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Background and Aims: Conventional hot snare endoscopic mucosal resection (H-EMR) is effective for the management of large (≥20 mm) non-pedunculated colon polyps (LNPCPs) however, electrocautery-related complications may incur significant morbidity. With a superior safety profile, cold snare EMR (C-EMR) of LNPCPs is an attractive alternative however evidence is lacking. We conducted a randomised trial to compare the efficacy and safety of C-EMR to H-EMR., Methods: Flat, 15-50 mm adenomatous LNPCPs were prospectively enrolled and randomly assigned to C-EMR or H-EMR with margin thermal ablation at a single tertiary centre. The primary outcome was endoscopically visible and/or histologically confirmed recurrence at 6 months surveillance colonoscopy. Secondary outcomes were clinically significant post-EMR bleeding (CSPEB), delayed perforation and technical success., Results: 177 LNPCPs in 177 patients were randomised to C-EMR arm (n=87) or H-EMR (n=90). Treatment groups were equivalent for technical success 86/87 (98.9%) C-EMR versus H-EMR 90/90 (100%); p=0.31. Recurrence was significantly greater in C-EMR (16/87, 18.4% vs 1/90, 1.1%; relative risk (RR) 16.6, 95% CI 2.24 to 122; p<0.001).Delayed perforation (1/90 (1.1%) vs 0; p=0.32) only occurred in the H-EMR group. CSPEB was significantly greater in the H-EMR arm (7/90 (7.8%) vs 1/87 (1.1%); RR 6.77, 95% CI 0.85 to 53.9; p=0.034)., Conclusion: Compared with H-EMR, C-EMR for flat, adenomatous LNPCPs, demonstrates superior safety with equivalent technical success. However, endoscopic recurrence is significantly greater for cold snare resection and is currently a limitation of the technique., Trial Registration Number: NCT04138030., Competing Interests: Competing interests: MJB: Research Support: Olympus Medical, Cook Medical, Boston Scientific. The remaining authors have no financial, professional or personal conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tumourigenesis in right-sided and left-sided colons demonstrated distinct features., Objective: We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis., Design: Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results., Results: Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11 + epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer., Conclusion: Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Residual or recurrent adenoma (RRA) after endoscopic mucosal resection (EMR) of large non-pedunculated colorectal polyps (LNPCPs) of ≥20 mm is a major limitation. Data on outcomes of the endoscopic treatment of recurrence are scarce, and no evidence-based standard exists. We investigated the efficacy of endoscopic retreatment over time in a large prospective cohort., Design: Over 139 months, detailed morphological and histological data on consecutive RRA detected after EMR for single LNPCPs at one tertiary endoscopy centre were prospectively recorded during structured surveillance colonoscopy. Endoscopic retreatment was performed on cases with evidence of RRA and was performed predominantly using hot snare resection, cold avulsion forceps with adjuvant snare tip soft coagulation or a combination of the two., Results: 213 (14.6%) patients had RRA (168 (78.9%) at first surveillance and 45 (21.1%) thereafter). RRA was commonly 2.5-5.0 mm (48.0%) and unifocal (78.7%). Of 202 (94.8%) cases which had macroscopic evidence of RRA, 194 (96.0%) underwent successful endoscopic therapy and 161 (83.4%) had a subsequent follow-up colonoscopy. Of the latter, endoscopic therapy of recurrence was successful in 149 (92.5%) of 161 in the per-protocol analysis, and 149 (73.8%) of 202 in the intention-to-treat analysis, with a mean of 1.15 (SD 0.36) retreatment sessions. No adverse events were directly attributable to endoscopic therapy. Further RRA after endoscopic therapy was endoscopically treatable in most cases. Overall, only 9 (4.2%, 95% CI 2.2% to 7.8%) of 213 patients with RRA required surgery.Thus 159 (98.8%, 95% CI 95.1% to 99.8%) of 161 cases with initially successful endoscopic treatment of RRA and follow-up remained surgery-free for a median of 13 months (IQR 25.0) of follow-up., Conclusions: RRA after EMR of LNPCPs can be effectively treated using simple endoscopic techniques with long-term adenoma remission of >90%; only 16% required retreatment. Therefore, more technically complex, morbid and resource-intensive endoscopic or surgical techniques are required only in selected cases., Trial Registration Numbers: NCT01368289 and NCT02000141., Competing Interests: Competing interests: MJB: research support from Olympus Medical, Cook Medical and Boston Scientific. DJT: research support from Olympus Medical., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop an interpretable