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1.  Gut Microbial Diversity Is Reduced in Smokers with Crohn's Disease 
Inflammatory Bowel Diseases  2016;22(9):2070-2077.
Article first published online 10 August 2016.
Background:
Smoking has a negative impact on Crohn's disease (CD), but the mechanisms underlying this association are unclear. We compared the gut microbiota composition of smoking with nonsmoking patients with CD using a metagenomic approach.
Methods:
Stool samples and clinical data were collected from current smokers and nonsmokers with CD from France and the Netherlands, matched for country, gender, age, disease activity, and body mass index. Fecal DNA was sequenced on an Illumina HiSeq 2500. On average, 40 million paired-end reads were generated per sample. Gene richness and the Shannon index were computed to assess microbial diversity. Wilcoxon's signed-rank tests for paired samples were performed to detect differences between the 2 groups.
Results:
In total, 21 smoking and 21 nonsmoking patients with CD were included. Compared with nonsmoking patients, gut microbial gene richness (P = 0.01), genus diversity (P < 0.01), and species diversity (P = 0.01) were decreased in smoking patients. This was accompanied by a reduced relative abundance of the genera Collinsella (P = 0.02), Enterorhabdus (P = 0.02), and Gordonibacter (P = 0.02) in smokers. No statistically significant differences at the species level were observed, although smokers had lower proportions of Faecalibacterium prausnitzii (P = 0.10).
Conclusions:
Gut microbial diversity is reduced in smokers with CD compared with nonsmokers with CD. The microbial profile differs between these groups at the genus level. Future studies should evaluate whether intestinal microbes mediate the adverse effects of smoking in CD.
doi:10.1097/MIB.0000000000000875
PMCID: PMC4991341  PMID: 27542127
smoking; microbiota; Crohn's disease; inflammatory bowel disease; sequencing
2.  Exposure to Ambient Air Pollution and the Risk of Inflammatory Bowel Disease: A European Nested Case–Control Study 
Digestive Diseases and Sciences  2016;61(10):2963-2971.
Background
Industrialization has been linked to the etiology of inflammatory bowel disease (IBD).
Aim
We investigated the association between air pollution exposure and IBD.
Methods
The European Prospective Investigation into Cancer and Nutrition cohort was used to identify cases with Crohn’s disease (CD) (n = 38) and ulcerative colitis (UC) (n = 104) and controls (n = 568) from Denmark, France, the Netherlands, and the UK, matched for center, gender, age, and date of recruitment. Air pollution data were obtained from the European Study of Cohorts for Air Pollution Effects. Residential exposure was assessed with land-use regression models for particulate matter with diameters of <10 μm (PM10), <2.5 μm (PM2.5), and between 2.5 and 10 μm (PMcoarse), soot (PM2.5 absorbance), nitrogen oxides, and two traffic indicators. Conditional logistic regression analyses were performed to calculate odds ratios (ORs) with 95 % confidence intervals (CIs).
Results
Although air pollution was not significantly associated with CD or UC separately, the associations were mostly similar. Individuals with IBD were less likely to have higher exposure levels of PM2.5 and PM10, with ORs of 0.24 (95 % CI 0.07–0.81) per 5 μg/m3 and 0.25 (95 % CI 0.08–0.78) per 10 μg/m3, respectively. There was an inverse but nonsignificant association for PMcoarse. A higher nearby traffic load was positively associated with IBD [OR 1.60 (95 % CI 1.04–2.46) per 4,000,000 motor vehicles × m per day]. Other air pollutants were positively but not significantly associated with IBD.
Conclusion
Exposure to air pollution was not found to be consistently associated with IBD.
Electronic supplementary material
The online version of this article (doi:10.1007/s10620-016-4249-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10620-016-4249-4
PMCID: PMC5020109  PMID: 27461060
Air pollution; Particulate matter; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis
4.  Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort 
Cancer Causes & Control  2016;27:919-927.
Background
The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC.
Methods
We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status.
Results
During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations.
Conclusion
WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine.
Impact
Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.
doi:10.1007/s10552-016-0772-z
PMCID: PMC4923177  PMID: 27294726
Abdominal obesity; Obesity; Cancer; Small intestine
5.  Current understanding of the functional roles of aberrantly expressed microRNAs in esophageal cancer 
The incidence of esophageal cancer is rising, mostly because the increasing incidence of esophageal adenocarcinoma in Western countries. Despite improvements in diagnosis and treatment, the overall 5-year survival rates remain low. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of target genes. Recently, disease specific miRNAs have been identified, which act as tumor suppressors or oncogenes. In this review, we will summarize the current knowledge about the function of aberrantly expressed miRNAs in esophageal cancer. We selected 5 miRNAs (miRNA-21, -143, -145, -196a and let-7) based on the available literature, and described their potential role in regulating pathways that are deregulated in esophageal cancer. Finally we will highlight the current achievements of using and targeting miRNAs. Because these miRNAs likely have important regulatory roles in cancer development, they open a therapeutic window for new treatment modalities.
doi:10.3748/wjg.v22.i1.1
PMCID: PMC4698477  PMID: 26755856
Esophageal cancer; Esophageal squamous cell carcinoma; Esophageal adenocarcinoma; MicroRNAs; Target genes
6.  BMP4 Signaling Is Able to Induce an Epithelial-Mesenchymal Transition-Like Phenotype in Barrett’s Esophagus and Esophageal Adenocarcinoma through Induction of SNAIL2 
PLoS ONE  2016;11(5):e0155754.
