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Background and aims The gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes. Methods A multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months. Results Thirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10−11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR = 1.30 × 10−12), but metabolite clusters were not associated with disease-free survival (p = 0.358). An association was identified between Met 1 and DNA mismatch-repair deficiency (p = 0.005). FBXW7 mutations were only found in cancers predominant in microbiota cluster 7. Conclusions Networks of pathobionts in the tumour mucosal niche are associated with tumour mutation and metabolic subtypes and predict favourable outcome following CRC resection.

Objective: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.Summary of background data: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.Methods: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.Results: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group.Conclusions: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions.Trial registration: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

ObjectivesHelicobacter pylori infection is a common cause of chronic gastritis worldwide and an established risk factor for developing gastric malignancy. The endoscopic appearances predicting H. pylori status are an ongoing area of research, as are their diagnostic accuracies. This study aimed to establish the diagnostic accuracy of several mucosal features predictive of H. pylori negative status and formulate a simple prediction model for use at the time of endoscopy.DesignPatients undergoing high-definition upper gastrointestinal (GI) endoscopy without magnification were recruited prospectively. During the endoscopy, the presence or absence of specific endoscopic findings was noted. Sydney protocol biopsies were used as the diagnostic reference standard, and urease test if taken. The results informed a logistic regression model used to produce a simple diagnostic approach. This model was subsequently validated using a further cohort of 30 patients.Results153 patients were recruited and completed the study protocol. The prevalence of active H. pylori infection was 18.3% (28/153). The overall diagnostic accuracy of the simple prediction model was 80.0%, and 100% of patients with active H. pylori infection were correctly classified. The presence of regular arrangement of collecting venules (RAC) showed a positive predictive value for H. pylori naïve status of 90.7%, rising to 93.6% for patients under the age of 60.ConclusionA simple endoscopic model may be accurate for predicting H. pylori status of a patient, and the need for biopsy-based tests. The presence of RAC in the stomach is an accurate predictor of H. pylori negative status, particularly in patients under the age of 60.Trial registration numberThe study was registered with ClinicalTrials.gov, No. NCT02385045.

Background and study aims There is growing interest in the endoscopic recognition of Helicobacter pylori infection, and application to routine practice. We present a systematic review of the current literature regarding diagnosis of H. pylori during standard (non-magnified) endoscopy, including adjuncts such as image enhancement and computer-aided diagnosis. Method The Medline and Cochrane databases were searched for studies investigating performance of non-magnified optical diagnosis for H. pylori, or those which characterized mucosal features associated with H. pylori infection. Studies were preferred with a validated reference test as the comparator, although they were included if at least one validated reference test was used. Results Twenty suitable studies were identified and included for analysis. In total, 4,703 patients underwent investigation including white light endoscopy, narrow band imaging, i-scan, blue-laser imaging, and computer-aided diagnostic techniques. The endoscopic features of H. pylori infection observed using each modality are discussed and diagnostic accuracies reported. The regular arrangement of collecting venules (RAC) is an important predictor of the H. pylori-naïve stomach. “Mosaic” and “mottled” patterns have a positive association with H. pylori infection. The “cracked” pattern may be a predictor of an H. pylori-negative stomach following eradication. Conclusions This review summarizes current progress made in endoscopic diagnosis of H. pylori infection. At present there is no single diagnostic approach that provides validated diagnostic accuracy. Further prospective studies are required, as is development of a validated classification system. Early studies in computer-aided diagnosis suggest potential for a high level of accuracy but real-time results are awaited.

Background Colonoscopy reduces the incidence of colorectal cancer (CRC) by allowing detection and resection of neoplastic polyps. Evidence shows that many small polyps are missed on a single colonoscopy. There has been a successful adoption of artificial intelligence (AI) technologies to tackle the issues around missed polyps and as tools to increase the adenoma detection rate (ADR). Objective The aim of this review was to examine the diagnostic accuracy of AI-based technologies in assessing colorectal polyps. Methods A comprehensive literature search was undertaken using the databases of Embase, MEDLINE, and the Cochrane Library. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Studies reporting the use of computer-aided diagnosis for polyp detection or characterization during colonoscopy were included. Independent proportions and their differences were calculated and pooled through DerSimonian and Laird random-effects modeling. Results A total of 48 studies were included. The meta-analysis showed a significant increase in pooled polyp detection rate in patients with the use of AI for polyp detection during colonoscopy compared with patients who had standard colonoscopy (odds ratio [OR] 1.75, 95% CI 1.56-1.96; P Conclusions With the aid of machine learning, there is potential to improve ADR and, consequently, reduce the incidence of CRC. The current generation of AI-based systems demonstrate impressive accuracy for the detection and characterization of colorectal polyps. However, this is an evolving field and before its adoption into a clinical setting, AI systems must prove worthy to patients and clinicians. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42020169786; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020169786

Background & aims: Duodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs). Methods: Sub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18–65 years with type-2 diabetes mellitus and body mass index 30–50 kg/m 2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group. Results: Weight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group. Conclusion: One year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation. Trial registration: ClinicalTrials.gov Identifier NCT02459561.

Objectives Helicobacter pylori infection is a common cause of chronic gastritis worldwide and an established risk factor for developing gastric malignancy. The endoscopic appearances predicting H. pylori status are an ongoing area of research, as are their diagnostic accuracies. This study aimed to establish the diagnostic accuracy of several mucosal features predictive of H. pylori negative status and formulate a simple prediction model for use at the time of endoscopy. Design Patients undergoing high-definition upper gastrointestinal (GI) endoscopy without magnification were recruited prospectively. During the endoscopy, the presence or absence of specific endoscopic findings was noted. Sydney protocol biopsies were used as the diagnostic reference standard, and urease test if taken. The results informed a logistic regression model used to produce a simple diagnostic approach. This model was subsequently validated using a further cohort of 30 patients. Results 153 patients were recruited and completed the study protocol. The prevalence of active H. pylori infection was 18.3% (28/153). The overall diagnostic accuracy of the simple prediction model was 80.0%, and 100% of patients with active H. pylori infection were correctly classified. The presence of regular arrangement of collecting venules (RAC) showed a positive predictive value for H. pylori naïve status of 90.7%, rising to 93.6% for patients under the age of 60. Conclusion A simple endoscopic model may be accurate for predicting H. pylori status of a patient, and the need for biopsy-based tests. The presence of RAC in the stomach is an accurate predictor of H. pylori negative status, particularly in patients under the age of 60. Trial registration number The study was registered with ClinicalTrials.gov, No. NCT02385045.

