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Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual’s lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

This is the first UK national guideline to concentrate on acute lower gastrointestinal bleeding (LGIB) and has been commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). The Guidelines Development Group consisted of representatives from the BSG Endoscopy Committee, the Association of Coloproctology of Great Britain and Ireland, the British Society of Interventional Radiology, the Royal College of Radiologists, NHS Blood and Transplant and a patient representative. A systematic search of the literature was undertaken and the quality of evidence and grading of recommendations appraised according to the GRADE(Grading of Recommendations Assessment, Development and Evaluation) methodology. These guidelines focus on the diagnosis and management of acute LGIB in adults, including methods of risk assessment and interventions to diagnose and treat bleeding (colonoscopy, computed tomography, mesenteric angiography, endoscopic therapy, embolisation and surgery). Recommendations are included on the management of patients who develop LGIB while receiving anticoagulants (including direct oral anticoagulants) or antiplatelet drugs. The appropriate use of blood transfusion is also discussed, including haemoglobin triggers and targets.

Polyps in the colon are widely known cancer precursors identified by colonoscopy. Whilst most polyps are benign, the polyp’s number, size and surface structure are linked to the risk of colon cancer. Several methods have been developed to automate polyp detection and segmentation. However, the main issue is that they are not tested rigorously on a large multicentre purpose-built dataset, one reason being the lack of a comprehensive public dataset. As a result, the developed methods may not generalise to different population datasets. To this extent, we have curated a dataset from six unique centres incorporating more than 300 patients. The dataset includes both single frame and sequence data with 3762 annotated polyp labels with precise delineation of polyp boundaries verified by six senior gastroenterologists. To our knowledge, this is the most comprehensive detection and pixel-level segmentation dataset (referred to as PolypGen ) curated by a team of computational scientists and expert gastroenterologists. The paper provides insight into data construction and annotation strategies, quality assurance, and technical validation.

ObjectiveIBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing.DesignExome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.Results10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase.ConclusionsEvolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.

Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations—serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and re-evaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements. Key recommendation: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10 mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement).

Upper gastrointestinal cancer is often missed during examinations and survival outcomes are still poor among patients in the Western world. As discussed in this Perspectives, following the Japanese example, an improved gastroscopy technique, advanced training for endoscopists and optimized screening procedures for risk stratification will be necessary to elicit a change in clinical practice and improve diagnosis and treatment. Survival rates for upper gastrointestinal cancers are poor and oesophageal cancer incidence is increasing. Upper gastrointestinal cancer is also often missed during examinations; a predicament that has not yet been sufficiently addressed. Improvements in the detection of premalignant lesions, early oesophageal and gastric cancers will enable organ-preserving endoscopic therapy, potentially reducing the number of advanced upper gastrointestinal cancers and resulting in improved prognosis. Japan is a world leader in high-quality diagnostic upper gastrointestinal endoscopy and the clinical routine in this country differs substantially from Western practice. In this Perspectives article, we review lessons learnt from Japanese gastroscopy technique, training and screening for risk stratification. We suggest a key performance indicator for upper gastrointestinal endoscopy with a minimum total procedure time of 8 min, and examine how quality assurance concepts in bowel cancer screening in the UK could be applied to upper gastrointestinal endoscopy and improve clinical practice.

Accurate optical diagnosis of small (<10 mm) colorectal polyps in vivo, without formal histopathology, could make colonoscopy more efficient and cost effective. The aim of this study was to assess whether optical diagnosis of small polyps is feasible and safe in routine clinical practice. Consecutive patients with a positive faecal occult blood test or previous adenomas undergoing surveillance at St Mark's Hospital (London, UK), from June 19, 2008, to June 16, 2009, were included in this prospective study. Four colonoscopists with different levels of experience predicted polyp histology using optical diagnosis with high-definition white light, followed by narrow-band imaging without magnification and chromoendoscopy, as required. The primary outcome was accuracy of polyp characterisation using optical diagnosis compared with histopathology, the current gold standard. Accuracy of optical diagnosis to predict the next surveillance interval was also assessed and compared with surveillance intervals predicted by current guidelines using histopathology. This study is registered with ClinicalTrials.gov, NCT00888771. 363 polyps smaller than 10 mm were detected in 130 patients, of which 278 polyps had both optical and histopathological diagnosis. By histology, 198 of these polyps were adenomas and 80 were non-neoplastic lesions (of which 62 were hyperplastic). Optical diagnosis accurately diagnosed 186 of 198 adenomas (sensitivity 0·94; 95% CI 0·90–0·97) and 55 of 62 hyperplastic polyps (specificity 0·89; 0·78–0·95), with an overall accuracy of 241 of 260 (0·93, 0·89–0·96) for polyp characterisation. Using optical diagnosis alone, 82 of 130 patients could be given a surveillance interval immediately after colonoscopy, and the same interval was found after formal histopathology in 80 patients (98%) using British guidelines and in 78 patients (95%) using US multisociety guidelines. For polyps less than 10 mm in size, in-vivo optical diagnosis seems to be an acceptable strategy to assess polyp histopathology and future surveillance intervals. Dispensing with formal histopathology for most small polyps found at colonoscopy could improve the efficiency of the procedure and lead to substantial savings in time and cost. Leigh Family Trust, London, UK.

