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1.  COX2 (PTGS2) gene methylation in epithelial, subepithelial lymphocyte and stromal tissue compartments in a spectrum of esophageal squamous neoplasia 
Cancer detection and prevention  2008;32(2):135-139.
Previous studies have shown important effects of stromal elements in carcinogenesis. To explore the tumor-stromal relationship in esophageal neoplasia, we examined methylation of COX-2 (PTGS2), a gene etiologically associated with the development of gastrointestinal cancers, in adjacent foci of epithelium, subepithelial lymphocytes and non-lymphocytic stromal cells found in sections of normal squamous epithelium, squamous dysplasia and invasive esophageal squamous cell carcinoma.
Adjacent foci of epithelium, subepithelial lymphocytic aggregates and non-lymphocytic stromal tissues were laser microdissected from six fully embedded, ethanol fixed, esophagectomy samples from Shanxi, China, a high-risk region for esophageal cancer. Promoter CpG site-specific hypermethylation status of COX-2 was determined using real-time methylation specific PCR (qMS-PCR) based on Taqman Chemistry. The methylation status of a subset of samples was confirmed by pyrosequencing.
Forty-nine microdissected foci were analyzed. COX-2 gene methylation was significantly more common in subepithelial lymphocytes (12/16 (75% of all foci)) than in epithelial foci (3/16 (19%)) or foci of non-lymphocytic stromal tissues (3/17 (18%)) (Fisher’s Exact p=0.05). Two of three epithelial samples and all three stromal samples that showed COX-2 methylation were adjacent to foci of methylated subepithelial lymphocytes. Pyrosequencing confirmed the methylation status in a subset of samples.
In these esopohageal cancer patients, COX-2 gene methylation was more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in both grades of dysplasia and in foci of invasive cancer. These findings raise the possibility that methylation of subepithelial lymphocytes may be important for tumorigenesis. Future studies of gene methylation should consider separate evaluation of epithelial and non-epithelial cell populations.
Condensed abstract
COX2 (PTGS2) gene methylation increases with disease severity and is more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in dysplastic and early invasive esophageal squamous cell cancer foci.
PMCID: PMC2629649  PMID: 18632220
esophagus; neoplasms; cancer; cyclooxgenase-2; precancerous conditions; methylation; lymphocytes; squamous cell cancer
2.  10 years after NHANES I: report of initial followup, 1982-84. 
Public Health Reports  1986;101(5):465-473.
The NHANES I Epidemiologic Followup Study (NHEFS) was jointly initiated by the National Center for Health Statistics and the National Institute on Aging in collaboration with other National Institutes of Health and Public Health Service agencies. The goal of NHEFS is to examine the relationship of baseline clinical, nutritional, and behavioral factors assessed in the first National Health and Nutrition Examination Survey (NHANES I-1971-75) to subsequent morbidity and mortality. Data collection for the initial phase of followup took place between 1982 and 1984 and included tracing of all NHANES I participants, determining their vital status, conducting in-depth interviews with surviving participants or with proxies for those who were deceased or incapacitated, conducting selected physical measurements, obtaining facility records for stays in hospitals or nursing homes that occurred during the period of followup, and obtaining death certificates for decedents. Ninety-three percent of the original cohort was successfully traced. Interviews were conducted for 93 percent of traced, surviving participants and 84 percent of traced, surviving participants and 84 percent of traced, deceased subjects. Physical measurements were obtained for approximately 95 percent of surviving, interviewed subjects. Death certificates are available for more than 95 percent of the decedents, and 18,136 facility records were received for 6,477 subjects.
