"True" Helicobacter pylori infection and non-cardia gastric cancer: A pooled analysis within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: Helicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status. METHODS: A pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted. RESULTS: The OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology. CONCLUSION: The NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

Identifying the Profile of Helicobacter pylori-Negative Gastric Cancers: A Case-Only Analysis within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: The prevalence of Helicobacter pylori-negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors. METHODS: Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serologic test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (OR). RESULTS: Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n = 166/853) and decreased to 7.0% (n = 55) when considering CagA status; estimates for all criteria were 21.8% (n = 276/1,325) and 6.6% (n = 97), respectively. HpNGC had a family history of gastric cancer more often [OR = 2.18; 95% confidence interval (CI), 1.03-4.61] and were current smokers (OR = 2.16; 95% CI, 0.52-9.02). CONCLUSION: This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives. IMPACT: Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.

Worldwide and Regional Efficacy Estimates of First-line Helicobacter pylori Treatments: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Eradication of Helicobacter pylori infection is challenging. We aimed to determine the optimal first-line H. pylori treatments at global and regional levels. METHODS: We searched Embase, PubMed, Cochrane CENTRAL, Web of Science, Scopus, WHO ICTRP, ClinicalTrials.gov, and ISRCTN registry, for randomized controlled trials published during 2011-2020. Utilizing a network meta-analysis in a Bayesian framework, success rates of 23 regimens were compared. The effect size was standardized risk ratio (RR) with 95% credible interval (CrI). Pooled eradication rate (ER) with 95% CrI was also reported for top combinations. The reference regimen was 7-day clarithromycin-based triple therapy. RESULTS: This review identified 121 trials comprising 34,759 participants. Globally, 14-day levofloxacin-based sequential therapy was the most efficient (RR: 1.43; 95% CrI, 1.26-1.59) with low certainty of evidence, followed by modified bismuth-containing quadruple therapy (proton pump inhibitor+bismuth compounds+clarithromycin+amoxicillin) for 10 days (RR: 1.35; 95% CrI, 1.22-1.48) and 14 days (RR: 1.27; 95% CrI, 1.12-1.42), and 14-day hybrid therapy (RR: 1.27; 95% CrI, 1.19-1.36). The corresponding ERs were 98.7% (95% CrI, 86.9-100.0), 93.2% (95% CrI, 84.2-100.0), 87.6% (95% CrI, 82.1-93.8), and 87.6% (95% CrI, 77.3-98.0), respectively. Continentally, the most effective combinations were: 10-day clarithromycin-based sequential therapy [(RR: 1.21; 95% CrI, 1.02-1.42), (ER: 89.5%, 95% CrI, 75.5-100.0)] for Africa, 14-day levofloxacin-based sequential therapy [(RR: 1.41; 95%CrI, 1.27-1.58), (ER: 98.7%, 95% CrI, 88.9-100.0)] for Asia, and 14-day clarithromycin-based triple therapy [(RR: 1.58; 95% CrI, 1.25-2.04), (ER: 94.8%; 95% CrI, 75.0-100.0)] for Europe. For Northern America, no sufficient data were found for network meta-analysis. In South America, none of the combinations were superior to the reference regimen. CONCLUSION: Although results of this network meta-analysis revealed optimal combinations for empiric therapy, the treatment preference would be based on the local pattern of antibacterial resistance, when the necessary information exists.

Gastric Cancer in Iran: An Overview of Risk Factors and Preventive Measures.

Despite all recent treatment advances and the worldwide decline in the incidence rate, gastric cancer (GC) remains an ongoing global health challenge and one of the major leading causes of cancer-specific deaths, particularly in high-incidence regions including Iran. Since GC is often diagnosed in advanced stages, the best action may be to enable early diagnosis of the disease or even prevent it in the first place through identification and control of the underlying risk factors. Endoscopy, as the gold standard method, is both expensive and invasive, making it an unfavorable device in this regard. Therefore, it is crucial to implement a reliable region-specific screening and surveillance program to identify high-risk individuals with more efficient screening modalities. Here, in addition to a review of current GC knowledge, we presented the data of newly-established Population-based Cancer Registries (PBCRs) in Iran. Our assessment confirmed earlier reports of a very high GC incidence rate in the northwestern and northern provinces of Iran, most notably Ardabil. Along with the important role of conventional risk factors such as Helicobacter pylori (HP) infection and high dietary intake of salt, of more interest, we highlighted new region-specific risk factors, namely hookah, and opium. In conclusion, it seems the best results in reducing GC incidence and mortality rates on larger scales arise from modifying behavioral and environmental risk factors and advancing genetic and molecular biomarkers in order to supersede endoscopy. Regular endoscopic screening and antibiotic chemoprophylaxis against HP are still more appropriate in high-risk groups with specified criteria.

