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Introduction: Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. Methods: Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. Results: Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54–76] vs 72 [63–79] years [P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. Conclusion: IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.

Introduction\ud The COLO-COHORT study aims to produce a multi-factorial risk prediction model for colorectal neoplasia that will be able to be used to target colonoscopy to those at greatest risk of colorectal neoplasia, ensuring that people are not investigated unnecessarily and maximising the use of limited endoscopy resources. The study will also explore the link between neoplasia and the human gut microbiome. Additionally, the study aims to generate a cohort of colonoscopy patients who are ‘research ready’ through the development of a consent-for-contact platform (C4C), to facilitate a range of CRC prevention studies to be conducted at scale and speed.\ud \ud Methods and Analysis\ud This is a multi-centre observational study involving sites across the UK. Recruitment is over a 6-year period (2019 – 2025). Patients recruited to the study are those attending for colonoscopy. Patients are recruited into two groups, namely; observational Group A (10,000 patients) and C4C Group B (10,000 patients), known as COLO-SPEED (Colorectal Cancer Screening Prevention Endoscopy and Early Diagnosis; https://colospeed.uk).\ud \ud Patients complete a health questionnaire, provide anthropometric measurements and submit biosamples (blood and stool - depending on the part of the study they are recruited into). Patients’ colonoscopy and histology findings are also recorded. Models of factors associated with presence of neoplasia at colonoscopy will be developed using logistic or multinomial regression. For internal validation, model discrimination and calibration will be assessed and bootstrapping and cross-validation approaches used. To enable long-term follow up for outcomes related to CRC and polyps, patients are asked to consent to follow up through data linkage with national databases.\ud \ud Dissemination\ud In keeping with good research practice, following analysis by the study team the study investigators will make the anonymised dataset available to other researchers. The C4C platform will also be accessible to other researchers. The study findings will be submitted for publication in peer reviewed journals and lay summaries will be disseminated to participants and the wider public.

Data from experimental studies have demonstrated that marine omega-3 polyunsaturated fatty acids (O3FAs) have anti-inflammatory and anticancer properties. In the last decade, large-scale randomised controlled trials of pharmacological delivery of O3FAs and prospective cohort studies of dietary O3FA intake have continued to investigate the relationship between O3FA intake and colorectal cancer (CRC) risk and mortality. Clinical data suggest that O3FAs have differential anti-CRC activity depending on several host factors (including pretreatment blood O3FA level, ethnicity and systemic inflammatory response) and tumour characteristics (including location in the colorectum, histological phenotype (eg, conventional adenoma or serrated polyp) and molecular features (eg, microsatellite instability, cyclooxygenase expression)). Recent data also highlight the need for further investigation of the effect of O3FAs on the gut microbiota as a possible anti-CRC mechanism, when used either alone or in combination with other anti-CRC therapies. Overall, these data point towards a precision approach to using O3FAs for optimal prevention and treatment of CRC based on mechanistic understanding of host, tumour and gut microbiota factors that predict anticancer activity of O3FAs.

Background Oral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome. However, it is not known whether this effect is associated with increased PUFA concentrations in the gut. Objectives We investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum. Methods Ileostomy fluid (IF) and blood were obtained at baseline, after first capsule dosing (median 2 h), and at a similar time after final dosing on day 28, in 11 individuals (median age 63 y) with a temporary ileostomy. Fatty acids were measured by LC–tandem MS. The ileal microbiome was characterized by 16S rRNA PCR and Illumina sequencing. Results There was a mean 6.0 ± 9.8-fold and 6.6 ± 9.6-fold increase in ileal EPA and DHA concentrations (primary outcome), respectively, at 28 d, which was associated with increased RBC ω-3 PUFA content (P ≤ 0.05). The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Bacteroides, Clostridium, and Streptococcus were abundant bacterial genera in the ileum. Ileal microbiome variability over time and between individuals was large, with no consistent change associated with acute ω-3 PUFA dosing. However, high concentrations of EPA and DHA in IF on day 28 were associated with higher abundance of Bacteroides (r2 > 0.86, P 0.94, P

A novel system was developed to deploy settlement panels to monitor biofouling growth in situ and evaluate antifouling coatings at depths representative of operational conditions of full-scale marine renewable energy devices. Biofouling loading, species diversity, and succession were assessed at depths ranging from 25-40 m at four tests sites in Orkney (UK) featuring extreme wave and tidal current exposure to more sheltered conditions. Evaluations were carried out over a period of 8 months with intermediate retrieval of samples after 3 months. Early pioneer fouling communities, comprised of colonial hydroids, were succeeded by tube-forming amphipods across sites while solitary tunicates dominated in greater shelter. The highest biofouling loading was observed on high-density polyethylene (HDPE) panels (6.17 kg m-2) compared with coated steel (3.34 kg m-2) panels after 8 months. Distinct assemblages were present at exposed vs sheltered sites. Better understanding of fouling and antifouling strategies may provide guidance to more effectively manage biofouling impacts in this sector.

Background & AimsArachidonic acid (ARA) is causally associated with colorectal cancer (CRC), a major public health concern. However, it is uncertain if ARA contributes to the development of colorectal polyps which are pre-malignant precursors of CRC. Therefore, this study aimed to investigate the association between lifelong exposure to elevated ARA and colorectal polyp incidence using Mendelian randomisation.MethodsSummary level GWAS data from European, Singaporean, and Chinese cohorts (n=10,171) identified 4 single nucleotide polymorphisms (SNPs) associated with blood ARA levels (p< 5 × 10−8). After pruning, 1 SNP was retained (rs174547; p=3.0×10−971) for 2-stage Mendelian randomisation to infer the causal effect of ARA on self-reported colorectal polyp outcomes within the UK Biobank (1,391 cases; 462,933 total).ResultsNo association between ARA and colorectal polyp incidence was observed [OR= 1.00 (95% CI: 0.99, 1.00); P-value = 0.50).ConclusionsBlood levels of ARA do not associate with colorectal polyp incidence. This work supports the contention that downstream lipid mediators, such as PGE2, are key for polyp formation during early-stage colorectal carcinogenesis

PurposeThe naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA.MethodsA panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models.ResultsGenetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours.ConclusionCyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies.

Population screening and endoscopic surveillance are used widely to prevent the development of and death from colorectal cancer (CRC). However, CRC remains a major cause of cancer mortality and the increasing burden of endoscopic investigations threatens to overwhelm some health services. This Perspective describes the rationale for and approach to improved risk stratification and decision-making for CRC prevention and diagnosis. Limitations of current approaches will be discussed using the UK as an example of the challenges faced by a particular health-care system, followed by discussion of novel risk biomarker utilization. We explore how risk stratification will be advantageous to current health-care providers and users, enabling more efficient use of limited colonoscopy resources. We discuss risk stratification in the setting of population screening as well as the surveillance of high-risk groups and investigation of symptomatic patients. We also address challenges in the development and validation of risk stratification tools and identify key research priorities., Population screening and endoscopic surveillance are widely used for colorectal cancer (CRC) prevention and early diagnosis. This Perspective explores the rationale for and approach to risk stratification for CRC prevention and diagnosis, including the limitations, advantages and future challenges for this approach.

