Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD. METHODS: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation. RESULTS: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration. CONCLUSIONS: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application.

Poor Diagnostic Reproducibility in the Identification of Nonconventional Dysplasia in Colitis Impacts the Application of Histologic Stratification Tools.

Due to their increased cancer risk, patients with longstanding inflammatory bowel disease are offered endoscopic surveillance with concomitant histopathologic assessments, aimed at identifying dysplasia as a precursor lesion of colitis-associated colorectal cancer. However, this strategy is beset with difficulties and limitations. Recently, a novel classification criterion for colitis-associated low-grade dysplasia has been proposed, and an association between nonconventional dysplasia and progression was reported, suggesting the possibility of histology-based stratification of patients with colitis-associated lesions. Here, a cohort of colitis-associated lesions was assessed by a panel of 6 experienced pathologists to test the applicability of the published classification criteria and try and validate the association between nonconventional dysplasia and progression. While confirming the presence of different morphologic patterns of colitis-associated dysplasia, the study demonstrated difficulties concerning diagnostic reproducibility between pathologists and was unable to validate the association of nonconventional dysplasia with cancer progression. Our study highlights the overall difficulty of using histologic assessment of precursor lesions for cancer risk prediction in inflammatory bowel disease patients and suggests the need for a different diagnostic strategy that can objectively identify high-risk phenotypes.

Multicentre derivation and validation of a colitis-associated colorectal cancer risk prediction web tool.

OBJECTIVE: Patients with ulcerative colitis (UC) diagnosed with low-grade dysplasia (LGD) have increased risk of developing advanced neoplasia (AN: high-grade dysplasia or colorectal cancer). We aimed to develop and validate a predictor of AN risk in patients with UC with LGD and create a visual web tool to effectively communicate the risk. DESIGN: In our retrospective multicentre validated cohort study, adult patients with UC with an index diagnosis of LGD, identified from four UK centres between 2001 and 2019, were followed until progression to AN. In the discovery cohort (n=246), a multivariate risk prediction model was derived from clinicopathological features using Cox regression. Validation used data from three external centres (n=198). The validated model was embedded in a web tool to calculate patient-specific risk. RESULTS: Four clinicopathological variables were significantly associated with AN progression in the discovery cohort: endoscopically visible LGD >1 cm (HR 2.7; 95% CI 1.2 to 5.9), unresectable or incomplete endoscopic resection (HR 3.4; 95% CI 1.6 to 7.4), moderate/severe histological inflammation within 5 years of LGD diagnosis (HR 3.1; 95% CI 1.5 to 6.7) and multifocality (HR 2.9; 95% CI 1.3 to 6.2). In the validation cohort, this four-variable model accurately predicted future AN cases with overall calibration Observed/Expected=1.01 (95% CI 0.64 to 1.52), and achieved 100% specificity for the lowest risk group over 13 years of available follow-up. CONCLUSION: Multicohort validation confirms that patients with large, unresected, multifocal LGD and recent moderate/severe inflammation are at highest risk of developing AN. Personalised risk prediction provided via the Ulcerative Colitis-Cancer Risk Estimator ( www.UC-CaRE.uk ) can support treatment decision-making.

Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study.

OBJECTIVE: Ulcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies. DESIGN: This was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression. RESULTS: A total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001). CONCLUSION: The risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.

Evolutionary history of human colitis-associated colorectal cancer.

OBJECTIVE: IBD 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. DESIGN: Exome 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. RESULTS: 10/12 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. CONCLUSIONS: Evolutionary 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.

The 2019 mathematical oncology roadmap.

Whether the nom de guerre is Mathematical Oncology, Computational or Systems Biology, Theoretical Biology, Evolutionary Oncology, Bioinformatics, or simply Basic Science, there is no denying that mathematics continues to play an increasingly prominent role in cancer research. Mathematical Oncology-defined here simply as the use of mathematics in cancer research-complements and overlaps with a number of other fields that rely on mathematics as a core methodology. As a result, Mathematical Oncology has a broad scope, ranging from theoretical studies to clinical trials designed with mathematical models. This Roadmap differentiates Mathematical Oncology from related fields and demonstrates specific areas of focus within this unique field of research. The dominant theme of this Roadmap is the personalization of medicine through mathematics, modelling, and simulation. This is achieved through the use of patient-specific clinical data to: develop individualized screening strategies to detect cancer earlier; make predictions of response to therapy; design adaptive, patient-specific treatment plans to overcome therapy resistance; and establish domain-specific standards to share model predictions and to make models and simulations reproducible. The cover art for this Roadmap was chosen as an apt metaphor for the beautiful, strange, and evolving relationship between mathematics and cancer.

Optimising inflammatory bowel disease surveillance and dysplasia management-Where do we stand?

