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1.  PAH exposure in esophageal tissue and risk of esophageal squamous cell carcinoma in northeastern Iran 
Gut  2010;59(9):1178-1183.
To evaluate the association of polycyclic aromatic hydrocarbon (PAH) exposure in esophageal epithelial tissue and esophageal squamous cell carcinoma (ESCC) case status in an ESCC case-control study in a high-risk population in northeastern Iran.
Immunohistochemical staining of tissue microarrays (TMAs) of non-tumoral esophageal biopsies from ESCC cases and control subjects. Immunohistochemistry was performed using monoclonal antibodies 8E11 and 5D11, raised against benzo[a]pyrene (B[a]P) diol epoxide (BPDE)-I-modified guanosine and BPDE-I-modified DNA, respectively. Staining intensity was quantified by image analysis, and the average staining in three replicates was calculated.
Rural region in northeastern Iran.
Cases were patients with biopsy-proven ESCC. Controls were GI clinic patients with no endoscopic or biopsy evidence of ESCC.
Main outcome measure
Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between antibody staining intensity and ESCC case status.
Cultured ESCC cells exposed to B[a]P in vitro showed dose-dependent staining with 8E11, but not with 5D11. With 8E11, sufficient epithelial tissue was available in the TMA cores to analyze 91 cases and 103 controls. Compared to the lowest quintile of 8E11 staining in the controls, adjusted ORs (95% CIs) for the 2nd to 5th quintiles were 2.42, 5.77, 11.3, and 26.6 (5.21–135), respectively (P for trend < 0.001). With 5D11, 89 cases and 101 controls were analyzed. No association between staining and case status was observed (ORs (95% CIs) for the 2nd to 5th quintiles were 1.26, 0.88, 1.06, and 1.63 (0.63–4.21), P for trend = 0.40).
Dramatically higher levels of 8E11 staining were observed in non-tumoral esophageal epithelium from ESCC patients than from control subjects. This finding strengthens the evidence for a causal role for PAHs in esophageal carcinogenesis in northeastern Iran.
PMCID: PMC3505022  PMID: 20584779
esophageal squamous cell carcinoma; polycyclic aromatic hydrocarbons; immunohistochemistry; tissue microarray
2.  Mortality and cancer in relation to ABO blood group phenotypes in the Golestan Cohort Study 
BMC Medicine  2015;13:8.
A few studies have shown an association between blood group alleles and vascular disease, including atherosclerosis, which is thought to be due to the higher level of von Willebrand factor in these individuals and the association of blood group locus variants with plasma lipid levels. No large population-based study has explored this association with overall and cause-specific mortality.
We aimed to study the association between ABO blood groups and overall and cause-specific mortality in the Golestan Cohort Study. In this cohort, 50,045 people 40- to 70-years old were recruited between 2004 and 2008, and followed annually to capture all incident cancers and deaths due to any cause. We used Cox regression models adjusted for age, sex, smoking, socioeconomic status, ethnicity, place of residence, education and opium use.
During a total of 346,708 person-years of follow-up (mean duration 6.9 years), 3,623 cohort participants died. Non-O blood groups were associated with significantly increased total mortality (hazard ratio (HR) = 1.09; 95% confidence interval (CI): 1.01 to 1.17) and cardiovascular disease mortality (HR = 1.15; 95% CI: 1.03 to 1.27). Blood group was not significantly associated with overall cancer mortality, but people with group A, group B, and all non-O blood groups combined had increased risk of incident gastric cancer. In a subgroup of cohort participants, we also showed higher plasma total cholesterol and low-density lipoprotein (LDL) in those with blood group A.
Non-O blood groups have an increased mortality, particularly due to cardiovascular diseases, which may be due to the effect of blood group alleles on blood biochemistry or their effect on von Willebrand factor and factor VIII levels.
Please see related commentary 10.1186/s12916-014-0250-y.
PMCID: PMC4295491  PMID: 25592833
Blood group; ABO; Rh; Mortality; Cancer; Cardiovascular disease
3.  Reproductive factors and risk of esophageal squamous cell carcinoma in northern Iran- A case-control study in a high risk area and literature review 
Several epidemiologic studies have suggested an inverse association between female reproductive factors and risk of esophageal squamous cell carcinoma (ESCC), but the evidence is not conclusive. We investigated the association of the number of pregnancies, live-births, and miscarriages/stillbirths in women and the association of the number of children in both sexes with ESCC risk in Golestan Province, a high-risk area in Iran.