PMCID: PMC1477775  PMID: 3094075
3.  Endoscopy in screening for digestive cancer 
The aim of this study is to describe the role of endoscopy in detection and treatment of neoplastic lesions of the digestive mucosa in asymptomatic persons. Esophageal squamous cell cancer occurs in relation to nutritional deficiency and alcohol or tobacco consumption. Esophageal adenocarcinoma develops in Barrett’s esophagus, and stomach cancer in chronic gastric atrophy with Helicobacter pylori infection. Colorectal cancer is favoured by a high intake in calories, excess weight, low physical activity. In opportunistic or individual screening endoscopy is the primary detection procedure offered to an asymptomatic individual. In organized or mass screening proposed by National Health Authorities to a population, endoscopy is performed only in persons found positive to a filter selection test. The indications of primary upper gastrointestinal endoscopy and colonoscopy in opportunistic screening are increasingly developing over the world. Organized screening trials are proposed in some regions of China at high risk for esophageal cancer; the selection test is cytology of a balloon or sponge scrapping; they are proposed in Japan for stomach cancer with photofluorography as a selection test; and in Europe, America and Japan; for colorectal cancer with the fecal occult blood test as a selection test. Organized screening trials in a country require an evaluation: the benefit of the intervention assessed by its impact on incidence and on the 5 year survival for the concerned tumor site; in addition a number of bias interfering with the evaluation have to be controlled. Drawbacks of screening are in the morbidity of the diagnostic and treatment procedures and in overdetection of none clinically relevant lesions. The strategy of endoscopic screening applies to early cancer and to benign adenomatous precursors of adenocarcinoma. Diagnostic endoscopy is conducted in 2 steps: at first detection of an abnormal area through changes in relief, in color or in the course of superficial capillaries; then characterization of the morphology of the lesion according to the Paris classification and prediction of the risk of malignancy and depth of invasion, with the help of chromoscopy, magnification and image processing with neutrophil bactericidal index or FICE. Then treatment decision offers 3 options according to histologic prediction: abstention, endoscopic resection, surgery. The rigorous quality control of endoscopy will reduce the miss rate of lesions and the occurrence of interval cancer.
PMCID: PMC3536848  PMID: 23293721
Esophagus; Stomach; Colon; Adenoma; Adenocarcinoma; Endoscopy; Screening
4.  Challenges in global improvement of oral cancer outcomes: findings from rural Northern India 
Tobacco Induced Diseases  2012;10(1):5.
In India, 72% of the population resides in rural areas and 30-40% of cancers are found in the oral cavity. The majority of Haryana residents live in villages where inadequate medical facilities, no proper primary care infrastructure or cancer screening tools and high levels of illiteracy all contribute to poor oral cancer (OC) outcomes. In this challenging environment, the objective of this study was to assess the association between various risk factors for OC among referrals for suscipious lesions and to design and pilot test a collaborative community-based effort to identify suspicious lesions for OC.
Setting: Community-based cross sectional OC screening.
Participants: With help from the Department of Health (DOH), Haryana and the local communities, we visited three villages and recruited 761 participants of ages 45-95 years. Participants received a visual oral cancer examination and were interviewed about their dental/medical history and personal habits. Pregnant women, children and males/females below 45 years old with history of OC were excluded.
Main outcome: Presence of a suspicious oral lesion.
Out of 761 participants, 42 (5.5%) were referred to a local dentist for follow-up of suspicious lesions. Males were referred more than females. The referral group had more bidi and hookah smokers than non smokers as compared to non referral group. The logistic regression analysis revealed that smoking bidi and hookah (OR = 3.06 and 4.42) were statistically significant predictors for suspicious lesions.
Tobacco use of various forms in rural, northern India was found to be quite high and a main risk factor for suspicious lesions. The influence of both the DOH and community participation was crucial in motivating people to seek care for OC.
PMCID: PMC3352301  PMID: 22494988
5.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.
We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.
Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.
Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres
6.  Ecological analysis of health care utilisation for China's rural population: association with a rural county's socioeconomic characteristics 
BMC Public Health  2010;10:664.
The problem of accessibility and affordability of health care is reported to be a major social concern in modern China. It is pronounced in rural households which represent 60% of China's population. There are a few large scale studies which have been conducted into socioeconomic inequalities in health care utilisation for rural populations. Those studies that exist are mainly bivariate analyses. The aim of this study is to examine the relationship between socioeconomic characteristics and health service utilisation among rural counties, using aggregated data from a nationally representative dataset, within a multivariate regression analysis framework.
Secondary data analysis was conducted on China's National Health Services Survey (NHSS) 2003. Aggregated data on health care utilisation, socioeconomic position, demographic characteristics and health status were used. The samples included 67 rural counties. Multivariate linear regression analyses were performed.
The results of the ecological multivariate analyses showed a positive relationship between private insurance coverage and the use of outpatient care (p-value < 0.05, standardised coefficient = 0.22). Annual income was positively correlated with annual medical expenditure (p-value < 0.01, standardised coefficient = 0.56). A rural county's area socioeconomic stratum, a composite measure frequently used in bivariate studies including the NHSS analysis report, could not explain any association with the use of health care.
This study highlights that richer rural households with a greater ability to pay are more able to use health services in China. The findings suggest that the scope of medical insurance might be restrictive, or the protection provided might be limited, and the health care costs might still be too high. Additional efforts are required to ensure that poorer Chinese rural households are able to utilise health care according to their needs, regardless of their income levels or private insurance coverage. This would require targeted strategies to assist low income families and a broad spectrum of interventions to address the social determinants of health.