The REDUCE-IT trial demonstrated that icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), reduced cardiovascular events in an at-risk population by a substantial degree. While the cardiovascular protective properties of this compound are now proven, several other potential uses are being actively explored in clinical studies. These areas of investigation include cancer, inflammatory bowel disease, infections, Alzheimer’s disease, dementia, and depression. The next decade promises to deepen our understanding of the beneficial effects that EPA may offer beyond cardiovascular risk reduction.

Aim: Tamoxifen (TAM) resistance remains a clinical issue in breast cancer. The authors previously reported that 15-hydroxyprostaglandin dehydrogenase (HPGD) was significantly downregulated in tamoxifen-resistant (TAMr) breast cancer cell lines. Here, the authors investigated the relationship between HPGD expression, TAM resistance and prediction of outcome in breast cancer. Methods: HPGD overexpression and silencing studies were performed in isogenic TAMr and parental human breast cancer cell lines to establish the impact of HPGD expression on TAM resistance. HPGD expression and clinical outcome relationships were explored using immunohistochemistry and in silico analysis. Results: Restoration of HPGD expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity. TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD. Exogenous PGE2 signalled through the EP4 receptor to reduce breast cancer cell sensitivity to TAM. Decreased HPGD expression was associated with decreased overall survival in ERα-positive breast cancer patients. Conclusions: HPGD downregulation in breast cancer is associated with reduced response to TAM therapy via PGE2-EP4 signalling and decreases patient survival. The data offer a potential target to develop combination therapies that may overcome acquired tamoxifen resistance.

Background Noninvasive markers of liver fibrosis such as aspartate aminotransferase-to-platelet ratio (APRI) and transient elastography (TE) have largely replaced liver biopsy for staging hepatitis C virus (HCV). As there is little longitudinal data, we compared changes in these markers before and after sustained virologic response (SVR) in human immunodeficiency virus (HIV)-HCV coinfected patients. Methods Participants from the Canadian Coinfection Cohort study who achieved SVR after a first treatment with either interferon/ribavirin or direct acting antivirals (DAAs), with at least 1 pre- and posttreatment fibrosis measure were selected. Changes in APRI or TE (DAA era only) were modeled using a generalized additive mixed model, assuming a gamma distribution and adjusting for sex, age at HCV acquisition, duration of HCV infection, and time-dependent body mass index, binge drinking, and detectable HIV RNA. Results Of 1981 patients, 151 achieved SVR with interferon and 553 with DAAs; 94 and 382 met inclusion criteria, respectively. In the DAA era, APRI increased (0.03 units/year; 95% credible interval (CrI): −.05, .12) before, declined dramatically during, and then changed minimally (−0.03 units/year; 95% CrI: −.06, .01) after treatment. TE values, however, increased (0.74 kPa/year; 95% CrI: .36, 1.14) before treatment, changed little by the end of treatment, and then declined (−0.55 kPa/year; 95% CrI: −.80, −.31) after SVR. Conclusions TE should be the preferred noninvasive tool for monitoring fibrosis regression following cure. Future studies should assess the risk of liver-related outcomes such as hepatocellular carcinoma according to trajectories of fibrosis regression measured using TE to determine if and when it will become safe to discontinue screening.

Metabolic syndrome (MetS) is a cluster of factors including obesity, hypertension, diabetes, hypercholesterolemia and hyperlipidaemia. It has been associated with an increased risk of colorectal neoplasia. This systematic review and meta-analysis assessed the association between MetS and (i) recurrence of adenomas or occurrence of CRC in patients with prior adenomas, and (ii) survival in patients with CRC.MEDLINE, Embase, Scopus and Web of Science were searched up to 22 November 2019. Two authors independently conducted title and abstract screening; full text of eligible studies was evaluated. Where ≥3 studies reported effect measures for a specific outcome, meta-analysis using random effects model was conducted. IThe search identified 1,764 articles, 55 underwent full text screening, resulting in a total of 15 eligible studies. Five studies reported on metachronous neoplasia, with differing outcomes precluded a meta-analysis. No consistent relationship between MetS and metachronous neoplasia was found. Ten studies reported on survival outcomes. MetS was associated with poorer CRC-specific survival (HR = 1.8, 95% CI: 1.04-3.12, IMetS is associated with poorer CRC-specific survival, but evidence is inconsistent on metachronous neoplasia. Further research is warranted to better understand the impact of MetS on the adenoma-carcinoma pathway.

Men who have sex with men (MSM) are at risk for sexually-transmitted hepatitis C (HCV). Evidence for HCV infection in the context of pre-exposure prophylaxis (PrEP) use in North America is limited. We sought to characterize baseline HCV prevalence and incidence in MSM receiving PrEP in British Columbia (BC), Canada.We followed individuals in the BC PrEP program from January 2018 to August 2019. We evaluated baseline prevalence and incident seroconversions (newly positive HCV antibody). A multivariable logistic regression model was performed in MSM for factors associated with HCV prevalence at enrollment, including reported prior sexually transmitted infection (STI), HIV Incidence Risk Index for MSM score, PrEP use because of a partner living with HIV, and location of residence.The median age of the cohort was 33 years, 98.3% male, with 3058 person years (PY) of follow-up. Baseline HCV prevalence was 0.82% (31/3907 MSM enrollees) and HCV incidence (n = 3) was 0.15 per 100 PY (95% confidence interval [CI] 0.03-0.45). In multivariable analysis, initiating PrEP because of a partner living with HIV (adjusted odds ratio [aOR] 5.02; 95% CI 1.87-13.47) and prior STI (aOR 2.34; 95% CI 1.04-5.24) were associated with positive HCV status.Baseline HCV prevalence and incidence was low amongst MSM in a population-based PrEP program in BC, Canada. HCV was associated with bridging from populations living with HIV and evidence of a reported prior STI as a PrEP indicator condition amongst MSM. PrEP initiation may be an opportunity for linkage to HCV screening and treatment.