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts.

OBJECTIVE: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. DESIGN: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. RESULTS: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. CONCLUSION: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.

Predictors of extra-articular manifestations in axial spondyloarthritis and their influence on TNF-inhibitor prescribing patterns: results from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis.

OBJECTIVES: Extra-articular manifestations (EAMs) are important systemic features of axial spondyloarthritis (axSpA), which may influence the choice of tumour necrosis factor-inhibitor (TNFi). We examined the cumulative incidence and predictors of EAMs and the influence of these on first TNFi choice in a 'real-world' cohort of patients with axSpA. METHODS: Clinical and patient-reported outcomes of 2420 patients with axSpA from 83 centres were collected by the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis. Lifestyle factors for EAMs (acute anterior uveitis (AAU), inflammatory bowel diseases (IBD), psoriasis) were compared with those without EAMs. Also, the association between pretreatment EAMs and choice of first TNFi (adalimumab, etanercept, certolizumab) was analysed. RESULTS: AAU was directly associated with human leukocyte antigen (HLA)-B27 (incidence rate ratio (IRR) 1.95, 95% CI 1.40 to 2.73) and inversely associated with ever-smoking (IRR=0.71, 95% CI 0.55 to 0.92). For both psoriasis and IBD, there was an inverse relationship with HLA-B27 (IRR 0.54, 95% CI 0.36 to 0.79 and IRR 0.63, 95% CI 0.43 to 0.91, respectively). A diagnosis of either AAU (OR 3.79, 95% CI 2.11 to 6.80) or IBD (OR 5.50, 95% CI 2.09 to 14.46) was associated with preference for adalimumab versus others. In contrast, a diagnosis of either AAU (OR 0.14, 95% CI 0.06 to 0.33) or IBD (OR 0.17, 95% CI 0.05 to 0.57) was associated with less preference for etanercept over other TNFi. CONCLUSION: The higher occurrence of AAU and lower occurrence of psoriasis and IBD in HLA-B27-positive patients with axSpA are consistent with current pathophysiology. Patients with previous AAU and IBD are more likely to be prescribed adalimumab and less likely to receive etanercept, consistent with the superior efficacy of monoclonal TNFi for these indications. Future work will determine whether EAMs influence TNFi survival, or effectiveness, and whether this varies between agents.

Sex differences in the prevalence of Helicobacter pylori infection: an individual participant data pooled analysis (StoP Project).

BACKGROUND: Helicobacter pylori (H. pylori) infection is more frequent among men, though the magnitude of the association might be inaccurate due to potential misclassification of lifetime infection and publication bias. Moreover, infection is common, and most studies are cross-sectional. Thus, prevalence ratios (PRs) may be easier to interpret than odds ratios (ORs). AIM: The aim of this study was to quantify the association between sex and H. pylori infection using controls from 14 studies from the Stomach Cancer Pooling (StoP) Project. PARTICIPANTS AND METHODS: H. pylori infection was defined based on IgG serum antibody titers or multiplex serology. Participants were also classified as infected if gastric atrophy was present, based on histological examination or serum pepsinogen (PG) levels (PG I≤70 and PG I/II ratio≤3). Summary ORs and PRs, adjusted for age, social class and smoking, and corresponding 95% confidence intervals (CIs), were estimated through random-effects meta-analysis. RESULTS: Men had significantly higher OR (OR: 1.33, 95% CI: 1.04-1.70) and PR (PR: 1.05, 95% CI: 1.00-1.10) of infection, with stronger associations among hospital-based or older controls. Results were similar when considering the presence of gastric atrophy to define infection status, particularly among participants older than 65 years. CONCLUSION: This collaborative pooled-analysis supports an independent effect of sex on the prevalence of H. pylori infection, while minimizing misclassification of lifetime infection status and publication bias.

