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The advent of immunotherapy has revolutionised the treatment of metastatic lung cancer and it has recently been established as the standard of care in the radical treatment of lung cancer. However, immune-related adverse events (IrAEs) frequently occur in patients treated with immunotherapy, and rare IrAEs continue to be identified. We report a case of immunotherapy-induced coeliac disease due to adjuvant durvalumab post-chemoradiotherapy in a patient receiving curative treatment for lung cancer. The patient had raised anti-tissue transglutaminase IgA and histological findings consistent with coeliac disease. This is the first published case report of probable immunotherapy-induced coeliac disease both with the immunotherapy drug durvalumab and in the curative lung cancer setting.

BACKGROUNDPost-colonoscopy colorectal cancer (CRC) rates for patients with inflammatory bowel disease (IBD) are unacceptably high. During colonoscopy, an intravenous fluorescent anti-c-MET probe may improve endoscopic detection of lesions. However, c-MET expression in IBD lesions is poorly defined, limiting translational studies. AIMTo comprehensively define c-MET expression in sporadic and IBD-associated colorectal carcinogenesis. METHODSc-MET expression was immunohistochemically assessed in 319 formalin-fixed paraffin-embedded tissue specimens, colonoscopically or surgically retrieved between 1994-2017. Tissue included: 30 normal colorectal biopsies, 30 hyperplastic polyps (HP), 31 sessile serrated lesions (SSL), 55 tubular/tubulovillous adenomas with low (TA-LGD, n = 32) or high grade dysplasia (TA-HGD, n = 23), 26 sporadic (s)-CRCs, 16 quiescent IBD biopsies, 11 active/inflamed IBD biopsies, 18 IBD-associated dysplastic lesions (IBD-dys), and 102 IBD-CRCs. Expression was scored by two independent observers as: 0 = absent, 1 = weak, 2 = moderate or 3 = strong. Mann-Whitney U and Kruskal-Wallis tests were used to assess significance. RESULTSPositive epithelial cytoplasmic and membranous c-MET expression was observed in all tissues, indicating there is ubiquitous expression in the colorectum. c-MET expression was weak in normal colonic epithelium compared with each of the sporadic colonic lesions, including TA-LGD (P < 0.001), TA-HGD (P = 0.004), HP (P < 0.001), SSL (P < 0.001), and s-CRC (P < 0.001). Specifically, in sporadic (non-IBD) lesions, expression was stronger in TA-LGD compared with normal mucosa (P < 0.001), and stronger in s-CRC compared with TA-HGD (P = 0.004). However, there was no significant difference between TA-LGD and TA-HGD (P = 0.852). Further, there was no difference in c-MET expression between HP and SSL (P = 0.065). In IBD, expression was weaker in quiescent colonic mucosa compared with inflamed colonic mucosa (P < 0.001). There was no difference between inflamed colonic mucosa and IBD-dys (P = 0.512) or IBD-CRC (P = 0.296). However, expression was stronger in IBD-dys (P < 0.001) and IBD-CRC (P < 0.001) compared with quiescent IBD colonic mucosa. CONCLUSIONThe characterisation of c-MET expression suggest that an intravenous probe may improve the endoscopic detection of lesions in both non-IBD patients and IBD patients with quiescent disease.

Background and Aims Inflammatory Bowel Disease colitis-associated dysplasia is managed with either enhanced surveillance and endoscopic resection or prophylactic surgery. The rate of progression to cancer after a dysplasia diagnosis remains uncertain in many cases and patients have high thresholds for accepting proctocolectomy. Individualised discussion of management options is encouraged to take place between patients and their multidisciplinary teams for best outcomes. We aimed to develop a toolkit to support a structured, multidisciplinary and shared decision-making approach to discussions about dysplasia management options between clinicians and their patients. Methods Evidence from systematic literature reviews, mixed-methods studies conducted with key stakeholders and decision-making expert recommendations were consolidated to draft consensus statements by the DECIDE steering group. These were then subjected to an international, multidisciplinary modified electronic Delphi process until an a priori threshold of 80% agreement was achieved to establish consensus for each statement. Results 31 members (15 gastroenterologists, 14 colorectal surgeons and two nurse specialists) from 9 countries formed the Delphi panel. We present the 18 consensus statements generated after two iterative rounds of anonymous voting. Conclusions By consolidating evidence for best practice using literature review, key stakeholder and decision-making expert consultation we have developed international consensus recommendations to support healthcare professionals counselling patients on the management of high cancer risk colitis-associated dysplasia. The final toolkit includes clinician and patient decision aids to facilitate shared decision-making.