Background A widely used method in assessing small bowel permeability is the lactulose:mannitol test, where the lactulose:mannitol ratio (LMR) is measured. However, there is discrepancy in how the test is conducted and in the values of LMR obtained across studies. This meta-analysis aims to determine LMR in healthy subjects, coeliac and Crohn’s disease. Methods A literature search was performed using PRISMA guidance to identify studies assessing LMR in coeliac or Crohn’s disease. 19 studies included in the meta-analysis measured gut permeability in coeliac disease, 17 studies in Crohn’s disease. Outcomes of interest were LMR values and comparisons of standard mean difference (SMD) and weighted mean difference (WMD) in healthy controls, inactive Crohn’s, active Crohn’s, treated coeliac and untreated coeliac. Pooled estimates of differences in LMR were calculated using the random effects model. Results Pooled LMR in healthy controls was 0.014 (95% CI: 0.006–0.022) while pooled LMRs in untreated and treated coeliac were 0.133 (95% CI: 0.089–0.178) and 0.037 (95% CI: 0.019–0.055). In active and inactive Crohn’s disease, pooled LMRs were 0.093 (95% CI: 0.031–0.156) and 0.028 (95% CI: 0.015–0.041). Significant differences were observed in LMR between: (1) healthy controls and treated coeliacs (SMD = 0.409 95% CI 0.034 to 0.783, p = 0.032), (2) healthy controls and untreated coeliacs (SMD = 1.362 95% CI: 0.740 to 1.984, p p = 0.001), (4) healthy controls and inactive Crohn’s (SMD = 1.265 95% CI: 0.845 to 1.686, p p p = 0.001). High heterogeneity was observed, which was attributed to variability in protocols used across different studies. Conclusion The use of gut permeability measurements in screening and monitoring of coeliac and Crohn’s disease is promising. LMR is useful in performing this function with significant limitations. More robust alternative tests with higher degrees of clinical evidence are needed if measurements of gut permeability are to find widespread clinical use.

Malignant melanoma (MM) has become the fifth most frequent cancer in the UK. It is the most common carcinoma to metastasize to the gastrointestinal (GI) tract. MM particularly has an affinity to spread to the small bowel, which is followed by the involvement of the stomach and large intestine. Excellent endoscopic options including video capsule endoscopy and enteroscopy are available for a precise diagnosis of GI involvement by a metastatic MM. The complete surgical resection of GI metastatic MM in carefully selected patients not only provides symptom control, but has also been associated with an increase in overall survival. The approval of BRAF-targeted therapies and immune checkpoint inhibitors has transformed therapeutic approaches for patients with metastatic MM over the past decade. Currently, the overall survival of patients with advanced metastatic MM who have been treated with a combination of immunotherapeutic agents reaches 52% at five years. The role of surgery for patients with the metastatic involvement of the GI tract with MM is evolving in the era of effective systemic treatments.

BACKGROUND Colonoscopy reduces the incidence of colorectal cancer (CRC) by allowing detection and resection of neoplastic polyps. Evidence shows that many small polyps are missed on a single colonoscopy. There has been a successful adoption of artificial intelligence (AI) technologies to tackle the issues around missed polyps and as tools to increase the adenoma detection rate (ADR). OBJECTIVE The aim of this review was to examine the diagnostic accuracy of AI-based technologies in assessing colorectal polyps. METHODS A comprehensive literature search was undertaken using the databases of Embase, MEDLINE, and the Cochrane Library. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Studies reporting the use of computer-aided diagnosis for polyp detection or characterization during colonoscopy were included. Independent proportions and their differences were calculated and pooled through DerSimonian and Laird random-effects modeling. RESULTS A total of 48 studies were included. The meta-analysis showed a significant increase in pooled polyp detection rate in patients with the use of AI for polyp detection during colonoscopy compared with patients who had standard colonoscopy (odds ratio [OR] 1.75, 95% CI 1.56-1.96; PP CONCLUSIONS With the aid of machine learning, there is potential to improve ADR and, consequently, reduce the incidence of CRC. The current generation of AI-based systems demonstrate impressive accuracy for the detection and characterization of colorectal polyps. However, this is an evolving field and before its adoption into a clinical setting, AI systems must prove worthy to patients and clinicians. CLINICALTRIAL PROSPERO International Prospective Register of Systematic Reviews CRD42020169786; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020169786

Introduction Trimethylamine N-oxide (TMAO) is formed in the liver from trimethylamine, and is exclusively generated by gut microbiota from the metabolism of dietary carnitine and choline. Elevated plasma levels have been implicated in the pathogenesis of Type 2 Diabetes and cardiovascular disease. The Endobarrier is an endoscopically implanted duodenal jejunal bypass liner (DJBL) designed to mimic the effects of bariatric surgery leading to significant weight loss and improvements in glycaemic control and we present novel data of its effects on the plasma metabolic profile of these patients. Methods The Endobarrier Trial (NCT02459561) is a large multicentre, randomised, controlled trial across two sites in the UK which recruited 170 patients with Type 2 Diabetes and BMI 30–50 kg/m2. Participants were randomised to receive the DJBL (n=85) for one year or conventional medical therapy, diet and exercise (n=85). Plasma samples were collected from all participants at baseline, 6 months and 1 year and analysed using 1H NMR spectroscopy and multivariate statistical analysis to identify key metabolic perturbations between both patient cohorts. Results A total of 112 patients were followed up for one year. 309 plasma samples were processed and then analysed. A typical 1H NMR plasma spectrum is shown in figure 1. Reduction in plasma concentrations of trimethylamine N-oxide (TMAO) were found in the DJBL group at 6 months and 1 year compared with the control group. Conclusions Raised levels of Plasma TMAO have been associated with the development of diabetes and in this study were found to reduce following 6 months and 1 year of DJBL therapy compared with controls. This is the first study of its kind to explore alterations in the metabolic profiles of patients receiving the DJBL by utilising high field 1H nuclear magnetic resonance (NMR) spectroscopy technique. These results may provide a possible insight into the mechanisms of how this device may elicit its effect on weight loss and glycaemic improvement, by reducing plasma TMAO and potentially altering the gut microbial metabolic function.

