Costing the economic burden of prolonged sedentary behaviours in France.

BACKGROUND: There is strong evidence showing that sedentary behaviour time increase the risk to develop several chronic diseases and to premature death. The economic consequences of this risk have never been evaluated in France. The aim of this study was to estimate the economic burden of prolonged sedentary behaviour in France. METHODS: Based on individual sedentary behaviour time, relative risk to develop cardiovascular disease, colon cancer, breast cancer and all-causes of premature mortality were identified. From relative risk and prevalence of sedentary behaviour time, a population attributable fraction approach was used to estimate the yearly number of cases for each disease. Data from the National Health Insurance were used to calculate the annual average costs per case for each disease. Disease-specific and total healthcare costs attributable to prolonged sedentary behaviour time were calculated. Indirect costs from productivity loss due to morbidity and premature mortality were estimated using a friction cost approach. RESULTS: In France, 51 193 premature deaths/year appear related to a prolonged daily sedentary behaviour time. Each year prolonged sedentary behaviour cost 494 million € for the national health insurance. Yearly productivity loss due to premature mortality attributable to prolonged sedentary behaviour cost 507 million € and yearly productivity loss due to morbidity cost between 43 and 147 million €. CONCLUSION: Significant saving and many deaths could be avoided by reducing prolonged sedentary behaviour prevalence in France. To address this issue, strong responses should be implemented to tackle sedentary behaviour, complementary to physical activity promotion.

Meat Intake Is Associated with a Higher Risk of Ulcerative Colitis in a Large European Prospective Cohort Studyø.

BACKGROUND AND AIMS: We aimed to investigate the association between protein intake and risk of inflammatory bowel disease [IBD] in the European Prospective Investigation into Cancer and Nutrition. METHODS: A total of 413 593 participants from eight European countries were included. Dietary data were collected at baseline from validated food frequency questionnaires. Dietary data were calibrated to correct errors in measures related to each country-specific questionnaire. Associations between proteins [total, animal, and vegetable] or food sources of animal proteins, and IBD risk were estimated by Cox proportional hazard models. RESULTS: After a mean follow-up of 16 years, 177 patients with Crohn's disease [CD] and 418 with ulcerative colitis [UC], were identified. There was no association between total protein, animal protein, or vegetable protein intakes and CD or UC risks. Total meat and red meat intakes were associated with UC risk (hazard ratio [HR] for the 4th vs 1st quartile = 1.40, 95% confidence interval [CI] = 0.99-1.98, p-trend = 0.01; and 1.61, 95% CI = 1.10-2.36, p-trend = 0.007, respectively]. There was no association between other food sources of animal protein [processed meat, fish, shellfish, eggs, poultry] and UC. We found no association between food sources of animal proteins and CD risk. CONCLUSIONS: Meat and red meat consumptions are associated with higher risks of UC. These results support dietary counselling of low meat intake in people at high-risk of IBD.

Prediagnostic Serum Vitamin D Levels and the Risk of Crohn's Disease and Ulcerative Colitis in European Populations: A Nested Case-Control Study.

Background: A low vitamin D status has been put forward as a potential risk factor for the development of inflammatory bowel disease (IBD). This study investigated the association between prediagnostic circulating vitamin D concentrations and dietary intakes of vitamin D, and the risk of Crohn's disease (CD) and ulcerative colitis (UC). Methods: Among 359,728 participants of the European Prospective Investigation into Cancer and Nutrition cohort, individuals who developed CD or UC after enrollment were identified. Each case was matched with2 controls by center, gender, age, date of recruitment, and follow-up time. At cohort entry, blood samples were collected and dietary vitamin D intakes were obtained from validated food frequency questionnaires. Serum 25-hydroxyvitamin D levels were measured using liquid chromatography-tandem mass spectrometry. Conditional logistic regression was performed to determine the odds of CD and UC. Results: Seventy-two participants developed CD and 169 participants developed UC after a median follow-up of 4.7 and 4.1 years, respectively. Compared with the lowest quartile, no associations with the 3 higher quartiles of vitamin D concentrations were observed for CD (p trend = 0.34) or UC (p trend = 0.66). Similarly, no associations were detected when serum vitamin D levels were analyzed as a continuous variable. Dietary vitamin D intakes were not associated with CD (p trend = 0.39) or UC (p trend = 0.83). Conclusions: Vitamin D status was not associated with the development of CD or UC. This does not suggest a major role for vitamin D deficiency in the etiology of IBD, although larger studies are needed to confirm these findings.