Data from 297 histopathologically confirmed ESCC cases (149 women) and 568 controls (290 women) individually matched to cases for age, sex, and neighborhood of residence were included in this analysis. Conditional logistic regression was used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs).
The average numbers of live-births and miscarriages/stillbirths among controls were 8.2 and 0.8, respectively. Women with 6 or more live-births were at approximately one-third the risk of ESCC as those with 0–3 live-births; the OR (95% CI) for having 6–7 live-births was 0.33 (0.12–0.92). In contrast, the number of miscarriages/stillbirths was associated with an increase in ESCC risk. The OR (95% CI) for ≥ 3 versus no miscarriages/stillbirths was 4.43 (2.11–9.33). The number of children in women was suggestive an inverse association with ESCC, but this association was not statistically significant; in men, no association was seen.
The findings of this study support a protective influence of female hormonal factors on ESCC risk. However, further epidemiological and mechanistic studies are needed to prove a protective association.
PMCID: PMC3731403  PMID: 23238586
case-control study; esophageal cancer; miscarriage; parity; reproductive; squamous cell carcinoma
4.  Opium; an emerging risk factor for gastric adenocarcinoma 
Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products, and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9 – 5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95%CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance.
PMCID: PMC3644384  PMID: 23319416
Opium; Adenocarcinoma; Cardia
5.  Variation in PAH-related DNA adduct levels among non-smokers: the role of multiple genetic polymorphisms and nucleotide excision repair phenotype 
Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly-selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in 8 DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by 32P-postlabelling. Multivariable regression models were compared by Akaike’s information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 108 nucleotides (mean: 5.8±3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r=0.4, p<0.001). Compared with the environmental model, adding phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA adduct levels 3-4 times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of phase I genes and NER capacity.
PMCID: PMC3597757  PMID: 23175176
Polycyclic aromatic hydrocarbons; DNA adducts; nucleotide excision repair; polymorphism
6.  Association of tooth loss and oral hygiene with risk of gastric adenocarcinoma 
Poor oral health and tooth loss have been proposed as possible risk factors for some chronic diseases, including gastric cancer. However only a small number of studies have tested these associations.
We conducted a case-control study in Golestan Province, Iran, that enrolled 309 cases diagnosed with gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-locations) and 613 sex, age and neighborhood matched controls. Data on oral health were obtained through physical examination and questionnaire including tooth loss, the number of decayed, missing, and filled teeth, and frequency of tooth brushing. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models adjusted for potential confounders. Standard one degree-of-freedom linear trend test and a multiple degree of freedom global test of the effect of adding oral hygiene variables to the model were also calculated.
Our results showed apparent associations between tooth loss and DMFT score with risk of gastric cancer, overall and at each anatomic subsite. However, these associations were not monotonic and were strongly confounded by age. The results also showed that subjects who brushed their teeth less than daily were at significantly higher risk for gastric cardia adenocarcinoma OR (95% CI) of 5.6 (1.6–19.3).
We found evidence for an association between oral health and gastric cancer, but the non- monotonic association, the relatively strong effect of confounder adjustment, and inconsistent results across studies must temper the strength of any conclusions.
PMCID: PMC3644330  PMID: 23503651
Adenocarcinoma; Tooth loss; Oral health; Stomach
7.  Gastroesophageal Reflux Disease and overall and Cause-specific Mortality: A Prospective Study of 50000 Individuals 
Only a few studies in Western countries have investigated the association between gastroesophageal reflux disease (GERD) and mortality at the general population level and they have shown mixed results. This study investigated the association between GERD symptoms and overall and cause-specific mortality in a large prospective population-based study in Golestan Province, Iran.
Baseline data on frequency, onset time, and patient-perceived severity of GERD symptoms were available for 50001 participants in the Golestan Cohort Study (GCS). We identified 3107 deaths (including 1146 circulatory and 470 cancer-related) with an average follow-up of 6.4 years and calculated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for multiple potential confounders.