Objective: The endoscopic findings associated with Helicobacter pylori –naïve status, current infection or past infection are an area of ongoing interest. Previous studies have investigated parameters with a potential diagnostic value. The aim of this study was to perform meta-analysis of the available literature to validate the diagnostic accuracy of mucosal features proposed in the Kyoto classification. Data sources: The databases of MEDLINE and Embase, clinicalTrials.gov and the Cochrane Library were systematically searched for relevant studies from October 1999 to October 2019. Methods: A bivariate random effects model was used to produce pooled diagnostic accuracy calculations for each of the studied endoscopic findings. Diagnostic odds ratios and sensitivity and specificity characteristics were calculated to identify significant predictors of H pylori status. Results: Meta-analysis included 4380 patients in 15 studies. The most significant predictor of an H pylori -naïve status was a regular arrangement of collecting venules (diagnostic odds ratio 55.0, sensitivity 78.3%, specificity 93.8%). Predictors of active H pylori infection were mucosal oedema (18.1, 63.7%, 91.1%) and diffuse redness (14.4, 66.5%, 89.0%). Map-like redness had high specificity for previous H pylori eradication (99.0%), but poor specificity (13.0%). Conclusion: The regular arrangement of collecting venules, mucosal oedema, diffuse redness and map-like redness are important endoscopic findings for determining H pylori status. This meta-analysis provides a tentative basis for developing future endoscopic classification systems.

BackgroundThe EndoBarrier®(GI Dynamics Inc., Boston, MA, USA) is an endoluminal duodenal–jejunal bypass liner developed for the treatment of patients with obesity and type 2 diabetes mellitus. Meta-analyses of its effects on glycaemia and weight have called for larger randomised controlled trials with longer follow-up.ObjectivesThe primary objective was to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level reduction of ≥ 20%. The secondary objectives were to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level of DesignA multicentre, open-label, randomised controlled trial.SettingImperial College Healthcare NHS Trust and University Hospital Southampton NHS Foundation Trust.ParticipantsPatients aged 18–65 years with a body mass index of 30–50 kg/m2and with inadequately controlled type 2 diabetes mellitus who were on oral glucose-lowering medications.InterventionsParticipants were randomised equally to receive intensive medical therapy alongside a duodenal–jejunal bypass liner device (n = 85) or intensive medical therapy alone for 12 months (n = 85), and were followed up for a further 12 months.ResultsThere was no significant difference between groups in the percentage of patients achieving the glycaemic primary or secondary outcomes [primary outcome at 12 months: duodenal–jejunal bypass liner group 54.5% vs. control group 55.2% (odds ratio 0.93, 95% confidence interval 0.44 to 1.98;p = 0.85); primary outcome at 24 months: duodenal–jejunal bypass liner group 39.7% vs. control group 36.5% (odds ratio 1.13, 95% confidence interval 0.52 to 2.47;p = 0.75)]. Significantly more patients in the duodenal–jejunal bypass liner group than in the control group lost > 15% of their total body weight (duodenal–jejunal bypass liner group 24.2% vs. control group 3.7%; odds ratio 8.33, 95% confidence interval 1.78 to 39.0;p = 0.007) and achieved blood pressure targets (duodenal–jejunal bypass liner group 68.2% vs. control group 44.4%; odds ratio 2.57, 95% confidence interval 1.21 to 5.48;p = 0.014). These differences were observed at 12 months but not at 24 months. There were more adverse events in the duodenal–jejunal bypass liner group, including one liver abscess. The increase in peripheral insulin sensitivity was superior in the duodenal–jejunal bypass liner group. Spectroscopic analyses of plasma, urine and faeces revealed several distinct metabolic perturbations in the duodenal–jejunal bypass liner group but not in the control group. Brain reward responses to food cues were not different between groups. The number of mean quality-adjusted life-years gained was similar in both groups and the additional costs of the duodenal–jejunal bypass liner may outweigh the value of the health benefits by £2560 per patient treated.ConclusionsThe results show that the endoluminal duodenal–jejunal bypass liner was not superior to intensive medical therapy for glycaemic control and was associated with more adverse events. The duodenal–jejunal bypass liner was associated with significant weight loss and improvement in cardiometabolic parameters at 12 months but not at 24 months. Economic evaluation showed that the bypass liner was not cost-effective for glycaemic control or for weight loss.Trial registrationCurrent Controlled Trials ISRCTN30845205.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full inEfficacy and Mechanism Evaluation; Vol. 7, No. 6. See the NIHR Journals Library website for further project information. This study was executed with the support of GI Dynamics Inc. and with the kind support of Nutricia Advanced Medical Nutrition for providing oral nutritional supplements.

Objective: The endoscopic findings associated with Helicobacter pylori–naïve status, current infection or past infection are an area of ongoing interest. Previous studies have investigated parameters with a potential diagnostic value. The aim of this study was to perform meta-analysis of the available literature to validate the diagnostic accuracy of mucosal features proposed in the Kyoto classification. Data sources: The databases of MEDLINE and Embase, clinicalTrials.gov and the Cochrane Library were systematically searched for relevant studies from October 1999 to October 2019. Methods: A bivariate random effects model was used to produce pooled diagnostic accuracy calculations for each of the studied endoscopic findings. Diagnostic odds ratios and sensitivity and specificity characteristics were calculated to identify significant predictors of H pylori status. Results: Meta-analysis included 4380 patients in 15 studies. The most significant predictor of an H pylori-naïve status was a regular arrangement of collecting venules (diagnostic odds ratio 55.0, sensitivity 78.3%, specificity 93.8%). Predictors of active H pylori infection were mucosal oedema (18.1, 63.7%, 91.1%) and diffuse redness (14.4, 66.5%, 89.0%). Map-like redness had high specificity for previous H pylori eradication (99.0%), but poor specificity (13.0%). Conclusion: The regular arrangement of collecting venules, mucosal oedema, diffuse redness and map-like redness are important endoscopic findings for determining H pylori status. This meta-analysis provides a tentative basis for developing future endoscopic classification systems.

