Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn's disease: results from two large prospective cohort studies.

OBJECTIVE: To examine the relationship between Mediterranean diet and risk of later-onset Crohn's disease (CD) or ulcerative colitis (UC). DESIGN: We conducted a prospective cohort study of 83 147 participants (age range: 45-79 years) enrolled in the Cohort of Swedish Men and Swedish Mammography Cohort. A validated food frequency questionnaire was used to calculate an adherence score to a modified Mediterranean diet (mMED) at baseline in 1997. Incident diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modelling to calculate HRs and 95% CI. RESULTS: Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC with an average follow-up of 17 years. Higher mMED score was associated with a lower risk of CD (Ptrend=0.03) but not UC (Ptrend=0.61). Compared with participants in the lowest category of mMED score (0-2), there was a statistically significant lower risk of CD (HR=0.42, 95% CI 0.22 to 0.80) but not UC (HR=1.08, 95% CI 0.74 to 1.58). These associations were not modified by age, sex, education level, body mass index or smoking (all Pinteraction >0.30). The prevalence of poor adherence to a Mediterranean diet (mMED score=0-2) was 27% in our cohorts, conferring a population attributable risk of 12% for later-onset CD. CONCLUSION: In two prospective studies, greater adherence to a Mediterranean diet was associated with a significantly lower risk of later-onset CD.

Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989-2012: a matched case-control study.

BACKGROUND: Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of oral antibiotic exposure and risk patterns is lacking. OBJECTIVE: To assess the association between oral antibiotic use and CRC risk. DESIGN: A matched case-control study (incident CRC cases and up to five matched controls) was performed using the Clinical Practice Research Datalink from 1989 to 2012. RESULTS: 28 980 CRC cases and 137 077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomical location. Antibiotic use increased the risk of colon cancer in a dose-dependent fashion (ptrend <0.001). The risk was observed after minimal use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (ptrend=0.003), particularly with length of antibiotic exposure >60 days (adjusted OR (aOR), 0.85, 95% CI 0.79 to 0.93) as compared with no antibiotic exposure. Penicillins, particularly ampicillin/amoxicillin increased the risk of colon cancer (aOR=1.09 (1.05 to 1.13)), whereas tetracyclines reduced the risk of rectal cancer (aOR=0.90 (0.84 to 0.97)). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, pinteraction<0.001; proximal colon versus distal colon, pinteraction=0.019). The antibiotic-cancer association was found for antibiotic exposure occurring >10 years before diagnosis (aOR=1.17 (1.06 to 1.31)). CONCLUSION: Oral antibiotic use is associated with an increased risk of colon cancer but a reduced risk of rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestinal tract.

No Association Between Consumption of Sweetened Beverages and Risk of Later-Onset Crohn's Disease or Ulcerative Colitis.

BACKGROUND & AIMS: Consumption of sweetened beverages has been associated with inflammation based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: We conducted a prospective cohort study of 83,042 participants (age, 44-83 y) enrolled in the Cohort of Swedish Men or the Swedish Mammography Study. Dietary and lifestyle data were collected using a validated food frequency questionnaire at baseline in 1997. Diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modeling to calculate hazard ratios and 95% CIs. RESULTS: Through December of 2014, we confirmed 143 incident cases of CD (incidence rate, 11 cases/100,000 person-years) and 349 incident cases of UC (incidence rate, 28 cases/100,000 person-years) over 1,264,345 person-years of follow-up evaluation. Consumption of sweetened beverages was not associated with increased risk of CD (Ptrend = .34) or UC (Ptrend = .40). Compared with participants who reported no consumption of sweetened beverages, the multivariable-adjusted hazard ratios for 1 or more servings per day were 1.02 for CD (95% CI, 0.60-1.73) and 1.14 for UC (95% CI, 0.83-1.57). The association between consumption of sugar-sweetened beverages and risk of CD or UC were not modified by age, sex (cohort), body mass index, or smoking (all Pinteraction ≥ .12). CONCLUSIONS: In analyses of data from 2 large prospective cohort studies from Sweden, we observed no evidence for associations between consumption of sweetened beverages and later risk of CD or UC.