PMCID: PMC2988739  PMID: 21044343
7.  "A Latino Advantage in Oral Health-Related Quality of Life is Modified by Nativity Status" 
Social science & medicine (1982)  2010;71(1):205-211.
Explanations for the social gradient in health status are informed by the rare exceptions. This cross-sectional observational study examined one such exception, the “Latino paradox” by investigating the presence of a Latino advantage in oral health-related quality of life and the effect of nativity status on this relationship. A nationally representative sample of adults (n = 4208) completed the National Health and Nutrition Examination Survey (NHANES) 2003–2004. The impact of oral disorders on oral health-related quality of life was evaluated using the NHANES Oral Health Impact Profile. Exposures of interest were race, ethnicity and nativity status. Covariates included sociodemographic characteristics, smoking status, self-rated health, access to dental care and number of teeth. Unconditional logistic regression models estimated odds of impaired oral health-related quality of life for racial/ethnic and nativity groups compared to the Non-Latino white population. Overall prevalence of impaired oral health-related quality of life was 15.1%. A protective effect of Latino ethnicity was modified by nativity status, such that Latino immigrants experienced substantially better outcomes than non-Latino whites. However the effect was limited to first-generation Latinos. U.S. born Latinos did not share the oral health-related quality of life advantage of their foreign-born counterparts. This advantage was not attributable to the healthy migrant phenomenon since immigrants of non-Latino origin did not differ from Non-Latino whites. The excess risk among Non-Hispanic Blacks was rendered non-significant after adjustment for socioeconomic position. A protective effect conferred by Latino nativity is unexpected given relatively disadvantaged socioeconomic position of this group, their language barrier and restrictions to needed dental care. As the Latino advantage in oral health-related quality of life is not explained by healthy immigrant selection, cultural explanations seem more likely than explanations based on characteristics of individuals.
PMCID: PMC2885514  PMID: 20434250
USA; Acculturation; Hispanic; Disparities; Epidemiology; Social Class; Oral Health; nativity; Latino paradox; ethnicity
8.  Epidemiology of esophageal cancer 
Esophageal cancer (EsC) is one of the least studied and deadliest cancers worldwide because of its extremely aggressive nature and poor survival rate. It ranks sixth among all cancers in mortality. In retrospective studies of EsC, smoking, hot tea drinking, red meat consumption, poor oral health, low intake of fresh fruit and vegetables, and low socioeconomic status have been associated with a higher risk of esophageal squamous cell carcinoma. Barrett’s esophagus is clearly recognized as a risk factor for EsC, and dysplasia remains the only factor useful for identifying patients at increased risk, for the development of esophageal adenocarcinoma in clinical practice. Here, we investigated the epidemiologic patterns and causes of EsC. Using population based cancer data from the Surveillance, Epidemiology and End Results Program of the United States; we generated the most up-to-date stage distribution and 5-year relative survival by stage at diagnosis for 1998-2009. Special note should be given to the fact that esophageal cancer, mainly adenocarcinoma, is one of the very few cancers that is contributing to increasing death rates (20%) among males in the United States. To further explore the mechanism of development of EsC will hopefully decrease the incidence of EsC and improve outcomes.
PMCID: PMC3769895  PMID: 24039351
Risk factor; Barrett’s esophagus; Cyclin D1 G870A; Esophageal neoplasm; Susceptibility; Polymorphism
9.  Influence of cigarette smoking on the overall perception of dental health among adults aged 20-79 years, United States, 1988-1994. 
Public Health Reports  2005;120(2):124-132.
OBJECTIVE: Investigation into the relationship between lifestyle factors (particularly cigarette smoking) and perceived oral health has been limited. Data from the third National Health and Nutrition Examination Survey (NHANES II), 1988-1994, were used to explore this relationship in a large sample of U.S. adults. METHODS: This study used data on 13,357 dentate participants in NHANES III aged 20-79 years. In NHANES III, information on perceived dental health, sociodemographic attributes, smoking status, frequency of dental visits, dental insurance, and general health perception were collected during a home interview, and oral health status was assessed at a mobile examination center. RESULTS: Overall, 34.4% of individuals in the study sample reported having an unfavorable perception of their dental health by qualifying it as "fair" or "poor." Furthermore, 46.6% of smokers had an unfavorable dental health perception, compared to 28.3% of non-smokers. An interaction between smoking and race/ethnicity was found in logistic regression modeling. Stratified results show that cigarette smoking was not a significant predictor for an unfavorable dental health perception among individuals who self-identified as Mexican American, but smoking was a significant predictor for an unfavorable dental health perception among those who identified as non-Hispanic black or non-Hispanic white. CONCLUSIONS: This is the first study to describe the effects of smoking on dental health perception while controlling for examined oral health status. Because perceived dental health is a potential indicator for dental care utilization, a better knowledge of the factors that influence dental health perception is not only important for dental services planning, but also for understanding oral health-related quality of life issues. Additionally, given that smoking may negatively affect dental health perception, these findings have potential implications for smoking cessation activities conducted by dental care providers.