The rapid rise of obesity and type 2 diabetes poses a global threat to healthcare and is a major cause of mortality and morbidity. Bariatric surgery has revolutionised the treatment of both these conditions but is invasive and associated with an increased risk of complications. The EndoBarrier is a device placed endoscopically in the duodenum, which is designed to mimic the effects of gastric bypass surgery with the aim of inducing weight loss and improving glycaemic control. This review outlines the current clinical evidence of the device, its efficacy, potential mechanisms of action, and utility in clinical practice.

BACKGROUND AND AIMS: Obesity associated with diabetes mellitus is a significant worldwide problem associated with considerable health care costs. Whilst surgical intervention is effective, it is invasive, costly and associated with complications. This study aims to evaluate the safety and efficacy of the EndoBarrier®, a duodenal-jejunal sleeve bypass as an alternative treatment of diabetes mellitus in obese patients. MATERIALS AND METHODS: This was a multi-centre, non-randomised trial recruiting obese patients with type 2 diabetes from three sites in the UK. Eligible participants had a BMI of 30-50 kg/m2and HbA1c levels of 7.5-10%. The study comprised a 12-month period with the EndoBarrier® inserted and a 6-month follow-up period after it had been explanted. The primary study outcomes were weight, BMI, HbA1c levels and fasting insulin and glucose levels. RESULTS: Forty-five patients were recruited and 31 patients (69%) completed the 12-month study period. Significant reductions in weight (95%CI 0.62-29.38; p

Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.

Purpose of Review Obesity is increasing at an alarming rate and now poses a global threat to humankind. In recent years, we have seen the emergence of medical devices to combat the obesity epidemic. These therapeutic strategies are discussed in this review dividing them into gastric and duodenal therapies. Recent Findings Traditionally, medical devices for obesity such as the intragastric balloon have focused on reducing gastric size, but more recently there has been a shift towards developing devices that modulate neural and hormonal responses to induce early satiety thus reducing oral intake. Summary Medical devices for obesity treatment may have a role in those patients who are struggling to control their weight despite significant lifestyle modifications such as diet and exercise and who decline or are unfit for bariatric surgery. For the wider adoption and integration of these devices in the obesity treatment paradigm, more long-term efficacy and safety data from randomised controlled trials are required.

Obesity is a major health and economic crisis facing the modern world. It is associated with excess mortality and morbidity and is directly linked to common conditions such as type 2 diabetes mellitus, coronary heart disease and sleep apnoea. The management of obesity and its associated complications has evolved in recent years, with a shift towards more definitive strategies such as bariatric surgery. This review encompasses the dietary, pharmacological and surgical strategies currently available for the management of obesity.

Objective In this consensus statement, an international panel of experts deliver their opinions on key questions regarding the contribution of the human microbiome to carcinogenesis. Design International experts in oncology and/or microbiome research were approached by personal communication to form a panel. A structured, iterative, methodology based around a 1-day roundtable discussion was employed to derive expert consensus on key questions in microbiome-oncology research. Results Some 18 experts convened for the roundtable discussion and five key questions were identified regarding: (1) the relevance of dysbiosis/an altered gut microbiome to carcinogenesis; (2) potential mechanisms of microbiota-induced carcinogenesis; (3) conceptual frameworks describing how the human microbiome may drive carcinogenesis; (4) causation versus association; and (5) future directions for research in the field. The panel considered that, despite mechanistic and supporting evidence from animal and human studies, there is currently no direct evidence that the human commensal microbiome is a key determinant in the aetiopathogenesis of cancer. The panel cited the lack of large longitudinal, cohort studies as a principal deciding factor and agreed that this should be a future research priority. However, while acknowledging gaps in the evidence, expert opinion was that the microbiome, alongside environmental factors and an epigenetically/genetically vulnerable host, represents one apex of a tripartite, multidirectional interactome that drives carcinogenesis. Conclusion Data from longitudinal cohort studies are needed to confirm the role of the human microbiome as a key driver in the aetiopathogenesis of cancer.

IntroductionImmune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce.MethodsWe conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria.Results127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013).ConclusionThis is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

Background and Aim There are currently limited training and assessment tools available to novice endoscopists. A potential tool for the objective assessment of endoscopist visual search strategy is eye-tracking technology. The aim of this study is to assess whether eye-tracking technology can be used to differentiate the visual gaze patterns (VGP) of experienced and novice endoscopists, and to characterize any differences arising between the two groups. Method With the use of portable eye-tracking glasses, VGP of novice (n = 20) and experienced (n = 14) endoscopists were compared while viewing a colonoscopy withdrawal through the hepatic flexure. Analysis was performed by comparing the central versus peripheral distribution and the horizontal distribution of novice and experienced endoscopist fixations, along with comparison of basic eye-tracking metrics. Results This study found that experienced endoscopists had a significantly higher percentage of fixations within the periphery of the screen (13.4% vs 23.0%, P = 0.013). Experienced endoscopists also had a significantly greater percentage of fixations on the left side of the screen (18.6% vs 33.5%, P = 0.005) that displayed the poorly visualized “inside bend” of the hepatic flexure. Conclusion This study has detailed specific VGP acquired through expertise, which can potentially explain why adenomas are regularly missed at the hepatic flexure during colonoscopy. These may be useful for the training of novice colonoscopists, and further validation may utilize VGP in the development of an objective proficiency based curriculum to improve the detection of pathology and overall quality in endoscopy.