Background
Bone morphogenetic protein 4 (BMP4) signaling is involved in the development of Barrett’s esophagus (BE), a precursor of esophageal adenocarcinoma (EAC). In various cancers, BMP4 has been found to induce epithelial-mesenchymal transition (EMT) but its function in the development of EAC is currently unclear.
Aim
To investigate the expression of BMP4 and several members of the BMP4 pathway in EAC. Additionally, to determine the effect of BMP4 signaling in a human Barrett’s esophagus (BAR-T) and adenocarcinoma (OE33) cell line.
Methods
Expression of BMP4, its downstream target ID2 and members of the BMP4 pathway were determined by Q-RT-PCR, immunohistochemistry and Western blot analysis using biopsy samples from EAC patients. BAR-T and OE33 cells were incubated with BMP4 or the BMP4 antagonist, Noggin, and cell viability and migration assays were performed. In addition, expression of factors associated with EMT (SNAIL2, CDH1, CDH2 and Vimentin) was evaluated by Q-RT-PCR and Western blot analysis.
Results
Compared to squamous epithelium (SQ), BMP4 expression was significantly upregulated in EAC and BE. In addition, the expression of ID2 was significantly upregulated in EAC and BE compared to SQ. Western blot analysis confirmed our results, showing an upregulated expression of BMP4 and ID2 in both BE and EAC. In addition, more phosphorylation of SMAD1/5/8 was observed. BMP4 incubation inhibited cell viability, but induced cell migration in both BAR-T and OE33 cells. Upon BMP4 incubation, SNAIL2 expression was significantly upregulated in BAR-T and OE33 cells while CDH1 expression was significantly downregulated. These results were confirmed by Western blot analysis.
Conclusion
Our results indicate active BMP4 signaling in BE and EAC and suggest that this results in an invasive phenotype by inducing an EMT-like response through upregulation of SNAIL2 and subsequent downregulation of CDH1.
doi:10.1371/journal.pone.0155754
PMCID: PMC4871520  PMID: 27191723
7.  BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia 
OBJECTIVES
Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD).
METHODS
We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations.
RESULTS
In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients.
CONCLUSIONS
In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.
doi:10.1038/ajg.2015.55
PMCID: PMC4436697  PMID: 25869390
8.  Evolution of Costs of Inflammatory Bowel Disease over Two Years of Follow-Up 
PLoS ONE  2016;11(4):e0142481.
Background
With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up.
Methods and Findings
In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of €7,835 in CD and €3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02–3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61–13.86)).
Conclusions
BD-related costs remained stable over two years. However, the proportion of anti-TNF-related healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC.
doi:10.1371/journal.pone.0142481
PMCID: PMC4839678  PMID: 27099937
9.  A Nested Case–Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) 
PLoS Medicine  2016;13(4):e1001988.
Background
Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.
Methods and Findings
The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10–2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01–1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65–1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49–0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic—based on their C-peptide level—was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.
Conclusions
These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
Gunter and colleagues analyse a large European dataset to determine how body size and metabolic profile associates with the risk of developing colorectal cancer.
Editors' Summary
Background
Colorectal cancer is the third most common cancer worldwide and is a leading cause of cancer-related death, killing around 700,000 people every year. It develops when cells in the colon (the final part of the digestive system, which is also known as the large intestine or large bowel) or the rectum (the lower end of the colon) acquire genetic changes that allow them to divide uncontrollably to form a tumor and to move around the body (metastasize). Symptoms of colorectal cancer include blood in the stool, a change in bowel habits, and unexplained weight loss. Treatments for colorectal cancer include surgery, chemotherapy, and radiation. As with other types of cancer, these treatments are more likely to be successful if started when the tumor is very small. Consequently, many countries run screening programs that use colonoscopy, the fecal occult blood test, and other tests to detect the earliest signs of colorectal cancer in apparently healthy people.
Why Was This Study Done?