Dietary antioxidant intake and the risk of developing Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: We investigated in a cohort study, for the first time using 7-day food diaries (7-DFDs), for age-dependent inverse associations with antioxidants, which have anti-carcinogenic properties, and development of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). METHODS: A total of 24,068 well individuals completed 7-DFDs and donated blood. Vitamins C and E, carotenes, zinc and selenium intakes, and plasma vitamin C were measured. Participants were monitored for 15 years for BO and OAC. Hazard ratios (HRs) were estimated for: quintiles of intake and in participants younger and >=65 years at recruitment, the midpoint of BO peak prevalence. RESULTS: A total of 197 participants developed BO and 74 OAC. There were no significant associations between antioxidants and BO or OAC in the whole cohort or if >65 years at recruitment. In participants <65 years, for BO, there was an inverse trend across plasma vitamin C quintiles (trend HR = 0.82; 95% CI = 0.71-0.96, P = 0.01), OAC for plasma vitamin C (trend HR = 0.58; 95% CI = 0.37-0.92, P = 0.02) and for dietary vitamins C and E (trend HR = 0.71 95% CI = 0.51-0.99, P = 0.04 and trend HR = 0.70; 95% CI = 0.51-0.96; P = 0.03). CONCLUSIONS: Data supports a role for dietary antioxidants prevent BO and OAC, perhaps at the earlier stages of carcinogenesis.

Dietary oleic acid is inversely associated with pancreatic cancer - Data from food diaries in a cohort study.

BACKGROUND: Dietary oleic acid may prevent pancreatic ductal adenocarcinoma (PDA) by reducing hyperinsulinaemia which can otherwise promote DNA damage and tumour growth. Results from previous epidemiological studies investigating oleic acid are inconsistent. This study aims to clarify the relationship between dietary oleic acid intake and the risk of developing PDA using nutritional information from food diaries plus published serum biomarker data from HbA1c. METHODS: 23,658 participants, aged 40-74 years, were recruited into EPIC-Norfolk and completed 7-day food diaries which recorded; foods, brands and portion sizes to calculate nutrient intakes. Serum HbA1c was measured at recruitment in 11,147 participants (48.7% of cohort). Hazard ratios (HRs) for quintiles of dietary oleic acid intake and serum HbA1c were estimated using Cox regression. Additional analyses were made according to whether body mass index (BMI) was greater or less than 25 kg/m2 as this influences hyperinsulinaemia. RESULTS: 88 participants (55% women) developed PDA after a mean follow-up of 8.4 years (SD = 3.9) (mean age at diagnosis = 72.6 years, SD = 8.8). A decreased risk of PDA was associated with increased dietary oleic acid intake (highest vs lowest quintile, HR = 0.29, 95% CI = 0.10-0.81, P trend across quintiles = 0.011), with statistical significance maintained when BMI>25 kg/m2 but not if BMI<25 kg/m2. An elevated serum HbA1c was associated with increased risk of disease (highest vs lowest quintiles, HR = 6.32, 95% CI = 1.38-28.89, P for trend = 0.004). CONCLUSIONS: The data supports a protective role of oleic acid against development of PDA in those with higher BMIs possibly through influencing hyperinsulinaemia. Oleic acid intake should be accurately measured in future aetiological studies.

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use.

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug-drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress.

Association Between Statin Use After Diagnosis of Esophageal Cancer and Survival: A Population-Based Cohort Study.

BACKGROUND & AIMS: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), commonly prescribed in the primary and secondary prevention of cardiovascular disease, promote apoptosis and limit proliferation of esophageal cancer cell lines. We investigated whether statin use after a diagnosis of esophageal cancer is associated with reduced esophageal cancer-specific and all-cause mortality. METHODS: We identified a cohort of 4445 men and women in the United Kingdom diagnosed with esophageal cancer from January 2000 through November 2009 using the General Practice Research Database. The National Cancer Registry and Office of National Statistics datasets established the histologic subtype and cancer-specific mortality, respectively. Cox proportional hazard regression analysis with time-dependent exposures estimated the association between statin use after diagnosis and esophageal cancer-specific and all-cause mortality. RESULTS: The median survival time of the entire cohort was 9.2 months (interquartile range [IQR], 3.7-23.2 mo). Among subjects who used statins after a diagnosis of esophageal cancer, the median survival time was 14.9 months (IQR, 7.1-52.3 mo) compared with 8.1 months for nonusers (IQR, 3.3-20 mo). In the entire cohort, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86) and all-cause mortality (HR, 0.67; 95% CI, 0.58-0.77). In patients with esophageal adenocarcinoma, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (HR, 0.61; 95% CI 0.38-0.96) and all-cause mortality (HR, 0.63; 95% 0.43-0.92). This effect was not observed in patients with esophageal squamous cell carcinoma. There was no evidence for effect modification of these associations with statin use before the cancer diagnosis. CONCLUSIONS: In a large population-based cohort, statin use after a diagnosis of esophageal adenocarcinoma, but not esophageal squamous cell carcinoma, was associated with reduced esophageal cancer-specific and all-cause mortality.

Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments.

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.

Exposure to Ambient Air Pollution and the Risk of Inflammatory Bowel Disease: A European Nested Case-Control Study.

BACKGROUND: Industrialization has been linked to the etiology of inflammatory bowel disease (IBD). AIM: We investigated the association between air pollution exposure and IBD. METHODS: The European Prospective Investigation into Cancer and Nutrition cohort was used to identify cases with Crohn's disease (CD) (n = 38) and ulcerative colitis (UC) (n = 104) and controls (n = 568) from Denmark, France, the Netherlands, and the UK, matched for center, gender, age, and date of recruitment. Air pollution data were obtained from the European Study of Cohorts for Air Pollution Effects. Residential exposure was assessed with land-use regression models for particulate matter with diameters of <10 µm (PM10), <2.5 µm (PM2.5), and between 2.5 and 10 µm (PMcoarse), soot (PM2.5 absorbance), nitrogen oxides, and two traffic indicators. Conditional logistic regression analyses were performed to calculate odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: Although air pollution was not significantly associated with CD or UC separately, the associations were mostly similar. Individuals with IBD were less likely to have higher exposure levels of PM2.5 and PM10, with ORs of 0.24 (95 % CI 0.07-0.81) per 5 µg/m(3) and 0.25 (95 % CI 0.08-0.78) per 10 µg/m(3), respectively. There was an inverse but nonsignificant association for PMcoarse. A higher nearby traffic load was positively associated with IBD [OR 1.60 (95 % CI 1.04-2.46) per 4,000,000 motor vehicles × m per day]. Other air pollutants were positively but not significantly associated with IBD. CONCLUSION: Exposure to air pollution was not found to be consistently associated with IBD.

Statin use is associated with reduced risk of histologic subtypes of esophageal cancer: a nested case-control analysis.

BACKGROUND & AIMS: Most patients with esophageal adenocarcinoma (EAC) or squamous cell cancer (ESCC) present with advanced, incurable disease. Statins have reported anti-carcinogenic effects and may be chemoprotective. We investigated the association between regular use of statins and the main histologic subtypes of esophageal malignancy (EAC, esophagogastric junctional adenocarcinoma, and ESCC) in the UK general population. METHODS: We identified all individuals in the UK General Practice Research Database diagnosed with esophageal cancer from 2000 through 2009. Patients were linked to the National Cancer Registry to confirm histologic subtypes. Each patient was matched with up to 4 controls for age, sex, and practice. We performed a nested case-control analysis using conditional logistic regression to estimate the risk of each subtype with regular statin use, adjusted for body mass index, smoking, alcohol intake, and concomitant use of medications. RESULTS: In total, 581 participants with EAC, 213 with esophagogastric junctional adenocarcinoma, and 332 with ESCC were matched to 2167, 783, and 1242 controls, respectively. Regular statin use was inversely associated with development of EAC (odds ratio = 0.58; 95% confidence interval: 0.39-0.87) (with significant dose and duration responses) and esophagogastric junctional adenocarcinoma (odds ratio = 0.29; 95% confidence interval: 0.09-0.92) (with high-dose use only). Statin use for 1-4 years was inversely associated with ESCC (odds ratio = 0.51; 95% confidence interval: 0.27-0.98). CONCLUSIONS: In a nested case-control analysis of a UK population-based cohort, statin use was inversely associated with histologic subtypes of esophageal cancer. Randomized controlled trials are warranted to determine whether statins have chemopreventive effects in high-risk groups.