The authors report a mechanistic basis for intestinal polyp formation in patients with hereditary mixed polyposis syndrome that involves the aberrant epithelial expression of morphogens and leads to the formation of ectopic intestinal crypts by progenitor cells outside the stem cell niche, a mechanism that seems to also be involved in human ectopic serrated polyps. Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1 . Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5 -negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Polyps are well-known cancer precursors identified by colonoscopy. However, variability in their size, appearance, and location makes the detection of polyps challenging. Moreover, colonoscopy surveillance and removal of polyps are highly operator-dependent procedures and occur in a highly complex organ topology. There exists a high missed detection rate and incomplete removal of colonic polyps. To assist in clinical procedures and reduce missed rates, automated methods for detecting and segmenting polyps using machine learning have been achieved in past years. However, the major drawback in most of these methods is their ability to generalise to out-of-sample unseen datasets from different centres, populations, modalities, and acquisition systems. To test this hypothesis rigorously, we, together with expert gastroenterologists, curated a multi-centre and multi-population dataset acquired from six different colonoscopy systems and challenged the computational expert teams to develop robust automated detection and segmentation methods in a crowd-sourcing Endoscopic computer vision challenge. This work put forward rigorous generalisability tests and assesses the usability of devised deep learning methods in dynamic and actual clinical colonoscopy procedures. We analyse the results of four top performing teams for the detection task and five top performing teams for the segmentation task. Our analyses demonstrate that the top-ranking teams concentrated mainly on accuracy over the real-time performance required for clinical applicability. We further dissect the devised methods and provide an experiment-based hypothesis that reveals the need for improved generalisability to tackle diversity present in multi-centre datasets and routine clinical procedures.

Novel endoscopic technologies could allow optical diagnosis and resection of colonic polyps without histopathological testing. Our aim was to establish the sensitivity, specificity, and real-time negative predictive value of three types of narrowed spectrum endoscopy (narrow-band imaging [NBI], image-enhanced endoscopy [i-scan], and Fujinon intelligent chromoendoscopy [FICE]), confocal laser endomicroscopy (CLE), and autofluorescence imaging for differentiation between neoplastic and non-neoplastic colonic lesions. We identified relevant studies through a search of Medline, Embase, PubMed, and the Cochrane Library. Clinical trials and observational studies were eligible for inclusion when the diagnostic performance of NBI, i-scan, FICE, autofluorescence imaging, or CLE had been assessed for differentiation, with histopathology as the reference standard, and for which a 2 × 2 contingency table of lesion diagnosis could be constructed. We did a random-effects bivariate meta-analysis using a non-linear mixed model approach to calculate summary estimates of sensitivity and specificity, and plotted estimates in a summary receiver-operating characteristic curve. We included 91 studies in our analysis: 56 were of NBI, ten of i-scan, 14 of FICE, 11 of CLE, and 11 of autofluorescence imaging (more than one of the investigated modalities assessed in eight studies). For NBI, overall sensitivity was 91·0% (95% CI 88·6–93·0), specificity 85·6% (81·3–89·0), and real-time negative predictive value 82·5% (75·4–87·9). For i-scan, overall sensitivity was 89·3% (83·3–93·3), specificity 88·2% (80·3–93·2), and real-time negative predictive value 86·5% (78·0–92·1). For FICE, overall sensitivity was 91·8% (87·1–94·9), specificity 83·5% (77·2–88·3), and real-time negative predictive value 83·7% (77·5–88·4). For autofluorescence imaging, overall sensitivity was 86·7% (79·5–91·6), specificity 65·9% (50·9–78·2), and real-time negative predictive value 81·5% (54·0–94·3). For CLE, overall sensitivity was 93·3% (88·4–96·2), specificity 89·9% (81·8–94·6), and real-time negative predictive value 94·8% (86·6–98·1). All endoscopic imaging techniques other than autofluorescence imaging could be used by appropriately trained endoscopists to make a reliable optical diagnosis for colonic lesions in daily practice. Further research should be focused on whether training could help to improve negative predictive values. None.