Fibre intake and the development of inflammatory bowel disease: A European prospective multi-centre cohort study (EPIC-IBD).

BACKGROUND AND AIMS: Population-based prospective cohort studies investigating fibre intake and development of inflammatory bowel disease are lacking. Our aim was to investigate the association between fibre intake and the development of Crohn's disease [CD] and ulcerative colitis [UC] in a large European population. METHODS: In total, 401326 participants, aged 20-80 years, were recruited in eight countries in Europe between 1991 and 1998. At baseline, fibre intake [total fibres, fibres from fruit, vegetables and cereals] was recorded using food frequency questionnaires. The cohort was monitored for the development of inflammatory bowel disease. Each case was matched with four controls and odds ratios [ORs] for the exposures were calculated using conditional logistic regression. Sensitivity analyses according to smoking status were computed. RESULTS: In total, 104 and 221 participants developed incident CD and UC, respectively. For both CD and UC, there were no statistically significant associations with either quartiles, or trends across quartiles, for total fibre or any of the individual sources. The associations were not affected by adjusting for smoking and energy intake. Stratification according to smoking status showed null findings apart from an inverse association with cereal fibre and CD in non-smokers [Quartile 4 vs 1 OR = 0.12, 95% confidence interval = 0.02-0.75, p = 0.023, OR trend across quartiles = 0.50, 95% confidence interval = 0.29-0.86, p = 0.017]. CONCLUSION: The results do not support the hypothesis that dietary fibre is involved in the aetiology of UC, although future work should investigate whether there may be a protective effect of specific types of fibre according to smoking status in CD.

Features of Autoimmune Pancreatitis Associated With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Few people know of autoimmune pancreatitis (AIP), a rare disorder associated with inflammatory bowel diseases (IBD). We aimed to describe phenotype and outcomes of IBD and AIP when associated. METHODS: We performed a retrospective study of cases of AIP in IBD identified from the multicenter Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif in Belgium and France from July 2012 through July 2015. Patients were diagnosed with AIP based on the International Consensus Diagnostic Criteria for AIP. A definitive AIP diagnosis was based on histological analysis of pancreatic resection specimens or samples collected by fine-needle aspiration during endoscopic ultrasound. Patients with probable type 1 AIP were identified based on imaging findings, clinical and/or radiologic responses to steroids, level of serum immunoglobulin G4, and involvement of other organs. Patients with probable type 2 AIP were identified based on imaging findings, clinical and/or radiologic responses to steroids, and association with IBD. The primary objective was to collect information on the characteristics of AIP in patients with IBD. We also compared features of patients with IBD with and without AIP in a case-control analysis, using multivariate analysis. RESULTS: We analyzed data from 91 individuals with AIP and IBD (47 women) seen at 23 centers (58 had ulcerative colitis [UC] and 33 Crohn's disease [CD]). Eighty-nine patients had type 2 AIP, and 2 patients had type 1 AIP. The mean age at diagnosis of AIP was 35 ± 12 years, and for IBD it was 32 ± 12 years. AIP preceded IBD in 19 patients (21%). Over a mean follow-up period of 5.7 ± 4.9 years, 31 patients (34%) relapsed, 11 patients (12%) developed diabetes, and 17 patients (19%) developed exocrine pancreatic insufficiency. In patients with UC, factors independently associated with AIP included proctitis (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.3-6.3; P = .007) and colectomy (OR, 7.1; 95% CI, 2.5-20; P = .0003). In patients with CD, AIP was significantly associated with fewer perianal lesions (OR, 0.16; 95% CI, 0.03-0.77; P = .023), non-stricturing non-penetrating CD (OR, 6.7; 95% CI, 1.25-33.3; P = .0029), and higher rate of colectomy (OR, 27.8; 95% CI, 3.6-217; P = .0029). CONCLUSIONS: In a multicenter retrospective analysis of patients with AIP and IBD, followed for an average of 5.7 ± 4.9 years, we found most to have type 2 AIP. Two-thirds of patients have UC, often with proctitis. One-third of patients have CD, often with inflammatory features. Patients with IBD and AIP have higher rates of colectomy than patients with just IBD.

Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities.

BACKGROUND AND AIM: Immune checkpoint inhibitors targeting CTLA-4 and PD-1 improve survival in cancer patients but may induce immune-related adverse events, including colitis. The immunological characteristics of anti-CTLA-4 [αCTLA-4]- and anti-PD-1 [αPD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of αCTLA-4-induced colitis and αPD-1-induced colitis. METHODS: Colonic biopsies from patients with αCTLA-4-induced colitis, αPD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNFα] concentration was assessed in biopsy supernatants. RESULTS: CD8+ T cells were found in the lamina propria and epithelium in αPD-1-induced colitis, whereas CD4+ T cells were found in the lamina propria in αCTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in αCTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between αCTLA-4- or αPD-1-induced colitis and IBD patients. Higher numbers of activated ICOS+ conventional CD4+ T cells were observed in αCTLA-4-induced colitis compared with patients with IBD. Among ICOS+CD4+ T cells, conventional CD4+ T cells were the main T cell population in patents with αCTLA-4-induced colitis, whereas Treg cells were predominant in IBD or αPD-1-induced colitis. High mucosal TNFα concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFα concentrations were associated with steroid sensitivity. CONCLUSIONS: These observations show that αCTLA-4- and αPD-1-induced colitis have distinct immunological characteristics. Mucosal TNFα concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.

Dietary Polyphenols in the Aetiology of Crohn's Disease and Ulcerative Colitis-A Multicenter European Prospective Cohort Study (EPIC).

BACKGROUND: Oxidative stress may be involved in the aetiology of inflammatory bowel disease and whether dietary polyphenols, which possess antioxidants properties, prevent its development is unknown. METHODS: A total of 401,326 men and women aged 20 to 80 years from 8 countries were recruited between 1991 and 1998 and at baseline completed validated food frequency questionnaires. Dietary polyphenol intake was measured using Phenol-Explorer, a database with information on the content of 502 polyphenols. Incident cases of Crohn's diseases (CD) and ulcerative colitis (UC) were identified during the follow-up period of up to December 2010. A nested case-control study using conditional logistic regression estimated the odds ratios (ORs), and 95% confidence intervals, for polyphenol intake (categories based on quartiles) and developing CD or UC. RESULTS: In total, 110 CD (73% women) and 244 UC (57% women) cases were identified and matched to 440 and 976 controls, respectively. Total polyphenol intake was not associated with CD (P trend = 0.17) or UC (P trend = 0.16). For flavones and CD, there were reduced odds for all quartiles, which were statistically significant for the third (OR3rd versus 1st quartile = 0.33; 95% confidence interval, 0.15-0.69) and there was an inverse trend across quartiles (P = 0.03). Similarly, for resveratrol, there was an inverse association with CD (OR4th versus 1st quartile = 0.40; 95% confidence interval, 0.20-0.82) with an inverse trend across quartiles (P = 0.02). No significant associations between subtypes of polyphenols and UC were found. Effect modification by smoking in CD was documented with borderline statistical significance. CONCLUSIONS: The data supports a potential role of flavones and resveratrol in the risk of developing CD; future aetiological studies should investigate these dietary components and further examine the potential for residual confounding.

Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort.

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.

Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation.