Background High costs of direct-acting antivirals (DAAs) have led health-care insurers to limit access worldwide. Using a natural experiment, we evaluated the impact of removing fibrosis stage restrictions on hepatitis C (HCV) treatment initiation rates among people living with human immunodeficiency virus (HIV), and then examined who was left to be treated. Methods Using data from the Canadian HIV-HCV Coinfection Cohort, we applied a difference-in-differences approach. Changes in treatment initiation rates following the removal of fibrosis stage restrictions were assessed using a negative binomial regression with generalized estimating equations. The policy change was then specifically assessed among people who inject drugs (PWID). We then identified the characteristics of participants who remained to be treated using a modified Poisson regression. Results Between 2010–2018, there were a total of 585 HCV initiations among 1130 eligible participants. After removing fibrosis stage restrictions, DAA initiations increased by 1.8-fold (95% confidence interval [CI] 1.3–2.4) controlling for time-invariant differences and secular trends. Among PWID the impact appeared even stronger, with an adjusted incidence rate ratio of 3.6 (95% CI 1.8–7.4). However, this increased treatment uptake was not sustained. At 1 year following universal access, treatment rates declined to 0.8 (95% CI .5–1.1). Marginalized participants (PWID and those of indigenous ethnicity) and those disengaged from care were more likely to remain HCV RNA positive. Conclusions After the removal of fibrosis restrictions, HCV treatment initiations nearly doubled immediately, but this treatment rate was not sustained. To meet the World Health Organization elimination targets, the minimization of structural barriers and adoption of tailored interventions are needed to engage and treat all vulnerable populations., People coinfected with human immunodeficiency virus and hepatitis C virus were 1.8 times more likely to initiate treatments after fibrosis stage restrictions were removed, after controlling for temporal trends. Marginalized populations and those disengaged from care remain to be treated.

With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent good results for mismatch repair (MMR)-deficient CRC and other malignancies, such as melanoma, the vast majority of MMR-proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR-proficient CRCs commonly develop from precursor adenomas with enhanced Wnt-signalling due to adenomatous polyposis coli (APC) mutations. In melanomas with enhanced Wnt signalling due to stabilized β-catenin, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro-environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied. To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, the present study utilized the ApcMin/+ mouse as a model of MMR-proficient CRC, using enhanced green fluorescent protein (EGFP) expression in the mouse lysozyme (M-lys) lys-EGFP/+ mouse as a pan-myelomonocytic cell marker and a panel of murine macrophage surface markers. Total intestinal lamina propria mononuclear cell (LPMNC) numbers significantly decreased with age (2.32±1.39×107 [n=4] at 33 days of age vs. 1.06±0.24×107 [n=8] at 109 days of age) during intestinal adenoma development in ApcMin/+ mice (P=0.05; unpaired Student's t-test), but not in wild-type littermates (P=0.35). Decreased total LPMNC numbers were associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in ApcMin/+ mouse intestine, but not spleen, compared with wild-type mice. Furthermore, during the early stage of intestinal adenoma development, there was a two-fold reduction of M-lys expressing cells (P=0.05) and four-fold reduction of ER-HR3 (macrophage sub-set) expressing cells (P=0.05; two tailed Mann-Whitney U test) in mice with reduced total intestinal LPMNCs (n=3). Further studies are necessary to determine the relevance of these findings to immune-surveillance of colorectal adenomas or MMR-proficient CRC CKI therapy resistance.

Introduction Obesity and non-alcoholic fatty liver disease (NAFLD) is associated with colorectal neoplasia.1 2 In the UK, colonoscopy is performed for patient symptoms, Bowel Cancer Screening Programme (BCSP), family history or surveillance. We aimed to further explore obesity and NAFLD as risk factors with a view to developing a risk model. Methods OSCAR was a cross sectional study recruiting patients attending for colonoscopy. Patients’ medical history, smoking habits, alcohol intake, medication, family history of CRC, waist circumference/height/weight and bloods results were recorded. Multivariate logistic regression was undertaken to test associations between obesity, NAFLD, other risk factors and colorectal adenomas. Preliminary results are reported. Results 1430 patients were recruited (BCSP 410 [28.6%]; symptomatic 1020 [71.3%]). 698 were male (48.8%) with median age: 59 years. The burden of obesity and liver disease was high (reported in a further abstract). 457 patients (31.9%) had colorectal adenomas, 170 (11.9%) had advanced adenomas, and 59 (4.1%) had CRC. Statin use, smoking, metabolic syndrome, abnormal fatty liver index and ALT level were significantly associated with adenoma in univariate analysis, but not in the multivariable model. Variables in the final multivariate model are displayed below. Neither obesity nor NAFLD (established diagnosis; patient reported or in medical notes) were independently associated with adenoma risk in univariate or multivariate analysis (Obesity: multivariable (mv) OR 1.14 [95%CI 0.9–1.4]; NAFLD: mvOR 0.7 [95%CI 0.3–1.5]). Conclusions Older age, referral route, alcohol excess and hypertension were significantly associated with colorectal adenoma. After accounting for these factors, obesity and NAFLD were not independently associated with adenoma. Further work is exploring adenoma burden and more detailed modelling. References Okabayashi K, et al. Body mass index category as a risk factor for colorectal adenomas: a systematic review and meta-analysis. Am J Gastroenterol. 2012;107(8):1175–85. Ding W, et al. Association between nonalcoholic fatty liver disease and colorectal adenoma: A systematic review and meta-analysis. Int J Clin Exp Med. 2015;8(1):322–333.

The preventability estimate for colorectal cancer (CRC) is approximately 50%, highlighting the huge potential for altering modifiable lifestyle factors (including diet and body fatness) in order to reduce risk of this common malignancy. There is strong evidence that dietary factors (including intake of wholegrains, fibre, red and processed meat and alcohol) affect CRC risk. The lack of positive intervention trials and limited mechanistic understanding likely explain limited public health impact of epidemiological observations, to date. An alternative strategy for nutritional prevention of CRC is use of supplements that provide higher individual nutrient exposure than obtained through the diet (chemoprevention). There are positive data for calcium and/or vitamin D and the n-3 fatty acid EPA from polyp prevention trials using colorectal adenoma as a CRC risk biomarker. Although CRC is an obesity-related malignancy, there remains a paucity of observational data supporting intentional weight loss for CRC risk reduction. Some types of obesity surgeries (Roux-en-Y gastric bypass) might actually increase subsequent CRC risk due to alteration of local intestinal factors. There is intense interest in nutritional therapy of patients after diagnosis of CRC, in order to impact on recurrence and overall survival (now often termed cancer interception). In conclusion, nutritional prevention of CRC continues to hold much promise. Increased mechanistic understanding of the role of individual nutrients (linked to intestinal microbiota), as well as a precision medicine approach to CRC chemoprevention and interception based on both tumour and host factors, should enable translation of nutritional interventions into effective CRC risk reduction measures.