Supplementary Table S1 Phenotypic characteristics of IBD-CRC cases. Supplementary Table S2A Selected somatic mutations in IBD-CRC hypermutators. Supplementary Table S2B Selected somatic mutations in IBD-CRC non-hypermutators. Supplementary Table S3 Cosine similarities of IBD-CRC signatures and Alexandrov signatures. Supplementary Table S4 Genes implicated in susceptibility to colorectal cancer. Supplementary Table S5 Selected germline variants. Supplementary Table S6 Estimated cellularity, ploidy and SCNAs in IBD-CRC samples.

Purpose: Inflammatory bowel disease–associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management.Experimental Design: Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined.Results: Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA POLE. Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified.Conclusions: IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. Clin Cancer Res; 24(20); 5133–42. ©2018 AACR.

Supplementary Materials and Methods

Peer reviewed: True, INTRODUCTION: In the past 5 years, there have been several advances in the management of inflammatory bowel disease (IBD). We aim for a new guideline to update the most recent guideline published in 2019. We present the prospective operating procedure and technical summary protocol in the manuscript. METHODS: 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) will be followed in the development of the guideline, approach as laid out in the GRADE handbook, supported by the WHO. The guideline development group is formed by a variety of disciplines, across both primary and secondary care that took part in an online Delphi process and split into key areas. A final consensus list of thematic questions within a 'patient, intervention, comparison, outcome' format has been produced and agreed in the final phase of the Delphi process.There will be a detailed technical evidence review with source data including systematic reviews appraised with AMSATAR 2 tool (Assessment of multiple systematic reviews), randomised controlled trial data that will be judged for risk of bias with the Cochrane tool and observational studies for safety concerns assessed through the Robins-I tool. Based on the available evidence, some of the recommendations will be based on GRADE while others will be best practice statements.A full Delphi process will be used to make recommendations using online response systems.This set of procedures has been approved by the Clinical Services and Standards Committee, the British Society of Gastroenterology executive board and aligned with IBD UK standards.

A 75-year-old man was admitted with a 3-month history of worsening diarrhoea and weight loss. He was on long-term immunosuppression following cardiac transplantation. Investigations revealed herpes simplex oesophagitis and stool samples were positive for norovirus. Treatment with acyclovir and nitazoxanide resulted in a complete resolution of symptoms. Norovirus is a common cause of infectious gastroenteritis, but immunosuppressed patients may present with chronic diarrhoea rather than an acute illness. This case highlights the importance of a low clinical threshold for testing for norovirus infection in immunocompromised patients.

Background: Biologics and small molecules for inflammatory bowel disease (IBD) may increase infection risk. Herpes zoster causes acute and long-term symptoms, but vaccination is not recommended in patients with IBD, unless >50 years of age.Aims: To examine risk of Herpes zoster infection with all licensed biologics and small molecules for IBD using network meta-analysis.Methods: We searched the literature to 4th October 2022, for randomised controlled trials of these drugs in luminal Crohn's disease or ulcerative colitis reporting data on occurrence of Herpes zoster infection during follow-up. We used a frequentist approach and a random effects model, pooling data as relative risks (RRs) with 95% confidence intervals (CIs).Results: We identified 25 trials (9935 patients). Only tofacitinib 10 mg b.d. (RR = 6.90; 95% CI 1.56-30.63, number needed to harm (NNH) = 97; 95% CI 19-1022) and upadacitinib 45 mg o.d. (RR = 7.89; 95% CI 1.04-59.59, NNH = 83; 95% CI 10-14,305) were significantly more likely to increase risk of Herpes zoster infection. Janus kinase inhibitors were the most likely drug class to increase risk of infection, and risk increased with higher doses (RR with lowest dose = 3.16; 95% CI 1.02-9.84, NNH = 265; 95% CI 65-28,610, RR with higher dose = 5.91; 95% CI 2.21-15.82, NNH = 117; 95% CI 39-473).Conclusions: In a network meta-analysis, the janus kinase inhibitor tofacitinib, and all janus kinase inhibitors considered as a class, were most likely to increase risk of Herpes zoster infection. Risk increased with higher doses.