artificial intelligence algorithm to rule out normal large bowel endoscopic biopsies, saving pathologist resources and helping with early diagnosis., Design: A graph neural network was developed incorporating pathologist domain knowledge to classify 6591 whole-slides images (WSIs) of endoscopic large bowel biopsies from 3291 patients (approximately 54% female, 46% male) as normal or abnormal (non-neoplastic and neoplastic) using clinically driven interpretable features. One UK National Health Service (NHS) site was used for model training and internal validation. External validation was conducted on data from two other NHS sites and one Portuguese site., Results: Model training and internal validation were performed on 5054 WSIs of 2080 patients resulting in an area under the curve-receiver operating characteristic (AUC-ROC) of 0.98 (SD=0.004) and AUC-precision-recall (PR) of 0.98 (SD=0.003). The performance of the model, named Interpretable Gland-Graphs using a Neural Aggregator (IGUANA), was consistent in testing over 1537 WSIs of 1211 patients from three independent external datasets with mean AUC-ROC=0.97 (SD=0.007) and AUC-PR=0.97 (SD=0.005). At a high sensitivity threshold of 99%, the proposed model can reduce the number of normal slides to be reviewed by a pathologist by approximately 55%. IGUANA also provides an explainable output highlighting potential abnormalities in a WSI in the form of a heatmap as well as numerical values associating the model prediction with various histological features., Conclusion: The model achieved consistently high accuracy showing its potential in optimising increasingly scarce pathologist resources. Explainable predictions can guide pathologists in their diagnostic decision-making and help boost their confidence in the algorithm, paving the way for its future clinical adoption., Competing Interests: Competing interests: SG, DS and NR are co-founders of Histofy. DS reports personal fees from Royal Philips, outside the submitted work. NR and FM report research funding from GlaxoSmithKline., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Colon capsule endoscopy (CCE) has shown promise for colorectal neoplasia detection compared with optical colonoscopy (OC), but has not been compared with other screening tests in average risk screening patients., Design: Patients 50 to 75 years of age (African Americans, 45-75 years) were randomised to CCE or CT colonography (CTC) and subsequent blinded OC. The primary endpoint was diagnostic yield of polyps ≥6 mm with CCE or CTC. Secondary endpoints included accuracy for size and histology, examination completeness, number/proportion of subjects with polyps and adenomas ≥6 mm and ≥10 mm, subject satisfaction and safety., Results: From 320 enrolled subjects, data from 286 (89.4%) were evaluable. The proportion of subjects with any polyp ≥6 mm confirmed by OC was 31.6% for CCE versus 8.6% for CTC (pPr non-inferiority and superiority=0.999). The diagnostic yield of polyps ≥10 mm was 13.5% with CCE versus 6.3% with CTC (pPr non-inferiority=0.9954). The sensitivity and specificity of CCE for polyps ≥6 mm was 79.2% and 96.3% while that of CTC was 26.8% and 98.9%. The sensitivity and specificity of CCE for polyps ≥10 mm was 85.7% and 98.2% compared with 50% and 99.1% for CTC. Both tests were well tolerated/safe., Conclusion: CCE was superior to CTC for detection of polyps ≥6 mm and non-inferior for identification of polyps ≥10 mm. CCE should be considered comparable or superior to CTC as a colorectal neoplasia screening test, although neither test is as effective as OC., Trial Registration Number: ClinicalTrials.gov no: NCT02754661., Competing Interests: Competing interests: These authors disclose the following: BDC: Consultant to Medtronic, Salix, Allergan, Takeda; Speakers’ Bureau for Salix, Allergan, Takeda, AlfaSigma, RedHill, QOL. ER: Consultant to Olympus; IP with Medtronic. DMK: Consultant to Medtronic, Ferring, Salix, MotusGI; Research support from Medtronic, MotusGI. DP: Speakers’ Bureau: Gilead Life Sciences, Merck; Advisory Boards: Gilead, Novartis, Intercept. NPP: Consultant to Medtronic. IF-U received honorarium from Medtronic. IJS: Consultant to Medtronic. DKR: Consultant to Olympus Corporation, Boston Scientific, Medtronic, Aries Pharmaceutical, Braintree Laboratories, Lumendi Ltd, Norgine, Endokey, GI Supply; Research support: EndoAid, Olympus Corporation, Medivators, Erbe USA Inc.; Ownership: Satisfai Health., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: JEE has served on clinical advisory boards for Lumendi, Boston Scientific and Paion; has served on the clinical advisory board and has share options in Satisfai Health; and reports speaker fees from Falk. He is an associate editor for the Journal of Gastroenterology and Hepatology.