Severe daily symptoms (defined as symptoms interfering with daily work or causing nighttime awakenings on a daily bases, reported by 4.3% of participants) were associated with cancer mortality (HR 1.48, 95% CI: 1.04-2.05). This increase was too small to noticeably affect overall mortality. Mortality was not associated with onset time or frequency of GERD and was not increased with mild to moderate symptoms.
We have observed an association with GERD and increased cancer mortality in a small group of individuals that had severe symptoms. Most patients with mild to moderate GERD can be re-assured that their symptoms are not associated with increased mortality.
PMCID: PMC4034667  PMID: 24872865
Cardiovascular disease; Esophageal cancer; Gastroesophageal reflux disease; Mortality
8.  A U-shaped relationship between haematocrit and mortality in a large prospective cohort study 
Background Only a limited number of studies have investigated the correlation between haematocrit (HCT) and mortality in the general population, and few of those studies have had data on a wide range of low and high levels of HCT. We investigated the association between baseline HCT and mortality in a prospective cohort study of 49 983 adult subjects in Iran with a broad spectrum of HCT values.
Methods Data on socio-demographic and life-style factors, past medical history, and levels of HCT were collected at enrollment. During a mean follow-up of 5 years (follow-up success rate ∼99%), 2262 deaths were reported. Cox proportional hazards regression models were used to estimate hazard ratios and corresponding 95% confidence intervals.
Results There was a U-shaped relationship between categories of HCT and mortality in both sexes: both low and high levels of HCT were associated with increased overall mortality and mortality from cardiovascular disease. The U-shaped relationship persisted after several sensitivity analyses were done, including analyses restricted to non-smokers and non-users of opium; analyses excluding deaths from accidents and other external causes as well as deaths of persons with self-reported ischemic heart disease at the baseline interview for the study; and analyses excluding the first 2 years of follow-up. Self-reported past medical history and lack of data about lipids and other cellular blood components were the major limitations of the study.
Conclusions Low and high levels of HCT are associated with increased mortality in the general population. The findings in the present study can be of particular importance for low- and middle-income countries in which a substantial proportion of the population lives with suboptimal levels of HCT.
PMCID: PMC3619954  PMID: 23569195
Anaemia; cancer; cardiovascular disease; erythrocytosis; haematocrit; mortality
9.  Determinants of Gastroesophageal Reflux Disease, Including Hookah Smoking and Opium Use– A Cross-Sectional Analysis of 50,000 Individuals 
PLoS ONE  2014;9(2):e89256.
Gastroesophageal reflux disease (GERD) is a common cause of discomfort and morbidity worldwide. However, information on determinants of GERD from large-scale studies in low- to medium-income countries is limited. We investigated the factors associated with different measures of GERD symptoms, including frequency, patient-perceived severity, and onset time.
We performed a cross-sectional analysis of the baseline data from a population-based cohort study of ∼50,000 individuals in in Golestan Province, Iran. GERD symptoms in this study included regurgitation and/or heartburn.
Approximately 20% of participants reported at least weekly symptoms. Daily symptoms were less commonly reported by men, those of Turkmen ethnicity, and nass chewers. On the other hand, age, body mass index, alcohol drinking, cigarette smoking, opium use, lower socioeconomic status, and lower physical activity were associated with daily symptoms. Most of these factors showed similar associations with severe symptoms. Women with higher BMI and waist to hip ratio were more likely to report frequent and severe GERD symptoms. Hookah smoking (OR 1.34, 95% CI 1.02–1.75) and opium use (OR 1.70, 95% CI 1.55–1.87) were associated with severe symptoms, whereas nass chewing had an inverse association (OR 0.87, 95% CI 0.76–0.99). After exclusion of cigarette smokers, hookah smoking was still positively associated and nass chewing was inversely associated with GERD symptoms (all frequencies combined).
GERD is common in this population. The associations of hookah and opium use and inverse association of nass use with GERD symptoms are reported for the first time. Further studies are required to investigate the nature of these associations. Other determinants of GERD were mostly comparable to those reported elsewhere.
PMCID: PMC3931722  PMID: 24586635
10.  Smoking water-pipe, chewing nass, and prevalence of heart disease – A cross-sectional analysis of baseline data from the Golestan Cohort Study, Iran 
Heart (British Cardiac Society)  2012;99(4):272-278.