Environmental factors in the relapse and recurrence of inflammatory bowel disease: a review of the literature.

INTRODUCTION: The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability. RESULTS: The clinical epidemiological data consistently reports positive associations between smoking and relapses in CD, and inverse ones with UC. For NSAIDs and estrogens, the epidemiological findings are inconsistent, although general antibiotic use was associated with a reduced risk of relapse in CD. High levels of stress were positively associated with relapse, although psychological interventions did not have therapeutic benefits. The limited work on diet has reported sulphur-containing foods are positively associated with relapse in UC, but there is no work in CD. Ecological data reported positive correlations between air pollution levels and IBD hospitalisations. CONCLUSIONS: In the future, to clarify this area, more clinical epidemiological work is required where detailed drug types and doses, and complete dietary intakes are measured, in specific forms of IBD. Such work could provide guidance to both patients and doctors to help maintain remission.

Is there a role for vitamin C in preventing osteoporosis and fractures? A review of the potential underlying mechanisms and current epidemiological evidence.

Osteoporosis and related fractures are a major global health issue, but there are few preventative strategies. Previously reported associations between higher intakes of fruits and vegetables and skeletal health have been suggested to be partly attributable to vitamin C. To date, there is some evidence for a potential role of vitamin C in osteoporosis and fracture prevention but an overall consensus of published studies has not yet been drawn. The present review aims to provide a summary of the proposed underlying mechanisms of vitamin C on bone and reviews the current evidence in the literature, examining a potential link between vitamin C intake and status with osteoporosis and fractures. The Bradford Hill criteria were used to assess reported associations. Recent animal studies have provided insights into the involvement of vitamin C in osteoclastogenesis and osteoblastogenesis, and its role as a mediator of bone matrix deposition, affecting both the quantity and quality of bone collagen. Observational studies have provided some evidence for this in the general population, showing positive associations between dietary vitamin C intake and supplements and higher bone mineral density or reduced fracture risk. However, previous intervention studies were not sufficiently well designed to evaluate these associations. Epidemiological data are particularly limited for vitamin C status and for fracture risk and good-quality randomised controlled trials are needed to confirm previous epidemiological findings. The present review also highlights that associations between vitamin C and bone health may be non-linear and further research is needed to ascertain optimal intakes for osteoporosis and fracture prevention.

Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers.

OBJECTIVE: To investigate whether the dietary antioxidants vitamins C and E, selenium and zinc decrease the risk of developing pancreatic cancer, for the first time using 7-day food diaries, the most accurate dietary methodology in prospective work. DESIGN: 23,658 participants, aged 40-74 years, recruited into the EPIC-Norfolk Study completed 7-day food diaries which recorded foods, brands and portion sizes. Nutrient intakes were calculated in those later diagnosed with pancreatic cancer and in 3970 controls, using a computer program with information on 11,000 foods. Vitamin C was measured in serum samples. The HRs of developing pancreatic cancer were estimated across quartiles of intake and thresholds of the lowest quartile (Q1) against a summation of the three highest (Q2-4). RESULTS: Within 10 years, 49 participants (55% men), developed pancreatic cancer. Those eating a combination of the highest three quartiles of all of vitamins C and E and selenium had a decreased risk (HR=0.33, 95% CI 0.13 to 0.84, p<0.05). There were threshold effects (Q2-4 vs Q1) for selenium (HR=0.49, 95% CI 0.26 to 0.93, p<0.05) and vitamin E (HR=0.57, 95% CI 0.29 to 1.09, p<0.10). The HRs of quartiles for antioxidants, apart from zinc, were <1, but not statistically significant. For vitamin C, there was an inverse association with serum measurements (HR trend=0.67, 95% CI 0.49 to 0.91, p=0.01), but the threshold effect from diaries was not significant (HR=0.68, 95% CI 0.37 to 1.26). CONCLUSION: The results support measuring antioxidants in studies investigating the aetiology of pancreatic cancer. If the association is causal, 1 in 12 cancers might be prevented by avoiding the lowest intakes.

Serological markers predict inflammatory bowel disease years before the diagnosis.