Association of Diverticulitis with Prolonged Spondyloarthritis: An Analysis of the ASAS-COMOSPA International Cohort.

This study examined the relationship between spondyloarthritis (SpA) duration and gastrointestinal comorbidities other than inflammatory bowel disease (IBD). We evaluated the association between SpA duration and upper gastrointestinal ulcers, hepatitis B (HBV), hepatitis C (HCV) and diverticulitis using data from a large international cross-sectional study. Binary regression models were created, adjusted for age, sex, body mass index (BMI), smoking, alcohol, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), biologics, steroids, IBD history and country. Subgroup analysis was performed by disease phenotype. The data of 3923 participants were analysed. The prevalence of gastrointestinal conditions were 10.7% upper gastrointestinal ulcers; 4.7% viral hepatitis and 1.5% diverticulitis. While SpA duration was not associated with upper gastrointestinal ulcers, HBV or HCV, longer SpA duration was significantly associated with diverticulitis (odds ratios (OR) = 1.18, 95% confidence interval (CI): 1.03⁻1.34), reflecting an 18% increase for every five years of SpA duration. Other significant associations with diverticulitis were age and high alcohol intake but not medication history. In subgroup analyses, the association was strongest with those with axial SpA. The reasons for this association of increased diverticulitis with disease duration in SpA, especially those with axial disease, are unclear but may reflect shared underlying gut inflammation. Diverticulitis should be considered, in addition to IBD, when SpA patients present with lower gastrointestinal symptoms.

Increased Risk of Hypertension Associated with Spondyloarthritis Disease Duration: Results from the ASAS-COMOSPA Study.

OBJECTIVE: Spondyloarthritis (SpA) is associated with a number of cardiovascular (CV) comorbidities. We examined the association of SpA disease duration and delay in diagnosis with CV-related conditions. METHODS: Using data from the COMOSPA study, the associations between SpA disease duration and CV-related conditions were evaluated in univariable and multivariable logistic regression models. Each model examined 1 CV-related factor as dependent and "SpA disease duration" as a predictor, adjusted for relevant confounders. RESULTS: Data from 3923 subjects (median SpA disease duration 5.1 yrs, interquartile range 1.3-11.8 yrs) were available for analysis. The main CV-related conditions were hypertension (HTN; 22.4%), ischemic heart disease (2.6%), stroke (1.3%), and diabetes mellitus (5.5%). HTN was associated with SpA disease duration in both univariable and multivariable analysis, with an OR of 1.129 (95% CI 1.072-1.189; p < 0.001) for each 5-year increase in SpA disease duration. Other factors associated with HTN were age, male sex, current body mass index, ever steroid therapy, and ever synthetic disease-modifying antirheumatic drug therapy, but not nonsteroidal antiinflammatory drugs (NSAID). In subgroup analysis, the strongest association of HTN and disease duration was seen in subjects with the axial-only SpA phenotype (OR 1.202, 95% CI 1.053-1.372) but not in those with peripheral-only SpA (OR 0.902, 95% CI 0.760-1.070). The other CV conditions were not associated with SpA disease duration. CONCLUSION: Duration of SpA disease in the ASAS-COMOSPA cohort is associated with higher odds of HTN, particularly in those with axial disease, but not with other CV-related conditions. The association with HTN does not appear to be related to NSAID exposure.

Smoking and Helicobacter pylori infection: an individual participant pooled analysis (Stomach Cancer Pooling- StoP Project).

Smoking has been associated with acquisition and increased persistence of Helicobacter pylori infection, as well as with lower effectiveness of its eradication. A greater prevalence of infection among smokers could contribute to the increased risk for gastric cancer. We aimed to estimate the association between smoking and seropositivity to H. pylori through an individual participant data pooled analysis using controls from 14 case-control studies participating in the Stomach Cancer Pooling Project. Summary odds ratios and prevalence ratios (PRs), adjusted for age, sex and social class, and the corresponding 95% confidence intervals (CIs) were estimated through random-effects meta-analysis. Heterogeneity was quantified using the I statistic and publication bias with Egger's test. There was no significant association between smoking (ever vs. never) and H. pylori seropositivity (adjusted odds ratio = 1.08; 95% CI: 0.89-1.32; adjusted PR = 1.01; 95% CI: 0.98-1.05). The strength of the association did not increase with the intensity or duration of smoking; stratified analyses according to sex, age, region or type of sample did not yield a consistent pattern of variation or statistically significant results, except for participants younger than 55 years and who had been smoking for more than 30 years (adjusted PR = 1.08; 95% CI: 1.02-1.15). This is the first collaborative analysis providing pooled estimates for the association between smoking and H. pylori seropositivity, based on detailed and uniform information and adjusting for major covariates. The results do not support an association between smoking and H. pylori infection.