Introduction: The progressive miniaturisation of photonics components presents the opportunity to obtain unprecedented microscopic images of colonic polyps in real-time, during endoscopy. This information has the potential to act as an ‘optical biopsy’ to aid clinical decision making, including the possibility of adopting new paradigms such as a ‘resect and discard’ approach for low-risk lesions. The technologies discussed in this review include Confocal Laser Endomicroscopy, Optical Coherence Tomography, Multiphoton Microscopy, Raman Spectroscopy and Hyperspectral Imaging. These are in different stages of development and clinical readiness, but all show the potential to produce reliable in-vivo discrimination of different tissue types. Methods: A structured literature search of the imaging techniques for colorectal polyps has been conducted. The significant developments in endoscopic imaging was identified for each modality, and the status of current development was discussed. Conclusions: Of the advanced imaging techniques discussed, Confocal Laser Endomicroscopy is in clinical use, and under optimal conditions with an experienced operator, can provide accurate histological assessment of tissue. The remaining techniques show potential for incorporation into endoscopic equipment and practice, although further component development is needed, followed by robust prospective validation of accuracy. Optical Coherence Tomography illustrates tissue ‘texture’ well and gives good assessment of mucosal thickness and layers. Multiphoton Microscopy produces high resolution images at a subcellular resolution. Raman Spectroscopy and Hyperspectral Imaging are less developed endoscopically but provide a tissue ‘fingerprint’ which can distinguish between tissue types. Molecular Imaging may become a powerful adjunct to other techniques, with its ability to precisely label specific molecules within tissue and thereby enhance imaging.

Objective: i-Scan is a digital image enhancement technology, reported to improve diagnostic performance during endoscopy. Previous studies have investigated the accuracy of i-scan for distinguishing between neoplastic and non-neoplastic colonic polyps and suggested diagnostic accuracy close to that required for use in routine clinical practice. The aim of this study was to perform a meta-analysis of the available literature investigating diagnostic accuracy for i-scan optical diagnosis when made in real time for colorectal polyps Data sources: The databases of Medline, Embase and the Cochrane Library were searched for relevant studies. Methods: A bivariate random effects model was used to produce pooled sensitivity and specificity values, and univariable meta-regression was applied for subgroup analysis. Results: The meta-analysis included 15 studies, and diagnosis of 2817 polyps. The area under the hierarchical summary receiver-operating characteristic curve was 0.96. The pooled sensitivity of i-scan optical diagnosis was 0.92 (95% confidence interval 0.85–0.95). The specificity was 0.90 (95% confidence interval 0.83–0.94). Conclusions: This meta-analysis updates and summarizes the available evidence concerning the diagnostic performance of i-scan for small colorectal polyps. An acceptable degree of accuracy was found, showing potential to support a ‘resect and discard’ strategy for colonic polyps. There was not found to be a significant difference in diagnostic performance between different clinical settings (i.e. teaching hospitals or general hospitals).

Sporadic colorectal cancer (CRC) remains a major cause of worldwide mortality. Epidemiological evidence of markedly increased risk in populations that migrate to Western countries, or adopt their lifestyle, suggests that CRC is a disease whose aetiology is defined primarily by interactions between the host and his environment. The gut microbiome sits directly at this interface and is now increasingly recognised as a modulator of colorectal carcinogenesis. Bacteria such as Fusobacterium nucleatum and Escherichia coli (E. Coli) are found in abundance in patients with CRC and have been shown in experimental studies to promote neoplasia. A whole armamentarium of bacteria-derived oncogenic mechanisms has been defined, including the subversion of apoptosis and the production of genotoxins and pro-inflammatory factors. But the microbiota may also be protective: for example, they are implicated in the metabolism of dietary fibre to produce butyrate, a short chain fatty acid, which is anti-inflammatory and anti-carcinogenic. Indeed, although our understanding of this immensely complex, highly individualised and multi-faceted relationship is expanding rapidly, many questions remain: Can we define friends and foes, and drivers and passengers? What are the critical functions of the microbiota in the context of colorectal neoplasia?

BACKGROUND: Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.METHODS: The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77.FINDINGS: Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2-9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01-1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98-1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01-1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14-2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.INTERPRETATION: High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus.FUNDING: Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

Uncertainty exists about risk:benefit of proximal intestinal exclusion with Endobarrier (EB), a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on-line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2017, data had been entered on 403 patients {age 51.3 ± 11.8 year, 62% male, 89% europid, 74% diabetes, BMI 42.6 ± 10.2 kg/m2} from 13 centres in 4 countries: Australia, Austria, Czech Republic and United Kingdom. EB led to many benefits, including: in those with both baseline and explant data, mean ± SD weight fell by 14.5 ± 10.3 kg from 125.3 ± 26.7 to 110.8 ± 26.4 kg (n = 265 p Disclosure R.E.J. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. L. Munro: None. J.J. McMaster: None. J. Bessell: None. J.M. Bascomb: None. J.E. Collins: None. L. Kow: None. J. Chisholm: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc.. P.N. Pferschy: None. J.P. Teare: Research Support; Self; GI Dynamics Inc.. J.C. Mason: None. J.P. Byrne: None. M.C. Wyres: None. M.L. Cull: None. W. Burbridge: Other Relationship; Self; Menarini Group. S.P. Irwin: None. M. Yadagiri: None. E. Fogden: None. M. Anderson: None. P. Sen Gupta: None. M. Benes: None.

Obesity is a global health problem which is on the rise and is strongly associated with the development of type 2 diabetes and other comorbidities. Bariatric surgery is now an established treatment for both these conditions, leading to impressive results in weight loss and glycemic control. More recently, we have seen the development of various endoscopic devices as potential alternatives or adjuncts to bariatric surgery. In this state-of-the-art review, we outline the current landscape of endoscopic treatments available for the management of both obesity and diabetes, including the clinical evidence supporting their use, efficacy, safety, and potential mechanisms of action.

