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1.  Adenoma detection rates in an opportunistic screening colonoscopy program in Iran, a country with rising colorectal cancer incidence 
BMC Gastroenterology  2014;14(1):196.
Data on the quality of colonoscopies in populations with rising colorectal cancer (CRC) incidence is scarce. We aimed to calculate the adenoma detection rates (ADR), and assess the quality of colonoscopies in an opportunistic screening colonoscopy program in Iran.
All the colonoscopy and pathology reports of asymptomatic adults over age 50 who underwent screening colonoscopy between June 2007 and March 2013 were reviewed. The colonoscopy quality indicators including ADR were calculated, and patient factors associated with the adenoma detection were determined.
A total of 713 asymptomatic adults aged 50 years and older who underwent their first-time screening colonoscopy were included in this study. ADR and advanced-ADR were 33.00% (95% CI: 29.52-36.54) and 13.18% (95% CI: 10.79-15.90), respectively. We observed a significantly higher rate of cecal intubation in patients with fair or better bowel preparation compared to those with poor prep, 90.00% vs. 70.45%, respectively (P < 0.001). Bowel preparation (adjusted OR: 2.49, 95% CI: 1.75-3.55), older age (≥60) (adjusted OR: 1.70, 95% CI: 1.22-2.36), and male gender (adjusted OR: 1.39, 95% CI: 1.01-1.92) were associated with the adenoma detection.
Our ADR in both genders meets and exceeds the recommended colonoscopy quality benchmarks. The polyp and adenoma detection rates in the current study are comparable to those reported from Western countries where the incidence of CRC is traditionally high. These data are in line with the epidemiologic transition of CRC in Iran.
PMCID: PMC4245784  PMID: 25404264
Screening colonoscopy; Colonic polyps; Colon cancers
2.  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
3.  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
4.  Characteristics of Colorectal Polyps and Cancer; a Retrospective Review of Colonoscopy Data in Iran 
Early diagnosis and endoscopic resection of adenomatous polyps is the main approach for screening and prevention of colorectal cancer (CRC). We aimed to assess polyp detection rate (PDR) and to characterize demographic, clinical, and pathological features of colorectal polyps in an Iranian population.
We retrospectively analyzed the data from 5427 colonoscopies performed during 2007-2012 at Masoud Clinic, the main endoscopy center associated with Sasan Alborz Biomedical Research Center, in Tehran, Iran.
Our sample included 2928 (54%) women and 2499 (46%) men, with the mean age of 48.3 years (SD=16.1). The most common reasons for colonoscopy included screening in 25.0%, and gastrointestinal bleeding in 15.2%. Cecal intubation was successful in 86% of patients. The quality of bowel preparation was fair to excellent in 78.1% (n=4235) of colonoscopies. Overall PDR was 42.0% (95% CI: 40.6-43.3). The PDR in men (51.1%, 95% CI: 49.1-53.1) was significantly higher than women (34.2%, 95% CI: 32.4-35.9, p<0.001). Polyps were more frequently observed in patients after the 6th decade of life (F=3.2; p=0.004). CRC was detected in 2.9% (73/2499) of men and 1.9% (57/2928) of women (p=0.02). The mean age for patients with cancer was significantly higher than that for individuals with polyps, 60.9 (SD=13.4) year vs. 56.9 (SD=13.7) year, respectively (p=0.001). Almost 82.8% of the lesions were precancerous with tubular type predominance (62.3%) followed by tubulo-villous (10.3%), villous (6.6%), and serrated (3.6%). Hyperplastic/inflammatory polyps comprised 17.2% of lesions.
Distal colon was more prone to develop polyps and cancer than proximal colon in our series. These findings provide a great infrastructure for next preventive programs and have implications for colorectal cancer screening at population-level.
PMCID: PMC4119671  PMID: 25093062
Colon Cancer; Colonoscopy; Colonic Polyps
5.  LRP6 Enhances Glucose Metabolism by Promoting TCF7L2-dependent Insulin Receptor Expression and IGF Receptor stabilization in Humans 
Cell metabolism  2013;17(2):197-209.
Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are not well understood. A rare nonconservative mutation in Wnt-coreceptor LRP6 (LRP6R611C) has shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscles and skin fibroblasts of healthy non-diabetic LRP6R611C mutation carriers. LRP6 mutation carriers exhibited hyperinsulinemia and reduced insulin sensitivity compared to the non-carrier relatives in response to oral glucose ingestion, which correlated with a significant decline in tissue expression of the insulin receptor (IR) and insulin signaling activity. Further investigations showed that LRP6R611C mutation diminishes TCF7L2-dependent transcription of IR while it increases the stability of IGFR and enhances mTORC1 activity. These findings identify Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance.
PMCID: PMC3589523  PMID: 23395167
6.  Clinical Feature of Intrahepatic B-Lymphocytes in Chronic Hepatitis B 
Humoral immunity constitutes major defense mechanism against viral infections. However, the association of hepatic injury and B-cells population in chronic hepatitis B virus (HBV) carriers has not been studied well. In this study, fifty seven hepatitis B surface antigen (HBsAg) positive and HBeAg negative patients were studied to determine the expression of CD20, a cell surface marker expressed on B-cells, in liver biopsy sections using immunohistochemistry. The patients' clinical data at the time of liver biopsy were acquired from their medical records. There was a significant association between log HBV DNA and both ALT (r = 0.36, P = 0.006) and histologic activity index (HAI) total score (r = 0.3, P = 0.02), respectively. The CD20 was expressed in all 57 liver biopsy samples with a submembranous and membranous staining pattern and its expression was significantly associated with HAI total score (r = 0.32, P = 0.01) and stage of fibrosis (r = 0.31, P = 0.02). The susceptible B lymphocytes to hepatitis B virus might be implicated in the development of immune mediated inflammation of HBV-induced hepatic injury. The present data also support that the liver is potentially one of the secondary lymphoid organs.
PMCID: PMC3918850  PMID: 24579055
7.  Correlation between Cigarette Smoking and Urine Cotinine Level in Gastric Cancer Patients 
Various substances in cigarette smoke including nicotine have been shown to promote/induce cancer cell proliferation. Since cotinine has a longer half life and stability in the blood, it has become the preferred biomarker for cigarette smoking exposure.
Seventy-three gastric cancer patients were included in this study. The tumor tissues were stained with H & E for pathological evaluation. The cotinine levels were measured in urine using a competitive ELISA. Tumors were 90% adenocarcinoma with 63% intestinal and 37% diffuse subtypes. Tumors were poorly (45.2%) or moderately differentiated (41.1%) and localized mainly (77%) in the upper part of stomach. The levels of cotinine were significantly different between smoker (283.83 ± 178.10 ng/mL) and non-smoker (39.28 ± 113.34 ng/mL) groups (p < 0.001). However, there is no-significant correlation between tumor characteristics and cotinine level in smoker patients.
Cotinine level correlates with smoking in gastric patients, however, correlation with the tumor features has not been observed.
PMCID: PMC3985260  PMID: 24734086
Gastric cancer; Cigarette; Smoking; Cotinine; Urine
8.  Serum Ghrelin; A New Surrogate Marker of Gastric Mucosal Alterations in Upper Gastrointestinal Carcinogenesis 
PLoS ONE  2013;8(9):e74440.
A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting.
In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared.
Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70–44.59) for cardia and 6.58 (1.26–34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36–23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10–0.64)].
Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.
PMCID: PMC3787044  PMID: 24098650
9.  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
10.  Clinical Features and Long Term Outcome of 102 Treated Autoimmune Hepatitis Patients 
Hepatitis Monthly  2012;12(2):92-99.
There is limited data on the natural history of autoimmune hepatitis (AIH) and on the long-term follow-up of AIH patients who have been referred for regular medical attention.
We evaluated the clinical presentation and natural history of AIH in a large cohort of type I AIH patients from Iran.
Patients and Methods
Between 1997 and 2008, 102 patients were enrolled in the study. Patients were diagnosed using the International Autoimmune Hepatitis Group criteria and were followed up for an average of 60 months. Clinical and biochemical data were gathered from all the patients at both the beginning and the end of the follow-up period. Liver biopsy was performed in all patients before treatment, and the biopsies were performed in 28 patients after treatment.