Patients with longstanding extensive colitis are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into colonoscopy screening programmes with the aim of detecting pre-cancerous dysplastic change. However, current surveillance programs face multiple limitations relating to low levels of patient enrolment, missed lesions resulting in interval cancers, and uncertainties in the management of dysplasia. Patient counselling regarding the endoscopic and surgical management options of dysplastic lesions can prove particularly challenging, due to the variable risk of progression to cancer. In this review, we discuss the histopathological diagnosis of inflammatory bowel disease (IBD)-associated dysplasia, describe the techniques to maximise dysplasia detection, and present a standardised multi-disciplinary approach to managing patients with dysplasia. The challenges presented by this patient cohort highlight the clear clinical need for further research into the development and validation of non-invasive markers of CRC risk in IBD patients undergoing surveillance.

Systematic Review: The Impact and Importance of Body Composition in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Alterations in body composition are common in inflammatory bowel disease [IBD] and have been associated with differences in patient outcomes. We sought to consolidate knowledge on the impact and importance of body composition in IBD. METHODS: We performed a systematic search of MEDLINE, EMBASE and conference proceedings by combining two key research themes: inflammatory bowel disease and body composition. RESULTS: Fifty-five studies were included in this review. Thirty-one focused on the impact of IBD on body composition with a total of 2279 patients with a mean age 38.4 years. Of these, 1071 [47%] were male. In total, 1470 [64.5%] patients had Crohn's disease and 809 [35.5%] had ulcerative colitis. Notably, fat mass and fat-free mass were reduced, and higher rates of sarcopaenia were observed in those with active IBD compared with those in clinical remission and healthy controls. Twenty-four additional studies focused on the impact of derangements in body composition on IBD outcomes. Alterations in body composition in IBD are associated with poorer prognoses including higher rates of surgical intervention, post-operative complications and reduced muscle strength. In addition, higher rates of early treatment failure and primary non-response are seen in patients with myopaenia. CONCLUSIONS: Patients with IBD have alterations in body composition parameters in active disease and clinical remission. The impacts of body composition on disease outcome and therapy are broad and require further investigation. The augmentation of body composition parameters in the clinical setting has the potential to improve IBD outcomes in the future.

Mainstreaming of genomic medicine in gastroenterology, present and future: a nationwide survey of UK gastroenterology trainees.

OBJECTIVE: Genomics and personalised medicine are increasingly relevant for patients with gastroenterological conditions. We aim to capture the current state of genomics training in gastroenterology to review current understanding, clinical experience and long-term educational needs of UK trainees. DESIGN AND SETTING: A web-based nationwide survey of all UK gastroenterology specialty trainees was conducted in 2017. RESULTS: 100 trainees (14% of UK gastroenterology trainees) completed this survey. Only 9% and 16% of respondents believe that their local training programme adequately prepares them for the future clinical practice using genomic medicine and personalised medicine, respectively. Barriers identified include the need for greater trainee education (95%), inadequate clinical guidance to base interventions on the results of genomic testing (53%), concerns over misinterpretation by patients (43%) and overuse/misuse of testing by clinicians (34%).Survey respondents felt prepared to perform HFE genotyping (98%), assess TPMT status (97%) and interpret HLA subtyping for suspected coeliac disease (85%). However, only a minority felt prepared to perform the following investigations: polyposis screening (34%), hereditary pancreatitis screening (30%), testing for Lynch yndrome (33%) and KRAS testing for colorectal cancer (20%).Most respondents would support holding dedicated training days on genomic medicine (83%), formal training provisions for the mainstreaming of genomic testing (64%), an update to the UK gastroenterology specialty training curriculum and examinations (57%) and better-defined referral pathways for local genomic services (91%). CONCLUSION: Most gastroenterology trainees in this survey feel ill equipped to practise genomic and personalised medicine as consultants. We propose specific revisions to the UK gastroenterology specialty curriculum that addresses trainees needs.

From Colitis to Cancer: An Evolutionary Trajectory That Merges Maths and Biology.

Patients with inflammatory bowel disease have an increased risk of developing colorectal cancer, and this risk is related to disease duration, extent, and cumulative inflammation burden. Carcinogenesis follows the principles of Darwinian evolution, whereby somatic cells acquire genomic alterations that provide them with a survival and/or growth advantage. Colitis represents a unique situation whereby routine surveillance endoscopy provides a serendipitous opportunity to observe somatic evolution over space and time in vivo in a human organ. Moreover, somatic evolution in colitis is evolution in the 'fast lane': the repeated rounds of inflammation and mucosal healing that are characteristic of the disease accelerate the evolutionary process and likely provide a strong selective pressure for inflammation-adapted phenotypic traits. In this review, we discuss the evolutionary dynamics of pre-neoplastic clones in colitis with a focus on how measuring their evolutionary trajectories could deliver a powerful way to predict future cancer occurrence. Measurements of somatic evolution require an interdisciplinary approach that combines quantitative measurement of the genotype, phenotype and the microenvironment of somatic cells-paying particular attention to spatial heterogeneity across the colon-together with mathematical modeling to interpret these data within an evolutionary framework. Here we take a practical approach in discussing how and why the different "evolutionary ingredients" can and should be measured, together with our viewpoint on subsequent translation into clinical practice. We highlight the open questions in the evolution of colitis-associated cancer as a stimulus for future work.