Summary Background There is a paucity of evidence to support safe and effective management of patients with acute severe ulcerative colitis during the COVID-19 pandemic. We sought to identify alterations to established conventional evidence-based management of acute severe ulcerative colitis during the early COVID-19 pandemic, the effect on outcomes, and any associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes. Methods The PROTECT-ASUC study was a multicentre, observational, case-control study in 60 acute secondary care hospitals throughout the UK. We included adults (≥18 years) with either ulcerative colitis or inflammatory bowel disease unclassified, who presented with acute severe ulcerative colitis and fulfilled the Truelove and Witts criteria. Cases and controls were identified as either admitted or managed in emergency ambulatory care settings between March 1, 2020, and June 30, 2020 (COVID-19 pandemic period cohort), or between Jan 1, 2019, and June 30, 2019 (historical control cohort), respectively. The primary outcome was the proportion of patients with acute severe ulcerative colitis receiving rescue therapy (including primary induction) or colectomy. The study is registered with ClinicalTrials.gov , NCT04411784 . Findings We included 782 patients (398 in the pandemic period cohort and 384 in the historical control cohort) who met the Truelove and Witts criteria for acute severe ulcerative colitis. The proportion of patients receiving rescue therapy (including primary induction) or surgery was higher during the pandemic period than in the historical period (217 [55%] of 393 patients vs 159 [42%] of 380 patients; p=0·00024) and the time to rescue therapy was shorter in the pandemic cohort than in the historical cohort (p=0·0026). This difference was driven by a greater use of rescue and primary induction therapies with biologicals, ciclosporin, or tofacitinib in the COVID-19 pandemic period cohort than in the historical control period cohort (177 [46%] of 387 patients in the COVID-19 cohort vs 134 [36%] of 373 patients in the historical cohort; p=0·0064). During the pandemic, more patients received ambulatory (outpatient) intravenous steroids (51 [13%] of 385 patients vs 19 [5%] of 360 patients; p=0·00023). Fewer patients received thiopurines (29 [7%] of 398 patients vs 46 [12%] of 384; p=0·029) and 5-aminosalicylic acids (67 [17%] of 398 patients vs 98 [26%] of 384; p=0·0037) during the pandemic than in the historical control period. Colectomy rates were similar between the pandemic and historical control groups (64 [16%] of 389 vs 50 [13%] of 375; p=0·26); however, laparoscopic surgery was less frequently performed during the pandemic period (34 [53%] of 64] vs 38 [76%] of 50; p=0·018). Five (2%) of 253 patients tested positive for SARS-CoV-2 during hospital treatment. Two (2%) of 103 patients re-tested for SARS-CoV-2 during the 3-month follow-up were positive 5 days and 12 days, respectively, after discharge from index admission. Both recovered without serious outcomes. Interpretation The COVID-19 pandemic altered practice patterns of gastroenterologists and colorectal surgeons in the management of acute severe ulcerative colitis but was associated with similar outcomes to a historical cohort. Despite continued use of high-dose corticosteroids and biologicals, the incidence of COVID-19 within 3 months was low and not associated with adverse COVID-19 outcomes. Funding None.

The COVID-19 pandemic disrupted healthcare services across the world with only essential care being continued.1 2 For paediatric and adult patients with inflammatory bowel disease (IBD), this resulted in significant changes to accessing health services. In some services, IBD advice lines were stopped, specialist nurses and medical staff were redeployed to support acute admissions, outpatient clinics were deferred, and home care services were under threat.3 4 In addition, there was a reluctance from patients to come to hospital or contact their services due to concerns over their personal safety.5 6 The Crohn's and Colitis United Kingdom (CCUK) ‘life in lockdown’ patient survey reported that patients felt their IBD teams kept them well informed of coronavirus and their condition. Importantly, one in five patients reported that they also received inaccurate information on other aspects such as shielding.7 The pandemic has also highlighted the disparities in accessing healthcare8 and addressing these alongside organisational transformation will support personalised care, which is one of the main recommendations of the Inflammatory Bowel Disease United Kingdom (IBD UK) standards.9 Healthcare services have restarted routine clinical practices responding swiftly to regional and national lockdowns in the second wave.10 Additionally, local data have allowed clinical teams to refine service delivery supporting those most vulnerable to poorer outcomes if they develop COVID-19.11 12 The British Society of Gastroenterology (BSG) has commissioned independent reviews on the redesign of outpatient services focusing on telemedicine and restarting endoscopy safely.13–20 The COVID-19 pandemic effect on clinical research and trial activity are being addressed separately by the BSG IBD research committee.1 21 We are currently in our second wave of the pandemic and a third national lockdown with increasing pressure to maintain specialist services as well as directly supporting care for patients with COVID-19. …

A frequent dilemma faced in the inflammatory bowel disease (IBD) clinic is how to best treat a patient with a previous cancer diagnosis. The changing demographics of our patient population will make this quandary more common. Previous guidance has emphasised the importance of lengthy postcancer drug holidays and cautious use of IBD therapies. However, accumulating evidence suggests this approach may be unnecessarily conservative. This review considers recent evidence on the safety of IBD drugs, cancer and recurrent cancer risk in patients with IBD and provides a framework for shared decision making involving patient, gastroenterologist and oncologist.

