eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.

Vitamin d receptor gene variants and esophageal adenocarcinoma risk: a population-based case-control study.

PURPOSE: Polymorphisms in the vitamin D receptor (VDR) gene may be of etiological importance in determining cancer risk. The aim of this study was to assess the association between common VDR gene polymorphisms and esophageal adenocarcinoma (EAC) risk in an all-Ireland population-based case-control study. METHODS: EAC cases and frequency-matched controls by age and gender recruited between March 2002 and December 2004 throughout Ireland were included. Participants were interviewed, and a blood sample collected for DNA extraction. Twenty-seven single nucleotide polymorphisms in the VDR gene were genotyped using Sequenom or TaqMan assays while the poly(A) microsatellite was genotyped by fluorescent fragment analysis. Unconditional logistic regression was applied to assess the association between VDR polymorphisms and EAC risk. RESULTS: A total of 224 cases of EAC and 256 controls were involved in analyses. After adjustment for potential confounders, TT homozygotes at rs2238139 and rs2107301 had significantly reduced risks of EAC compared with CC homozygotes. In contrast, SS alleles of the poly(A) microsatellite had significantly elevated risks of EAC compared with SL/LL alleles. However, following permutation analyses to adjust for multiple comparisons, no significant associations were observed between any VDR gene polymorphism and EAC risk. CONCLUSIONS: VDR gene polymorphisms were not significantly associated with EAC development in this Irish population. Confirmation is required from larger studies.

The association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.

BACKGROUND & AIMS: Alcohol consumption may increase gastroesophageal reflux symptoms, cause damage to the esophageal mucosa, and/or promote carcinogenesis. However, reports about the association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma are conflicting. METHODS: Information relating to alcohol consumption, at age 21 and 5 years before the interview date, was collected from 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma patients and 260 frequency-matched population controls. Logistic regression analyses were used to compare alcohol consumption in the 3 case groups to controls with adjustment for potential confounders. RESULTS: Population controls reporting gastroesophageal reflux symptoms were less likely than controls without symptoms to drink alcohol 5 years before the interview date (odds ratio [OR], 0.44, 0.20-0.99). No associations were observed between total alcohol consumption 5 years before the interview date and reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma (OR, 1.26, 0.78-2.05; OR, 0.72, 0.43-1.21; and OR, 0.75, 0.46-1.22, respectively). Wine was inversely associated with reflux esophagitis (OR, 0.45, 0.27-0.75). Total alcohol consumption at age 21 years was significantly associated with reflux esophagitis (OR, 2.24, 1.35-3.74) but not with Barrett's esophagus or esophageal adenocarcinoma (OR, 1.06, 0.63-1.79 and OR, 1.27, 0.77-2.10, respectively). CONCLUSIONS: Alcohol consumption in early adulthood may lead to the development of reflux esophagitis. More recent alcohol consumption does not appear to confer any increased risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma. In fact, wine consumption may reduce the risk of these 3 esophageal disorders.

Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.

OBJECTIVE: To examine the association between dietary glycemic index (GI), glycemic load (GL), total carbohydrate, sugars, starch, and fiber intakes and the risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. METHODS: In an all-Ireland study, dietary information was collected from patients with esophageal adenocarcinoma (n = 224), long-segment Barrett's esophagus (n = 220), reflux esophagitis (n = 219), and population-based controls (n = 256). Multiple logistic regression analysis examined the association between dietary variables and disease risk by tertiles of intake and as continuous variables, while adjusting for potential confounders. RESULTS: Reflux esophagitis risk was positively associated with starch intake and negatively associated with sugar intake. Barrett's esophagus risk was significantly reduced in people in the highest versus the lowest tertile of fiber intake (OR 0.44 95%CI 0.25-0.80). Fiber intake was also associated with a reduced risk of esophageal adenocarcinoma, as was total carbohydrate intake (OR 0.45 95%CI 0.33-0.61 per 50 g/d increase). However, an increased esophageal adenocarcinoma risk was detected per 10 unit increase in GI intake (OR 1.42 95%CI 1.07-1.89). CONCLUSIONS: Our findings suggest that fiber intake is inversely associated with Barrett's esophagus and esophageal adenocarcinoma risk. Esophageal adenocarcinoma risk is inversely associated with total carbohydrate consumption but positively associated with high GI intakes.

Oesophageal cancer: caregiver mental health and strain.