The efficacy of first-line regimens for Helicobacter pylori eradication in different continents: A systematic review and network meta-analysis protocol.

BACKGROUND: Striking prevalence of Helicobacter pylori infection has been convoluted with considerable resistance to various antibiotics worldwide. Although many eradication regimens have been introduced as the first-line therapies against H pylori, lack of appropriate multiple comparison studies makes hard to implement such results to the clinical practice. This project attempts to utilize a comprehensive network meta-analysis to pool the results of clinical trial comparing various first-line eradication therapies simultaneously in different continents. METHODS: We will include all randomized controlled trials assessing the first-line regimens for treatment of H pylori published in last 10 years. We will search the databases of PubMed, EMBASE, Scopus, Web of Science and Cochrane Central Register of Controlled Trials, International Standard Randomised Controlled Trial Number registry, World Health Organisation International Clinical Trials Registry Platform, and ClinicalTrials.gov for randomized controlled trials published since January 2009 without language limitation. The primary and secondary outcomes will be H pylori eradication rate and adverse events, respectively. Subgroup analyses will be conducted for different continents. Two reviewers will independently contribute in study selection and data extraction. For evaluating quality of studies, Cochrane Collaboration tool score will be used. We will conduct network meta-analysis for treatment comparisons using STATA software version 13. RESULTS: These findings will be submitted to a peer-reviewed journal for publication. CONCLUSION: Our results will provide the guidance for clinicians in deferent regions to select the best possible therapeutic regimen for treatment of H pylori infected patients. REGISTRATION NUMBER: This systematic review and network meta-analysis has been registered in the PROSPERO International Prospective Register of Systematic Reviews, with registration number CRD42017077061.

Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome.

OBJECTIVES: To determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management. METHODS: The Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: <2.0×10^9/L; grade 2: <1.5×10^9/L; grade 3: <1.0×10^9/L; grade 4: <0.5×10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades. RESULTS: 77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6-48) months. Neutropaenia occurred at a median (range) of 12 (0-120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p<0.0001). Binomial regression analysis confirmed the latter (p<0.0001, B: -0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878). CONCLUSION: Neutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels.

Alcohol intake and gastric cancer: Meta-analyses of published data versus individual participant data pooled analyses (StoP Project).

BACKGROUND: Individual participant data pooled analyses allow access to non-published data and statistical reanalyses based on more homogeneous criteria than meta-analyses based on systematic reviews. We quantified the impact of publication-related biases and heterogeneity in data analysis and presentation in summary estimates of the association between alcohol drinking and gastric cancer. METHODS: We compared estimates obtained from conventional meta-analyses, using only data available in published reports from studies that take part in the Stomach Cancer Pooling (StoP) Project, with individual participant data pooled analyses including the same studies. RESULTS: A total of 22 studies from the StoP Project assessed the relation between alcohol intake and gastric cancer, 19 had specific data for levels of consumption and 18 according to cancer location; published reports addressing these associations were available from 18, 5 and 5 studies, respectively. The summary odds ratios [OR, (95%CI)] estimate obtained with published data for drinkers vs. non-drinkers was 10% higher than the one obtained with individual StoP data [18 vs. 22 studies: 1.21 (1.07-1.36) vs. 1.10 (0.99-1.23)] and more heterogeneous (I2: 63.6% vs 54.4%). In general, published data yielded less precise summary estimates (standard errors up to 2.6 times higher). Funnel plot analysis suggested publication bias. CONCLUSION: Meta-analyses of the association between alcohol drinking and gastric cancer tended to overestimate the magnitude of the effects, possibly due to publication bias. Additionally, individual participant data pooled analyses yielded more precise estimates for different levels of exposure or cancer subtypes.