Interleukin (IL)-17 and IL-23 are crucial for mediating gut mucosal inflammation in inflammatory bowel disease (IBD), which has led to new therapeutic strategies. We assessed the relevancy of IL-17 and IL-23 serum levels as potential biomarkers towards severe IBD discrimination and disease-related complications. Sixty-two patients diagnosed with Crohn’s disease (CD) and ulcerative colitis (UC) were included. Serum IL-17 and IL-23 were measured by sandwich enzyme-linked immunosorbent assays (ELISA). IL-23 and fecal calprotectin (FCal) were significantly higher in severe CD (p &lt, 0.001) and UC (p &lt, 0.001 and p = 0.001, respectively), compared to mild or moderate. Elevated C-reactive protein (CRP) was correlated with severe disease only in CD (p = 0.008), whereas for UC, disease severity was associated with increased IL-17 values (p &lt, 0.001). Diagnostic role of IL-23 was superior to FCal in discriminating between severe and mild to moderate CD (p &lt, 0.001). IL-23 levels were also significantly higher in CD patients with intestinal complications (p = 0.04). Both IL-17 and IL-23 correlate with IBD severity, and IL-23 might be a promising novel biomarker for severe CD. Identifying the dominant IL pathway involved in IBD severity could serve as guidance for clinical decision-making on biologic therapy.

ObjectiveIBD prevalence is estimated to be rising, but no detailed, recent UK data are available. The last reported prevalence estimate in the UK was 0.40% in 2003. We aimed to establish the current, and project future, prevalence in Lothian, Scotland.DesignWe conducted an all-age multiparameter search strategy using inpatient IBD international classification of disease (ICD-10) coding (K50/51)(1997–2018), IBD pathology coding (1990–2018), primary and secondary care prescribing data (2009–2018) and a paediatric registry, (1997–2018) to identify ‘possible’ IBD cases up to 31/08/2018. Diagnoses were manually confirmed through electronic health record review as per Lennard-Jones/Porto criteria. Autoregressive integrated moving average (ARIMA) regression was applied to forecast prevalence to 01/08/2028.ResultsIn total, 24 601 possible IBD cases were identified of which 10 499 were true positives. The point prevalence for IBD in Lothian on 31/08/2018 was 784/100 000 (UC 432/100 000, Crohn’s disease 284/100 000 and IBD unclassified (IBDU) 68/100 000). Capture–recapture methods identified an additional 427 ‘missed’ cases (95% CI 383 to 477) resulting in a ‘true’ prevalence of 832/100 000 (95% CI 827 to 837).Prevalence increased by 4.3% per year between 2008 and 2018 (95% CI +3.7 to +4.9%, p80 years of age.ConclusionsWe report a rigorously validated IBD cohort with all-age point prevalence on 31/08/2018 of 1 in 125, one of the highest worldwide.

The cumulative impact of chronic inflammation in patients with inflammatory bowel diseases predisposes to the development of inflammatory bowel disease-associated colorectal cancer [IBD-CRC]. Inflammation can induce mutagenesis, and the relapsing–remitting nature of this inflammation, together with epithelial regeneration, may exert selective pressure accelerating carcinogenesis. The molecular pathogenesis of IBD-CRC, termed the ‘inflammation–dysplasia–carcinoma’ sequence, is well described. However, the immunopathogenesis of IBD-CRC is less well understood. The impact of novel immunosuppressive therapies, which aim to achieve deep remission, is mostly unknown. Therefore, this timely review summarizes the clinical context of IBD-CRC, outlines the molecular and immunological basis of disease pathogenesis, and considers the impact of novel biological therapies.

SARS-CoV-2 has caused a global health crisis and mass vaccination programmes provide the best opportunity for controlling transmission and protecting populations. Despite the impressive clinical trial results of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines, important unanswered questions remain, especially in patients with pre-existing conditions. In this position statement endorsed by the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) section and IBD Clinical Research Group, we consider SARS-CoV-2 vaccination strategy in patients with IBD. The risks of SARS-CoV-2 vaccination are anticipated to be very low, and we strongly support SARS-CoV-2 vaccination in patients with IBD. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV-2 vaccination may be diminished in some patients with IBD, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in patients treated with anti-TNF drugs, are likely to outweigh these theoretical concerns. Key areas for further research are discussed, including vaccine hesitancy and its effect in the IBD community, the effect of immunosuppression on vaccine efficacy, and the search for predictive biomarkers of vaccine success.