Being obese—having too much body fat—is associated with an increased colorectal cancer risk (other risk factors include age, having a family history of colorectal cancer, and eating a high-fat, low-fiber diet). Obesity is also associated with several other chronic diseases, and recent evidence suggests that some obese individuals have a higher risk of developing these diseases than others. For example, overweight/obese individuals who have hyperinsulinemia (abnormally high blood levels of insulin; “metabolically unhealthy”) seem to have a higher risk of cardiovascular disease than their non-hyperinsulinemic (“metabolically healthy”) overweight counterparts. If certain combinations of metabolic health status and body size (“metabolically defined body size phenotypes”) are also associated with colorectal cancer, measurement of insulin levels in conjunction with body fat (adiposity) measurements such as body mass index (BMI; an indicator of body fat calculated by dividing a person’s weight in kilograms by their height in meters squared) might improve colorectal cancer risk assessment. In this nested case–control study, the researchers assess the associations between metabolically defined body size phenotypes and colorectal cancer risk. A nested case–control study identifies everyone in a group (here, participants in the European Prospective Investigation into Cancer and Nutrition [EPIC] study) who has a specific condition, identifies matched individuals in the same group without the condition, and asks whether these controls and the cases differ in terms of a specific characteristic or outcome.
What Did the Researchers Do and Find?
The researchers matched 737 participants in the EPIC study who developed colorectal cancer after study enrollment with 737 controls and used serum concentrations of C-peptide, a marker of insulin secretion, and BMI measurements to classify each individual as metabolically healthy/normal weight, metabolically healthy/overweight, metabolically unhealthy/normal weight, or metabolically unhealthy/overweight. Specifically, the researchers categorized people as metabolically unhealthy if they had a C-peptide level above an arbitrarily chosen cut-off value based on the distribution of C-peptide levels in the control participants and as overweight if they had a BMI of ≥25 kg/m2 (the standard definition of overweight). Compared to metabolically healthy normal weight individuals, metabolically unhealthy normal weight and overweight individuals had an increased colorectal cancer risk; metabolically healthy overweight individuals had a similar colorectal cancer risk to metabolically healthy normal weight individuals. Among overweight individuals, metabolically healthy individuals had a lower colorectal cancer risk than metabolically unhealthy individuals. Finally, similar associations were seen when the researchers used waist circumference instead of BMI as the measure of adiposity.
What Do These Findings Mean?
These findings suggest that normal weight individuals with hyperinsulinemia (the metabolically unhealthy normal weight phenotype) have a higher risk of colorectal cancer than normal weight individuals without hyperinsulinemia. They also suggest that metabolically unhealthy overweight individuals have a higher risk of colorectal cancer than metabolically healthy overweight individuals. The accuracy of these findings may be limited by the method the researchers used to classify individuals as hyperinsulinemic—there is no universally accepted clinical definition for using C-peptide level to diagnose hyperinsulinemia. Nevertheless, these findings suggest that the assessment of insulin levels in conjunction with adiposity measures might be a better way to assess an individual’s colorectal cancer risk than simply measuring adiposity, and might help to identify those individuals at high risk of colorectal cancer who are most likely to benefit from targeted interventions designed to prevent the onset of clinical disease.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001988.
The US National Cancer Institute provides information for patients about all aspects of colorectal cancer; it also provides more detailed information colorectal cancer for health professionals and information on cancer risk and obesity
The UK National Health Service Choices website has information and personal stories about colorectal cancer and information on obesity
The not-for-profit organization Cancer Research UK provides information about colorectal cancer and about the association between cancer and obesity
MedlinePlus provides links to further resources about colorectal cancer and about obesity
Wikipedia has a page on hyperinsulinemia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information about the EPIC study is available
doi:10.1371/journal.pmed.1001988
PMCID: PMC4821615  PMID: 27046222
10.  Quality indicators for colonoscopy: Current insights and caveats 
Colonoscopy is the diagnostic modality of choice for investigation of symptoms suspected to be related to the colon and for the detection of polyps and colorectal cancer (CRC). Colonoscopy with removal of detected polyps has been shown to reduce the incidence and mortality of subsequent CRC. In many countries, population screening programs for CRC have been initiated, either by selection of patients for colonoscopy with fecal occult blood testing or by offering colonoscopy directly to average-risk individuals. Several endoscopy societies have formulated quality indicators for colonoscopy. These quality indicators are almost always incorporated as process indicators, rather than outcome measures. This review focuses on the quality indicators bowel preparation, cecal intubation rate, withdrawal time, adenoma detection rate, patient comfort, sedation and complication rate, and discusses the scientific evidence supporting them, as well as their potential shortcomings and issues that need to be addressed. For instance, there is still no clear and generally accepted definition of adequate bowel preparation, no robust scientific evidence is available supporting a cecal intubation rate ≥ 90% and the association between withdrawal time and occurrence of interval cancers has not been clarified. Adenoma detection rate is currently the only quality indicator that has been shown to be associated with interval colorectal cancer, but as an indicator it does not differentiate between subjects with one or more adenoma detected.
doi:10.4253/wjge.v6.i12.571
PMCID: PMC4265954  PMID: 25512766
Colonoscopy; Quality indicators; Bowel preparation; Cecal intubation; Withdrawal time; Adenoma detection rate; Screening; Complication; Interval colorectal cancer; Post-colonoscopy colorectal cancer
11.  Increased Belching After Sleeve Gastrectomy 
Obesity Surgery  2015;26:132-137.