Colorectal cancer (CRC) is the fourth most common cancer in the UK; 95% of CRCs develop from colorectal adenomas. Adults in England aged 60–74 years are screened for colorectal cancer through the national Bowel Cancer Screening Programme (BCSP) which aims to detect colorectal cancer early, and also remove colorectal adenomas. However, adenoma recurrence is common. The World Cancer Research Fund (WCRF) estimates that around 45% of CRC cases could be prevented by a healthy lifestyle. There are no specific dietary guidelines to protect against adenoma recurrence and patients do not receive dietary advice in the care pathway. Nonetheless understanding the dietary intake of people with adenoma who are at high-risk of developing CRC and their subsequent dietary behaviour post-diagnosis may design future intervention strategies.This study aims to describe the diet of colorectal adenoma patients and evaluate whether there were elective changes in diet following diagnosis.The data used in this study were obtained from colorectal adenoma patients at high risk of recurrence, recruited to the seAFOod polyp prevention trial through the English BCSP. Dietary intake was assessed using the EPIC Food Frequency Questionnaire at two time points: during the 12 months before and during the 12 months after adenoma diagnosis. FETA dietary analysis software was used to extract data. Paired Sample-T-Tests and Wilcoxon Signed-Rank Test were used to assess change in intake using SPSS version 25.Of the 709 patients recruited to the main study, 526 completed the FFQ on both occasions, of whom 81.7% were males. The mean age was 65 years (SD 4.8), 83.4% were overweight or obese with mean BMI = 29.5 kg/m2 (SD 5.7). The majority of nutrient intakes met UK DRVs, with the exception of low intake of fibre, vitamin D and selenium. Following diagnosis, a significant reduction was detected in daily intake of energy (from 7.7 to 7.5 MJ, p < 0.05) meat and meat products (from 124 to 111 g, p < 0.005), non-alcoholic beverages (from 939 to 898 g, p < 0.05) and nuts (from 5.5 to 4.3 g, p < 0.05). Subgroup analysis revealed that dietary changes were confined to men where the reduction in energy was by 293 kj/day and in meat by 1.5 portions per week.Patients do modify diet following a diagnosis of adenoma and changes correspond to WCRF healthy diet guidelines. Whether detected difference between males and females was due to the sample size or due to actual difference in behavior is not clear.

Supplemental Digital Content is available in the text, Objective: To examine the impact of sustained virologic response (SVR) and illicit (injection and noninjection) drug use on kidney function among hepatitis C virus (HCV) and HIV co-infected individuals. Design: Longitudinal observational cohort study of HCV-HIV co-infected patients. Methods: Data from 1631 patients enrolled in the Canadian Co-Infection Cohort between 2003 and 2016 were analyzed. Patients who achieved SVR were matched 1 : 2 with chronically infected patients using time-dependent propensity scores. Linear regression with generalized estimating equations was used to model differences in estimated glomerular filtration rates (eGFR) between chronic HCV-infected patients and those achieving SVR. The relationship between illicit drug use and eGFR was explored in patients who achieved SVR. Results: We identified 384 co-infected patients who achieved SVR (53% treated with interferon-free antiviral regimens) and 768 propensity-score matched patients with chronic HCV infection. Most patients were men (78%) and white (87%), with a median age of 51 years (interquartile range: 45–56). During 1767 person-years of follow-up, 4041 eGFR measurements were available for analysis. Annual rates of decline in eGFR were similar between patients with SVR [−1.32 (ml/min per 1.73 m2)/year, 95% confidence interval (CI) −1.75 to −0.90] and chronic infection [−1.19 (ml/min per 1.73 m2) per year, 95% CI −1.55 to −0.84]. Among SVR patients, recent injection cocaine use was associated with rapid eGFR decline [−2.16 (ml/min per 1.73 m2)/year, 95% CI −4.17 to −0.16]. Conclusion: SVR did not reduce the rate of kidney function decline among HCV–HIV co-infected patients. Increased risk of chronic kidney disease in co-infection may not be related to persistent HCV replication but to ongoing injection cocaine use.

Familial adenomatous polyposis (FAP) is a genetic disorder characterized by the development of hundreds of polyps throughout the colon. Without prophylactic colectomy, most individuals with FAP develop colorectal cancer at an early age. Treatment with EPA in the free fatty acid form (EPA-FFA) has been shown to reduce polyp burden in FAP patients. Since high-purity EPA-FFA is subject to rapid oxidation, a stable form of EPA compound has been developed in the form of magnesium l-lysinate bis-eicosapentaenoate (TP-252). We assessed the chemopreventive efficacy of TP-252 on intestinal tumor formation using ApcΔ14/+ mice and compared it with EPA-FFA. TP-252 was supplemented in a modified AIN-93G diet at 1, 2 or 4% and EPA-FFA at 2.5% by weight and administered to mice for 11 weeks. We found that administration of TP-252 significantly reduced tumor number and size in the small intestine and colon in a dose-related manner and as effectively as EPA-FFA. To gain further insight into the cancer protection afforded to the colon, we performed a comprehensive lipidomic analysis of total fatty acid composition and eicosanoid metabolites. Treatment with TP-252 significantly decreased the levels of arachidonic acid (AA) and increased EPA concentrations within the colonic mucosa. Furthermore, a classification and regression tree (CART) analysis revealed that a subset of fatty acids, including EPA and docosahexaenoic acid (DHA), and their downstream metabolites, including PGE3 and 14-hydroxy-docosahexaenoic acid (HDoHE), were strongly associated with antineoplastic activity. These results indicate that TP-252 warrants further clinical development as a potential strategy for delaying colectomy in adolescent FAP patients.

ObjectiveOmega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22).DesignA randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry.ResultsBoth omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects.ConclusionOmega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure.Trial registration numberISRCTN18662143.

TTC7A deficiency typically causes severe gastrointestinal manifestations such as multiple intestinal atresia or early-onset inflammatory bowel disease. In some cases, this is associated with severe combined immunodeficiency. Partial loss-of-function mutations appear to be associated with a milder phenotype resulting in common variable immunodeficiency-like condition with enteropathy.