5-Aza-2'-deoxycytidine (5-aza-dC) is a nucleoside analogue with cytotoxic and DNA demethylating effects. Here we show that 5-aza-dC induces the proteasomal degradation of free (non-chromatin bound) DNMT1 through a mechanism which is dependent on DNA synthesis and the targeting of incorporated 5-aza-dC residues by DNMT1 itself. Thus, 5-aza-dC induces Dnmt1 degradation in wild-type mouse ES cells, but not in Dnmt [3a(-/-), 3b(-/-)] mouse ES cells which express Dnmt1 but lack DNA methylation (< 0.7% of CpG methylated) and contain few hemi-methylated CpG sites, these being the preferred substrates for Dnmt1. We suggest that adducts formed between DNMT1 and 5-aza-dC molecules in DNA induce a ubiquitin-E3 ligase activity which preferentially targets free DNMT1 molecules for degradation by the proteasome. The proteasome inhibitor MG132 prevents DNMT1 degradation and reduces hypomethylation induced by 5-aza-dC.

ObjectiveManagement of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point.DesignWe convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey.ResultsPanellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4–6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab.ConclusionWe have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.

ObjectiveTo determine the challenges in diagnosis, monitoring, support provision in the management of inflammatory bowel disease (IBD) patients and explore the adaptations of IBD services.MethodsInternet-based survey by invitation of IBD services across the UK from 8 to 14 April 2020.ResultsRespondents from 125 IBD services completed the survey. The number of whole-time equivalent gastroenterologists and IBD nurses providing elective outpatient care decreased significantly between baseline (median 4, IQR 4–7.5 and median 3, IQR 2–4) to the point of survey (median 2, IQR 1–4.8 and median 2, IQR 1–3) in the 6-week period following the onset of the COVID-19 pandemic (pConclusionsIBD services in the UK have implemented several adaptive strategies in order to continue to provide safe and high-quality care for patients. National Health Service organisations will need to consider the impact of these changes in current service delivery models and staffing levels when planning exit strategies for post-pandemic IBD care. Careful planning to manage the increased workload and to maintain IBD services is essential to ensure patient safety.

Background & Aims Vedolizumab is an anti-a4b7 monoclonal antibody that is licensed for the treatment of moderate to severe Crohn’s disease and ulcerative colitis. The aims of this study were to establish the real-world effectiveness and safety of vedolizumab for the treatment of inflammatory bowel disease. Methods This was a retrospective study involving seven NHS health boards in Scotland between June 2015 and November 2017. Inclusion criteria included: a diagnosis of ulcerative colitis or Crohn’s disease with objective evidence of active inflammation at baseline (Harvey–Bradshaw Index[HBI] ≥5/Partial Mayo ≥2 plus C-reactive protein [CRP] >5 mg/L or faecal calprotectin ≥250 µg/g or inflammation on endoscopy/magnetic resonance imaging [MRI]); completion of induction; and at least one clinical follow-up by 12 months. Kaplan–Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, and deep remission [clinical remission plus mucosal healing]. Rates of serious adverse events were described quantitatively. Results Our cohort consisted of 180 patients with ulcerative colitis and 260 with Crohn’s disease. Combined median follow-up was 52 weeks (interquartile range [IQR] 26–52 weeks). In ulcerative colitis, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 57.4%, 47.3%, and 38.5%, respectively. In Crohn’s disease, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 58.4%, 38.9%, and 28.3% respectively. The serious adverse event rate was 15.6 per 100 patient-years of follow-up. Conclusions Vedolizumab is a safe and effective treatment for achieving both clinical remission and mucosal healing in ulcerative colitis and Crohn’s disease.