OBJECTIVE: To investigate strain and mental health among family caregivers of oesophageal cancer patients and possible factors associated with caregiver mental health and strain. METHODS: Patients with oesophageal adenocarcinoma in Ireland were recruited into the FINBAR study (the main aim of which was to investigate factors influencing the Barrett's adenocarcinoma relationship). Carers completed the 13-item Caregiver Strain Index and the General Health Questionnaire-30 (GHQ) in the context of a brief interview with trained research staff that was undertaken separately from the interview with each cancer patient. RESULTS: Two hundred and twenty-seven patients participated in the FINBAR study. A total of 39 patients did not have a family carer or the carer could not be identified. Fifty percent (94/188) of carers completed the questionnaires. Mean (SD) scores for strain (6.65, SD=3.63) and mental health status (10.21, SD=7.30) were high and 71% of carers scored >5 on the GHQ indicating psychological distress. There was a statistically significant positive relationship between level of strain experienced by caregivers and the severity of their mental health status and whether or not carers scored >5 on the GHQ. Relatives were 1.70 (95% CI 1.34-2.15) times more likely to be defined as high scorers with each unit increase in the CSI score. CONCLUSIONS: A significant proportion of caregivers experienced high levels of strain and psychological distress. There is a need to provide appropriate support and services targeted specifically at reducing the considerable strain of caring for patients with oesophageal cancer, particularly for carers of patients from lower socioeconomic groups.

Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma has increased in recent years, and Barrett's esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of "prosurvival genes," including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser(608) Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barrett's esophagus or reflux esophagitis or between the iNOS Ser 608 Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.

No association between hOGG1, XRCC1, and XPD polymorphisms and risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma: results from the factors influencing the Barrett's adenocarcinoma relationship case-control study.

Reflux of gastric contents can lead to development of reflux esophagitis and Barrett's esophagus. Barrett's esophagus is a risk factor for esophageal adenocarcinoma. Damage to DNA may lead to carcinogenesis but is repaired through activation of pathways involving polymorphic enzymes, including human 8-oxoguanine glycosylase 1 (hOGG1), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum group D (XPD). Of the single nucleotide polymorphisms identified in these genes, hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln are particularly common in Caucasians and have been associated with lower DNA repair capacity. Small studies have reported associations with XPD Lys 751 Gln and esophageal adenocarcinoma. XRCC1 Arg 399 Gln has been linked to Barrett's esophagus and reflux esophagitis. In a population-based case-control study, we examined associations of the hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), reflux esophagitis (n = 230), and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. There were no statistically significant associations between these polymorphisms and risk of esophageal adenocarcinoma, Barrett's esophagus, or reflux esophagitis.

Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case-control study.

OBJECTIVE: A number of studies have shown an inverse association between infection with Helicobacter pylori and oesophageal adenocarcinoma (OAC). The mechanism of the apparent protection against OAC by H pylori infection and, in particular, the role of gastric atrophy is disputed. The relationship between all stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence and H pylori infection and gastric atrophy was explored. METHODS: A case-control study involving 260 population controls, 227 OAC, 224 Barrett's oesophagus (BO) and 230 reflux oesophagitis (RO) patients recruited within Ireland was carried out. H pylori and CagA (cytotoxin-associated gene product A) infection was diagnosed serologically by western blot, and pepsinogen I and II levels were measured by enzyme immunoassay. Gastric atrophy was defined as a pepsinogen I/II ratio of <3. RESULTS: H pylori seropositivity was inversely associated with OAC, BO and RO; adjusted ORs (95% CIs), 0.49 (0.31 to 0.76), 0.35 (0.22 to 0.56) and 0.42 (0.27 to 0.65), respectively. Gastric atrophy was uncommon (5.3% of all subjects), but was inversely associated with non-junctional OAC, BO and RO; adjusted ORs (95% CIs), 0.34 (0.10 to 1.24), 0.23 (0.05 to 0.96) and 0.27 (0.08 to 0.88), respectively. Inverse associations between H pylori and the disease states remained in gastric atrophy-negative patients. CONCLUSION: H pylori infection and gastric atrophy are associated with a reduced risk of OAC, BO and RO. While use of the pepsinogen I/II ratio as a marker for gastric atrophy has limitations, these data suggest that although gastric atrophy is involved it may not fully explain the inverse associations observed with H pylori infection.

Preoperative selection of symptomatic breast cancer patients appropriate for lymphatic mapping and sentinel node biopsy.