Introduction
Laparoscopic sleeve gastrectomy (LSG) is considered to be an effective procedure for patients with morbid obesity. Belching is frequently reported after this procedure, but it has not been well studied in the bariatric population. This study aims to assess the changes in belching before and after sleeve gastrectomy, as measured with impedance monitoring.
Methods
In a prospective study, patients underwent 24-h pH-impedance monitoring before and 3 months after LSG. Using this technique, belches can be identified. Preoperative and postoperative upper gastrointestinal symptoms were assessed using the Reflux Disease Questionnaire (RDQ).
Results
Fifteen patients (1 M/14 F, mean age 42.2 ± 11.0 years, mean weight 134.5 ± 21.1 kg, mean BMI 46.4 ± 6.0 kg/m2) participated in this study. Belching occurred significantly more often after LSG, with an increase in symptom score from 2.9 ± 2.6 before to 5.3 ± 3.5 3 months after LSG (p = 0.04). The total number of gastric belches increased from 29.7 ± 11.7 before to 59.5 ± 38.3/24 h 3 months after LSG (p = 0.03). The total number of supragastric belches did not change after LSG. The number of swallows decreased from 746.9 ± 302.4 before to 555.7 ± 172.5 3 months after the procedure (p = 0.03). The number of air swallows tended to decrease (p = 0.08).
Esophageal acid exposure increased significantly, from 3.7 ± 2.9 % before to 12.6 ± 10.5 % after LSG (p = 0.01).
Conclusion
Subjectively (as reported by patients) and objectively (as measured by impedance monitoring), an increase in gastric belches is seen after LSG, while the number of (air) swallows tends to decrease after the procedure and the incidence of supragastric belches remains constant. The altered anatomy as well as increased gastroesophageal reflux after LSG may play a role in the increase of belching.
doi:10.1007/s11695-015-1718-3
PMCID: PMC4700067  PMID: 26101047
Sleeve gastrectomy; Belching; Impedance monitoring; Reflux; Swallows
12.  Endoscopic innovations to increase the adenoma detection rate during colonoscopy 
Up to a quarter of polyps and adenomas are missed during colonoscopy due to poor visualization behind folds and the inner curves of flexures, and the presence of flat lesions that are difficult to detect. These numbers may however be conservative because they mainly come from back-to-back studies performed with standard colonoscopes, which are unable to visualize the entire mucosal surface. In the past several years, new endoscopic techniques have been introduced to improve the detection of polyps and adenomas. The introduction of high definition colonoscopes and visual image enhancement technologies have been suggested to lead to better recognition of flat and small lesions, but the absolute increase in diagnostic yield seems limited. Cap assisted colonoscopy and water-exchange colonoscopy are methods to facilitate cecal intubation and increase patients comfort, but show only a marginal or no benefit on polyp and adenoma detection. Retroflexion is routinely used in the rectum for the inspection of the dentate line, but withdrawal in retroflexion in the colon is in general not recommended due to the risk of perforation. In contrast, colonoscopy with the Third-Eye Retroscope® may result in considerable lower miss rates compared to standard colonoscopy, but this technique is not practical in case of polypectomy and is more time consuming. The recently introduced Full Spectrum Endoscopy™ colonoscopes maintains the technical capabilities of standard colonoscopes and provides a much wider view of 330 degrees compared to the 170 degrees with standard colonoscopes. Remarkable lower adenoma miss rates with this new technique were recently demonstrated in the first randomized study. Nonetheless, more studies are required to determine the exact additional diagnostic yield in clinical practice. Optimizing the efficacy of colorectal cancer screening and surveillance requires high definition colonoscopes with improved virtual chromoendoscopy technology that visualize the whole colon mucosa while maintaining optimal washing, suction and therapeutic capabilities, and keeping the procedural time as low and patient discomfort as optimal as possible.
doi:10.3748/wjg.v20.i9.2200
PMCID: PMC3942825  PMID: 24605019
Colonoscopy; Endoscopic innovations; Adenoma detection; Polyp detection; Gastrointestinal endoscopy
13.  Refractory Esophageal Strictures: What To Do When Dilation Fails 
Opinion statement
Benign esophageal strictures arise from a diversity of causes, for example esophagogastric reflux, esophageal resection, radiation therapy, ablative therapy, or the ingestion of a corrosive substance. Most strictures can be treated successfully with endoscopic dilation using bougies or balloons, with only a few complications. Nonetheless, approximately one third of patients develop recurrent symptoms after dilation within the first year. The majority of these patients are managed with repeat dilations, depending on their complexity. Dilation combined with intra lesional steroid injections can be considered for peptic strictures, while incisional therapy has been demonstrated to be effective for Schatzki rings and anastomotic strictures. When these therapeutic options do not resolve the stenosis, stent placement should be considered. Self bougienage can be proposed to a selected group of patients with a proximal stenosis. As a final step surgery is an option, but even then the risk of stricture formation at the anastomotic site remains. This chapter reviews refractory benign esophageal strictures and the treatment options that are currently available.
doi:10.1007/s11938-014-0043-6
PMCID: PMC4328110  PMID: 25647687
Refractory benign esophageal stricture; Dysphagia; Dilation; Incisional therapy; Intralesional steroid injection; Stent placement; Self-expandable plastic stent; Self-expandable metal stent; Biodegradable stent placement; Esophagectomy; Self-bougienage
14.  Biophotonic endoscopy: a review of clinical research techniques for optical imaging and sensing of early gastrointestinal cancer 
Endoscopy International Open  2015;3(5):E380-E392.