Biochemical remission was achieved by 80 (79.4%) patients. Of these, 53 (66.5%) showed near-normal liver histology or liver function test results and sonogram. The remaining 27 (33.5%) patients also achieved clinical and biochemical remission, but developed compensated cirrhosis. After a period of remission, 24 patients (32.5%) relapsed. Among the 22 (21.6%) patients who showed ultimate treatment failure, 6 underwent orthotopic liver transplantation and 3 died of liver failure while awaiting a transplant. Sixteen (72.7%) of the 22 patients who did not respond to therapy were non-compliant with medications and had irregular follow-up. The overall 10-year survival rate in the cohort was 96%.
Long-term survival in AIH patients is very good. Prompt diagnosis and appropriate first-line and salvage therapy that includes close follow-up will make liver transplantation a rare necessity in the treatment of this disease.
PMCID: PMC3321327  PMID: 22509185
Hepatitis; Autoimmune; Natural History; Liver Cirrhosis; Hepatitis, Chronic; Iran
11.  Metformin in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial 
Nonalcoholic steatohepatitis (NASH) is a common liver disease that can progress to cirrhosis or hepatocellular carcinoma. It is estimated that up to 3% of the Iranian population have this condition. Although the pathogenesis of NASH is incompletely understood, there is significant evidence pointing to the importance of insulin resistance. Metformin is an oral hypoglycemic agent known to improve insulin resistance. This study examines the effectiveness of metformin on biochemical and histological improvement among NASH patients in a randomized double-blind controlled trial.
This study enrolled 33 biopsy-proven NASH patients. Other causes of liver disorders were excluded. Subjects were randomized to receive either metformin, 500 mg twice daily, or an identical-looking placebo. Overweight patients were also instructed to lose weight. Treatment continued for 6 months. Patients were regularly visited and liver enzyme levels recorded. Compliance and any adverse drug effects were recorded.
In the metformin group, the mean aspartate aminotransferase (AST) level dropped from 61.2 IU/L to 32.7 IU/L and the mean alanine aminotransferase (ALT) level dropped from 85.1 IU/L to 50.8 IU/L. The mean AST level in the placebo group dropped from 54.3 IU/L to 37.9 IU/L, whereas the mean ALT level dropped from 111.8 IU/L to 55.4 IU/L in the placebo group. The decrease in liver enzymes was significant in both groups, but the magnitude of decrease was not significantly different.
The improvement observed in liver enzyme levels is totally attributable to weight loss. Metformin had no significant effect on liver enzyme levels.
PMCID: PMC4017700  PMID: 24829630
Nonalcoholic Steatohepatitis; Metformin; Nonalcoholic Fatty Liver Disease
12.  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
13.  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
14.  Eosinophilic Gastroenteritis: A Case Series from Iran 
Eosinophilic gastroenteritis (EG) is a rare inflammatory disorder of the gastrointestinal (GI) tract. There have been several case series of patients with EG from the western world and East Asia. However, there has not been a report of patients with EG from the Middle East region. The aim of this study is to describe clinical characteristics and treatment response in a series of EG patients from Iran.
We retrospectively reviewed charts with a diagnosis of EG from 1997 to 2010 at Shariati Hospital and the private clinics of the authors. Clinical characteristics of the patients were evaluated, and the treatment response and relapse rate were assessed.
Twenty-two patients (9 male) with EG were identified. Mean age of the patients was 45.1±15.5 (range: 27-75) years. Median duration between symptom onset and diagnosis was 12 (range 1- 48) months. Twenty (90%) patients had mucosal involvement, one (5%) had muscular involvement and one (5%) had subserosal involvement.
Patients were followed for a median duration of 36.5 (range 4-123) months. Two patients had spontaneous remission with supportive care. The remaining 20 patients responded well to oral corticosteroid treatments. The relapse rate was 33%. Episodes of relapse were successfully controlled with a repeat course of corticosteroids. Two patients with several relapses required maintenance treatment with azathioprine.