Water-pipe and smokeless tobacco use have been associated with several adverse health outcomes. However, little information is available on the association between water-pipe use and heart disease (HD). Therefore, we investigated the association of smoking water-pipe and chewing nass (a mixture of tobacco, lime, and ash) with prevalent HD.
Cross-sectional study.
Baseline data (collected in 2004–2008) from a prospective population-based study in Golestan Province, Iran.
50,045 residents of Golestan (40–75 years old; 42.4% male).
Main outcome measures
ORs and 95% CIs from multivariate logistic regression models for the association of water-pipe and nass use with HD prevalence.
A total of 3051 (6.1%) participants reported a history of HD, and 525 (1.1%) and 3726 (7.5%) reported ever water-pipe or nass use, respectively. Heavy water-pipe smoking was significantly associated with HD prevalence (highest level of cumulative use versus never use, OR= 3.75; 95% CI 1.52 – 9.22; P for trend= 0.04). This association persisted when using different cutoff points, when restricting HD to those taking nitrate compound medications, and among never cigarette smokers. There was no significant association between nass use and HD prevalence (highest category of use versus never use, OR= 0.91; 95% CI 0.69 – 1.20).
Our study suggests a significant association between HD and heavy water-pipe smoking. Although the existing evidence suggesting similar biological consequences of water-pipe and cigarette smoking make this association plausible, results of our study were based on a modest number of water-pipe users and need to be replicated in further studies.
PMCID: PMC3671096  PMID: 23257174
hookah; ischemic heart disease; nass; tobacco; water-pipe
11.  The gastro-esophageal malignancies in Northern Iran research project: impact on the health research and health care systems in Iran 
Archives of Iranian medicine  2013;16(1):46-53.
Since 2000, considerable progress has been made in health research in Iran. An example of this progress has been the Gastro- Esophageal Malignancies in Northern Iran (GEMINI). The original aim of this project was to identify etiologic factors and prevention measures for upper gastrointestinal cancers in Northern provinces of Iran, but its achievements have gone much beyond the initial goal. This project is one of the largest studies in the Middle East and North African region, has helped build and strengthen research capacity at both individual and institutional levels in Iran, and has provided international credibility to research institutes and the wider research system in Iran. The success of GEMINI reveals the feasibility of large-scale studies in developing countries and serves as a successful model not only for health research institutes within Iran, but also for research systems in other developing countries. The outcomes of the project are numerous, including establishment of research networks, development of efficient methods for planning and implementation of research projects, and introduction of methodologies for project management, data management and usage of health technology. Finally and perhaps most importantly, GEMINI is among the few projects that has had a significant impact on the attitudes and concerns of decision makers in the health sector in Iran. It signifies the importance of investment in human resources and has proved that health policies should be health-based rather than patient-based. Here we review the impact of GEMINI on the health research system and the broader health care system of Iran and put these into a more global perspective.
PMCID: PMC3659328  PMID: 23273237
research design; prospective studies; pilot projects; feasibility studies; planning techniques; methods; cancer epidemiology; gastroenterology
12.  InterSCOPE Study: Associations Between Esophageal Squamous Cell Carcinoma and Human Papillomavirus Serological Markers 
The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case–control studies conducted in regions with differing background risks of esophageal cancer.
We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case–control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided.
We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036).
We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers.
PMCID: PMC3260131  PMID: 22228147
13.  Predicting esophageal squamous cell carcinoma and squamous dysplasia: risk modeling in a high risk area in Iran 
Archives of Iranian Medicine  2012;15(1):18-21.
Identifying people at higher risk of having squamous dysplasia, the precursor lesion for esophageal squamous cell carcinoma (ESCC), would allow targeted endoscopic screening.
We used multivariate logistic regression models to predict ESCC and dysplasia as outcomes. The ESCC model was based on data from the Golestan Case-Control Study (total n=871; cases=300), and the dysplasia model was based on data from a cohort of subjects from a GI clinic in Northeast Iran (total n=724; cases=26). In each of these analyses, we fit a model including all risk factors known in this region to be associated with ESCC. Individual risks were calculated using the linear combination of estimated regression coefficients and individual-specific values for covariates. We used cross-validation to determine the area under the curve (AUC) and to find the optimal cut points for each of the models.