Detection, characterization, and staging constitute the fundamental elements in the endoscopic diagnosis of gastrointestinal diseases, but histology still remains the diagnostic gold standard.
New developments in endoscopic techniques may challenge histopathology in the near future. An ideal endoscopic technique should combine a wide-field, “red flag” screening technique with an optical contrast or microscopy method for characterization and staging, all simultaneously available during the procedure. In theory, biophotonic advances have the potential to unite these elements to allow in vivo “optical biopsy.”
These techniques may ultimately offer the potential to increase the rates of detection of high risk lesions and the ability to target biopsies and resections, and so reduce the need for biopsy, costs, and uncertainty for patients. However, their utility and sensitivity in clinical practice must be evaluated against those of conventional histopathology.
This review describes some of the most recent applications of biophotonics in endoscopic optical imaging and metrology, along with their fundamental principles and the clinical experience that has been acquired in their deployment as tools for the endoscopist. Particular emphasis has been placed on translational label-free optical techniques, such as fluorescence spectroscopy, fluorescence lifetime imaging microscopy (FLIM), two-photon and multi-photon microscopy, second harmonic generation (SHG) and third harmonic generation (THG) imaging, optical coherence tomography (OCT), diffuse reflectance, Raman spectroscopy, and molecular imaging.
doi:10.1055/s-0034-1392513
PMCID: PMC4612244  PMID: 26528489
15.  Frequent Use of Antibiotics Is Associated with Colorectal Cancer Risk: Results of a Nested Case–Control Study 
Background
Microbiotical dysbiosis induced by a Western diet seems to be associated with an increased risk of developing colorectal cancer (CRC). Few other factors with an effect on the colonic microbiota and their association with CRC have been evaluated.
Aim
We investigated whether the use of antibiotics is associated with CRC risk.
Methods
Data on the use of antibiotics and comedication were extracted from a health insurance database for subjects with a diagnostic-related group for CRC between 2006 and 2011 and four age- and sex-matched controls. Antibiotic use was categorized according to the number of prescriptions during a 5-year follow-up period (1–6 years prior to CRC). Multivariable conditional binary logistic regression analysis was used to estimate odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for different levels of use.
Results
A total of 4029 cases (47 % male, mean age at diagnosis 71 ± 11 years) and 15,988 controls were included. Antibiotics had been prescribed to 2630 (65.3 %) cases and 10,234 (64.0 %) controls (p = 0.13). An increasing use of antibiotics was associated with an increasing risk of CRC [multivariable OR for high (≥8 prescriptions) vs. no prescriptions: 1.26, 95 % CI 1.11–1.44, p-trend <0.01]. For each increase of 5 prescriptions, the OR for CRC was 1.05 (95 % CI 1.01–1.09).
Conclusion
We found an association between the use of antibiotics, especially when used frequently, and the risk of developing CRC. Further studies are needed to establish under which conditions the use of antibiotics increases the risk of developing CRC.
doi:10.1007/s10620-015-3828-0
PMCID: PMC4700063  PMID: 26289256
Colorectal cancer; Antibiotics; Microbiota; Pharmacoepidemiology
16.  Technical advances in endoscopic ultrasound-guided fiducial placement for the treatment of pancreatic cancer 
Endoscopy International Open  2015;3(4):E373-E377.
Radiation therapy has an important role in the treatment of locally advanced or metastatic pancreatic cancer and can be used alone or in conjunction with surgery and/or systemic chemotherapy. Because of the challenge of delivering an accurate and optimal radiation dose, image-guided radiation therapy can be used to improve targeting. Fiducial markers can be placed in the tumor and used for localization in patients undergoing image-guided radiation therapy. The safety and feasibility of endoscopic ultrasound (EUS)-guided placement of fiducials has been assessed and reported for the management of pancreatic cancer. We herein review the technique, efficacy, and safety profile of EUS-guided fiducial placement. In addition, we highlight recent advances and technological upgrades in EUS-guided fiducial delivery systems for pancreatic cancer most relevant to practicing gastroenterologists and interventional endoscopists.
doi:10.1055/s-0034-1392274
PMCID: PMC4554510  PMID: 26355267
17.  Retrograde-viewing device improves adenoma detection rate in colonoscopies for surveillance and diagnostic workup 
AIM: To determine which patients might benefit most from retrograde viewing during colonoscopy through subset analysis of randomized, controlled trial data.