Background Haemolytic uraemic syndrome is a rarely seen in adults often leading to critical illness. This case highlights how difficult it can be to establish a diagnosis and treat when a patient presents with bloody diarrhoea. Case presentation A 17-year-old Iraqi man presented to the emergency department with abdominal pain and bloody diarrhoea. He was initially treated as acute appendicitis, undergoing an appendectomy but following a recurrence in his symptoms a colonoscopy was performed. A diagnosis of shiga toxin-producing Escherichia coli leading to HUS was suspected following histology obtained at colonoscopy and this was confirmed on antibody testing. Despite intravenous fluids and supportive therapy the patient’s symptoms and condition deteriorated. He developed seizures and acute renal failure requiring intubation and plasma exchange in the intensive care setting. He eventually required treatment with ecluzimab therapy; a monoclonal antibody and subsequently made a full recovery. Conclusions Haemolytic uraemic syndrome is a triad of progressive renal failure, thrombocytopenia and haemolytic anaemia which is a condition rarely seen in adults. It is usually associated with an E. coli infection and supportive therapy remains the mainstay of treatment.

1 In 1957, Equen et al reported the retrieval of foreign bodies in the esophagus, stomach, and duodenum by using magnets. For many years afterward, the clinical role for magnets and magnetic technologies in the GI tract remained quiescent. However, recently there has been a resurgence of interest. Advanced endoscopic therapeutic techniques such as natural orifice transluminal endoscopic surgery (NOTES) and endoscopic anastomosis creation have been developed as a minimally invasive alternative to surgery. Although these techniques reduce hospital stay, recovery time, and adverse events associated with conventional surgery, their wider uptake has been slow. This is in part due to the complex and demanding nature of the techniques, requiring a highly skilled operator. Difficulties often are encountered with tissue traction, anchoring, and accuracy of dissection as a result of a lack of triangulation of instruments and distal force transmission. The properties of magnets may present a technological solution to some these challenges. Their ability to exert untethered force over distance means magnets could be used in endoluminal resections and coupling and anchoring for singleincision laparoscopy as well as in NOTES procedures. In addition, applications to specific clinical indications have resulted in the advancement of magnetic compression anastomosis and sphincter augmentation, which are already clinically demonstrated. The endoscopic and surgical communities have traditionally perceived magnets with justified scepticism because of the widely recognized perils of magnet ingestion. Early successes with innovative therapeutic uses of magnets allowed clinicians to view magnets differently, as

Endoluminal therapeutic procedures such as endoscopic submucosal dissection are increasingly attractive given the shift in surgical paradigm towards minimally invasive surgery. This novel three-channel articulated robot was developed to overcome the limitations of the flexible endoscope which poses a number of challenges to endoluminal surgery. The device enables enhanced movement in a restricted workspace, with improved range of motion and with the accuracy required for endoluminal surgery.To evaluate a novel flexible robot for therapeutic endoluminal surgery.Bench-top studies.Research laboratory.Targeting and navigation tasks of the robot were performed to explore the range of motion and retroflexion capabilities. Complex endoluminal tasks such as endoscopic mucosal resection were also simulated.Successful completion, accuracy and time to perform the bench-top tasks were the main outcome measures.The robot ranges of movement, retroflexion and navigation capabilities were demonstrated. The device showed significantly greater accuracy of targeting in a retroflexed position compared to a conventional endoscope.Bench-top study and small study sample.We were able to demonstrate a number of simulated endoscopy tasks such as navigation, targeting, snaring and retroflexion. The improved accuracy of targeting whilst in a difficult configuration is extremely promising and may facilitate endoluminal surgery which has been notoriously challenging with a conventional endoscope.

Introduction Obesity is a modern pandemic. One of the major complications of obesity is the development of diabetes which leads to considerable mortality, morbidity and enormous health care costs. 1 The EndoBarrier is an endoscopically implantable duodenal-jejunal sleeve bypass (DJSB); anchored in the duodenum, preventing ingested food from coming into contact with the proximal intestine and induces weight loss and improvement in glycaemic control. The aim of this prospective study was to assess the safety and efficacy of the EndoBarrier in obese patients with type 2 diabetes. Method This was a non-randomised study conducted at three investigational sites (Southampton, London, and Manchester) over an 18 month period with clinical and biochemical assessments carried out at 3 monthly intervals. The device was implanted for 12 months with 6 months follow up. All patients were obese with poorly controlled diabetes. Adverse events were recorded and statistical analysis was performed. Results A total of 45 subjects were enrolled into the study At 12 months following implant: 1) HbA1c significantly reduced from baseline at 0.8% below the mean at baseline (95% CI 0.1–1.6; p 2) Mean weight loss was 15 kg (95% CI 0.62–29.38; p 3) BMI was reduced by 4.9kg/m 2 (95% CI 1.1–8.7; p 14 patients withdrew from the study, 6 required premature EndoBarrier removal. Of these, only 2 patients presented with device related complications (device migration and gastrointestinal bleeding), the others withdrew due to unrelated medical adverse events. Conclusion The EndoBarrier appears to be a safe and effective treatment strategy in those who are overweight and have poor glycaemic control despite medical therapy, or in those who are eligible but decline bariatric surgery. Larger randomised controlled trials with longer follow-up periods post-explant of the device need to be performed to investigate the device’s effects on long term glycaemic control and weight. Reference Control C. f. D. & Prevention. Prevalence of overweight and obesity among adults with diagnosed diabetes-United States, 1988–1994 and 1999–2002. MMWR. Morbidity and mortality weekly report2004;53:1066. Disclosure of Interest None Declared

Standard endoscopic tools restrict clinicians to making subjective visual assessments of lesions detected in the bowel, with classification results depending strongly on experience level and training. Histological examination of resected tissue remains the diagnostic gold standard, meaning that all detected lesions are routinely removed. This subjects the patient to risk of polypectomy-related injury, and places significant workload and economic burdens on the hospital. An objective endoscopic classification method would allow hyperplastic polyps, with no malignant potential, to be left in situ, or low grade adenomas to be resected and discarded without histology. A miniature multimodal flexible endoscope is proposed to obtain hyperspectral reflectance and dual excitation autofluorescence information from polyps in vivo. This is placed inside the working channel of a conventional colonoscope, with the external scanning and detection optics on a bedside trolley. A blue and violet laser diode pair excite endogenous fluorophores in the respiration chain, while the colonoscope's xenon light source provides broadband white light for diffuse reflectance measurements. A push-broom HSI scanner collects the hypercube. System characterisation experiments are presented, defining resolution limits as well as acquisition settings for optimal spectral, spatial and temporal performance. The first in vivo results in human subjects are presented, demonstrating the clinical utility of the device. The optical properties (reflectance and autofluorescence) of imaged polyps are quantified and compared to the histologically-confirmed tissue type as well as the clinician’s visual assessment. Further clinical studies will allow construction of a full robust training dataset for development of classification schemes.