OBJECTIVE: Anti-neutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) have been detected in the serum of patients with ulcerative colitis (UC) and Crohn's disease (CD) and their unaffected family members. The aim of this study was to establish the value of serological markers as predictors of UC and CD. DESIGN: Individuals who developed CD or UC were identified from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. At recruitment, none of the participants had a diagnosis of CD or UC. For each incident case, two controls were randomly selected matched for centre, date of birth, sex, date of recruitment and time of follow-up. Serum of cases and controls obtained at recruitment were analysed for ASCA IgG, ASCA IgA, perinuclear anti-neutrophil cytoplasmic antibody (pANCA), antibodies against Escherichia coli outer membrane porin C (OmpC) and flagellin CBir1. Conditional logistic regression was used to determine risk of CD and UC. Receiver operating characteristic curves were constructed to test accuracy. RESULTS: A total of 77 individuals were diagnosed with CD and 167 with UC after a mean follow-up of 4.5 (SD 3.2) and 4.4 (SD 3.1) years following blood collection, respectively. Combinations of pANCA, ASCA, anti-CBir1 and anti-OmpC were most accurate in predicting incident CD and UC (area under curve 0.679 and 0.657, respectively). The predictive value of the combination of markers increased when time to diagnosis of CD or UC decreased. CONCLUSION: A panel of serological markers is able to predict development of CD and UC in individuals from a low-risk population.

Body mass index and the risk for Crohn's disease and ulcerative colitis: data from a European Prospective Cohort Study (The IBD in EPIC Study).

OBJECTIVES: Obesity is associated with a proinflammatory state that may be involved in the etiology of inflammatory bowel disease (IBD), for which there are plausible biological mechanisms. Our aim was to perform the first prospective cohort study investigating if there is an association between obesity and the development of incident IBD. METHODS: A total of 300,724 participants were recruited into the European Prospective Investigation into Cancer and Nutrition study. At recruitment, anthropometric measurements of height and weight plus physical activity and total energy intake from validated questionnaires were recorded. The cohort was monitored identifying participants who developed either Crohn's disease (CD) or ulcerative colitis (UC). Each case was matched with four controls and conditional logistic regression used to calculate odds ratios (ORs) for body mass index (BMI) adjusted for smoking, energy intake, and physical activity. RESULTS: In the cohort, 177 participants developed incident UC and 75 participants developed incident CD. There were no associations with the four higher categories of BMI compared with a normal BMI for UC (Ptrend=0.36) or CD (Ptrend=0.83). The lack of associations was consistent when BMI was analyzed as a continuous or binary variable (BMI 18.5<25.0 vs. ≥25 kg/m(2)). Physical activity and total energy intake, factors that influence BMI, did not show any association with UC (physical activity, Ptrend=0.79; total energy intake, Ptrend=0.18) or CD (physical activity, Ptrend=0.42; total energy, Ptrend=0.11). CONCLUSIONS: Obesity as measured by BMI is not associated with the development of incident UC or CD. Alternative measures of obesity are required to further investigate the role of obesity in the development of incident IBD.

Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial.

BACKGROUND: Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 years of age can substantially reduce colorectal cancer incidence and mortality. METHODS: This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. FINDINGS: 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11.2 years (IQR 10.7-11.9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer [538 vs 189]). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0.77, 95% CI 0.70-0.84) and mortality by 31% (0.69, 0.59-0.82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0.67, 0.60-0.76) and mortality by 43% (0.57, 0.45-0.72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0.50, 0.42-0.59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145-277) and 489 (343-852), respectively. INTERPRETATION: Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. FUNDING: Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed.

An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis.