PMCID: PMC1497695  PMID: 15842113
The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northern China. This cancer has a very poor prognosis, mostly because it is usually diagnosed at a late stage. Detection an earlier stage can dramatically improve prognosis. Microscopic evaluation of esophageal balloon cytology (EBC) specimens has been the most common method for early detection of ESCC, but this technique is limited by low sensitivity and specificity. The use of molecular markers may improve these screening characteristics. This study evaluates whether measurement of gene methylation in EBC specimens may have utility for the detection of esophageal squamous dysplasia and early ESCC. We evaluated the presence of methylation in eight genes shown to be methylated in ESCC in previous studies in EBC specimens from 147 patients with endoscopic biopsy diagnoses ranging from normal mucosa through severe squamous dysplasia. Methylation status was determined using quantitative methylation-specific PCR techniques. The sensitivity and specificity of methylation of each individual gene and combinations of these genes to detect biopsy-proven high-grade (moderate or severe) squamous dysplasia was determined. For individual genes, the sensitivities ranged from 9–34% and the specificities ranged from 77–99%. Using a panel of four genes (AHRR, p16INK4a, MT1G, and CLDN3) resulted in sensitivity and specificity of 50% and 68%, respectively. This study suggests that evaluation of gene methylation in EBC samples may have utility for early detection of esophageal squamous dysplasia and early ESCC, however, identification of more sensitive methylation markers will be required for development of a clinically useful screening test.
PMCID: PMC2615136  PMID: 19137073
gene methylation; early detection; cytology; esophageal squamous cell cancer
11.  Calibration of Self-Reported Oral Health to Clinically Determined Standards 
Self-report of oral health is an inexpensive approach to assessing an individual’s oral health status, but it is heavily influenced by personal views and usually differs from that of clinically determined oral health status. To assist researchers and clinicians in estimating oral health self-report, we summarize clinically determined oral health measures that can objectively measure oral health and evaluate the discrepancies between self-reported and clinically determined oral health status. We test hypotheses of trends across covariates, thereby creating optimal calibration models and tools that can adjust self-reported oral health to clinically determined standards.
Using National Health and Nutrition Examination Survey (NHANES) data, we examined the discrepancy between self-reported and clinically determined oral health. We evaluated the relationship between the degree of this discrepancy and possible factors contributing to this discrepancy, such as patient characteristics and general health condition. We used a regression approach to develop calibration models for self-reported oral health.
The relationship between self-reported and clinically determined oral health is complex. Generally, there is a discrepancy between the two that can best be calibrated by a model that includes general health condition, number of times a person has received health care, gender, age, education, and income.
The model we developed can be used to calibrate and adjust self-reported oral health status to that of clinically determined standards and for oral health screening of large populations in federal, state, and local programs, enabling great savings in resources used in dental care.
PMCID: PMC3058231  PMID: 21054482
Oral health; calibration; nomogram; cross validation; bootstrap
12.  Effect of household and village characteristics on financial catastrophe and impoverishment due to health care spending in Western and Central Rural China: A multilevel analysis 
The study aimed to examine the effect of household and community characteristics on financial catastrophe and impoverishment due to health payment in Western and Central Rural China.
A household survey was conducted in 2008 in Hebei and Shaanxi provinces and the Inner Mongolia Autonomous Region using a multi-stage sampling technique. Independent variables included village characteristics, household income, chronic illness status, health care use and health spending. A composite contextual variable, named village deprivation, was derived from socio-economic status and availability of health care facilities in each village using factor analysis. Dependent variables were whether household health payment was more than 40% of household's capacity to pay (catastrophic health payment) and whether household per capita income was put under Chinese national poverty line (1067 Yuan income per year) after health spending (impoverishment). Mixed effects logistic regression was used to assess the effect of the independent variables on the two outcomes.
Households with low per capita income, having elderly, hospitalized or chronically ill members, and whose head was unemployed were more likely to incur financial catastrophe and impoverishment due to health expenditure. Both catastrophic and impoverishing health payments increased with increased village deprivation. However, the presence of a village health clinic had no effect on the two outcomes, nor did household enrollment in the New Rural Cooperative Medical Scheme (national health insurance).
