromium, mercury, and scandium using instrumental neutron activation analysis. Multivariate adjusted logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals. Median nail selenium, zinc, chromium, and mercury levels were 1.01, 74.59, 0.77, and 0.018 μg/g in cases and 1.02, 75.71, 0.71, and 0.023 μg/g in controls, respectively. The adjusted odds ratios comparing each fourth quartile of mineral status versus the first quartile were as follows: selenium = 0.78 (95% CI, 0.41-1.49); zinc=0.80 (95% CI, 0.42-1.53); chromium = 0.91 (95% CI, 0.46-1.80); and mercury=0.61 (95% CI, 0.27-1.38), and all trend tests were non-significant. The nail selenium concentration in our controls reflects relatively high selenium status. No evidence of association between selenium or chromium concentrations in toenails and the risk of ESCC was detected in this population., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Nut consumption has been associated with decreased risk of colorectal, endometrial, lung, and pancreatic cancers. Polyphenols, fiber, vitamins, and minerals in nuts may confer this observed protective effect. To our knowledge, no prospective study has evaluated the effect of nut consumption on esophageal and gastric cancers. Objective: The objective was to evaluate the associations between nut and peanut butter consumption and the risk of esophageal and gastric cancers and their different subtypes. Design: In this study we used data from the NIH-AARP Diet and Health Study, which enrolled 566,407 persons who were 50-71 y old at baseline (1995-1996). The median follow-up time was 15.5 y. Intakes of nuts and peanut butter were assessed through the use of a validated food-frequency questionnaire. We used Cox proportional hazard models to estimate HRs and 95% CIs for esophageal and gastric cancers and their subtypes. Results: We identified 966 incident cases of esophageal adenocarcinomas, 323 cases of esophageal squamous cell carcinoma, 698 cases of gastric cardia adenocarcinoma, and 732 cases of gastric noncardia adenocarcinoma. Compared with those who did not consume nuts or peanut butter [lowest category of consumption (C0)], participants in the highest category of nut consumption (C3) had a lower risk of developing gastric noncardia adenocarcinoma [C3 compared with C0, HR: 0.73 (95% CI: 0.57, 0.94)]. This inverse association was also seen for peanut butter consumption [C3 compared with C0, HR: 0.75 (95% CI: 0.60, 0.94)]. We observed no significant associations between the highest and lowest intakes of nuts or peanut butter and the risk of gastric cardia adenocarcinoma, esophageal adenocarcinoma, or esophageal squamous cell carcinoma. Conclusions: Among older American adults, both nut and peanut butter consumption were inversely associated with the risk of gastric noncardia adenocarcinoma. This trial was registered at clinicaltrials.gov as NCT00340015., (© 2017 American Society for Nutrition.)

Background: Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Previous studies have shown that flavonoid intake reduces the risk of certain cancers; however, few studies to date have examined associations of flavonoids with upper gastrointestinal cancers or used prospective cohorts. Objective: Our study examined the association between intake of flavonoids (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, and isoflavones) and risk of head and neck, esophageal, and gastric cancers. Methods: The NIH-AARP Diet and Health Study is a prospective cohort study that consists of 469,008 participants. Over a mean 12-y follow-up, 2453 head and neck (including 1078 oral cavity, 424 pharyngeal, and 817 laryngeal), 1165 esophageal (890 adenocarcinoma and 275 squamous cell carcinoma), and 1297 gastric (625 cardia and 672 noncardia) cancer cases were identified. We used Cox proportional hazards regression models to estimate HRs and CIs for the associations between flavonoid intake assessed at study baseline and cancer outcomes. For 56 hypotheses examined, P -trend values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Results: The highest quintile of total flavonoid intake was associated with a 24% lower risk of head and neck cancer (HR: 0.76; 95% CI: 0.66, 0.86; BH-adjusted 95% CI: 0.63, 0.91; P -trend = 0.02) compared with the lowest quintile. Notably, anthocyanidins were associated with a 28% lower risk of head and neck cancer (HR: 0.72; 95% CI: 0.62, 0.82; BH-adjusted 95% CI: 0.59, 0.87; P -trend = 0.0005), and flavanones were associated with a 22% lower risk of head and neck cancer (HR: 0.78; 95% CI: 0.68, 0.89; BH-adjusted 95% CI: 0.64, 0.94; P -trend: 0.02). No associations between flavonoid intake and risk of esophageal or gastric cancers were found. Conclusions: Our results indicate that flavonoid intake is associated with lower head and neck cancer risk. These associations suggest a protective effect of dietary flavonoids on head and neck cancer risk, and thus potential as a risk reduction strategy., Competing Interests: Author disclosures: LS, AFS, CB, SMD, LLK, TPZ, CCA, RH, BIG, MBC, and JLP, no conflicts of interest. The funding source had no role in the design or conduct of the study., (© 2017 American Society for Nutrition.)

Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC. We evaluated the association between SNPs and FH of UGI cancer among ESCC cases in a stage-1 case-only analysis of the National Cancer Institute (NCI, 541 cases with FH and 1399 without FH) and Henan GWAS (493 cases with FH and 869 without FH) data (discovery phase). The top SNPs (or their surrogates) from discovery were advanced to a stage-2 evaluation in additional Henan subjects (2801 cases with FH and 3136 without FH, replication phase). A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P < 10 -5 in the stage-1 meta-analysis of NCI and Henan GWAS data. In stage-2, the association for rs79747906 (located at 18p11.31, P = 5.79 × 10 -6 in discovery) was replicated (P = 0.006), with a pooled-OR of 1.59 (95%CI: 1.11-2.28). We identified potential genetic variants associated with FH of UGI cancer. Our findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases.

Background: Gastrin, which induces gastric acid secretion, and a structurally similar hormone, cholecystokinin (CCK)-a potent acid inhibitor, may each play a role in gastric cancer. However, few studies have investigated this hypothesis in humans. We therefore investigated whether serum gastrin or CCK concentrations at baseline were associated with the incidence of gastric non-cardia adenocarcinomas (GNCA), oesophagogastric junctional adenocarcinomas (EGJA) or gastric carcinoid tumours over 24 years of follow-up in a study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish smokers., Methods: Totals of 283 incident GNCA, 96 EGJA and 10 gastric carcinoid cases, and 778 matched controls, were included in our analysis. Gastrin and CCK were measured using specific radioimmunoassays. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by multivariable logistic regression with adjustment for all known or suspected confounding factors, including Helicobacter pylori seropositivity., Results: Those with high gastrin (Q4 vs Q1), had an increased risk of GNCA (fully adjusted OR: 1.92; 95% CI: 1.21, 3.05) and gastric carcinoids, though the small number of carcinoid cases meant the fully adjusted model was unstable (age-adjusted continuous model OR: 4.67; 95% CI: 2.67, 8.15). CCK was associated with risk of GNCA only for those in Q3 relative to Q1 (OR: 0.56; 95% CI: 0.33, 0.96), and no significant trend was observed., Conclusions: Our data suggest that high serum concentrations of gastrin may be associated independently with an increased risk of gastric cancer; the role of CCK in cancer risk is less clear., (Published by Oxford University Press on behalf of the International Epidemiological Association 2017. This work is written by US Government employees and is in the public domain in the United States.)

Background and Aims: In recent years high-resolution microendoscopy (HRME) has shown potential to improve screening for esophageal squamous cell neoplasia. Furthering its utility in a clinical setting, especially in lower-resource settings, could be accomplished by reducing the size and cost of the system as well as incorporating the ability of real-time, objective feedback. This article describes a tablet-interfaced HRME with fully automated, real-time image analysis., Methods: The performance of the tablet-interfaced HRME was assessed by acquiring images from the oral mucosa in a normal volunteer. An automated, real-time analysis algorithm was developed and evaluated using training, test, and validation images from a previous in vivo study of 177 patients referred for screening or surveillance endoscopy in China. The algorithm was then implemented in a tablet HRME that was used to obtain and analyze images from esophageal tissue in 3 patients. Images were displayed alongside the probability that the imaged region was neoplastic., Results: The tablet-interfaced HRME demonstrated comparable imaging performance at a lower cost compared with first-generation laptop-interfaced HRME systems. In a post-hoc quantitative analysis, the algorithm identified neoplasia with a sensitivity and specificity of 95% and 91%, respectively, in the validation set compared with 84% and 95% achieved in the original study., Conclusions: The tablet-based HRME is a low-cost tool that provides quantitative diagnostic information to the endoscopist in real time. This could be especially beneficial in lower-resource settings for operators with less experience interpreting HRME images., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. All rights reserved.)