The model had an area under the curve of 0.77 (95% CI: 0.74–0.80) to predict ESCC with 74% sensitivity and 70.4% specificity for the optimum cut point. The area under the curve was 0.71 (95% CI: 0.64–0.79) for dysplasia diagnosis, and the classification table optimized at 61.5% sensitivity and 69.5% specificity. In this population, the positive and negative predictive values for diagnosis of dysplasia were 6.8% and 97.8%, respectively.
Our models were able to discriminate between ESCC cases and controls in about 77%, and between individuals with and without squamous dysplasia in about 70% of the cases. Using risk factors to predict individual risk of ESCC or squamous dysplasia still has limited application in clinical practice, but such models may be suitable for selecting high risk individuals in research studies, or increasing the pretest probability for other screening strategies.
PMCID: PMC3294378  PMID: 22208438
14.  Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies 
PLoS ONE  2012;7(3):e32711.
Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC).
Methodology/Principal Findings
We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17–2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63–1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure.
Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies.
PMCID: PMC3291619  PMID: 22396792
15.  Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study 
Objective To investigate the association between tea drinking habits in Golestan province, northern Iran, and risk of oesophageal squamous cell carcinoma.
Design Population based case-control study. In addition, patterns of tea drinking and temperature at which tea was drunk were measured among healthy participants in a cohort study.
Setting Golestan province, northern Iran, an area with a high incidence of oesophageal squamous cell carcinoma.
Participants 300 histologically proved cases of oesophageal squamous cell carcinoma and 571 matched neighbourhood controls in the case-control study and 48 582 participants in the cohort study.
Main outcome measure Odds ratio of oesophageal squamous cell carcinoma associated with drinking hot tea.
Results Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume consumed of over one litre a day. 39.0% of participants drank their tea at temperatures less than 60°C, 38.9% at 60-64°C, and 22.0% at 65°C or higher. A moderate agreement was found between reported tea drinking temperature and actual temperature measurements (weighted κ 0.49). The results of the case-control study showed that compared with drinking lukewarm or warm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.9) was associated with an increased risk of oesophageal cancer. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea 2-3 minutes after pouring (2.49, 1.62 to 3.83) or less than two minutes after pouring (5.41, 2.63 to 11.1) was associated with a significantly increased risk. A strong agreement was found between responses to the questions on temperature at which tea was drunk and interval from tea being poured to being drunk (weighted κ 0.68).
Conclusion Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer.
PMCID: PMC3269898  PMID: 19325180
16.  Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran 
PLoS ONE  2011;6(12):e29488.
Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC.
Methodology/Principal Findings
Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 “hotspots” but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence.
ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.
PMCID: PMC3246475  PMID: 22216294
17.  Accuracy and Cut-Off Values of Pepsinogens I, II and Gastrin 17 for Diagnosis of Gastric Fundic Atrophy: Influence of Gastritis 
PLoS ONE  2011;6(10):e26957.
To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study.
We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology.
309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 µg/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 µg/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6–97.9) and its specificity decreased to 88.8% (95%CI 80.8–94.3).
Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis.
PMCID: PMC3204997  PMID: 22066020
18.  Diabetes Mellitus and Its Correlates in an Iranian Adult Population 
PLoS ONE  2011;6(10):e26725.
The rising epidemic of diabetes imposes a substantial economic burden on the Middle East. Using baseline data from a population based cohort study, we aimed to identify the correlates of diabetes mellitus (DM) in a mainly rural population from Iran. Between 2004 and 2007, 50044 adults between 30 and 87 years old from Golestan Province located in Northeast Iran were enrolled in the Golestan Cohort Study. Demographic and health-related information was collected using questionnaires. Individuals' body sizes at ages 15 and 30 were assessed by validated pictograms ranging from 1 (very lean) to 7 in men and 9 in women. DM diagnosis was based on the self-report of a physician's diagnosis. The accuracy of self-reported DM was evaluated in a subcohort of 3811 individuals using fasting plasma glucose level and medical records. Poisson regression with robust variance estimator was used to estimate prevalence ratios (PR's). The prevalence of self-reported DM standardized to the national and world population was 5.7% and 6.2%, respectively. Self-reported DM had 61.5% sensitivity and 97.6% specificity. Socioeconomic status was inversely associated with DM prevalence. Green tea and opium consumption increased the prevalence of DM. Obesity at all ages and extreme leanness in childhood increased diabetes prevalence. Being obese throughout life doubled DM prevalence in women (PR: 2.1; 95% CI: 1.8, 2.4). These findings emphasize the importance of improving DM awareness, improving general living conditions, and early lifestyle modifications in diabetes prevention.