Village deprivation independently increases the risk for financial hardship due to health payment after adjusting for known household-level factors. This suggests that policy makers need to view the individual, household and village as separate units for policy targeting.
PMCID: PMC3080794  PMID: 21466714
13.  Epidemiology of Esophageal Cancer in Japan and China 
Journal of Epidemiology  2013;23(4):233-242.
In preparation for a collaborative multidisciplinary study of the pathogenesis of esophageal cancer, the authors reviewed the published literature to identify similarities and differences between Japan and China in esophageal cancer epidemiology. Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type, while the incidence of esophageal adenocarcinoma remains extremely low in both countries. Numerous epidemiologic studies in both countries show that alcohol consumption and cigarette smoking are contributing risk factors for ESCC. There are differences, however, in many aspects of esophageal cancer between Japan and China, including cancer burden, patterns of incidence and mortality, sex ratio of mortality, risk factor profiles, and genetic variants. Overall incidence and mortality rates are higher in China than in Japan, and variation in mortality and incidence patterns is greater in China than in Japan. During the study period (1987–2000), the decline in age-adjusted mortality rates was more apparent in China than in Japan. Risk factor profiles differed between high- and low-incidence areas within China, but not in Japan. The association of smoking and drinking with ESCC risk appears to be weaker in China than in Japan. Genome-wide association studies in China showed that variants in several chromosome regions conferred increased risk, but only genetic variants in alcohol-metabolizing genes were significantly associated with ESCC risk in Japan. A well-designed multidisciplinary epidemiologic study is needed to examine the role of diet and eating habits in ESCC risk.
PMCID: PMC3709543  PMID: 23629646
esophageal cancer; epidemiology; risk factor
14.  China's Rural Public Health System Performance: A Cross-Sectional Study 
PLoS ONE  2013;8(12):e83822.
In the past three years, the Government of China initiated health reform with rural public health system construction to achieve equal access to public health services for rural residents. The study assessed trends of public health services accessibility in rural China from 2008 to 2010, as well as the current situation about the China's rural public health system performance.
The data were collected from a cross-sectional survey conducted in 2011, which used a multistage stratified random sampling method to select 12 counties and 118 villages from China. Three sets of indicators were chosen to measure the trends in access to coverage, equality and effectiveness of rural public health services. Data were disaggregated by provinces and by participants: hypertension patients, children, elderly and women. We examined the changes in equality across and within region.
China's rural public health system did well in safe drinking water, children vaccinations and women hospital delivery. But more hypertension patients with low income could not receive regular healthcare from primary health institutions than those with middle and high income. In 2010, hypertension treatment rate of Qinghai in Western China was just 53.22% which was much lower than that of Zhejiang in Eastern China (97.27%). Meanwhile, low performance was showed in effectiveness of rural public health services. The rate of effective treatment for controlling their blood pressure within normal range was just 39.7%.
The implementation of health reform since 2009 has led the public health development towards the right direction. Physical access to public health services had increased from 2008 to 2010. But, inter- and intra-regional inequalities in public health system coverage still exist. Strategies to improve the quality and equality of public health services in rural China need to be considered.
PMCID: PMC3873379  PMID: 24386284
15.  The Prevalence of Erosive Esophagitis Is Not Significantly Increased in a Healthy Korean Population - Could It Be Explained?: A Multi-center Prospective Study 
Researches on the potential risk factors for the development of erosive esophagitis have been conducted extensively, however, the results are conflicting. The aim of this multicenter study was to identify the prevalence rate and risk factors of erosive esophagitis and their interactions with residency status.
A total of 4,023 eligible subjects at 8 tertiary health care centers were evaluated using questionnaires, laboratory tests and endoscopy. Univariate and multivariate analyses were conducted to identify independent risk factors for erosive esophagitis.
The prevalence rate of reflux esophagitis was 8.8%. Los Angeles grade A was common type of erosive esophagitis. Residence in a large urban areas was negatively associated with the development of erosive esophagitis (OR, 0.60; 95% CI, 0.40-0.90). The high body mass index (≥ 25 kg/m2) was more frequent in residents of small and medium-sized cities than those in big cities (38.8% and 26.9%, respectively; P < 0.001). Seronegativity of Helicobacter pylori was associated with increased erosive esophagitis (OR, 1.91; 95% CI, 1.48-2.46). Triglyceride ≥ 150 mg/dL (OR, 1.65; 95% CI, 1.08-2.07), fasting glucose level ≥ 126 mg/dL (OR, 1.73; 95% CI, 1.06-2.81), and hiatal hernia (OR, 3.11; 95% CI, 1.87-5.16) were also associated with erosive esophagitis.