BackgroundThe omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer (CRC) chemoprevention, aligned with an excellent safety profile.ObjectivesThe objectives were to determine whether or not EPA prevents colorectal adenomas, either alone or in combination with aspirin, and to assess the safety/tolerability of EPA, in the free fatty acid (FFA) form or as the triglyceride (TG), and aspirin.DesignThis was a randomised, blinded, placebo-controlled, 2 × 2 factorial trial.SettingThe NHS Bowel Cancer Screening Programme (BCSP).ParticipantsPatients (aged 55–73 years) identified as ‘high risk’ (i.e. those who have five or more colorectal adenomas of InterventionsThe interventions were capsules containing 2000 mg of 99% EPA–FFA or 2780 mg of 90% EPA–TG (equivalent to 2000 mg of FFA) taken daily, or identical placebo capsules; and 300 mg of aspirin taken daily, or an identical placebo, enteric-coated tablet. Both were taken for ≈1 year until surveillance colonoscopy. All participants and staff were unaware of treatment allocation.Main outcome measuresThe primary outcome was the number of participants with one or more colorectal adenomas [adenoma detection rate (ADRa)] at surveillance colonoscopy. Outcomes were analysed for all participants with observable follow-up data by an ‘at-the-margins’ approach, adjusted for BCSP site and by the need for repeat baseline endoscopy. Secondary outcome measures – these included the number of colorectal adenomas per patient [mean adenomas per patient (MAP)], ‘advanced’ ADRa and colorectal adenoma location (right/left) and type (conventional/serrated).ResultsBetween November 2011 and June 2016, 709 participants were randomised, with 707 providing data (80% male, mean age 65 years). The four treatment groups (EPA + aspirin,n = 177; EPA,n = 179; aspirin,n = 177; placebo,n = 176) were well matched for baseline characteristics. Tissue EPA levels and tolerability were similar for FFA and TG users. There was no evidence of any difference in ADRa between EPA users (62%) and non-users (61%) [risk difference –0.9%, 95% confidence interval (CI) –8.8% to 6.9%] or for aspirin users (61%) versus non-users (62%) (risk difference –0.6%, 95% CI –8.5% to 7.2%). There was no evidence of an interaction between EPA and aspirin for ADRa. There was no evidence of any effect on advanced ADRa of either EPA (risk difference –0.6%, 95% CI –4.4% to 3.1%) or aspirin (risk difference –0.3%, 95% CI –4.1% to 3.5%). Aspirin use was associated with a reduction in MAP [incidence rate ratio (IRR) 0.78, 95% CI 0.68 to 0.90), with preventative efficacy against conventional (IRR 0.82, 95% CI 0.71 to 0.94), serrated (IRR 0.46, 95% CI 0.25 to 0.87) and right-sided (IRR 0.73, 95% CI 0.61 to 0.88) lesions, but not left-sided (IRR 0.85, 95% CI 0.69 to 1.06) adenomas. There was evidence of chemopreventive efficacy of EPA on conventional (IRR 0.86, 95% CI 0.74 to 0.99) and left-sided (IRR 0.75, 95% CI 0.60 to 0.94) adenomas, but not on total MAP (IRR 0.91, 95% CI 0.79 to 1.05) or serrated (IRR 1.44, 95% CI 0.79 to 2.60) or right-sided (IRR 1.02, 95% CI 0.85 to 1.22) adenomas. EPA and aspirin treatment were well tolerated, with excess mild/moderate gastrointestinal (GI) adverse events (AEs) in the EPA alone group. There were six GI bleeding AEs.ConclusionEPA and aspirin treatment were not associated with a reduction in ADRa. However, both agents displayed evidence of chemopreventive efficacy, based on adenoma number reduction, which was specific to adenoma type and location, and is compatible with known anti-CRC activity of aspirin.LimitationsLimitations of the trial included the failure to recruit to the target sample size of 853, and an unexpected switch of EPA formulation mid-trial.Future workA future objective should be to understand the mechanism(s) of action of EPA and aspirin using the trial biobank. Established trial infrastructure will enable future trials in the BCSP.Trial registrationCurrent Controlled Trials ISRCTN05926847.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

Background Inflammation has been associated with increased morbidity and mortality in HIV-positive patients. We compared inflammatory biomarkers with dual therapy using lopinavir/ritonavir plus lamivudine (LPV/r+3TC) versus triple therapy using LPV/r plus two nucleoside reverse transcriptase inhibitors (LPV/r+2NRTIs) in treatment-naive HIV-positive adults. Methods This was a substudy among Argentinian participants in the randomized trial GARDEL. We measured hsCRP, IL-6, MCP-1, TNF, D-dimer and sCD14 from plasma collected at baseline, week 24 and week 48. Generalized estimating equations with an identity/logit link were used to model the average impact of dual versus triple therapy on each biomarker over time, controlling for baseline levels. Additional models estimated the average effect of virologic suppression on biomarker levels over time, adjusting for age, sex, and baseline CD4 count. Results Of 191 trial participants enrolled in Argentina, 172 had baseline and follow-up measurements and were included. Median (IQR) age was 35.5 (28.5, 45) years and CD4 cell count was 310 (219, 414) cells/mm3. Dual therapy was not associated with significantly different biomarker levels over 48 weeks relative to triple therapy. Virologic suppression was associated with statistically significant decreases in MCP-1, TNF and D-dimer levels and an unexpected increase in sCD14 levels. No change was observed in hsCRP or the proportion of participants with undetectable IL-6 levels. Conclusions In addition to having virologic non-inferiority, LPV/r+3TC dual therapy is generally associated with similar inflammatory biomarker levels over 48 weeks compared to LPV/r+2NRTIs triple therapy in treatment-naive adults. Further study of dual treatment regimens is warranted.

Obesity is a risk factor for colorectal cancer. Yet, some research indicates that weight-reducing bariatric surgery also increases colorectal cancer risk. Our study was undertaken because current evidence examining bariatric surgery and risk of colorectal cancer is limited and inconsistent. This population-based cohort study included adults with a documented obesity diagnosis in Denmark, Finland, Iceland, Norway or Sweden in 1980-2015. The incidence of colorectal cancer in participants with obesity who had and had not undergone bariatric surgery was compared to the incidence in the corresponding background population by calculating standardized incidence ratios (SIR) with 95% confidence intervals (CI). Additionally, operated and nonoperated participants with obesity were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CIs adjusted for confounders. Among 502,772 cohort participants with an obesity diagnosis, 49,931(9.9%) underwent bariatric surgery. The overall SIR of colon cancer was increased after bariatric surgery (SIR 1.56; 95% CI 1.28-1.88), with higher SIRs ≥10 years postsurgery. The overall HR of colon cancer in operated compared to nonoperated participants was 1.13 (95% CI 0.92-1.39) and 1.55 (95% CI 1.04-2.31) 10-14 years after bariatric surgery. Bariatric surgery did not significantly increase the risk of rectal cancer (SIR 1.14, 95% CI 0.83-1.52; HR 1.08, 95% CI 0.79-1.49), but the risk estimates increased with longer follow-up periods. Our study suggests that bariatric surgery is associated with an increased risk of colon cancer, while the support for an increased risk of rectal cancer was weaker.