BACKGROUND: Dairy products may be involved in the etiology of inflammatory bowel disease by modulating gut microbiota and immune responses, but data from epidemiological studies examining this relationship are limited. We investigated the association between prediagnostic intake of these foods and dietary calcium, and the subsequent development of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: In total, 401,326 participants were enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. At recruitment, consumption of total and specific dairy products (milk, yogurt, and cheese) and dietary calcium was measured using validated food frequency questionnaires. Cases developing incident CD (n = 110) or UC (n = 244) during follow-up were matched with 4 controls. Conditional logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for total energy intake and smoking. RESULTS: Compared with the lowest quartile, the ORs for the highest quartile of total dairy products and dietary calcium intake were 0.61 (95% CI, 0.32-1.19, p trend = 0.19) and 0.63 (95% CI, 0.28-1.42, p trend = 0.23) for CD, and 0.80 (95% CI, 0.50-1.30, p trend = 0.40) and 0.81 (95% CI, 0.49-1.34, p trend = 0.60) for UC, respectively. Compared with nonconsumers, individuals consuming milk had significantly reduced odds of CD (OR 0.30, 95% CI, 0.13-0.65) and nonsignificantly reduced odds of UC (OR 0.85, 95% CI, 0.49-1.47). CONCLUSIONS: Milk consumption may be associated with a decreased risk of developing CD, although a clear dose-response relationship was not established. Further studies are warranted to confirm this possible protective effect.

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).

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.

Conditions of prescription of anti-TNF agents in newly treated patients with inflammatory bowel disease in France (2011-2013).

BACKGROUND: Tumour necrosis factor inhibitors (anti-TNFs) are active but expensive drugs that induce and maintain remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). AIMS: To assess the trends in anti-TNF prescription and the conditions of prescription of these drugs in patients with inflammatory bowel disease (IBD) in France. METHODS: Incidence study of anti-TNF use was performed based on French medico-administrative databases (SNIIRAM/PMSI). IBD patients who initiated adalimumab or infliximab between 2011 and 2013 were selected. RESULTS: The number of new anti-TNF users increased from 4571 to 5875 between 2011 and 2013 (+29%). More specifically, the number of patients not treated with immunosuppressants (IS) during the previous 12 months increased from 2100 to 3007 (+43%), among whom 379 patients in 2011 and 570 patients in 2013 started combination therapy (+50%). These trends were observed for both CD and UC. Patients who were naïve of IS were hospitalised more frequently than those treated with IS prior to anti-TNF therapy. CONCLUSION: This study shows a rapid increase in new prescriptions of anti-TNF for both CD and UC in France between 2011 and 2013. These results suggest a change in medical practices, with anti-TNF agents prescribed more often as first-line maintenance treatment.

Risk of Incident Cancer in Inflammatory Bowel Disease Patients Starting Anti-TNF Therapy While Having Recent Malignancy.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and history of malignancy within the last 5 years are usually contraindicated for receiving anti-tumor necrosis factor (anti-TNF) agents. The aim of this study is to assess survival without incident cancer in a cohort of IBD patients exposed to anti-TNF while having previous malignancy within past 5 years. METHODS: Data from IBD patients with previous malignancy diagnosed within the last 5 years before starting an anti-TNF agent were collected through a Groupe d'Etude Thérapeutiques des Affections Inflammatoires du tube Digestif multicenter survey. Inclusion date corresponded to the first anti-TNF administration after cancer diagnosis. RESULTS: Twenty centers identified 79 cases of IBD patients with previous malignancy diagnosed 17 months (median; range: 1-65) before inclusion. The most frequent cancer locations were breast (n = 17) and skin (n = 15). After a median follow-up of 21 (range: 1-119) months, 15 (19%) patients developed incident cancer (8 recurrent and 7 new cancers), including 5 basal-cell carcinomas. Survival without incident cancer was 96%, 86%, and 66% at 1, 2, and 5 years, respectively. Crude incidence rate of cancer was 84.5 (95% CI, 83.1-85.8) per 1000 patient-years. CONCLUSIONS: In a population of refractory IBD patients with recent malignancy, anti-TNF could be used taking into account a mild risk of incident cancer. Pending prospective and larger studies, a case-by-case joint decision taken with the oncologist is recommended for managing these patients in daily practice.

Prospective association of liver function biomarkers with development of hepatobiliary cancers.