Objective: The endoscopic findings associated with Helicobacter pylori–naïve status, current infection or past infection are an area of ongoing interest. Previous studies have investigated parameters with a potential diagnostic value. The aim of this study was to perform meta-analysis of the available literature to validate the diagnostic accuracy of mucosal features proposed in the Kyoto classification. Data sources: The databases of MEDLINE and Embase, clinicalTrials.gov and the Cochrane Library were systematically searched for relevant studies from October 1999 to October 2019. Methods: A bivariate random effects model was used to produce pooled diagnostic accuracy calculations for each of the studied endoscopic findings. Diagnostic odds ratios and sensitivity and specificity characteristics were calculated to identify significant predictors of H pylori status. Results: Meta-analysis included 4380 patients in 15 studies. The most significant predictor of an H pylori-naïve status was a regular arrangement of collecting venules (diagnostic odds ratio 55.0, sensitivity 78.3%, specificity 93.8%). Predictors of active H pylori infection were mucosal oedema (18.1, 63.7%, 91.1%) and diffuse redness (14.4, 66.5%, 89.0%). Map-like redness had high specificity for previous H pylori eradication (99.0%), but poor specificity (13.0%). Conclusion: The regular arrangement of collecting venules, mucosal oedema, diffuse redness and map-like redness are important endoscopic findings for determining H pylori status. This meta-analysis provides a tentative basis for developing future endoscopic classification systems.

Background The full scope of benefits offered by NOTES over traditional laparoscopy, if any, is not yet fully clear. Perceived patient demand for truly “scarless surgery” is often referenced one of the driving factors in the continued development of this relatively new technique. The true scale of patient preference and demand for NOTES as a surgical technique is unknown. This review aims to summarise currently available literature on the topic of patient perceptions of NOTES to guide future development of the technique. Methods A comprehensive search of PubMed and Web of Science electronic databases was performed on 1st Jan 2014. To be considered for inclusion, articles were required to assess and report the perception of NOTES in a sample of laypersons (patients or general public). The primary endpoint assessed was acceptance or preference rates expressed by patients for NOTES procedures. Reasons given for preference or rejection of NOTES were recorded, as well as preferred access routes and any predicting factors of NOTES acceptance. Results Initial search returned 1,334 results, resulting in 15 articles included in final data synthesis. These polled a total of 4,420 subjects. Acceptance of NOTES ranged between 41 and 84 %. Compared to a laparoscopic approach, preference rates for NOTES ranged from 0 to 78 %. Reasons for preferring NOTES were largely centred on potentially reduced recovery time, complications (particularly with reference to hernias) and postoperative pain. Improved cosmesis also played a role, but was secondary to the above issues. Overall, study quality was poor. Conclusions This review suggests significant public interest in NOTES and scarless surgery in general. Further research and consideration of differences in public perceptions across regions, countries and cultures are required.

Developments to the design of the flexible endoscope are transforming the field of gastroenterology. There is a drive to improve colonic adenoma detection rates leading to advancements in the design of the colonoscope. Novel endoscopes now allow increased visualisation of colonic mucosa, including behind colonic folds, and aim to reduce pain associated with the procedure. In addition, a shift in surgical paradigm towards minimally invasive endoluminal surgery has meant innovations in flexible platforms are being sought. There are a number of limitations of the basic endoscope. These include a lack of stability and triangulation of instruments. Modifications to the flexible endoscope design form the basis of a number of newly developed and research platforms, some of which are discussed in this review.

Recruiting participants into clinical trials is notoriously difficult and poses the greatest challenge when planning any investigative study. Poor recruitment may not only have financial ramifications owing to increased time and resources being spent but could adversely influence the clinical impact of a study if it becomes underpowered. Herein, we present our own experience of recruiting into a nationally funded, multicentre, randomised controlled trial (RCT) of the Endobarrier versus standard medical therapy in obese patients with type 2diabetes. Despite these both being highly prevalent conditions, there were considerable barriers to the effectiveness of different recruitment strategies across each study site. Although recruitment from primary care proved extremely successful at one study site, this largely failed at another site prompting the implementation of multimodal recruitment strategies including a successful media campaign to ensure sufficient participants were enrolled and the study was adequately powered. From this experience, we propose where appropriate the early engagement and investment in media campaigns to enhance recruitment into clinical trials. Trial Registration:ISRCTN30845205.

Background 95% of metastatic colorectal cancers (mCRCs) have normal mismatch repair proficient (pMMR) expression and a stable microsatellite phenotype (MSS). As a consequence, checkpoint inhibiting immunotherapy currently plays no role in these tumours. We recently found that RAS/RAF wild type (WT) mCRCs (50% of all CRCs) that first responded to cetuximab and then acquired resistance had converted from an immune-excluded or immune-desert phenotype before treatment to an inflamed phenotype at progression. This progression was characterized by increased CD8+ T cell infiltrates and upregulation of PDL1 and LAG3 immune checkpoints. To assess if the cetuximab induced immune infiltrates can be exploited for therapeutic benefit, the iSCORE trial will treat 25 patients with combined anti-PD1 (nivolumab) and anti-LAG3 (relatlimab) immunotherapy starting ideally within 4 weeks after progression on immunogenic FOLFIRI chemotherapy and cetuximab. Trial design iSCORE is designed to evaluate the efficacy of nivolumab and relatlimab in patients with RAS/RAF WT mCRC who have had radiological response to first line FOLFIRI and cetuximab, but then progressed. Eligible patients will receive nivolumab 480mg and relatlimab 160mg every 4 weeks. The primary endpoint is disease control rate (DCR) at 6 months from treatment initiation. With an A’Hern single stage design for efficacy, 5% significance and a power of 80%, 25 patients would need to be treated and a minimum of 6 would need to be progression free at 6 months in order to support an increase of the DCR at 6 months from Clinical trial identification NCT03867799. Legal entity responsible for the study The Royal Marsden NHS Foundation Trust. Funding The Royal Marsden NHS Foundation Trust, Bristol-Myers Squibb. Disclosure D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. I. Chau: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (self): Eli-Lilly. M. Gerlinger: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KG. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.