METHODS: The Third Eye® Retroscope® Randomized Clinical Evaluation (TERRACE) was a randomized, controlled, multicenter trial designed to evaluate the efficacy of a retrograde-viewing auxiliary imaging device that is used during colonoscopy to provide a second video image which allows viewing of areas on the proximal aspect of haustral folds and flexures that are difficult to see with the colonoscope’s forward view. We performed a post-hoc analysis of the TERRACE data to determine whether certain subsets of the patient population would gain more benefit than others from use of the device. Subjects were patients scheduled for colonoscopy for screening, surveillance or diagnostic workup, and each underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC), randomized to SC followed by TEC or vice versa.
RESULTS: Indication for colonoscopy was screening in 176/345 subjects (51.0%), surveillance after previous polypectomy in 87 (25.2%) and diagnostic workup in 82 (23.8%). In 4 subjects no indication was specified. Previously reported overall results had shown a net additional adenoma detection rate (ADR) with TEC of 23.2% compared to SC. Relative risk (RR) of missing adenomas with SC vs TEC as the initial procedure was 1.92 (P = 0.029). Post-hoc subset analysis shows additional ADRs for TEC compared to SC were 4.4% for screening, 35.7% for surveillance, 55.4% for diagnostic and 40.7% for surveillance and diagnostic combined. The RR of missing adenomas with SC vs TEC was 1.11 (P = 0.815) for screening, 3.15 (P = 0.014) for surveillance, 8.64 (P = 0.039) for diagnostic and 3.34 (P = 0.003) for surveillance and diagnostic combined. Although a multivariate Poisson regression suggested gender as a possibly significant factor, subset analysis showed that the difference between genders was not statistically significant. Age, bowel prep quality and withdrawal time did not significantly affect the RR of missing adenomas with SC vs TEC. Mean sizes of adenomas detected with TEC and SC were similar at 0.59 cm and 0.56 cm, respectively (P = NS).
CONCLUSION: TEC allows detection of significantly more adenomas compared to SC in patients undergoing surveillance or diagnostic workup, but not in screening patients (ClinicalTrials.gov Identifier: NCT01044732).
doi:10.3748/wjg.v18.i26.3400
PMCID: PMC3396192  PMID: 22807609
Colonoscopy; Colorectal cancer; Adenomas; Miss rates; Retrograde-viewing
18.  Pre-diagnostic concordance with the WCRF/AICR guidelines and survival in European colorectal cancer patients: a cohort study 
BMC Medicine  2015;13:107.
Background
Cancer survivors are advised to follow lifestyle recommendations on diet, physical activity, and body fatness proposed by the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) for cancer prevention. Previous studies have demonstrated that higher concordance with these recommendations measured using an index score (the WCRF/AICR score) was associated with lower cancer incidence and mortality. The aim of this study was to evaluate the association between pre-diagnostic concordance with WCRF/AICR recommendations and mortality in colorectal cancer (CRC) patients.
Methods
The association between the WCRF/AICR score (score range 0–6 in men and 0–7 in women; higher scores indicate greater concordance) assessed on average 6.4 years before diagnosis and CRC-specific (n = 872) and overall mortality (n = 1,113) was prospectively examined among 3,292 participants diagnosed with CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (mean follow-up time after diagnosis 4.2 years). Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality.
Results
The HRs (95% CIs) for CRC-specific mortality among participants in the second (score range in men/women: 2.25–2.75/3.25–3.75), third (3–3.75/4–4.75), and fourth (4–6/5–7) categories of the score were 0.87 (0.72–1.06), 0.74 (0.61–0.90), and 0.70 (0.56–0.89), respectively (P for trend <0.0001), compared to participants with the lowest concordance with the recommendations (category 1 of the score: 0–2/0–3). Similar HRs for overall mortality were observed (P for trend 0.004). Meeting the recommendations on body fatness and plant food consumption were associated with improved survival among CRC cases in mutually adjusted models.
Conclusions
Greater concordance with the WCRF/AICR recommendations on diet, physical activity, and body fatness prior to CRC diagnosis is associated with improved survival among CRC patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0332-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0332-5
PMCID: PMC4423114  PMID: 25948112
Colorectal cancer; Diet; Healthy lifestyle; Physical activity; Survival; Weight
19.  Cryospray ablation using pressurized CO2 for ablation of Barrett’s esophagus with early neoplasia: early termination of a prospective series 
Endoscopy International Open  2015;3(2):E107-E112.
Background: Cryotherapy is a relatively novel ablation modality for the endoscopic ablation of Barrett’s esophagus (BE). Data on the use of pressurized carbon dioxide (CO2) gas for cryoablation are scarce.
Study aim: To determine the efficacy and safety of cryospray ablation using pressurized CO2 gas in the treatment of BE with early neoplasia.