The prevalence rate of erosive esophagitis and its risk factors in this study were similar to the result of 8.0% of nationwide study in 2006. Residency and obesity are more important independent risk factors than H. pylori infection status for development of erosive esophagitis in Korea. These results suggest that the prevalence rate of erosive esophagitis in Korea might not increase as in the Western countries.
PMCID: PMC3548130  PMID: 23350050
Esophagitis; Helicobacter pylori; Risk factors
16.  Cytokeratin immunoexpression in esophageal squamous cell carcinoma of high-risk population in Northeast India 
Esophageal cancer is a frequently fatal malignancy, and is described in certain regions in Northeast India with an incidence of esophageal squamous cell carcinoma is many fold higher than the rest of the population. The population in Northeast India is at higher risk due to poor nutritional status, consumption of fermented betel quid and other oral tobacco products besides smoking and alcohol intake. Cytokeratins are the major constituents of the esophageal epithelium and may show gain or loss of cytokeratins as the cancer progresses from normal epithelium to invasive phenotype. In the present study we studied the immunohistochemical expression of five cytokeratins (CK4, CK5, CK8, CK14, and CK17) in the normal esophageal epithelium and esophageal squamous cell carcinoma from both the general population and the high-risk population of Assam in Northeast India. The cytokeratin expression profile was similar to other published data in general. Further analysis demonstrated differences in cytokeratin expression between the general and the high-risk tumor samples. CK5 and CK 8 expression altered in the high-risk population. The significance of these differences is unclear, but suggests a connection to the etiological factors.
PMCID: PMC2836392  PMID: 19417629
Cytokeratins; esophageal cancer; high-risk; immunohistochemistry; squamous cell carcinoma; tissue microarray
17.  Squamous dysplasia – the precursor lesion for esophageal squamous cell carcinoma 
Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all esophageal cancers worldwide, and esophageal squamous dysplasia (ESD) is the only histopathology that predicts the development of ESCC. The prevalence of ESD parallels rates of invasive ESCC, and is typically found in 25% or more of adults above the age of 35 years in populations in north central China, where risk for ESCC is among the highest in the world. Results of chemoprevention and early detection studies to prevent progression of ESD suggest that these approaches, coupled with emerging endoscopic therapies, offer promise for the prevention of esophageal cancer mortality in high-risk populations. Future research on ESD and ESCC should focus on finding additional modifiable risk factors and on identifying biomarkers to incorporate into early detection strategies.
PMCID: PMC3681095  PMID: 23549398
18.  Association of serum levels of lipid and its novel constituents with the different stages of esophageal carcinoma 
The aim of the study was to evaluate the association of immunoglobulin G type of autoantibodies to oxidized low-density lipoprotein (oxLDL-lgG) and oxLDL-lgM with the progression of esophageal squamous cell carcinoma (ESSC).
Residents from Feicheng, China aged 40 to 69 years were screened for esophageal lesions in a screening program conducted during the period of January 2008 to December 2006. There were 33 controls with normal esophageal squamous epithelium cells, 37 patients with basal cell hyperplasia, 47 with esophageal squamous cell dysplasia, and 43 with ESCC. All the participants were diagnosed by biopsy and histopathological examination. Adiponectin, oxidized low-density lipoprotein (oxLDL), autoantibodies against oxLDL (oxLDL-ab), OxLDL-lgG, and OxLDL-lgM were determined by enzyme linked immunosorbent assay (ELISA). Total cholesterol, High-density lipoprotein (HDL), triglyceride, serum albumin, and blood pressure were co-estimated. Analysis of covariance for lipid levels was used to control the influence of covariates.
The level of oxLDL-lgM increased gradually along with esophageal carcinoma progression. The oxLDL-lgM levels in the ESCC group were the highest after possible covariates were controlled. Binary logistic regression showed that oxLDL-lgM had a positive correlation with the development of esophageal carcinoma, while oxLDL and oxLDL-ab had a negative correlation with ESSC. No significant association between the levels of oxLDL-lgG and adiponectin and the different stages of ESSC was observed.
The present study shows that the decreased oxLDL and oxLDL-ab and the elevated oxLDL-lgM serum levels may relate to the development and progression of ESSC.
PMCID: PMC2775732  PMID: 19863824
19.  Preliminary characterization of the oral microbiota of Chinese adults with and without gingivitis 
BMC Oral Health  2011;11:33.
Microbial communities inhabiting human mouth are associated with oral health and disease. Previous studies have indicated the general prevalence of adult gingivitis in China to be high. The aim of this study was to characterize in depth the oral microbiota of Chinese adults with or without gingivitis, by defining the microbial phylogenetic diversity and community-structure using highly paralleled pyrosequencing.