Switching from Remicade to CT-P13 allows for significant cost savings and has been shown to be non-inferior to continued therapy with Remicade for the treatment of Crohn’s disease. The aim of this work was to prospectively evaluate clinical outcomes in a cohort of patients with Crohn’s disease switching from Remicade to CT-P13. A prospective service evaluation was performed. The Harvey-Bradshaw index, CRP, faecal calprotectin and serum for infliximab/antibody levels were collected prior to patients' final Remicade infusion and at 6 and 12 months after switching to CT-P13 as part of routine clinical care. All adverse events during follow-up were also recorded. One hundred and ten patients on Remicade switched to CT-P13. No significant difference was observed between the Harvey-Bradshaw Index (p = 0.07), CRP (p = 0.13), faecal calprotectin (p = 0.25) or trough infliximab levels (p = 0.47) comparing before and at 6 and 12 months after the switch to CT-P13. Seven patients developed new infliximab antibodies after switching from Remicade to CT-P13. The majority of patients remained on CT-P13 at 12 months (84.5%) and the rate of adverse events and serious adverse events was 53.8 and 13.5 per 100 patient-years of follow-up, respectively. Switching to CT-P13 resulted in a cost saving of approximately 46.4%. The transition to CT-P13 from Remicade for the treatment of Crohn’s disease is safe and has no negative effect on clinical outcomes at 12 months.

Adalimumab is an established treatment for Crohn's disease. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut inflammation. We therefore aimed to characterize the relationship between adalimumab levels and biologic remission during maintenance therapy.A single-center prospective cross-sectional study was undertaken on Crohn's disease patients who had received adalimumab therapy for a minimum of 12 weeks after induction. Data on clinical activity (Harvey-Bradshaw Index), C-reactive protein (CRP), adalimumab drug and antibody levels, and fecal calprotectin were collected. Biologic remission was defined as a CRP5 mg/L and fecal calprotectin250 µg/g. Adalimumab drug and antibody levels were processed using the Immundiagnostik monitor enzyme-linked immunosorbent assay.One hundred fifty-two patients had drug and antibody samples matched with CRP and fecal calprotectin. Patients in biologic remission had significantly higher adalimumab levels compared with others (12.0 µg/mL vs 8.0 µg/mL, P0.0001). Receiver operating characteristic curve analysis demonstrated an optimal adalimumab level of8.5 µg/mL (sensitivity, 82.2%; specificity, 55.7%; likelihood ratio, 1.9) for predicting biologic remission. Multivariable logistic regression revealed that adalimumab levels8.5 µg/mL were independently associated with biologic remission (odds ratio, 5.27; 95% confidence interval, 2.43-11.44; P0.0001).Higher adalimumab levels are associated with biologic remission. An optimal level of8.5 µg/mL was identified.

Introduction Adalimumab (ADA) is a well-established treatment for Crohn’s disease (CD). Despite this limited data are available regarding the relationship of serum ADA levels, and antibodies to ADA (ATA) with clinical outcomes. Methods We performed a prospective cross-sectional study to investigate the association of serum ADA levels and ATA on clinical outcomes. Inclusion criteria were a diagnosis of CD and minimum of 12 weeks therapy. Patients were written to in advance of their next clinic visit and advised to omit their ADA dose if due within 72 hour from their appointment. Harvey Bradshaw Index (HBI), serum ADA levels/ATA, CRP and faecal calprotectin (FC) were simultaneously collected at clinic. Biochemical remission was defined as FC Results At the time of drug level testing, 259 patients were on ADA maintenance therapy. A total of 195 samples were available for analysis from 178 patients; matched HBI, FC and CRP were available for 171 patients. Median duration of ADA therapy was 2.4 years (IQR 1.2–4.3) with 37/178 (20.8%) patients receiving concomitant immunosuppression. Median ADA levels were higher in patients receiving weekly (n=55) (14.0 µg/ml, 8.0–17.4) vs. fortnightly dosing (n=123) (11.0 µg/ml, 7.0–14.5, p=0.0095). 29/178 (16.3%) patients were positive for ATA. A clear negative correlation was observed between ADA levels and ATA (Spearman’s r=−0.567, p 50 AU/ml, respectively (p 8.8 µg/ml was identified for predicting biochemical remission (82.7% sens, 55.6% spec, positive LR 1.86). ADA levels but not ATA independently predicted biochemical remission in a multivariate logistic regression model. Conclusions Higher ADA levels were independently associated with biochemical remission; levels of >8.8 µg/ml, higher than previously suggested, might be an appropriate target in the maintenance treatment of CD.