Methods: In this prospective single center case series, we aimed to include 30 patients with BE and early neoplasia. Nodular neoplastic lesions were treated with endoscopic mucosal resection (EMR). Residual BE mucosa was treated with cryospray ablation every 4 weeks until the complete BE segment was eliminated or up to seven treatment sessions. If no reduction of the BE segment was observed after two subsequent treatment sessions, cryoablation was terminated. Patients were contacted at days 1 and 4 post-treatment to evaluate the level of discomfort. Endoscopic and histologic follow-up evaluations were performed up to 24 months post-treatment.
Results: After the inclusion of 10 patients, insufficient effect of cryoablation was observed, resulting in early termination of the study. In total, seven patients with intramucosal carcinoma (IMC) and three with high grade dysplasia (HGD) were included. Prior EMR was performed in nine patients. A median of 2.5 (IQR 2.0 – 4.0) cryoablation sessions were performed. At 6 months of follow-up, complete eradication of intestinal metaplasia was observed in 11 % (1 /9; one patient died, not treatment or disease related) of the patients and complete eradication of dysplasia in 44 % (4 /9). In three patients, HGD or IMC was detected during follow-up, and was endoscopically treated. Apart from a gastric perforation as a result of gastric distension caused by CO2 gas during the first treatment, cryospray treatments were well tolerated.
Conclusion: After a short learning curve, cryoablation using CO2 gas was found to be a safe and well tolerated treatment modality. However, in our experience, the efficacy of CO2 cryoablation combined with EMR for nodular lesions is disappointing for the treatment of BE associated neoplasia.
doi:10.1055/s-0034-1390759
PMCID: PMC4477021  PMID: 26135648
20.  Surveillance for hepatocellular carcinoma in chronic liver disease: Evidence and controversies 
Primary liver cancer is the sixth most common cancer in the world and the third cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers and generally occurs in patients with underlying chronic liver disease such as viral hepatitis, hemochromatosis, primary biliary cirrhosis and non-alcoholic steatohepatitis. Especially cirrhotic patients are at risk of HCC and regular surveillance could enable early detection and therapy, with potentially improved outcome. We here summarize existing evidence for surveillance including ultrasound, other radiological modalities and various serum biomarkers, and current international guideline recommendations for surveillance. Ultrasound and α-fetoprotein (alone or in combination) are most frequently used for surveillance, but their sensitivities and specificities are still far from perfect, and evidence for surveillance remains weak and controversial. Various other potential surveillance tools have been tested, including serum markers as des-carboxyprothrombin, lectin-bound α-fetoprotein, and (most recently) circulating TIE2-expressing monocytes, and radiological investigations such as computed tomography-scan or magnetic resonance imaging-scan. Although early results appear promising, these tools have generally been tested in diagnostic rather than surveillance setting, and in most cases, no detailed information is available on their cost-effectiveness. For the near future, it remains important to define those patients with highest risk of HCC and most benefit from surveillance, and to restrict surveillance to these categories.
doi:10.3748/wjg.v19.i40.6744
PMCID: PMC3812474  PMID: 24187450
Hepatocellular carcinoma; Surveillance; Chronic liver disease
21.  Lifestyle, dietary factors and antibody levels to oral bacteria in cancer-free participants of a European cohort study 
Cancer causes & control : CCC  2013;24(11):10.1007/s10552-013-0265-2.
Background
Increasing evidence suggests that oral microbiota play a pivotal role in chronic diseases, in addition to the well-established role in periodontal disease. Moreover, recent studies suggest that oral bacteria may also be involved in carcinogenesis; periodontal disease has been linked several cancers. In this study, we examined whether lifestyle factors have an impact on antibody levels to oral bacteria.
Methods
Data on demographic characteristics, lifestyle factors, and medical conditions were obtained at the time of blood sample collection. For the current analysis, we measured antibody levels to 25 oral bacteria in 395 cancer-free individuals using an immunoblot array. Combined total immunglobin G (IgG) levels were obtained by summing concentrations for all oral bacteria measured.
Results
IgG antibody levels were substantially lower among current and former smokers (1697 and 1677 ng/mL, respectively) than never smokers (1960 ng/mL; p-trend = 0.01), but did not vary by other factors, including BMI, diabetes, physical activity, or by dietary factors, after adjusting for age, sex, education, country and smoking status. The highest levels of total IgG were found among individuals with low education (2419 ng/mL).
Conclusions
Our findings on smoking are consistent with previous studies and support the notion that smokers have a compromised humoral immune response. Moreover, other major factors known to be associated with inflammatory markers, including obesity, were not associated with antibody levels to a large number of oral bacteria.
doi:10.1007/s10552-013-0265-2
PMCID: PMC3823529  PMID: 23901020
22.  Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study 
BMC Medicine  2014;12:168.
Background
Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors – healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Methods
In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated.
Results
After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend <0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend <0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend <0.0001) for rectal cancer, respectively (P-difference by cancer sub-site = 0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index.