PMCID: PMC3203882  PMID: 22053206
19.  Cavernous hemangioma of the liver: factors affecting disease progression in general hepatology practice 
Although for asymptomatic hepatic hemangiomas, conservative management is generally recommended, factors affecting disease course are still not very well understood.
To determine disease characteristics of cavernous hemangioma and factors affecting its progression in patients from a general hepatology clinic in Tehran, Iran.
We reviewed medical records of 198 patients with cavernous hemangioma of the liver visiting a large private hepatology clinic in Tehran from 1997 to 2007. Of a total of 198 cases, 129 could be followed up for a period of 3.2±2.5 years, and 80 of these had 1 to 5 repeat sonographies.
Patients were between 27 and 84 years old (mean age 44.3±10.9), and 131 (66.2%) were female. Thirty-six patients (18.2%) had giant hemangiomas. Abdominal pain was the primary reason for evaluation in 100 (50.5%) patients. Abdominal pain at the beginning of follow-up was significantly associated with having irritable bowel syndrome (OR=8.3; 95%CI: 3.1-28.7) or other GI diseases (OR=3.9; 95%CI: 2.6-10.2), but not with hemangioma size, number or location. During follow-up, having a single giant lesion at the time of diagnosis, adjusted for age, sex and presence of IBS, was a strong predictor of persistent pain during follow-up (OR=11.1; 95%CI: 3.2-38.6). In repeat sonographies, 35% showed increased size, which was significantly associated only with having a single lesion (p=0.04).
Many symptoms in hepatic hemangioma are attributable to accompanying GI diseases. Patients with a single giant lesion are more likely to have persistent pain, and single lesions are more likely to grow in size.
PMCID: PMC3076672  PMID: 21383624
liver; hemangioma; ultrasonography
21.  Socio-economic status and oesophageal cancer: results from a population-based case–control study in a high-risk area 
Background Cancer registries in the 1970s showed that parts of Golestan Province in Iran had the highest rate of oesophageal squamous cell carcinoma (OSCC) in the world. More recent studies have shown that while rates are still high, they are approximately half of what they were before, which might be attributable to improved socio-economic status (SES) and living conditions in this area. We examined a wide range of SES indicators to investigate the association between different SES components and risk of OSCC in the region.
Methods Data were obtained from a population-based case–control study conducted between 2003 and 2007 with 300 histologically proven OSCC cases and 571 matched neighbourhood controls. We used conditional logistic regression to compare cases and controls for individual SES indicators, for a composite wealth score constructed using multiple correspondence analysis, and for factors obtained from factors analysis.
Results We found that various dimensions of SES, such as education, wealth and being married were all inversely related to OSCC. The strongest inverse association was found with education. Compared with no education, the adjusted odds ratios (95% confidence intervals) for primary education and high school or beyond were 0.52 (0.27–0.98) and 0.20 (0.06–0.65), respectively.
Conclusions The strong association of SES with OSCC after adjustment for known risk factors implies the presence of yet unidentified risk factors that are correlated with our SES measures; identification of these factors could be the target of future studies. Our results also emphasize the importance of using multiple SES measures in epidemiological studies.
PMCID: PMC2720396  PMID: 19416955
Oesophageal cancer; socio-economic status; case–control; epidemiology; Iran; factor analysis; correspondence analysis
22.  Verbal Autopsy: Reliability and Validity Estimates for Causes of Death in the Golestan Cohort Study in Iran 
PLoS ONE  2010;5(6):e11183.
Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medical records. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran.
A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists (“reviewers”) independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard.
VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa>0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95%CI: 0.78–0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95%CI: 0.85–0.99).
VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country.
PMCID: PMC2887437  PMID: 20567597
23.  Patterns of food and nutrient consumption in northern Iran, a high-risk area for esophageal cancer 
Nutrition and cancer  2009;61(4):475-483.
To investigate patterns of food and nutrient consumption in Golestan province, a high-incidence area for esophageal cancer (EC) in northern Iran.