B vitamins play an essential role in DNA synthesis and methylation, and may protect against oesophageal and gastric cancers. In this case-cohort study, subjects were enrolled from the General Population Nutrition Intervention Trial in Linxian, China. Subjects included 498 oesophageal squamous cell carcinomas (OSCCs), 255 gastric cardia adenocarcinomas (GCAs), and an age- and sex-matched sub-cohort of 947 individuals. Baseline serum riboflavin, pyridoxal phosphate (PLP), folate, vitamin B12, and flavin mononucleotide (FMN) were measured for all subjects. We estimated the associations with Cox proportional hazard models, with adjustment for potential confounders. Compared to those in the lowest quartile of serum riboflavin, those in the highest had a 44% lower risk of OSCC (HR: 0.56, 95% CI: 0.41 to 0.75). Serum vitamin B12 as a continuous variable was observed to be significantly inversely associated with OSCC (HR: 0.95, 95% CI: 0.89 to 1.01, P for score test = 0.041). Higher serum FMN levels were significantly associated with increased risk of OSCC (HR: 1.08, 95% CI: 1.01 to 1.16) and GCA (HR: 1.09, 95% CI: 1.00 to 1.20). Our study prompted that B vitamins have the potential role as chemopreventive agents for upper gastrointestinal cancers.

The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy. The aims of this study were therefore to identify biomarkers for esophageal squamous dysplasia and carcinoma. A publicly available dataset was used to identify genes with differential expression in ESCC compared with normal esophagus. Each gene was ranked by a support vector machine separation score. Expression profiles were examined, before validation by qPCR and IHC. We found that 800 genes were overexpressed in ESCC compared with normal esophagus (P < 10(-5)). Of the top 50 genes, 33 were expressed in ESCC epithelium and not in normal esophagus epithelium or stroma using the Protein Atlas website. These were taken to qPCR validation, and 20 genes were significantly overexpressed in ESCC compared with normal esophagus (P < 0.05). TNFAIP3 and CHN1 showed differential expression with IHC. TNFAIP3 expression increased gradually through normal esophagus, mild, moderate and severe dysplasia, and SCC (P < 0.0001). CHN1 staining was rarely present in the top third of normal esophagus epithelium and extended progressively towards the surface in mild, moderate, and severe dysplasia, and SCC (P < 0.0001). Two novel promising biomarkers for ESCC were identified, TNFAIP3 and CHN1. CHN1 and TNFAIP3 may improve diagnostic accuracy of screening methods for ESCC. Cancer Prev Res; 9(7); 558-66. ©2016 AACR., (©2016 American Association for Cancer Research.)

Epidemiological and mechanistic evidence on the causative role of human papillomaviruses (HPV) in esophageal squamous cell carcinoma (ESCC) is unclear. We retrieved alcohol- and formalin-fixed paraffin-embedded ESCC tissues from 133 patients seropositive for antibodies against HPV early proteins, from high-incidence ESCC regions: South Africa, China and Iran. With rigorous care to prevent nucleic acid contamination, we analyzed these tissues for the presence of 51 mucosotropic human alpha-papillomaviruses by two sensitive, broad-spectrum genotyping methods, and for the markers of HPV-transformed phenotype: (i) HPV16/18 viral loads by quantitative real-time PCR, (ii) type-specific viral mRNA by E6*I/E6 full-length RT-PCR assays and (iii) expression of cellular protein p16(INK4a). Of 118 analyzable ESCC tissues, 10 (8%) were positive for DNA of HPV types: 16 (4 tumors); 33, 35, 45 (1 tumor each); 11 (2 tumors) and 16, 70 double infection (1 tumor). Inconsistent HPV DNA+ findings by two genotyping methods and negativity in qPCR indicated very low viral loads. A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16(INK4a) negative (HPV16 E1 seropositive patient). Another HPV16 DNA+ tumor from an HPV16 E6 seropositive patient showed p16(INK4a) upregulation but no HPV16 mRNA. In the tumor tissues of these serologically preselected ESCC patients, we did not find consistent presence of HPV DNA, HPV mRNA or p16(INK4a) upregulation. These results were supported by a meta-analysis of 14 other similar studies regarding HPV-transformation of ESCC. Our study does not support the etiological role of the 51 analyzed mucosotropic HPV types in the ESCC carcinogenesis., (© 2015 UICC.)