Conclusions
Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0168-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0168-4
PMCID: PMC4192278  PMID: 25319089
lifestyle factors; combined impact; population attributable risks; colorectal cancer; European Prospective Investigation into Cancer and Nutrition (EPIC)
23.  Squamous Tissue Lymphocytes in the Esophagus of Controls and Patients with Reflux Esophagitis and Barrett’s Esophagus Are Characterized by a Non-Inflammatory Phenotype 
PLoS ONE  2014;9(8):e106261.
Background and Objective
Reflux esophagitis (RE) is characterized by inflammation of the squamous epithelium (SQ) of the esophagus and may progress to Barrett’s esophagus (BE) characterized by intestinal metaplasia. The role of inflammation in this transition has been postulated but lacks experimental evidence. Here, the inflammatory responses in the esophagus of these patients were investigated.
Patients and Methods
Fifty-one esophageal biopsies from with patients BE (n = 19), RE (n = 8) and controls (n = 23) were analyzed. T-cells were analyzed before and after ex vivo expansion (14 days) by multicolor flow cytometric analysis. The following markers were studied: CD3, CD4, CD8 (T-cell markers), Granzyme B (marker of cytotoxicity), CD103 (αE/epithelial integrin) and NKg2a (inhibitory receptor on T-cells and NK-cells).
Results
Analysis of ex vivo cultures from normal looking SQ from controls, RE patients, and BE patients revealed no significant differences in the number and phenotypes of T-cells. In contrast, tissue from RE was different to normal SQ in four aspects: 1) higher percentages of CD3+CD4+-cells (72±7% vs 48±6%, p = 0.01) and 2) CD8+GranzymeB+ -cells (53±11% vs 26±4%, p<0.05), while 3) lower percentages of CD4+CD103+-cells (45±19% vs 80±3%, p = 0.02) and 4) CD8+NKg2a+- cells (31±12% vs 44±5%).
Conclusion
Despite the fact that both tissues are exposed to the same reflux associated inflammatory triggers, the immune response observed in RE is clearly distinct from that in SQ of BE. The differences in immune responses in BE tissue might contribute to its susceptibility for transformation into intestinal metaplasia.
doi:10.1371/journal.pone.0106261
PMCID: PMC4149547  PMID: 25170842
24.  Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial 
The lancet oncology  2014;15(3):353-360.
Summary
Background
Although colonoscopy is the accepted standard for detection of colorectal adenomas and cancers, many adenomas and some cancers are missed. To avoid interval colorectal cancer, the adenoma miss rate of colonoscopy needs to be reduced by improvement of colonoscopy technique and imaging capability. We aimed to compare the adenoma miss rates of full-spectrum endoscopy colonoscopy with those of standard forward-viewing colonoscopy.
Methods
We did an international, multicentre, randomised trial at three sites in Israel, one site in the Netherlands, and two sites in the USA between Feb 1, 2012, and March 31, 2013. Patients aged 18–70 years referred for colorectal cancer screening, polyp surveillance, or diagnostic assessment underwent same-day, back-to-back tandem colonoscopy with standard forward-viewing colonoscope and the full-spectrum endoscopy colonoscope. The patients were randomly assigned (1:1), via computer-generated randomisation with block size of 20, to which procedure was done first. The endoscopist was masked to group allocation until immediately before the start of colonoscopy examinations; patients were not masked. The primary endpoint was adenoma miss rates. We did per-protocol analyses. This trial is registered with ClinicalTrials.gov, number NCT01549535.
Findings
197 participants were enrolled. 185 participants were included in the per-protocol analyses: 88 (48%) were randomly assigned to receive standard forward-viewing colonoscopy first, and 97 (52%) to receive full-spectrum endoscopy colonoscopy first. By per-lesion analysis, the adenoma miss rate was significantly lower in patients in the full-spectrum endoscopy group than in those in the standard forward-viewing procedure group: five (7%) of 67 vs 20 (41%) of 49 adenomas were missed (p<0·0001). Standard forward-viewing colonoscopy missed 20 adenomas in 15 patients; of those, three (15%) were advanced adenomas. Full-spectrum endoscopy missed five adenomas in five patients in whom an adenoma had already been detected with first-pass standard forward-viewing colonoscopy; none of these missed adenomas were advanced. One patient was admitted to hospital for colitis detected at colonoscopy, whereas five minor adverse events were reported including vomiting, diarrhoea, cystitis, gastroenteritis, and bleeding.
Interpretation
Full-spectrum endoscopy represents a technology advancement for colonoscopy and could improve the efficacy of colorectal cancer screening and surveillance.
Funding
EndoChoice.
doi:10.1016/S1470-2045(14)70020-8
PMCID: PMC4062184  PMID: 24560453
25.  Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study 
Carcinogenesis  2013;34(6):1244-1250.
Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case–control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03–1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16–2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27–2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.
doi:10.1093/carcin/bgt045
PMCID: PMC3670256  PMID: 23389292

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