Services for spondyloarthritis: a survey of patients and rheumatologists.

Objectives: There have been significant advances in axial spondyloarthritis (axSpA), with implications for service delivery. We evaluated the state of axSpA rheumatology services and how people with axSpA perceive their care. Methods: An online patient survey was emailed to all members of the National Ankylosing Spondylitis Society and advertised widely via social media. Separately, a Web-based questionnaire about axSpA services was sent to rheumatologists at all 172 acute hospital trusts in the UK. Results: From the National Ankylosing Spondylitis Society survey, data for 1979 surveys (56% males) were available for analysis. The majority of respondents had longstanding disease and identified their diagnosis as AS, with only 44% aware of the term axSpA. Eighty-two per cent of respondents were currently attending a rheumatologist, with 43% on biologic agents. Satisfaction scores for rheumatology care were high. Respondents' concerns included access during disease flares and adverse effects of analgesics. From the rheumatology survey, the concept and terminology of axSpA was widely accepted by respondents (88%). The majority of centres had at least one rheumatologist with a specialist interest in axSpA (62%), dedicated axSpA clinics (58%) or a multidisciplinary team for axSpA (64%). BASDAI (99%), BASFI (74%) and BASMI (65%) were routinely performed. All centres had access to MRI scans, but scanning protocols varied and were often sub-optimal. Conclusion: Although overall satisfaction with rheumatology care was high, the results indicate significant unmet patient needs and discrepancies in service provision. This information will inform the development of quality standards for axSpA in order to improve quality and deliver equitable care for all patients.

Tobacco smoking and gastric cancer: meta-analyses of published data versus pooled analyses of individual participant data (StoP Project).

Tobacco smoking is one of the main risk factors for gastric cancer, but the magnitude of the association estimated by conventional systematic reviews and meta-analyses might be inaccurate, due to heterogeneous reporting of data and publication bias. We aimed to quantify the combined impact of publication-related biases, and heterogeneity in data analysis or presentation, in the summary estimates obtained from conventional meta-analyses. We compared results from individual participant data pooled-analyses, including the studies in the Stomach Cancer Pooling (StoP) Project, with conventional meta-analyses carried out using only data available in previously published reports from the same studies. From the 23 studies in the StoP Project, 20 had published reports with information on smoking and gastric cancer, but only six had specific data for gastric cardia cancer and seven had data on the daily number of cigarettes smoked. Compared to the results obtained with the StoP database, conventional meta-analyses overvalued the relation between ever smoking (summary odds ratios ranging from 7% higher for all studies to 22% higher for the risk of gastric cardia cancer) and yielded less precise summary estimates (SE ≤2.4 times higher). Additionally, funnel plot asymmetry and corresponding hypotheses tests were suggestive of publication bias. Conventional meta-analyses and individual participant data pooled-analyses reached similar conclusions on the direction of the association between smoking and gastric cancer. However, published data tended to overestimate the magnitude of the effects, possibly due to publication biases and limited the analyses by different levels of exposure or cancer subtypes.

Cigarette smoking and gastric cancer in the Stomach Cancer Pooling (StoP) Project.

Tobacco smoking is a known cause of gastric cancer, but several aspects of the association remain imprecisely quantified. We examined the relation between cigarette smoking and the risk of gastric cancer using a uniquely large dataset of 23 epidemiological studies within the 'Stomach cancer Pooling (StoP) Project', including 10 290 cases and 26 145 controls. We estimated summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects models. Compared with never smokers, the ORs were 1.20 (95% CI: 1.09-1.32) for ever, 1.12 (95% CI: 0.99-1.27) for former, and 1.25 (95% CI: 1.11-1.40) for current cigarette smokers. Among current smokers, the risk increased with number of cigarettes per day to reach an OR of 1.32 (95% CI: 1.10-1.58) for smokers of more than 20 cigarettes per day. The risk increased with duration of smoking, to reach an OR of 1.33 (95% CI: 1.14-1.54) for more than 40 years of smoking and decreased with increasing time since stopping cigarette smoking (P for trend<0.01) and became similar to that of never smokers 10 years after stopping. Risks were somewhat higher for cardia than noncardia gastric cancer. Risks were similar when considering only studies with information on Helicobacter pylori infection and comparing all cases to H. pylori+ controls only. This study provides the most precise estimate of the detrimental effect of cigarette smoking on the risk of gastric cancer on the basis of individual data, including the relationship with dose and duration, and the decrease in risk following stopping smoking.

ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.

OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.

A single nucleotide polymorphism in codon F31I and V57I of the AURKA gene in invasive ductal breast carcinoma in Middle East.

Although few studies have suggested a carcinogenic role for polymorphism of F31I and V57I codons of AURKA gene in invasive ductal carcinoma, contradictory results from different populations mandates regional investigations. We aimed to determine polymorphisms of F31I and V57I codons of AURKA gene and their association with cancer prognosis in patients compared with controls in an eastern population of Iran.A case-control study was conducted on specimens from 100 patients and 100 age- and gender-matched controls. DNA was extracted and the codons F31I and V57I were amplified. The different genotypes were analyzed by PCR-RFLP and electrophoresis.In codon F31I, the frequency of Phe/Ile was 70% and 82% in patients and healthy controls respectively, whereas (Ile/Ile) was 30% in patients and 18% in healthy (P = .047). Analyzing V57I genotypes showed a higher homozygote Val/Val genotype in patients compared with controls (76% vs 68%), whereas the frequency of heterozygous Val/Ile genotype was lower in patients (17%) than controls (30%), yielding a marginal association between breast cancer and Val/Val genotype (P = .048). No association was observed between SNPs of either F31I or V57I genotypes and histological grades. However, there was a significant association between tumor stages and F31I genotype (P for trend = .003).This is the first report of F31I and V57I polymorphisms in AURKA gene in breast cancer in Iran. Determination of allelic polymorphism of those codons will help to understand background genetic predisposition and could have prognostic value in management of breast cancer in the target population.

Abdominal Compression by Waist Belt Aggravates Gastroesophageal Reflux, Primarily by Impairing Esophageal Clearance.

BACKGROUND & AIMS: Central obesity promotes gastroesophageal reflux, which may be related to increased intra-abdominal pressure. We investigated the effect of increasing abdominal pressure by waist belt on reflux in patients with reflux disease. METHODS: We performed a prospective study of patients with esophagitis (n = 8) or Barrett's esophagus (n = 6); median age was 56 years and median body mass index was 26.8. Proton pump inhibitors were stopped at least 7 days before the study and H2 receptor antagonists were stopped for at least 24 hours before. The severity of upper GI symptoms was assessed and measurements of height, weight, and waist and hip circumference taken. Combined high-resolution pH measurement and manometry were performed in fasted state for 20 minutes and for 90 minutes following a standardized meal. The squamocolumnar junction was marked by endoscopically placed radiopaque clips. The procedures were performed with and without a waist belt (a weight-lifter belt applied tightly and inflated to a constant cuff pressure of 50 mmHg). We compared variables between groups using the Wilcoxon Signed Rank test and tested for correlations using Spearman Rho bivariate analysis. RESULTS: Without the belt, intragastric pressure correlated with waist circumference (r = 0.682; P = .008), with the range in pressure between smallest and largest waist circumference being 15 mmHg. The belt increased intragastric pressure by a median of 6.9 mmHg during fasting (P = .002) and by 9.0 mmHg after the meal (P = .001). Gastroesophageal acid reflux at each of the pH sensors extending 5.5 cm proximal to the peak lower esophageal sphincter pressure point was increased by approximately 8-fold by the belt (all P < .05). Following the meal, the mean number of reflux events with the belt was 4, vs 2 without (P = .008). Transient lower esophageal sphincter relaxations were not increased by the belt, but those associated with reflux were increased (2 vs 3.5; P = .04). The most marked effect of the belt was impaired esophageal clearance of refluxed acid (median values of 23.0 seconds without belt vs 81.1 seconds with belt) (P = .008). The pattern of impaired clearance was that of rapid re-reflux after peristaltic clearance. CONCLUSIONS: In a prospective study of patients with esophagitis or Barrett's esophagus, we found belt compression increased acid reflux following a meal. The intragastric pressure rise inducing this effect is well within the range associated with differing waist circumference and likely to be relevant to the association between obesity and reflux disease.