Twelve 24-hour dietary recalls were administered during a one year period to 131 healthy participants in a pilot cohort study. We compare here nutrient intake in Golestan with Recommended Daily Allowances (RDAs) and Lowest Threshold Intakes (LTIs). We also compare the intake of 27 food groups and nutrients among several population subgroups, using mean values from the twelve recalls.
Rural women had a very low level of vitamin intake, which was even lower than LTIs (P < 0.01). Daily intake of vitamins A and C was lower than LTI in 67% and 73% of rural women, respectively. Among rural men, the vitamin intakes were not significantly different from LTIs. Among urban women, the vitamin intakes were significantly lower than RDAs, but were significantly higher than LTIs. Among urban men, the intakes were not significantly different from RDAs. Compared to urban dwellers, intake of most food groups and nutrients, including vitamins, was significantly lower among rural dwellers. In terms of vitamin intake, no significant difference was observed between Turkmen and non-Turkmen ethnics.
The severe deficiency in vitamin intake among women and rural dwellers and marked differences in nutrient intake between rural and urban dwellers may contribute to the observed epidemiological pattern of EC in Golestan, with high incidence rates among women and people with low socioeconomic status, and the highest incidence rate among rural women.
PMCID: PMC2796961  PMID: 19838919
esophageal cancer; Iran; Caspian Littoral; Golestan: Turkmen; diet record
24.  Tooth loss and lack of regular oral hygiene are associated with higher risk of esophageal squamous cell carcinoma 
We tested the association between tooth loss and oral hygiene and the risk of esophageal squamous cell carcinoma (ESCC) in people living in a high risk area of Iran. We used a case-control study of pathologically-confirmed ESCC cases (N=283) and controls (N=560) matched on sex, age, and neighborhood. Subjects with ESCC had significantly more decayed, missing, or filled teeth with a median (interquartile range) of 31 (23-32) compared to controls 28 (2-32) (P=0.0045). And subjects with ESCC were significantly more likely than controls to fail to practice regular oral hygiene, 78% versus 58%. In multivariate adjusted conditional logistic regression models having 32 decayed, missing, or filled teeth compared to ≤15 conferred an OR (95% CI) of 2.10 (1.19-3.70). Compared to daily tooth brushing, practicing no regular oral hygiene conferred an OR (95% CI) of 2.37 (1.42-3.97). Restricting the analysis to subjects that had never smoked tobacco did not materially alter these results. We found significant associations between two markers of poor oral hygiene, a larger number of decayed, missing, or filled teeth and lack of daily tooth brushing, and risk of ESCC in a population at high risk for ESCC where many cases occur in never smokers. Our results are consistent with several previous analyses in other high risk populations.
PMCID: PMC2586052  PMID: 18990747
Tooth loss; tooth brushing; esophagus; squamous; cancer
25.  Opium use and mortality in Golestan Cohort Study: prospective cohort study of 50 000 adults in Iran 
Objectives To investigate the association between opium use and subsequent risk of death.
Design Prospective cohort study.
Setting The Golestan Cohort Study in north-eastern Iran collected detailed validated data on opium use and other exposures at baseline. Participants were enrolled between January 2004 and June 2008 and were followed to May 2011, with a follow-up success rate of over 99%.
Participants 50 045 participants aged 40-75 at baseline.
Main outcomes Mortality, all cause and major subcategories.
Results 17% (n=8487) of the participants reported opium use, with a mean duration of 12.7 years. During the follow-up period 2145 deaths were reported. The adjusted hazard ratio for all cause mortality associated with ever use of opium was 1.86 (95% confidence interval 1.68 to 2.06). Opium consumption was significantly associated with increased risks of deaths from several causes including circulatory diseases (hazard ratio 1.81) and cancer (1.61). The strongest associations were seen with deaths from asthma, tuberculosis, and chronic obstructive pulmonary disease (11.0, 6.22, and 5.44, respectively). After exclusion of people who self prescribed opium after the onset of major chronic illnesses, the associations remained strong with a dose-response relation.
Conclusion Opium users have an increased risk of death from multiple causes compared with non-users. Increased risks were also seen in people who used low amounts of opium for a long period and those who had no major illness before use.
PMCID: PMC3328545  PMID: 22511302

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