Introduction The GEMINI trials and an increasing body of real-world data have demonstrated the effectiveness and safety of vedolizumab (VDZ) in IBD. However, there is limited available data about its effect on hospitalisations and steroid use. Our aim was to address this in a large real-world cohort of IBD patients from across Scotland. Methods A multicenter retrospective cohort analysis of medical records was performed across 7 Scottish healthcare trusts. Primary outcomes were hospitalisation rates and overall steroid use in patients remaining on VDZ. Secondary outcomes were safety and intention to treat steroid free remission rates in patients with active disease. All data were prospectively collected as part of routine clinical care. Baseline demographics, clinical scores (HBI or Partial Mayo), faecal calprotectin (FC), endoscopy and radiology at 3, 6 and 12 months was recorded where available. Active disease was defined as endoscopic or radiographic evidence of disease or FC >200 mcg/g. Clinical remission was defined as HBI Results 340 (137 UC and 203 CD) patients were included in the primary analysis with a median follow-up of 9.4 months. Hospitalisation rates per patient-year were 0.60, 0.67, 0.36 and 0.16 at baseline, 3, 6 and 12 months of treatment respectively. Total number of hospitalisations reduced by 52.5% from 204 (12 months prior to VDZ) to 97 (12 months after VDZ). Proportion of patients on concomitant steroids reduced from 39.7% to 16.7% (n=332), 8.1% (n=270), 9.3% (n=194) at 3, 6 and 12 months respectively. In patients with active CD (n=153, 75.4%) steroid free clinical and steroid free biochemical remission rates were; 54.4% and 30.2% at 3 months; 47.7% and 32.1% at 6 months; 28.6% and 33.9% at 12 months. In patients with active UC (n=112, 81.8%) steroid free clinical and steroid free biochemical remission rates were; 57.4% and 40.9% at 3 months; 51.6% and 39.1% at 6 months; 37.5% and 41.2% at 12 months. Our cohort received >2066 VDZ infusions, 2 (0.6%) patients developed infusion reactions, 9 (2.6%) patients developed serious infections and 17 (5.0%) serious adverse events. Conclusions VDZ is associated with reduced hospitalisation and steroid use over 1 year. Steroid free remission rates and safety profile is in keeping with the published literature.

Purpose: Inflammatory bowel disease–associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management. Experimental Design: Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined. Results: Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA POLE. Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified. Conclusions: IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. Clin Cancer Res; 24(20); 5133–42. ©2018 AACR.

Introduction Inflammatory bowel disease-associated colorectal cancers (IBD-CRCs) occur infrequently but are associated with a higher mortality than sporadic CRCs. The poorly defined genetic and molecular pathogenesis of IBD-CRCs limits our ability to develop effective prevention, detection and treatment strategies. Since molecular changes identified at the time of surgery are most likely to represent informative biomarkers we elected to study primary IBD-CRC. Method 6The study was approved by the Lothian NHS Research Scotland BioResource (ref:15/ES/0094). Whole-exome sequencing and a comprehensive mutational analysis was performed on 35 FFPE IBD-CRCs and matched normal lymph node pairs from 32 patients (16 CD). Two of the patients had synchronous cancers. Results Ten (29%) of 35 IBD-CRCs were hypermutated and had a significantly higher 10 year survival than the non-hypermutator cancers (p=0.04). All hypermutator cancers were in the proximal colon; seven had loss of expression of MLH1, of which 5 had MLH1 promoter methylation. Two had somatic mutations in the proof-reading domain of DNA POLE. The hypermutated IBD-CRCs had a predicted increased neo-epitope load suggesting that these cancers may benefit from immune checkpoint blockade. Six distinct IBD-CRC mutational signatures were identified with four corresponding to known mutational mechanisms. Five genes including TP53, APC, PIK3CA, and KRAS were significantly mutated in the non-hypermutator IBD-CRCs and fourteen genes in the hypermutator IBD-CRCs, including RNF43 and AIM2, which are clinically actionable. Eleven of the 32 patients (34%) had germline mutations that may confer an inherited susceptibility to colorectal cancer; only two of these specific variants have a clinical pathogenic effect. Conclusion The hypermutated IBD-CRCs are associated with defects in MMR and DNA POLE; with a predicted higher neo-epitope load, which could be exploited using immunotherapies. Loss of MLH1 expression could be evaluated in potential colonic dysplastic or cancerous lesions detected in IBD patients. The identification of novel significantly mutated genes in hypermutated IBD-CRCs could be used to stratify therapy. These approaches would complement and individualise current surveillance and treatment programs for IBD-CRC. Disclosure of Interest None Declared