Objective: Postscreening colorectal cancer (PSCRC) after screening colonoscopy is associated with endoscopists' performance and characteristics of resected lesions. Prior studies have shown that adenoma detection rate (ADR) is a decisive factor for PSCRC, but correlations with other parameters need further analysis and ADR may change over time., Design: Cohort study including individuals undergoing screening colonoscopy between 1/2008 and 12/2019 performed by physicians participating in a quality assurance programme in Austria. Data were linked with hospitalisation data for the diagnosis of PSCRC (defined as CRC diagnosis >6 months after colonoscopy). ADR was defined dynamically in relation to the time point of subsequent colonoscopies; high-risk groups of patients were those with an adenoma ≥10 mm, or with high-grade dysplasia, or villous or tubulovillous histology, or a serrated lesion ≥10 mm or with dysplasia, or colonoscopies with ≥3 lesions. Main outcome was PSCRC for each risk group (negative colonoscopy, hyperplastic polyps, low-risk and high-risk group of patients) after colonoscopy by endoscopists with an ADR <20% compared with endoscopists with an ADR ≥20%., Results: 352 685 individuals were included in the study (51.0% women, median age 60 years) of which 10.5% were classified as high-risk group. During a median follow-up of 55.4 months, 241 (0.06%) PSCRC were identified; of 387 participating physicians, 19.6% had at least one PSCRC (8.4% two or more). While higher endoscopist ADR decreased PSCRC incidence (HR per 1% increase 0.97, 95% CI 0.95 to 0.98), affiliation to the high-risk group of patients was also associated with higher PSCRC incidence (HR 3.27, 95% CI 2.36 to 4.00). Similar correlations were seen with regards to high-risk, and advanced adenomas. The risk for PSCRC was significantly higher after colonoscopy by an endoscopist with an ADR <20% as compared with an endoscopist with an ADR ≥20% in patients after negative colonoscopy (HR 2.01, 95% CI 1.35 to 3.0, p<0.001) and for the high-risk group of patients (HR 2.51, 95% CI 1.49 to 4.22, p<0.001)., Conclusion: A dynamic calculation of the ADR takes into account changes over time but confirms the correlation of ADR and interval cancer. Both lesion characteristics and endoscopists ADR may play a similar role for the risk of PSCRC. This should be considered in deciding about appropriate surveillance intervals in the future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Adenoma detection rate (ADR) has been shown to correlate with interval cancers after screening colonoscopy and is commonly used as surrogate parameter for its outcome quality. ADR improvements by various techniques have been studied in randomised trials using either parallel or tandem methodololgy., Methods: A systematic literature search was done on randomised trials (full papers, English language) on tandem or parallel studies using either adenoma miss rates (AMR) or ADR as main outcome to test different novel technologies on imaging (new endoscope generation, narrow band imaging, iScan, Fujinon intelligent chromoendoscopy/blue laser imaging and wide angle scopes) and mechanical devices (transparent caps, endocuff, endorings and balloons). Available meta analyses were also screened for randomised studies., Results: Overall, 24 randomised tandem trials with AMR (variable definitions and methodology) and 42 parallel studies using ADR (homogeneous methodology) as primary outcome were included. Significant differences in favour of the new method were found in 66.7% of tandem studies (8222 patients) but in only 23.8% of parallel studies (28 059 patients), with higher rates of positive studies for mechanical devices than for imaging methods. In a random-effects model, small absolute risk differences were found, but these were double in magnitude for tandem as compared with parallel studies (imaging: tandem 0.04 (0.01, 0.07), parallel 0.02 (0.00, 0.04); mechanical devices: tandem 0.08 (0.00, 0.15), parallel 0.04 (0.01, 0.07)). Nevertheless, 94.2% of missed adenomas in the tandem studies were small (<1 cm) and/or non-advanced., Conclusions: A tandem study is more likely to yield positive results than a simple parallel trial; this may be due to the use of different parameters, variable definitions and methodology, and perhaps also a higher likelihood of bias. Therefore, we suggest to accept positive results of tandem studies only if accompanied by positive results from parallel trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Adenoma detection rate (ADR) is an important quality marker at lower GI endoscopy. Higher ADRs are associated with lower postcolonoscopy colorectal cancer rates. The English flexible sigmoidoscopy (FS) screening programme (BowelScope), offers a one-off FS to individuals aged 55 years. However, variation in ADR exists. Large studies have demonstrated improved ADR using Endocuff Vision (EV) within colonoscopy screening, but there are no studies within FS. We sought to test the effect of EV on ADR in a national FS screening population., Design: BowelScope: Accuracy of Detection Using ENdocuff Optimisation of Mucosal Abnormalities was a multicentre, randomised controlled trial involving 16 English BowelScope screening centres. Individuals were randomised to Endocuff Vision-assisted BowelScope (EAB) or Standard BowelScope (SB). ADR, polyp detection rate (PDR), mean adenomas per procedure (MAP), polyp characteristics and location, participant