Introduction. Since the first published work on natural orifice translumenal endoscopic surgery (NOTES) a decade ago, progress has been made in the domain of education and training, although questions posed by the original White Paper remain. This article aims to review the current status of education and training in NOTES. Methods. A review of the literature was conducted to evaluate the following: (1) What are the current training methods/modalities used for NOTES; what is the level of evidence to support their use? (2) How has NOTES clinical training been quantified; what is the evidence relating to performance of different NOTES operators? (3) What clinical NOTES training programs have been established and what are the wider training needs? Results. A total of 25 studies were included: 11 nonanimal studies, 8 animal studies, and 6 descriptions of education programs. Several animal and simulator models demonstrated construct validity, but no study showed human predictive validity. Logarithmic learning curves in animal models demonstrate 10 to 15 cases achieving a proficiency level. Current trends are that gastroenterologists prefer it for diagnostic and basic procedures, whereas surgeons prefer it for complex therapeutic cases. Conclusion. The development of a new specialty is intriguing but currently unviable. Training programs have been initiated, but information is limited; the common theme is surgeons receiving endoscopic training. Despite the research done, our knowledge of training and educating in NOTES procedures is limited, preventing a meta-analysis or formal review from being performed. Further research is needed to integrate NOTES into routine clinical procedure.

A dual reflectance and autofluorescence spectral imaging probe compatible with the biopsy channels of standard flexible endoscopes is demonstrated. Spatially-resolved haemoglobin and autofluorescent signals from porcine bowel were obtained in vivo.

Introduction. Despite the increasing awareness of natural orifice translumenal endoscopic surgery (NOTES), there remain obstacles to its wider implementation. We aim to examine the current evidence for the effects of variable uncontrolled insufflation pressures using either air or carbon dioxide in NOTES, as well the effects of NOTES procedures themselves, on physiological parameters. Method. We undertook a systematic review of all publications relating to the effects of NOTES on physiology, in particular compared with laparoscopy. Results. Eleven reports were identified comprising comparative trials involving a total of 237 pigs. With one exception, no difference was found between the effect of NOTES and laparoscopic surgery on cardiopulmonary parameters. No difference was found also for the effect on inflammatory mediators such as interleukin-6. Two studies also assessed the effects choice of insufflation gas, with no change in inflammatory markers. Two further studies assessing the effects of variable pneumoperitoneal pressures found negative cardiorespiratory effects with higher pressures. Discussion. Existing evidence is limited to small-sample animal trials but appears to show noninferiority for NOTES compared with laparoscopy. The development of a pressure regulation device for NOTES must be considered.

Introduction The colorectal cancer (CRC) microbiome is niche specific and individualised. Several putative driver organisms enriched on CRCs have been identified from human studies, but few data exist which properly account for important clinical variables in CRC. In this study, we used a meta-taxonomic approach to demonstrate how the CRC microbiome varies with disease stage, histological markers of prognosis and host molecular phenotypes. Method A prospective study was performed on patients undergoing colonoscopy and elective surgery for CRC at three hospitals in UK and Czech Republic. Tissue was sampled from tumours, adenomas, adjacent normal mucosa and mucosa from healthy colon controls. The V1-2 regions of the 16S rRNA gene were sequenced (Illumina MiSeq); data were processed in Mothur and analysed in Stamp and R. Species assignment was performed with NCBI BLAST for microbial genomes. False discovery rate p value correction accounted for multiple testing. Histological analysis and tumour molecular phenotyping were performed according to Royal College of Pathology guidelines. Results One hundred and ninety six patients were recruited: 158 CRC patients, 24 adenoma patients and 14 normal colon controls (median age 70; range 35–90). Tumours were staged as 6 T0, 4 T1, 23 T2, 97 T3, 27 T4; 99 N0, 40 N1, 27 N2; 6 M1. No significant differences were seen in diversity or taxonomy between the UK and Czech cohorts. Adenoma and healthy colon control samples were taxonomically indistinct. However, CRCs were characterised by reduced Shannon diversity (p Conclusion This large prospective analysis demonstrates that the CRC microbiome is stage-specific and appears to evolve with disease progression. We conclude that oral pathobionts which colonise advanced stage disease relate to markers of tumour prognosis, raising the possibility that they may be directly influencing tumour invasion. Disclosure of Interest None Declared

Objective The aims of this study were to (1) describe the visual attention strategies employed by surgeons that are associated with high performance in reorientation and (2) identify key structures guiding attention deployment of the surgeon in the process of self-orientation in common clinical natural orifice translumenal endoscopic surgery (NOTES) scenarios. Background Disorientation has been identified as one of the major barriers to be overcome before widespread clinical NOTES uptake. Understanding disorientation requires description of key perceptual-motor factors leading to disorientation, assessment of their relative impact, and quantification of navigation performance. Methods Twenty-one surgeons were shown a series of 8 images acquired during human NOTES operations from the flexible endoscope from different perspectives to induce disorientation. Gaze behavior was recorded using an eye tracker as the subjects were asked to establish the image orientation. Main outcome measures were times taken to establish orientation, eye-tracking parameters, and fixation sequences on organs and structures/regions of interest (ROI). Results High-performance subjects had a lower number of fixations and normalized dwell time per ROI compared with others, suggesting a more structured and focused approach to orientation. Orientation strategies associated with high performance were described using a validated algorithm for comparing visual reorientation behavior and amount of visual attention on individual ROIs in each scenario were quantified. Key areas of organs and structures during reorientation were illustrated using dwell time normalized visual maps. Conclusions Targeted orientation strategies revealed in this study are expected to aid in decreasing the learning curve associated with NOTES and increase performance even for experienced surgeons and gastroenterologists. Crucially, these data can provide guidance for designing orientation friendly NOTES platforms.