Six non-smoking Chinese, three with and three without gingivitis (age range 21-39 years, 4 females and 2 males) were enrolled in the present cross-sectional study. Gingival parameters of inflammation and bleeding on probing were characterized by a clinician using the Mazza Gingival Index (MGI). Plaque (sampled separately from four different oral sites) and salivary samples were obtained from each subject. Sequences and relative abundance of the bacterial 16 S rDNA PCR-amplicons were determined via pyrosequencing that produced 400 bp-long reads. The sequence data were analyzed via a computational pipeline customized for human oral microbiome analyses. Furthermore, the relative abundances of selected microbial groups were validated using quantitative PCR.
The oral microbiomes from gingivitis and healthy subjects could be distinguished based on the distinct community structures of plaque microbiomes, but not the salivary microbiomes. Contributions of community members to community structure divergence were statistically accessed at the phylum, genus and species-like levels. Eight predominant taxa were found associated with gingivitis: TM7, Leptotrichia, Selenomonas, Streptococcus, Veillonella, Prevotella, Lautropia, and Haemophilus. Furthermore, 98 species-level OTUs were identified to be gingivitis-associated, which provided microbial features of gingivitis at a species resolution. Finally, for the two selected genera Streptococcus and Fusobacterium, Real-Time PCR based quantification of relative bacterial abundance validated the pyrosequencing-based results.
This methods study suggests that oral samples from this patient population of gingivitis can be characterized via plaque microbiome by pyrosequencing the 16 S rDNA genes. Further studies that characterize serial samples from subjects (longitudinal study design) with a larger population size may provide insight into the temporal and ecological features of oral microbial communities in clinically-defined states of gingivitis.
PMCID: PMC3254127  PMID: 22152152
oral microbiota; gingivitis; saliva; plaque; pyrosequencing
20.  Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County 
BMC Gastroenterology  2011;11:74.
The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk.
A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants.
The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus.
The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.
PMCID: PMC3141752  PMID: 21672255
21.  Attributable Causes of Esophageal Cancer Incidence and Mortality in China 
PLoS ONE  2012;7(8):e42281.
To estimate the contribution of tobacco smoking, alcohol drinking, low vegetable intake and low fruit intake to esophageal cancer mortality and incidence in China.
Methodology/Principal Findings
We calculated the proportion of esophageal cancer attributable to four known modifiable risk factors [population attributable fraction (PAF)]. Exposure data was taken from meta-analyses and large-scale national surveys of representative samples of the Chinese population. Data on relative risks were also from meta-analyses and large-scale prospective studies. Esophageal cancer mortality and incidence came from the 3rd national death cause survey and population-based cancer registries in China. We estimated that 87,065 esophageal cancer deaths (men 67,686; women: 19,379) and 108,206 cases (men: 83,968, women: 24,238) were attributable to tobacco smoking, alcohol drinking, low vegetable intake and low fruit intake in China in 2005. About 17.9% of esophageal cancer deaths among men and 1.9% among women were attributable to tobacco smoking. About 15.2% of esophageal cancer deaths in men and 1.3% in women were caused by alcohol drinking. Low vegetable intake was responsible for 4.3% esophageal cancer deaths in men and 4.1% in women. The fraction of esophageal cancer deaths attributable to low fruit intake was 27.1% in men and 28.0% in women. Overall, 46% of esophageal cancers (51% in men and 33% in women) were attributable to these four modifiable risk factors.
Tobacco smoking, alcohol drinking, low vegetable intake and low fruit intake were responsible for 46% of esophageal cancer mortality and incidence in China in 2005. These findings provide useful data for developing guidelines for esophageal cancer prevention and control in China.
PMCID: PMC3410925  PMID: 22876312
22.  Environmental Causes of Esophageal Cancer 
This articles reviews the environmental risk factors and predisposing conditions for the two main histological types of esophageal cancer, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). Tobacco smoking, excessive alcohol consumption, drinking maté, low intake of fresh fruits and vegetables, achalasia, and low socioeconomic status increase the risk of ESCC. Results of investigations on several other potential risk factors, including opium consumption, intake of hot drinks, eating pickled vegetables, poor oral health, and exposure to human papillomavirus, polycyclic aromatic hydrocarbons, N-nitroso compounds, acetaldehyde, and fumonisins are also discussed. Gastroesophageal reflux, obesity, tobacco smoking, hiatal hernia, achalasia, and probably absence of H. pylori in the stomach increase the risk of EA. Results of studies investigating other factors, including low intake of fresh fruits and vegetables, consumption of carbonated soft drink, use of H2 blockers, non-steroidal anti-inflammatory drugs, and drugs that relax the lower esophageal sphincter are also discussed.