Background: In the two benchmark controlled trials in Crohn's disease (CD) supporting its use, methotrexate (MTX) was used as the immunosuppressant of choice in immunomodulatory-naive patients. However, in daily clinical practice MTX is used generally after thiopurine analogs have failed. Methods: The data are reported using intramuscular (IM) MTX (25 mg/week) in the induction of remission and oral MTX (15 mg/week) in 39 CD patients with a median age of 32 years, assessed retrospectively. In all, 97% patients had failed azathioprine and/or mercaptopurine therapy due to lack of efficacy in 14 (36%) and side effects in 24 (61%) patients; 21 patients (53%) were steroid-dependent with a median dose of 27.5 mg prednisolone/day for over a year. Results: In all, 72% of patients tolerated an induction regimen of 25 mg/week of IM MTX; 10% managed a reduced dose and 18% were intolerant. Remission was achieved in 71% of patients at 16 weeks. In the patients taking corticosteroids, withdrawal was achieved in 26% of patients and reduction in 47% at 16 weeks. Oral MTX therapy was continued in 22 patients after induction. In this group the probability of relapse was 78% at 50 weeks of oral therapy. Conclusions: Parenteral MTX therapy is efficacious in inducing remission in steroid-dependent CD patients, although its use is limited by side effects in ≈30% of patients. Low-dose oral therapy does not maintain long-term remission and is not a suitable alternative. (Inflamm Bowel Dis 2008)

The large-scale study of protein expression and protein function by using molecular technologies—proteomics—has become increasingly attractive, because the proteome reflects the intrinsic genetic program of the cell and the impact of its immediate environment. This Review describes conventional proteomic technologies currently being used and their limitations, and demonstrates their clinical applicability, with specific reference to published data of relevance to the gastroenterology field. Analysis of the human genome has increased our knowledge of the genes that are associated with disease. At the same time, however, it has become clear that having complete DNA sequences alone is not sufficient to elucidate the biological functions of the proteins that they encode. For this reason, proteomics—the analysis of proteins—has become increasingly attractive, because the proteome reflects both the intrinsic genetic programming of a cell and the impact of its immediate environment. The principal goals of clinical proteomics are to identify biomarkers for the early diagnosis of disease and potential targets for therapeutic intervention. Other goals include the identification of biomarkers for the early detection of disease recurrence (relapse) and how they might be combined with diagnostic imaging techniques to improve the sensitivity for detecting disease. This Review describes conventional proteomic technologies, their strengths and limitations, and demonstrates their application to clinical practice, with specific reference to their use in the gastroenterology field.

Introduction The DNA damage response (DDR) is an innate cellular response allowing cells to halt the cell cycle and repair DNA damage sustained by activating various mechanisms. The efficacy of conventional cancer treatment modalities is related in their ability to induce DNA damage. Constitutive activation of the ataxia telangectasia mutated (ATM) dependent DDR and repair pathways have been reported in (pre) malignant human tissues and may undermine the efficacy of current cancer therapies. Inhibition of proteins involved in the DDR cascade is an attractive therapeutic concept that may overcome resistance to current cytotoxics and potentiate the effects of radiotherapy. Methods A tumour microarray was created using 179 sporadic colorectal cancers; 152 were of the microsatellite stable phenotype. The microarray was interrogated using antibodies against proteins of the DDR signalling cascade. A colorectal cancer cell line model was utilised to asses the functionality of the constitutively activated DNA damage pathway. ATM inhibition in combination with ionising irradiation was analysed in the cell line model using radioactive quantification of DNA synthesis, flow cytometric cell separation, clonogenic survival and immunoblotting. Results Phosphorylated Chk2 threonine-68, a surrogate marker of the DDR, was present in 22% of microsatellite-stable colorectal tumours and 33% of tumours with the microsatellite instability phenotype. High p53 staining was present in 53% of microsatellite stable cancers and 26% microsatellite instable cancers. P21-null HCT116 cells display constitutive activation of the ATM DDR but display a defect in the ionising radiation induced S-phase checkpoint, termed radioresistant DNA synthesis. This radioresistant phenotype is associated with increased basal levels of Cdc25A protein, deficient DNA damage-induced degradation of Cdc25A and Chk2 mis-localisation. P21-null HCT116 and SW620 cells, which exhibit basal Chk2 threonine-68 phosphorylation, were unable to abrogate the S-phase checkpoint when treated with an ATM inhibitor, suggesting that the ATM–Chk2 arm is non-functional in these cells: inhibition of ATM did not potentiate the efficacy of ionising irradiation. Conclusion In a colorectal cancer cell line model constitutive activation of the ATM DDR pathway reflected a non-functional pathway and inhibition of ATM in these circumstances was unable to potentiate the efficacy of ionising irradiation. Basal Chk2 threonine-68 phosphorylation in colorectal cancer may reflect a deregulated ATM DDR pathway and/or checkpoint adaption. A predictive model is proposed that integrates functionality of the ATM-Chk2 axis, p53 mutation status and defects in DNA repair pathways when considering ATM inhibitor therapy. Disclosure of Interest None Declared