BACKGROUND: This study examines whether preoperative ultrasound-assessed tumour diameter and diagnostic core biopsy-determined grade can be used to select those most likely to benefit from SLNB (i.e. those that are "node negative") before their definitive operation. METHODS: Breast ultrasound (US) and a simultaneous core biopsy was performed in all patients at their initial presentation, and their estimates of tumor size and grade compared with the final pathological specimen (FPS). RESULTS: Of the T1 group 47% had lymphatic metastases as did 49% of those with grade I or II cancers. By combining these measures, however, subgroups of patients with lower rates of nodal metastases were identified (32% of patients with T1, non-grade III disease had lymphatic disease while only 15% of those with T < 1.5 cm, non-grade III cancers had such metastases). CONCLUSION: Combination of the US and ultrasound guided core biopsy (UGCB) may however identify subgroups unlikely to have axillary disease that are therefore suitable for SLNB.

Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.

AIM: To investigate risk factors associated with Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: This all-Ireland population-based case-control study recruited 224 Barrett's oesophagus patients, 227 oesophageal adenocarcinoma patients and 260 controls. All participants underwent a structured interview with information obtained about potential lifestyle and environmental risk factors. RESULTS: Gastro-oesophageal reflux was associated with Barrett's [OR 12.0 (95% CI 7.64-18.7)] and oesophageal adenocarcinoma [OR 3.48 (95% CI 2.25-5.41)]. Oesophageal adenocarcinoma patients were more likely than controls to be ex- or current smokers [OR 1.72 (95% CI 1.06-2.81) and OR 4.84 (95% CI 2.72-8.61) respectively] and to have a high body mass index [OR 2.69 (95% CI 1.62-4.46)]. No significant associations were observed between these risk factors and Barrett's oesophagus. Fruit but not vegetables were negatively associated with oesophageal adenocarcinoma [OR 0.50 (95% CI 0.30-0.86)]. CONCLUSION: A high body mass index, a diet low in fruit and cigarette smoking may be involved in the progression from Barrett's oesophagus to oesophageal adenocarcinoma.

A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma.

Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case-control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (> or =3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshottrade mark. The chi(2) test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy-Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43-1.08] to 1.25 (95% CI 0.73-2.16), and for BE from 0.84 (95% CI 0.52-1.30) to 1.30 (95% CI 0.85-1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.

Malignancy and mortality in a population-based cohort of patients with coeliac disease or "gluten sensitivity".

AIM: To determine the risk of malignancy and mortality in patients with a positive endomysial or anti-gliadin antibody test in Northern Ireland. METHODS: A population-based retrospective cohort study design was used. Laboratory test results used in the diagnosis of coeliac disease were obtained from the Regional Immunology Laboratory, cancer statistics from the Northern Ireland Cancer Registry and mortality statistics from the General Registrar Office, Northern Ireland. Age standardized incidence ratios of malignant neoplasms and standardized mortality ratios of all-cause and cause-specific mortality were calculated. RESULTS: A total of 13 338 people had an endomysial antibody and/or an anti-gliadin antibody test in Northern Ireland between 1993 and 1996. There were 490 patients who tested positive for endomysial antibodies and they were assumed to have coeliac disease. There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive. Malignant neoplasms were not significantly associated with coeliac disease; however, all-cause mortality was significantly increased following diagnosis. The standardized incidence and mortality ratios for non-Hodgkin's lymphoma were increased in coeliac disease patients but did not reach statistical significance. Lung and breast cancer incidence were significantly lower and all-cause mortality, mortality from malignant neoplasms, non-Hodgkin's lymphoma and digestive system disorders were significantly higher in gluten sensitive patients compared to the Northern Ireland population. CONCLUSION: Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies. Breast cancer is significantly reduced in the cohort of patients with gluten sensitivity.

Validation of lymphatic mapping and sentinel node biopsy in patients with symptomatic breast cancer.

BACKGROUND: Lymphatic mapping and sentinel node biopsy in breast cancer aims to allow lymph node negative women to avoid axillary clearance by providing a minimally invasive means of staging the axilla. However, before its implementation into routine clinical practice, initiating departments must verify their expertise in each of the surgical, radiological and pathological components necessary for its successful performance. Here, we present our validation experience. METHODS: Thirty patients with breast cancer of any stage (but without clinical axillary lymphadenopathy) undergoing definitive resection of their primary tumour underwent lymphatic mapping (using blue dye alone or in combination with radioisotope) and sentinel node biopsy concurrent with standard level II axillary clearance over a ten month period. RESULTS: All patients had sentinel nodes identified intraoperatively. The sentinel node in 29 patients correctly predicted the status of axillary involvement. One patient had non-sentinel nodal disease without metastases being identified in their sentinel node. Such a single false negative out of thirty patients is considered acceptable by current guidelines. CONCLUSION: Validation of expertise in sentinel node identification and analysis is feasible over a relatively short period of time in a regional symptomatic breast unit. We now feel confident in offering this procedure to selected patients with breast cancer in our catchment area in place of routine axillary clearance.

Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence.

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.

Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours.

BACKGROUND AND AIMS: Midgut carcinoid tumours are uncommon tumours with an unpredictable clinical behaviour and few useful prognostic markers. Somatostatin analogues are widely used in treatment but a survival advantage has not been proven. We analysed features associated with poor prognosis and assessed the clinical implications of the biochemical response to therapy. METHODS: Clinical and biochemical data were collected for patients with midgut carcinoid tumours attending a tertiary referral neuroendocrine clinic from 1978 to 2000. Using death as the end point, univariate and multivariate survival analyses were performed to identify prognostic indicators. The significance of altering biomarkers with therapy was also studied by including repeated measurements of the most prognostic biochemical parameter in a time dependent covariate survival analysis. RESULTS: We identified 139 patients with sufficient data for our analyses. Factors associated with a poor outcome on univariate analysis included: plasma neurokinin A (NKA), urinary 5-hydroxyindolacetic acid output, age, and >/=5 liver metastases. Plasma NKA was the strongest and only independent predictor of outcome on multivariate analysis. Patients in whom NKA continued to rise despite somatostatin analogues had a significantly worse survival than those in whom NKA stabilised or fell (one year survival rate 40% v 87%). Time dependent covariate analysis concluded that survival was better predicted by the most recent plasma NKA value rather than by the initial value. CONCLUSIONS: Plasma NKA is an accurate marker of prognosis for midgut carcinoid tumours. This is the first paper to support a survival advantage in patients in whom plasma NKA is altered by somatostatin analogues.

Incidence of colorectal cancer in a population-based cohort of patients with Barrett's oesophagus.

OBJECTIVE: Previous studies have shown a positive association between colorectal cancer and Barrett's oesophagus, but this association is disputed. No population-based studies have examined the incidence of this cancer in patients with Barrett's oesophagus. MATERIAL AND METHODS: The present study comprised a population-based cohort of patients with Barrett's oesophagus (constructed using pathology reports of all oesophageal biopsies in Northern Ireland 1993-99; cohort subclassified according to whether specialized intestinal metaplasia (SIM) was present, absent, or not commented on in biopsies). Cases of colorectal cancer were identified by linking with the Northern Ireland Cancer Registry. The comparison group used was the general population in Northern Ireland. RESULTS: A total of 2969 patients with Barrett's oesophagus were followed for a total of 14,014 person-years (mean 4.7 years). SIM was present in 1670 patients (56.2%), absent in 545 (18.4%) and not commented on in 754 (25.4%). Colorectal cancer was diagnosed in 39 patients; 22 patients had cancer diagnosed at least 6 months after diagnosis of Barrett's oesophagus. There was no increased risk of colorectal cancer: the standardized incidence ratio (SIR) for cancer diagnosed at least 6 months after entry into the cohort was 0.82 (95% CI, 0.48-1.17); this risk did not alter with SIM status or gender. To assess a possible effect of diagnostic bias, we calculated SIRs for cancers occurring after at least 3 months, after at least 1 month and at any time after diagnosis of Barrett's oesophagus. These were 0.94 (0.57-1.30), 1.09 (0.69-1.48) and 1.46 (1.00-1.92), respectively. CONCLUSIONS: The incidence of colorectal cancer was not elevated in patients with Barrett's oesophagus. Diagnostic bias may explain why previous studies have found an association.

Coeliac disease-associated antibodies correlate with psoriasis activity.

BACKGROUND: Antigliadin antibodies (AGA) have been reported in patients with psoriasis. OBJECTIVES: To determine if AGA and other coeliac disease (CD)-associated antibodies correlate with clinical features and activity in patients with psoriasis. METHODS: Patients with psoriasis (n = 130) were investigated for serum IgG and IgA AGA, IgA antitransglutaminase antibody and IgA antiendomysial antibody. Disease characteristics and associated bowel and joint symptoms were determined. All patients were invited to undertake endoscopy with duodenal biopsy. RESULTS: A significantly higher proportion of patients with elevated CD-associated antibody levels was currently on or had previously required systemic immunosuppressants (methotrexate, ciclosporin or etretinate; P = 0.04) or psoralen plus ultraviolet A phototherapy (P = 0.03). One case of CD was diagnosed. CONCLUSIONS: The presence of CD-associated antibodies in psoriasis patients correlates with greater disease activity.