PMCID: PMC2685172  PMID: 19327566
esophageal cancer; risk factor
23.  10 years after NHANES I: mortality experience at initial followup, 1982-84. 
Public Health Reports  1986;101(5):474-481.
The NHANES I Epidemiologic Followup Study (NHEFS) was initiated jointly by the National Center for Health Statistics and the National Institute on Aging in collaboration with other National Institutes of Health and Public Health Service agencies. The goal of NHEFS is to examine the relationship of baseline clinical, nutritional, and behavioral factors assessed in the first National Health and Nutrition Examination Survey (NHANES I-1971-75) to subsequent morbidity and mortality. Tracing for the initial followup began in 1981 and ended in 1984. This article compares the mortality experience of the NHEFS cohort with survival probabilities and cause-of-death distributions derived from U.S. vital statistics data. The analysis was done for 28 age-race-sex specific subgroups. The survival of each group of the NHEFS cohort corresponds quite closely to that expected on the basis of the U.S. life table survival probabilities. Mortality differentials by age, race, and sex are also quite similar between NHEFS and U.S. vital statistics. In addition, the cause-of-death distributions among NHEFS participants are quite similar to those expected based on national vital statistics. Thus, there do not seem to be any serious biases in the mortality data. The NHEFS, therefore, provides a unique resource for assessing the effects of baseline sociodemographic, health, and nutritional factors on future mortality in a large, heterogeneous sample that is representative of the nation's population.
PMCID: PMC1477776  PMID: 3094076
24.  Smoking and alcohol drinking increased the risk of esophageal cancer among Chinese men but not women in a high-risk population 
Cancer Causes & Control  2011;22(4):649-657.
Although the association for esophageal cancer with tobacco smoking and alcohol drinking has been well established, the risk appears to be less strong in China. To provide more evidence on the effect of smoking and alcohol consumption with esophageal cancer in China, particularly among Chinese women, a population-based case–control study has been conducted in Jiangsu, China, from 2003 to 2007. A total of 1,520 cases and 3,879 controls were recruited. Unconditional multivariate logistic regression analysis was applied. Results showed that the odds ratio (OR) and confidence interval (CI) for ever smoking and alcohol drinking were 1.57 (95% CI: 1.34–1.83) and 1.50 (95% CI: 1.29–1.74). Dose–response relationships were observed with increased intensity and longer duration of smoking/drinking. Risk of smoking and alcohol drinking at the highest joint level was 7.32 (95% CI: 4.58–11.7), when compared to those never smoked and never drank alcohol. Stratifying by genders, smoking and alcohol drinking increased the risk among men with an OR of 1.74 (95% CI: 1.44–2.09) and 1.76 (95% CI: 1.48–2.09); however, neither smoking nor alcohol consumption showed a significant association among women. In conclusion, smoking and alcohol drinking were associated with esophageal cancer risk among Chinese men, but not among Chinese women.
PMCID: PMC3059761  PMID: 21321789
Esophageal cancer; Smoking; Alcohol; Case–control studies; China
25.  Cost-benefit analysis of esophageal cancer endoscopic screening in high-risk areas of China 
AIM: To estimate the cost-benefit of endoscopic screening strategies of esophageal cancer (EC) in high-risk areas of China.
METHODS: Markov model-based analyses were conducted to compare the net present values (NPVs) and the benefit-cost ratios (BCRs) of 12 EC endoscopic screening strategies. Strategies varied according to the targeted screening age, screening frequencies, and follow-up intervals. Model parameters were collected from population-based studies in China, published literatures, and surveillance data.
RESULTS: Compared with non-screening outcomes, all strategies with hypothetical 100 000 subjects saved life years. Among five dominant strategies determined by the incremental cost-effectiveness analysis, screening once at age 50 years incurred the lowest NPV (international dollar-I$55 million) and BCR (2.52). Screening six times between 40-70 years at a 5-year interval [i.e., six times(40)f-strategy] yielded the highest NPV (I$99 million) and BCR (3.06). Compared with six times(40)f-strategy, screening thrice between 40-70 years at a 10-year interval resulted in relatively lower NPV, but the same BCR.
CONCLUSION: EC endoscopic screening is cost-beneficial in high-risk areas of China. Policy-makers should consider the cost-benefit, population acceptance, and local economic status when choosing suitable screening strategies.
PMCID: PMC3360447  PMID: 22654446
Cost-benefit analysis; Esophageal cancer; Endoscopy; Screening; High-risk area

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