Background and Aim: Piecemeal endoscopic resection for esophageal high grade intraepithelial neoplasia (HGIN) or early squamous cell carcinoma (ESCC) is usually performed by cap-assisted endoscopic resection. This requires submucosal lifting and multiple snares. Multiband mucosectomy (MBM) uses a modified variceal band ligator without submucosal lifting. In high-risk areas where ESCC is common and endoscopic expertise is limited, MBM may be a better technique. We aimed to compare MBM to the cap-assisted technique for piecemeal endoscopic resection of esophageal ESCCs., Methods: Patients with mucosal HGIN/ESCC (2 - 6 cm, maximum two-thirds of esophageal circumference) were included. Lesions, delineated by 1.25 % Lugol staining, were randomized to MBM or cap-assisted piecemeal resection. Endpoints were procedure time and costs, complete endoscopic resection, adverse events, and absence of HGIN/ESCC at 3-month and 12-month follow-up. , Results: Endoscopic resection was performed in 84 patients (59 men, mean age 60) using MBM (n = 42) or the endoscopic resection cap (n = 42). There were no differences in baseline characteristics. Endoscopic complete resection was achieved in all lesions. Procedure time was significantly shorter with MBM (11 vs. 22 minutes, P < 0.0001). One perforation, seen after using the endoscopic resection cap, was treated conservatively. Total costs of disposables were lower for MBM (€200 vs. €251, P = 0.04). At 3-month and 12-month follow-ups none of the patients had HGIN/ESCC at the resection site., Conclusion: Piecemeal endoscopic resection of esophageal ESCC with MBM is faster and cheaper than with the endoscopic resection cap. Both techniques are highly effective and safe. MBM may have significant advantages over the endoscopic resection cap technique, especially in countries where ESCC is extremely common but limited endoscopic expertise and resources exist. (Netherlands trial register: NTR 3246.)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. Cancer Res; 76(7); 1714-23. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants., Method: We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues., Results: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG&#95;hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome&#95;pid; POLD2) and the metabolics pathway (KEGG&#95;hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P =  .75E-14)., Conclusion: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs., (Published by Oxford University Press on behalf of the International Epidemiological Association 2015. This work is written by US Government employees and is in the public domain in the US.)

Objective: To evaluate the efficacy of radiofrequency ablation(RFA) combined with endoscopic resection(ER) for eradicating widespread early non-flat type esophageal squamous cell carcinoma (ESCC) and precancerous lesions., Methods: Retrospective analysis was performed on the clinical data of 4 patients with early non-flat type ESCC and precancerous lesions in January 2010 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences. Proportion of patients with histological complete response (CR) 3 months, 12 months to 5 years after operation and adverse events were observed., Results: These 4 patients were all male, aged from 47 to 71 (mean age 62) years, including 2 of ESCC, 1 of HGIN, 1 of MGIN confirmed by pathology. USL length was 6-12 (mean 8.5) cm. Treatment area (TA) length was 8-14 (mean 10.5) cm. Three cases were 0-II a (mean length 2 cm), and 1 case 0-II c (mean length 4 cm). Lesions of 2 cases were complete cycle, and other 2 cases occupied 3/4 circumference. Four patients completed their operations successfully. Total operation time was 42-105 (mean 66.8) min, RFA time was 3-12 (mean 8.25) min, and ER time was 6-20 (10.25) min, without bleeding and perforation. The mean hospital stay was 3 days. Pathology examination showed that 2 cases were ESCC G2 (lesion length 12, 8 cm; non-flat type lesion length 3, 4 cm), 1 was HGIN (lesion length 12 cm; non-flat type lesion length 1 cm) and 1 was MGIN (lesion length 6 cm; non-flat type lesion length 2 cm). Three cases were CR 3 months, 1 to 5 years after operation. One case had HGIN at 3-month and MGIN at 1-year and 3-year during follow up, and was CR after treatment with HALO. Postoperative esophageal stenosis occurred in 4 cases. Among them, 2 cases were mild without treatment, and 2 were severe, who were relieved by endoscopic water sac dilation for 5-8 (mean 6.5) times., Conclusion: RFA combined with ER is effective and safe in the treatment of patients with early non-flat esophageal squamous cell carcinoma and precancerous lesions.

Background & Aims: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol's chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE., Methods: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology., Results: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%-66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%-57%) could have been spared any biopsy., Conclusions: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)