ObjectiveAcademic medical training was overhauled in 2005 after the Walport report and Modernising Medical Careers to create a more attractive and transparent training pathway. In 2007 and 2016, national web-based surveys of gastroenterology trainees were undertaken to determine experiences, perceptions of and perceived barriers to out-of-programme research experience (OOP-R).Design, setting and patientsProspective, national web-based surveys of UK gastroenterology trainees in 2007 and 2016.Main outcome measureAttitudes to OOP-R of two cohorts of gastroenterology trainees.ResultsResponse rates were lower in 2016 (25.8% vs 56.7%) (p50% having already undertaken it. Doctor of Philosophy/medical doctorate remained the most popular OOP-R in both cohorts. Successful fellowship applications increased in 2016, and evidence of gender inequality in 2007 was no longer evident in 2016. In the 2016 cohort, 91.1% (n=144) felt the development of trainee-led research networks was important, with 74.7% (n=118) keen to get involved.ConclusionsThe majority of gastroenterology trainees who responded expressed a desire to undertake OOP-R, and participation rates in OOP-R remain high. Despite smaller absolute numbers responding than in 2007, 2016 trainees achieved higher successful fellowship application rates. Reassuringly more trainees in 2016 felt that OOP-R would be important in the future. Efforts are needed to tackle potential barriers to OOP-R and support trainees to pursue research-active careers.

Background: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episode). Methods: Formalin-fixed, paraffin-embedded sections from 71 CRCs (screen-detected 43, interval 28) underwent immunohistochemistry for CD31 and Ki-67, in order to measure the microvessel density (MVD) and proliferation index (PI), respectively, as well as microsatellite instability (MSI) testing. Results: Interval CRCs were larger (P=0.02) and were more likely to exhibit venous invasion (P=0.005) than screen-detected tumours. There was no significant difference in MVD or PI between interval and screen-detected CRCs. More interval CRCs displayed MSI-high (14%) compared with screen-detected tumours (5%). A significantly (P=0.005) higher proportion (51%) of screen-detected CRC resection specimens contained at least one polyp compared with interval CRC (18%) resections. Conclusions: We found no evidence of biological differences between interval and screen-detected CRCs, consistent with the low sensitivity of guaiac stool testing as the main driver of interval CRC. The contribution of synchronous adenomas to occult blood loss for screening requires further investigation.

Background & Aims: There are conflicting data for the role of obesity in Crohn’s disease (CD) and the effect on long-term clinical outcomes is poorly studied. Some evidence suggests obesity is associated with diminished responsiveness to biological agents, especially anti-tumour necrosis factor antibodies. Methods: We aimed to examine the influence of body mass index (BMI) on the response to infliximab in CD in a retrospective analysis. The outcomes of interest within 12 months were: (1) Composite loss of response (CD-related flare or surgery; LOR); (2) any CD-related surgery (CDRS); and (3) CD-related intestinal resectional surgery (CDRIS). Results: A total of 388 patients were included. The mean BMI was 24.2kg/m2 [± standard deviation (SD) 5.1]. Of the 388 patients, 137 (35.4%) were overweight (BMI: 25–29.9kg/m2) or obese (BMI: ≥30kg/m2)—160 (41.6%) patients had LOR during the 12 months follow-up; 121 (31.4%) required CDRS, and 109 (28.2%) required CDRIS. Multivariate analysis showed that increasing BMI (per unit, kg/m2 increase) reduced the risk of LOR [odds ratio (OR): 0.98], CDRS (OR: 0.95), and CDRIS (OR: 0.95). Rates for all outcomes were higher, but not significantly so, in the extreme categories (underweight and obese) and lower in the underweight categories compared with normal BMI. Exclusion of the obese category of patients strengthened this relationship. Conclusions: Body mass index at first infusion of infliximab has a non-linear relationship with outcomes at 12 months. The worst outcomes are at the extremes of weight (underweight and obese categories). Increasing BMI is associated with a modest reduction in risk of LOR, CDRS, and CDRIS within 12 months, increasing with the exclusion of the obese category.

Trial results are used to support licensure, inform cost-effectiveness analyses, and guide clinical decision making. We found the majority of coinfected patients were not included in clinical trials of direct-acting antivirals, raising concerns about the generalizability of these trial results., Background. Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)–HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials. Methods. Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada. Results. Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%–79%) and active illicit drug use (53%–55%). Conclusions. DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection—individuals for whom real-world data are urgently needed.

We read with great interest the article by Gudra et al 1 reporting a faecal immunochemical test (FIT; OC-Sensor, Eiken Chemical) commonly used in colonic neoplasia screening as a reliable sampling device for microbiome profiling when compared with immediately frozen samples from whole stool. The potential to use the FIT routinely completed by approximately 3 million participants annually as part of the English Bowel Cancer Screening Programme2 to understand the role of gut microbiome in colorectal neoplasia holds great promise, not least because of the convenience to individuals, cost-savings associated with use of routinely collected samples, and methodological advantages of samples collected before microbiome-altering procedures (eg, bowel cleansing).3 We aimed to validate and expand on the finding of Gudra et al 1 by investigating performance of the Bowel Cancer Screening Programme (BCSP) FIT, analysing more subjects, testing longer-term storage, investigating different methods of concentration and comparing with OMNIgene.GUT (OG; DNA Genotek), a widely used research device for stool DNA preservation at ambient temperature.4 We considered bacterial profile stability over time, mimicking real-world research scenarios with storage of FIT samples for up to 20 days prior to DNA extraction. We …

OBJECTIVE: To determine whether bariatric surgery is associated with a lower risk of cancer. SUMMARY BACKGROUND DATA: Obesity is strongly associated with many types of cancer. Few studies have examined the relationship between bariatric surgery and cancer risk. METHODS: We conducted a retrospective cohort study of patients undergoing bariatric surgery between 2005 and 2012 with follow-up through 2014 using data from a large integrated health insurance and care delivery systems with five study sites. The study included 22,198 subjects who had bariatric surgery and 66,427 non-surgical subjects matched on sex, age, study site, BMI and Elixhauser comorbidity index. Multivariable Cox proportional hazards models were used to examine incident cancer up to 10 years after bariatric surgery compared to the matched non-surgical patients. RESULTS: After a mean follow-up of 3.5 years, we identified 2,543 incident cancers. Patients undergoing bariatric surgery had a 33% lower hazard of developing any cancer during follow-up (HR 0.67, 95% C.I. 0.60, 0.74, p

Marine omega-3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA and disease-free survival (DFS) and overall survival according to KRAS and BRAF(V600E) mutations and DNA mismatch repair (MMR) status. Higher MO3PUFA intake was associated with improved 3-year DFS for KRAS-wildtype tumors (77% vs. 73%; HR, 0.84, 95% CI, 0.67-1.05), but not KRAS-mutant tumors (64% vs. 70%; HR, 1.30, 95% CI, 0.97-1.73; P(interaction)=0.02). Similar heterogeneity was found by MMR (P(interaction)=0.14): higher MO3PUFA was associated with better 3-year DFS for tumors with deficient MMR (72% vs. 67%), but not proficient MMR (72% vs. 72%). No heterogeneity was found by BRAF(V600E) mutation. Similar findings were obtained for overall survival. In conclusion, we found a suggestive beneficial association between higher MO3PUFA intake and improved survival among stage III colon cancer patients with wildtype KRAS and deficient MMR. Given the relatively small number of cases with tumor molecular assessments, further studies, preferably through pooled analyses of multiples cohorts, are needed to validate our findings.