Early clinical experience of the safety and efficacy of EndoClot in the management of non-variceal upper gastrointestinal bleeding.

BACKGROUND AND STUDY AIMS: EndoClot is a novel topical hemostatic powder approved for use in non-variceal upper gastrointestinal bleeding. This study examines its impact as rescue therapy in the management of gastrointestinal bleeding for which standard endoscopic therapy failed to achieve hemostasis. METHODS: This observational study covered a 24-month period. Data were collated from patients treated with EndoClot for comparison with a cohort of patients managed with standard endoscopic therapy. End points of this study included immediate hemostasis, 30-day rebleed rate, 30-day mortality rate, and adverse events. RESULTS: Between April 1, 2012, and March 31, 2014, gastroscopic procedures were performed in 1009 patients, of whom 173 required endoscopic therapy. EndoClot was used in 21 patients, with immediate hemostasis achieved in all cases, a 30-day rebleed rate of 4.8 % (95 % confidence interval [95 %CI] - 4.34 % to 3.94 %), and a 30-day mortality rate of 19.0 % (95 %CI 2.29 % - 35.91 %). Despite higher risk bleeds in this cohort of patients, Fisher's exact test demonstrated no significant difference between their 30-day mortality rate (P = 0.51) and rebleed rate (P = 0.31) and those of the patients treated with standard endoscopic hemostatic techniques. CONCLUSIONS: This study demonstrates that EndoClot can be used both safely and effectively in the management of non-variceal upper gastrointestinal bleeding.

Appropriate patient selection in the management of common bile duct stones: when not to do ERCP.

Background. Magnetic resonance cholangiopancreatography (MRCP) is noninvasive and accurate for diagnosing intra common bile duct stones (ICSs). However, given limited access, routine utilisation for investigating all patients with gallstone disease is neither practical nor cost-effective. Conversely, many individuals proceed directly to endoscopic retrograde cholangiopancreatography (ERCP), an invasive test with appreciable complications. Aim. Identify factors associated with ICS in order to improve risk-stratification for MRCP/ERCP. Methods. All patients having undergone cholecystectomy between November 2007 and October 2008 were reviewed. High-risk features for ICS were predefined, and their true presence confirmed by ERCP or intraoperative cholangiogram. Multivariate logistic regression was performed on candidate risk features. Results. Of 231 patients, 10.4% had ICS. Defining a high-risk group with "both" biochemical and ultrasound risk factors predicted ICS with 92% specificity and also bore strong association (OR 8.88). However, isolated hyperbilirubinaemia, ultrasound impression of CBD stones, and clinical risk factors did not (OR 1.10, 0.97, and 1.26). Normal liver biochemistry and normal ultrasound had a NPV of 99.5% for ICS. Conclusions. Ultrasound impression of CBD calculi without ductal dilatation is not predictive of ICS. Patients with normal liver biochemistry and normal CBD diameter on ultrasound are unlikely to have ICS and should not proceed to ERCP.

Pharmacokinetics and antibody responses to the CD3 antibody otelixizumab used in the treatment of type 1 diabetes.

Otelixizumab is a chimeric CD3 antibody that has been genetically engineered to remove the glycosylation site in the Fc domain. This limits its ability to bind to complement or Fc receptors and reduces the risk of adverse clinical reactions due to cytokine release. In a trial for treatment of type 1 diabetes, a short treatment with otelixizumab resulted in a reduced requirement for insulin lasting at least 18 months. In the course of this trial, the blood concentrations of the antibody were measured by flow cytometry to determine its pharmacokinetic profile. Dose-dependent accumulation of otelixizumab was demonstrated and modeling of the data indicated that the terminal half-life was approximately 1.5 days. Antibody responses to otelixizumab were measured by 2 methods: a bridging enzyme-linked immunosorbent assay and surface plasmon resonance. The surface plasmon resonance method had a greater sensitivity and was able to detect responses in all patients, starting at 8 days after the commencement of therapy. Neutralizing antibodies were detected in a significant proportion of patients by days 22 to 29. Although no adverse clinical effects were associated with these antibody responses and they did not appear to affect the clearance of the drug, they might have important implications for possible retreatment of the patients.