The clinical characteristics and treatment responses of EG patients from Iran are similar to reports from other parts of the world. Patients need to undergo close follow up after treatment to detect early signs of relapse.
PMCID: PMC4154914  PMID: 25197542
Eosinophilic gastroenteritis; Esophagus; Small intestine; Eosinophils
15.  Inflammatory Myofibroblastic Tumor of the Small Bowel: A Case Report 
Inflammatory Myofibroblastic Tumor (IMT) is a rare neoplastic lesion with tendency toward local aggressive behavior and recurrence. The tumor most commonly occurs in the pulmonary system of children and young adult, although it may rarely develop in older patients and other organs. Symptoms are non-specific and depend on the location of the tumor. The gastrointestinal tract is rarely the primary site of origin for this lesion. We report an unusual presentation of this rare lesion in a 58 year old woman with intussusception and partial intestinal obstruction.
PMCID: PMC4154918  PMID: 25197546
Inflammatory myofibroblastic tumor; Ileum; Gastrointestinal
16.  TP53 Mutations and HBX Status Analysis in Hepatocellular Carcinomas from Iran: Evidence for Lack of Association between HBV Genotype D and TP53 R249S Mutations 
High incidence of HCC is mostly due to the combination of two major risk factors, chronic infection with hepatitis B (HBV) and/or C (HCV) viruses and exposure to the mycotoxin aflatoxin B1, which induces a particular mutation at codon 249 in TP53 (R249S). Eight genotypes of HBV are diversely found in high and low incidence areas. Regardless of documented strong associations between TP53 R249S mutation and HBV genotypes B, C, A or E, there is no report of such association for genotype D despite of the presence of aflatoxin in areas with high prevalence of HBV genotype D. In Iran, 3% of the population is chronically infected with HBV, predominantly genotype D. Twenty-one histologically confirmed HCC cases from Iran were analyzed for TP53 R249S and HBV double mutations 1762T/1764A, hallmarks of more pathogenic forms of HBV. We did not detect any of these mutations. In addition, we report the only case identified so far carrying both R249S mutation and chronic HBV genotype D, a patient from The Gambia in West Africa. This paper suggests that association between HBV genotype D and aflatoxin-induced TP53 mutation is uncommon, explaining the relatively lower incidence of HCC in areas where genotype D is highly prevalent.
PMCID: PMC3159019  PMID: 21869931
17.  Prognostic Factors for Esophageal Squamous Cell Carcinoma—A Population-Based Study in Golestan Province, Iran, a High Incidence Area 
PLoS ONE  2011;6(7):e22152.
Golestan Province in northern Iran is an area with a high incidence of esophageal squamous cell carcinoma (ESCC). We aimed to investigate prognostic factors for ESCC and survival of cases in Golestan, on which little data were available. We followed-up 426 ESCC cases participating in a population-based case-control study. Data were analyzed using the Kaplan–Meier method and the Cox proportional hazard models. Median survival was 7 months. Age at diagnosis was inversely associated with survival, but the association was disappeared with adjustment for treatment. Residing in urban areas (hazard ratio, HR = 0.70; 95% CI 0.54–0.90) and being of non-Turkmen ethnic groups (HR = 0.76; 95% CI 0.61–0.96) were associated with better prognosis. In contrast to other types of tobacco use, nass (a smokeless tobacco product) chewing was associated with a slightly poorer prognosis even in models adjusted for other factors including stage of disease and treatment (HR = 1.38; 95% CI 0.99–1.92). Opium use was associated with poorer prognosis in crude analyses but not in adjusted models. Almost all of potentially curative treatments were associated with longer survival. Prognosis of ESCC in Golestan is very poor. Easier access to treatment facilities may improve the prognosis of ESCC in Golestan. The observed association between nass chewing and poorer prognosis needs further investigations; this association may suggest a possible role for ingestion of nass constituents in prognosis of ESCC.