BACKGROUND & AIMS: Dietary arachidonic acid, an n-6 polyunsaturated fatty acid (n-6 PUFA), might be involved in the etiology of ulcerative colitis (UC). We performed a prospective cohort study to determine whether high levels of arachidonic acid in adipose tissue samples (which reflects dietary intake) are associated with UC. METHODS: We analyzed data collected from 57,053 men and women in the EPIC-Denmark Prospective Cohort Study from 1993 to 1997. Adipose tissue biopsy samples were collected from gluteal regions at the beginning of the study, the cohort was monitored over subsequent years, and participants who developed UC were identified. A subcohort of 2510 randomly selected participants were used as controls. Concentrations of arachidonic acid were measured in adipose tissue samples. In the analysis, arachidonic acid levels were divided into quartiles; relative risks (RR) were calculated and adjusted for smoking, use of aspirin and nonsteroidal anti-inflammatory drugs, and levels of n-3 PUFAs. RESULTS: A total of 34 subjects (56% men) developed incident UC at a median age of 58.8 years (range, 50.0-69.0 years). Those in the highest quartile for arachidonic acid concentrations in adipose tissue had an RR for UC of 4.16 (95% confidence interval [CI]: 1.56-11.04); a trend per 0.1% increase in arachidonic acid of 1.77 in RR was observed (95% CI: 1.38-2.27). The fraction attributed the highest levels of arachidonic acid was 40.3%. CONCLUSIONS: Individuals with the highest relative concentrations of arachidonic acid in adipose tissue have a significantly greater risk of developing UC. Dietary modifications might therefore prevent UC or reduce disease symptoms.

Increasing fish consumption does not affect genotoxicity markers in the colon in an intervention study.

Observational studies suggest that fish consumption is associated with a decreased colorectal cancer (CRC) risk. A possible mechanism by which fish could reduce CRC risk is by decreasing colonic genotoxicity. However, concerns have also been raised over the levels of toxic compounds found in mainly oil-rich fish, which could increase genotoxicity. Therefore, the objective was to investigate the effects of fish on genotoxicity markers in the colon in a randomized controlled parallel intervention study. For a period of 6 months, subjects were randomly allocated to receive two extra weekly portions of (i) oil-rich fish (salmon), (ii) lean fish (cod) or (iii) just dietary advice (DA). The Comet Assay was used to measure the DNA damage-inducing potential of fecal water (n = 89) and DNA damage in colonocytes (n = 70) collected pre- and post-intervention as markers of genotoxicity. Genotoxicity of fecal water was not markedly changed after fish consumption: 1.0% increase in tail intensity (TI) [95% confidence interval (CI) -5.1; 7.0] in the salmon group and 0.4% increase in TI (95% CI -5.3; 6.1) in the cod group compared with the DA group. DNA damage in colonocytes was also not significantly changed after fish consumption, in either the salmon group (-0.5% TI, 95% CI -6.9; 6.0) or cod group (-3.3% TI, 95% CI -10.8; 4.3) compared with the DA group. Measurements of genotoxicity of fecal water and DNA damage in colonocytes did not correlate (r = 0.06, n = 34). In conclusion, increasing consumption of either oil-rich or lean fish did not affect genotoxicity markers in the colon.

Increased consumption of fatty and lean fish reduces serum C-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies.

Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA. Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (-0.5 mg/L; 95% CI -0.9, -0.2) and cod (-0.4 mg/L; 95% CI -0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish. In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.

An observational study to justify and plan a future phase III randomized controlled trial of metformin in improving overall survival in patients with inoperable pancreatic cancer without liver metastases.

PURPOSE: Metformin has plausible direct and indirect anti-cancer properties against pancreatic adenocarcinoma cells. However, metformin may only be efficacious in patients with inoperable pancreatic ductal adenocarcinoma (PDAC) without liver metastases. Absorption may be decreased by gastrointestinal symptoms and proton pump inhibitors (PPIs). We aimed to justify and inform a future phase III trial of metformin versus placebo on survival in inoperable PDAC by documenting prevalence of patients meeting eligibility criteria, gastrointestinal symptoms and PPI use. METHODS: Patient notes with PDAC were reviewed at a large teaching hospital over 2 years. Study variables were obtained from multiple sources of information. RESULTS: 141 participants were identified (51.8% female), of which 37.6% were not prescribed metformin at diagnosis and had no radiological hepatic metastases. Characteristics were similar between non-metformin and metformin users. In eligible patients, 65.2% reported nausea and vomiting and 46.2% were prescribed PPIs. CONCLUSION: Approximately, a third of all patients with inoperable PDAC are eligible for a future trial of metformin, allowing an estimate of the number of hospitals required for recruitment. Nausea and vomiting are common and should be managed effectively to prevent trial dropouts. PPI use is frequent and their influence on metformin's pharmacodynamic actions needs to be clarified.