Background & Aims Gastrointestinal (GI) surgery is an important part of the treatment algorithm for patients with Crohn’s disease (CD) that is complicated or does not respond to medical therapy. Cohort studies from Denmark and Canada have shown that the risk of primary surgery is decreasing but there is a lack of contemporary data on subsequent resections. We examined trends in first and second GI resections in patients with CD. Methods We performed a retrospective cohort study using the United Kingdom primary care database ResearchOne, collecting data from patients with Crohn’s disease from 1994 through 2013. We compared rates of first and second GI resections with etiological factors. Results Among 3059 incident cases of CD, 13%, 21%, and 26% of the patients underwent surgical resections after 1, 5, and 10 years, respectively. Of patients with an initial resection, 20% required an additional operation when followed for 10 years after the initial resection. We found a significant reduction in first surgery, from 44% to 21% after 10 years of disease, from 1994 to 2003 (χ2 for trend, P Conclusion In a retrospective analysis of a United Kingdom primary care database, we observed a significant reduction in first and subsequent GI surgeries among patients with CD over the past 20 years in England.

The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer chemoprevention, aligned with an excellent safety profile. Therefore, we aimed to test the efficacy of EPA and aspirin, alone and in combination and compared with a placebo, in individuals with sporadic colorectal neoplasia detected at colonoscopy.In a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial, patients aged 55-73 years who were identified during colonoscopy as being at high risk in the English Bowel Cancer Screening Programme (BCSP; ≥3 adenomas if at least one was ≥10 mm in diameter or ≥5 adenomas if these were10 mm in diameter) were recruited from 53 BCSP endoscopy units in England, UK. Patients were randomly allocated (1:1:1:1) using a secure web-based server to receive 2 g EPA-free fatty acid (FFA) per day (either as the FFA or triglyceride), 300 mg aspirin per day, both treatments in combination, or placebo for 12 months using random permuted blocks of randomly varying size, and stratified by BCSP site. Research staff and participants were masked to group assignment. The primary endpoint was the adenoma detection rate (ADR; the proportion of participants with any adenoma) at 1 year surveillance colonoscopy analysed in all participants with observable follow-up data using a so-called at-the-margins approach, adjusted for BCSP site and repeat endoscopy at baseline. The safety population included all participants who received at least one dose of study drug. The trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN05926847.Between Nov 11, 2011, and June 10, 2016, 709 participants were randomly assigned to four treatment groups (176 to placebo, 179 to EPA, 177 to aspirin, and 177 to EPA plus aspirin). Adenoma outcome data were available for 163 (93%) patients in the placebo group, 153 (85%) in the EPA group, 163 (92%) in the aspirin group, and 161 (91%) in the EPA plus aspirin group. The ADR was 61% (100 of 163) in the placebo group, 63% (97 of 153) in the EPA group, 61% (100 of 163) in the aspirin group, and 61% (98 of 161) in the EPA plus aspirin group, with no evidence of any effect for EPA (risk ratio [RR] 0·98, 95% CI 0·87 to 1·12; risk difference -0·9%, -8·8 to 6·9; p=0·81) or aspirin (RR 0·99 (0·87 to 1·12; risk difference -0·6%, -8·5 to 7·2; p=0·88). EPA and aspirin were well tolerated (78 [44%] of 176 had ≥1 adverse event in the placebo group compared with 82 [46%] in the EPA group, 68 [39%] in the aspirin group, and 76 [45%] in the EPA plus aspirin group), although the number of gastrointestinal adverse events was increased in the EPA alone group at 146 events (compared with 85 in the placebo group, 86 in the aspirin group, and 68 in the aspirin plus placebo group). Six upper-gastrointestinal bleeding events were reported across the treatment groups (two in the EPA group, three in the aspirin group, and one in the placebo group).Neither EPA nor aspirin treatment were associated with a reduction in the proportion of patients with at least one colorectal adenoma. Further research is needed regarding the effect on colorectal adenoma number according to adenoma type and location. Optimal use of EPA and aspirin might need a precision medicine approach to adenoma recurrence.Efficacy and Mechanism Evaluation Programme, a UK Medical Research Council and National Institute for Health Research partnership.

Background Patients co-infected with HIV and hepatitis C virus (HCV) are a priority target for HCV treatment. The simplicity and efficacy of direct-acting antivirals (DAA) should help overcome patient, provider, and structural barriers to scaling up treatment. Methods We estimated between-centre variation in DAA treatment uptake among 1734 patients enrolled at the 18 centres of the Canadian Co-Infection Cohort—a prospective cohort of adults co-infected with HIV and HCV. We then compared this variation to that observed during the interferon era. Time to treatment uptake was modeled using a Weibull time-to-event model adjusting for centre and patient characteristics thought to have an impact on treatment initiation in the DAA era. Results At the time of administrative censoring (December 31, 2016), 981 cohort participants were eligible for second-generation DAA therapy (HCV RNA positive after November 21, 2013) of whom 278 initiated DAAs (16 patients per 100 person-years). Patients with low monthly income, Indigenous ethnicity, recent injection drug use, HCV genotype 3, or unknown HCV genotype were less likely to start treatment. After adjusting for patient characteristics, the estimated between-centre variance (σ2) was 0.29 (95% credible interval [CrI]: 0.09-0.89), considerably lower than during the interferon era (σ2 = 0.87, 95% CrI: 0.49–1.5). This between-centre variance was further reduced by the addition of centre-level effects for jurisdiction (σ2 = 0.15, 95% CrI: 0.02-0.60). Conclusion Much of the variation in treatment uptake between centres can now be attributed to regional differences. This suggests that after the introduction of DAAs, treatment barriers have shifted towards prescribing and reimbursement restrictions based on liver fibrosis, which vary by jurisdiction. The removal of these restrictions, however, will need to be paired with strategies to overcome patient-level barriers, which continue to prevent marginalized people and active substance users from accessing treatment.