experience, procedural time and adverse events were measured. Comparison of ADR within the trial with national BowelScope ADR was also undertaken., Results: 3222 participants were randomised (53% male) to receive EAB (n=1610) or SB (n=1612). Baseline demographics were comparable between arms. ADR in the EAB arm was 13.3% and that in the SB arm was 12.2% (p=0.353). No statistically significant differences were found in PDR, MAP, polyp characteristics or location, participant experience, complications or procedural characteristics. ADR in the SB control arm was 3.1% higher than the national ADR., Conclusion: EV did not improve BowelScope ADR when compared with SB. ADR in both arms was higher than the national ADR. Where detection rates are already high, EV is unable to improve detection further., Trial Registration Numbers: NCT03072472, ISRCTN30005319 and CPMS ID 33224., Competing Interests: Competing interests: CJR has received grant funding from ARC medical, Norgine and Olympus medical. He was an expert witness for ARC Medical. PB has received grant funding from Norgine., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Low adenoma detection rates (ADR) are linked to increased postcolonoscopy colorectal cancer rates and reduced cancer survival. Devices to enhance mucosal visualisation such as Endocuff Vision (EV) may improve ADR. This multicentre randomised controlled trial compared ADR between EV-assisted colonoscopy (EAC) and standard colonoscopy (SC)., Design: Patients referred because of symptoms, surveillance or following a positive faecal occult blood test (FOBt) as part of the Bowel Cancer Screening Programme were recruited from seven hospitals. ADR, mean adenomas per procedure, size and location of adenomas, sessile serrated polyps, EV removal rate, caecal intubation rate, procedural time, patient experience, effect of EV on workload and adverse events were measured., Results: 1772 patients (57% male, mean age 62 years) were recruited over 16 months with 45% recruited through screening. EAC increased ADR globally from 36.2% to 40.9% (P=0.02). The increase was driven by a 10.8% increase in FOBt-positive screening patients (50.9% SC vs 61.7% EAC, P<0.001). EV patients had higher detection of mean adenomas per procedure, sessile serrated polyps, left-sided, diminutive, small adenomas and cancers (cancer 4.1% vs 2.3%, P=0.02). EV removal rate was 4.1%. Median intubation was a minute quicker with EAC (P=0.001), with no difference in caecal intubation rate or withdrawal time. EAC was well tolerated but caused a minor increase in discomfort on anal intubation in patients undergoing colonoscopy with no or minimal sedation. There were no significant EV adverse events., Conclusion: EV significantly improved ADR in bowel cancer screening patients and should be used to improve colonoscopic detection., Trial Registration Number: NCT02552017, Results; ISRCTN11821044, Results., Competing Interests: Competing interests: CJR has received research grants from ARC Medical, Olympus Medical, Aquilant Endoscopy, Norgine and travel grants from Boston Scientific and Cook Medical. He is an advisory board member for Ai4Gi. BPS has received speaker grants from Olympus Medical and research support from Norgine, Aquilant and Diagmed. He is an advisory board member for Creo Medical. ZPT was a non-paid speaker for Norgine Pharmaceutical. He has received research and educational grants from Norgine Pharmaceutical and medical equipment support from Olympus. He holds a Consultant Agreement for Creo Medical., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Competing Interests: Competing interests: None declared.

Background: Most colon cancers start with dysregulated Wnt/β-catenin signalling and remain a major therapeutic challenge. Examining whether HAMLET (human α-lactalbumin made lethal to tumour cells) may be used for colon cancer treatment is logical, based on the properties of the complex and its biological context., Objective: To investigate if HAMLET can be used for colon cancer treatment and prevention. Apc(Min)(/+) mice, which carry mutations relevant to hereditary and sporadic human colorectal tumours, were used as a model for human disease., Method: HAMLET was given perorally in therapeutic and prophylactic regimens. Tumour burden and animal survival of HAMLET-treated and sham-fed mice were compared. Tissue analysis focused on Wnt/β-catenin signalling, proliferation markers and gene expression, using microarrays, immunoblotting, immunohistochemistry and ELISA. Confocal microscopy, reporter assay, immunoprecipitation, immunoblotting, ion flux assays and holographic imaging were used to determine effects on colon cancer cells., Results: Peroral HAMLET administration reduced tumour progression and mortality in Apc(Min)(/+) mice. HAMLET accumulated specifically in tumour tissue, reduced β-catenin and related tumour markers. Gene expression analysis detected inhibition of Wnt signalling and a shift to a more differentiated phenotype. In colon cancer cells with APC mutations, HAMLET altered β-catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism for controlling β-catenin signalling. Remarkably, supplying HAMLET to the drinking water from the time of weaning also significantly prevented tumour development., Conclusions: These data identify HAMLET as a new, peroral agent for colon cancer prevention and treatment, especially needed in people carrying APC mutations, where colon cancer remains a leading cause of death.