INTRODUCTION: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. METHODS: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI). RESULTS: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT)=4.23, 95%CI:2.72-6.59; OR(ALP)=3.43, 95%CI:2.31-5.10;OR(AST)=3.00, 95%CI:2.04-4.42; OR(ALT)=2.69, 95%CI:1.89-3.84; OR(Bilirubin)=2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT)=4.98; 95%CI:1.75-14.17; OR(AST)=3.10, 95%CI:1.04-9.30; OR(ALT)=2.86, 95%CI:1.26-6.48, OR(ALP)=2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin)=1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP)=1.59, 95%CI:1.20-2.09). CONCLUSION: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.

Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study.

BACKGROUND: Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn's disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks. METHODS: Within the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case-control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis. RESULTS: No dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a "high sugar and soft drinks" pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00-2.82]; Ptrend = 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes. CONCLUSIONS: A diet imbalance with high consumption of sugar and soft drinks and low consumption of vegetables was associated with UC risk. Further studies are needed to investigate whether microbiota alterations or other mechanisms mediate this association.

The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms. OBJECTIVE: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC). DESIGN: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination. RESULTS: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively. CONCLUSION: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.

A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk.

BACKGROUND: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. METHODS: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. RESULTS: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P difference = .87) and after excluding case patients diagnosed within the first four follow-up years. CONCLUSIONS: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.

Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer.

Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 µg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 µg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development.

General and abdominal obesity and risk of esophageal and gastric adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition.

General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to gastric non-cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow-up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty-four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63-2.22 and HR = 3.76; 1.72-8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18-0.68, and HR=4.10; 1.94-8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09-3.37, and HR = 2.23; 1.28-3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.

Meat and fish consumption and the risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition.

Renal cell cancer (RCC) incidence varies worldwide with a higher incidence in developed countries and lifestyle is likely to contribute to the development of this disease. We examined whether meat and fish consumption were related to the risk of RCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 493,179 EPIC participants, recruited between 1992 and 2000. Until December 2008, 691 RCC cases have been identified. Meat and fish consumption was assessed at baseline using country-specific dietary assessment instruments; 24-hour recalls were applied in an 8% subsample for calibration purposes. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Women with a high consumption of red meat (HR = 1.36, 95% CI 1.14-1.62; calibrated, per 50 g/day) and processed meat (HR = 1.78, 95% CI 1.05-3.03; calibrated, per 50 g/day) had a higher risk of RCC, while no association existed in men. For processed meat, the association with RCC incidence was prominent in premenopausal women and was lacking in postmenopausal women (p interaction = 0.02). Neither poultry nor fish consumption were statistically significantly associated with the risk of RCC. The results show a distinct association of red and processed meat consumption with incident RCC in women but not in men. A biological explanation for these findings remains unclear.

Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: multicentre, prospective cohort study.

Inverse associations of coffee and/or tea in relation to hepatocellular carcinoma (HCC) risk have been consistently identified in studies conducted mostly in Asia where consumption patterns of such beverages differ from Europe. In the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 201 HCC cases among 486,799 men/women, after a median follow-up of 11 years. We calculated adjusted hazard ratios (HRs) for HCC incidence in relation to quintiles/categories of coffee/tea intakes. We found that increased coffee and tea intakes were consistently associated with lower HCC risk. The inverse associations were substantial, monotonic and statistically significant. Coffee consumers in the highest compared to the lowest quintile had lower HCC risk by 72% [HR: 0.28; 95% confidence intervals (CIs): 0.16-0.50, p-trend < 0.001]. The corresponding association of tea with HCC risk was 0.41 (95% CI: 0.22-0.78, p-trend = 0.003). There was no compelling evidence of heterogeneity of these associations across strata of important HCC risk factors, including hepatitis B or hepatitis C status (available in a nested case-control study). The inverse, monotonic associations of coffee intake with HCC were apparent for caffeinated (p-trend = 0.009), but not decaffeinated (p-trend = 0.45) coffee for which, however, data were available for a fraction of subjects. Results from this multicentre, European cohort study strengthen the existing evidence regarding the inverse association between coffee/tea and HCC risk. Given the apparent lack of heterogeneity of these associations by HCC risk factors and that coffee/tea are universal exposures, our results could have important implications for high HCC risk subjects.