Introduction Colorectal cancer (CRC) risk is increased in those with inflammatory bowel disease (IBD). Guidelines advocate surveillance colonoscopy for patients with longstanding IBD. Post-colonoscopy colorectal cancer (PCCRC) is a key quality indicator of colonoscopy. There is limited data exploring the rate of PCCRC in those with IBD and potential risk factors associated with IBD-related PCCRC. This study explored national and individual hospital rates of IBD-related PCCRC in England since 2006. Further analysis explored potential associations with IBD-related PCCRC in order to inform future quality improvement interventions. Methods We identified all those who had undergone a colonoscopy between 1/1/2006 and 31/12/2012 and developed a CRC before 31/12/2015 using linked national Hospital Episode Statistics and National Cancer Registration and Analysis Service data. IBD cases were identified by relevant ICD-10 codes. Using international consensus guidelines1,2 the rate of PCCRC within 3 years (PCCRC-3 yr) was calculated as the number of false negative colonoscopies (within 6–36 months of CRC) divided by the sum of the true positive (within 6 months of CRC) and false negative colonoscopies. The IBD-associated PCCRC-3 yr rate in each NHS hospital trust in England was ranked and trusts were separated into quintiles. Factors associated with IBD-related PCCRC were investigated. Results Between 2006 and 2012 we identified 7781 PCCRC, 800 (10%) with a diagnosis of IBD. Nationally, the IBD-PCCRC-3 yr rate was 35%, and varied between hospital trusts with those in the lowest quintile having a mean, unadjusted rate of 19% (SD ±7%) compared to 52% (SD ±7%) in the highest quintile. PCCRC cases were younger at diagnosis (60 years compared to 66 years), were less likely to have diverticular disease (10% compared to 16%), and had undergone more previous colonoscopies when compared to detected cases (within 6 months of colonoscopy). There was no significant difference for sex, bowel location, deprivation score, or metachronous tumours. Conclusion PCCRC-3 yr in those with IBD is high, and accounted for 10% of all PCCRC-3 yr in England between 2006 and 2012. There is a wide variation in the unadjusted rates between NHS trusts in England that is unlikely to be explained by natural variation. There is an urgent need to investigate avoidable reasons for cancers in those with IBD to optimise surveillance and prevention of CRC in IBD.

Background Obesity increases the risk of several types of cancer. Whether bariatric surgery influences the risk of obesity-related cancer is not clear. This study aimed to uncover the risk of hormone-related (breast, endometrial and prostate), colorectal and oesophageal cancers following obesity surgery. Methods This national population-based cohort study used data from the Hospital Episode Statistics database in England collected between 1997 and 2012. Propensity matching on sex, age, co-morbidity and duration of follow-up was used to compare cancer risk among obese individuals undergoing bariatric surgery (gastric bypass, gastric banding or sleeve gastrectomy) and obese individuals not undergoing such surgery. Conditional logistic regression provided odds ratios (ORs) with 95 per cent confidence intervals. Results In the study period, from a cohort of 716 960 patients diagnosed with obesity, 8794 patients who underwent bariatric surgery were matched exactly with 8794 obese patients who did not have surgery. Compared with the no-surgery group, patients who had bariatric surgery exhibited a decreased risk of hormone-related cancers (OR 0·23, 95 per cent c.i. 0·18 to 0·30). This decrease was consistent for breast (OR 0·25, 0·19 to 0·33), endometrium (OR 0·21, 0·13 to 0·35) and prostate (OR 0·37, 0·17 to 0·76) cancer. Gastric bypass resulted in the largest risk reduction for hormone-related cancers (OR 0·16, 0·11 to 0·24). Gastric bypass, but not gastric banding or sleeve gastrectomy, was associated with an increased risk of colorectal cancer (OR 2·63, 1·17 to 5·95). Longer follow-up after bariatric surgery strengthened these diverging associations. Conclusion Bariatric surgery is associated with decreased risk of hormone-related cancers, whereas gastric bypass might increase the risk of colorectal cancer.

Clinical trial results of direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) have shown improvements in health-related quality of life (HR-QoL). However, the extent to which these results are broadly generalizable to real-world settings is unknown. We investigated the real-world impact of oral DAA therapy on HR-QoL among individuals coinfected with HIV/HCV. We used data from the Canadian HIV/HCV Co-Infection Cohort Study that prospectively follows 1795 participants from 18 centres. Since 2007, clinical, lifestyle, and HR-QoL data have been collected biannually through self-administered questionnaires and chart review. HR-QoL was measured using the EQ-5D instrument. Participants initiating oral DAAs, having at least one visit before treatment initiation and at least one visit after DAA treatment response was ascertained, were included. Successful treatment response was defined as a sustained viral response (SVR). Segmented multivariate linear mixed models were used to evaluate the impact of SVR on HR-QoL, controlling for pretreatment trends. 227 participants met our eligibility criteria, 93% of whom achieved SVR. Before treatment, the EQ-5D utility index decreased 0.6 percentage-point/y (95% CI, -0.9, -0.3) and health state was constant over time. The immediate effect of SVR resulted in an increase of 2.3-units (-0.1, 4.7) in patients' health state and 2.0 percentage-point increase (-0.2, 4.0) in utility index. Health state continued to increase post-SVR by 1.4 units/y (-0.9, 3.7), while utility trends post-SVR plateaued over the observation period. Overall using real-world data, we found modest improvements in HR-QoL following SVR, compared to previously published clinical trials.

PurposeThe Comparative Outcomes And Service Utilization Trends (COAST) Study in British Columbia (BC), Canada, was designed to evaluate the determinants of health outcomes and health care services use among people living with HIV (PLHIV) as they age in the period following the introduction of combination antiretroviral therapy (cART). The study also assesses how age-associated comorbidities and health care use among PLHIV may differ from those observed in the general population.ParticipantsCOAST was established through a data linkage between two provincial data sources: The BC Centre for Excellence in HIV/AIDS Drug Treatment Program, which centrally manages cART dispensation across BC and contains prospectively collected data on demographic, immunological, virological, cART use and other clinical information for all known PLHIV in BC; and Population Data BC, a provincial data repository that holds individual event-level, longitudinal data for all 4.6 million BC residents. COAST participants include 13 907 HIV-positive adults (≥19 years of age) and a 10% random sample inclusive of 516 340 adults from the general population followed from 1996 to 2013.Findings to dateFor all participants, linked individual-level data include information on demographics, health service use (eg, inpatient care, outpatient care and prescription medication dispensations), mortality, and HIV diagnostic and clinical data. Publications from COAST have demonstrated the significant mortality reductions and dramatic changes in the causes of death among PLHIV from 1996 to 2012, differences in the amount of time spent in a healthy state by HIV status, and high levels of injury and mood disorder diagnosis among PLHIV compared with the general population.Future plansTo capture the dynamic nature of population health parameters, regular data updates and a refresh of the data linkage are planned to occur every 2 years, providing the basis for planned analysis to examine age-associated comorbidities and patterns of health service use over time.