PMCID: PMC3141005  PMID: 21811567
18.  Systemic lupus erythematosus presenting with eosinophilic enteritis: a case report 
Systemic lupus erythematosus (SLE) is a multisystem disorder that may present with various symptoms. It may involve the gastrointestinal tract in a variety of ways; some of the most well-known ones are transaminitis, lupus mesenteric vasculitis, lupus enteritis and mesenteric vascular leakage. We describe a case of a patient with SLE who presented with a five-month history of diarrhea caused by eosinophilic enteritis. To the best of our knowledge, there are few cases reported in the literature of patients with SLE who initially present with chronic diarrhea due to eosinophilic enteritis.
Case presentation
A 38-year-old Persian Iranian woman was admitted with a five-month history of diarrhea and abdominal pain. A physical examination showed nothing abnormal. Initially, she had only lymphopenia and mild eosinophilia. No autoimmune or infectious etiology was detected to justify these abnormalities. A thorough evaluation was not helpful in finding the etiology, until she developed a scalp lesion similar to discoid lupus erythematosus. Computed tomography showed small bowel wall thickening. Briefly, she manifested full-blown SLE, and it was revealed that the diarrhea was caused by eosinophilic enteritis.
Considering SLE in a patient who presents with chronic diarrhea and lymphopenia may be helpful in earlier diagnosis and therapy. This is an original case report of interest to physicians who practice internal medicine, family medicine and gastroenterology.
PMCID: PMC3143100  PMID: 21702974
19.  Association of p53/p21 expression with cigarette smoking and prognosis in esophageal squamous cell carcinoma patients 
AIM: To investigate the expression of p53 and p21 and associations with possible risk factors, such as cigarette smoking, in esophageal squamous cell carcinoma (ESCC) in northeastern Iran, a region with a high incidence of ESCC.
METHODS: The expression of p53 and p21 proteins was investigated immunohistochemically in tumor tissue from 80 ESCC patients and in 60 available paraffin-embedded blocks of adjacent normal specimens from the cases, along with normal esophageal tissue from 80 healthy subjects.
RESULTS: Positive expression of p53 protein was detected in 56.2% (45/80) of ESCC cases, and in none of the normal esophageal tissue of the control group (P < 0.001). Furthermore, 73.8% (59/80) of ESCC cases and 43.8% (35/80) of controls had positive expression of p21 protein (P < 0.001). Cigarette smoking was significantly associated with p53 over-expression in ESCC cases (P = 0.010, OR = 3.64; 95% CI: 1.32-10.02). p21 over-expression was associated with poorer clinical outcome among the ESCC patients (P = 0.009).
CONCLUSION: Over-expression of p53 in association with cigarette smoking may play a critical role in ESCC carcinogenesis among this high-risk population of northeastern Iran. Furthermore, p21 over-expression was found to be associated with poor prognosis, specifically in the operable ESCC patients.
PMCID: PMC2957605  PMID: 20954283
Esophageal squamous cell carcinoma; p53; p21; Immunohistochemistry; Survival; Smoking
20.  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
21.  p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in Esophageal Squamous Cell Carcinoma 
BMC Cancer  2010;10:138.
Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis. We assessed the aberrant methylation of the p16 gene and its impact on p16INK4a protein expression and correlations with p53 and MDM2 protein expressions in patients with ESCC in the Golestan province of northeastern Iran in which ESCC has the highest incidence of cancer, well above the world average.
Cancerous tissues and the adjacent normal tissue obtained from 50 ESCC patients were assessed with Methylation-Specific-PCR to examine the methylation status of p16. The expression of p16, p53 and MDM2 proteins was detected by immunohistochemical staining.
Abnormal expression of p16 and p53, but not MDM2, was significantly higher in the tumoral tissue. p53 was concomitantly accumulated in ESCC tumor along with MDM2 overexpression and p16 negative expression. Aberrant methylation of the p16INK4a gene was detected in 31/50 (62%) of esophageal tumor samples, while two of the adjacent normal mucosa were methylated (P < 0.001). p16INK4a aberrant methylation was significantly associated with decreased p16 protein expression (P = 0.033), as well as the overexpression of p53 (P = 0.020).
p16 hypermethylation is the principal mechanism of p16 protein underexpression and plays an important role in ESCC development. It is associated with p53 protein overexpression and may influence the accumulation of abnormally expressed proteins in p53-MDM2 and p16-Rb pathways, suggesting a possible cross-talk of the involved pathways in ESCC development.
PMCID: PMC2868052  PMID: 20388212
22.  The role of mutations in core protein of hepatitis B virus in liver fibrosis 
Virology Journal  2009;6:209.
The core protein of hepatitis B virus encompasses B- and T-cell immunodominant epitopes and subdivided into two domains: the N-terminal and the functional C-terminal consisted phosphorylation sites. Mutations of the core gene may change the conformation of the core protein or cause alteration of important epitopes in the host immune response. In this study twenty nine men (mean age 40 ± 9 years old) with chronic hepatitis B were recruited for direct sequencing of the core gene. Serum ALT and HBV DNA level were measured at the time of liver biopsy. The effects of core protein mutations on patients' characteristics and subsequently mutations in B cell, T helper and cytotoxic T lymphocyte (CTL) epitopes and also C-terminal domain of core protein on the activity of liver disease was evaluated. Liver fibrosis was significantly increased in patients with core protein mutation (1.0 ± 0.8 vs 1.9 ± 1.4 for mean stage of fibrosis P = 0.05). Mutations in CTL epitopes and in phosphorylation sites of C-terminal domain of core protein also were associated with higher liver fibrosis (P = 0.003 and P = 0.04; Fisher's exact test for both). Patients with mutation in C-terminal domain had higher serum ALT (62 ± 17 vs 36 ± 12 IU/l, p = 0.02). Patients with mutations in B cell and T helper epitopes did not show significant difference in the clinical features. Our data suggests that core protein mutations in CTL epitopes and C-terminal domain accompanied with higher stage of liver fibrosis may be due to alterations in the function of core protein.
PMCID: PMC2800847  PMID: 19939285
23.  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
24.  Prospective Acid Reflux Study of Iran (PARSI): Methodology and study design 
BMC Gastroenterology  2007;7:42.
Gastroesophageal reflux disease is a common and chronic disorder but long term, prospective studies of the fate of patients seeking medical advice are scarce. This is especially prominent when looking at non-erosive reflux disease (NERD) patients.
We designed a prospective cohort to assess the long term outcome of GERD patients referring to gastroenterologists. Consecutive consenting patients, 15 years of age and older, presenting with symptoms suggestive of GERD referring to our outpatient clinics undergo a 30 minute interview. Upper gastrointestinal endoscopy is performed for them with protocol biopsies and blood samples are drawn. Patients are then treated according to a set protocol and followed regularly either in person or by telephone for at least 10 years.
Our data show that such a study is feasible and follow-ups, which are the main concern, can be done in a fairly reliable way to collect data. The results of this study will help to clarify the course of various subgroups of GERD patients after coming to medical attention and their response to treatment considering different variables. In addition, the basic symptoms and biological database will fuel further molecular epidemiologic studies.
PMCID: PMC2212633  PMID: 18028533
25.  Epidemiology of upper gastrointestinal cancers in Iran: A sub site analysis of 761 cases 
AIM: To define the sub site distribution of upper gastrointestinal cancers in three provinces of Iran.
METHODS: The study was carried out in three provinces in Iran: Ardabil, Golestan, and Tehran. In Arbabil and Golestan, the data was collected from the sole referral center for gastrointestinal cancers and the local cancer registry. For Tehran province, data from two major private hospitals were used. All gastric and esophageal cancer patients diagnosed during the period from September 2000 and April 2002 were included in the study.
RESULTS: A total of 761 patients with upper gastrointestinal cancers were identified, 314 from Ardabil, 261 from Golestan, and 186 from Tehran. In Tehran, the relative rate of cancer increased from the upper esophagus to the distal stomach. In Golestan, the reverse pattern was observed. In Ardabil, the mid portion (distal esophagus and proximal stomach) was involved most frequently.
CONCLUSION: There were considerable variations in the sub site of upper gastrointestinal cancers in the three provinces studied. We cannot provide any explanation for this variation. Further research aimed at explaining the discrepancies in sub site distribution of upper gastrointestinal cancers may help identify important risk factors.
PMCID: PMC4171328  PMID: 17879408
Upper gastrointestinal tract; Gastrointestinal neoplasms; Iran

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