Establishing key performance indicators for inflammatory bowel disease in the UK.

Background and aims: Healthcare quality improvement (QI) is the systematic process to continuously improve the quality of care and outcomes for patients. The landmark Inflammatory Bowel Disease (IBD) UK National Audits provided a means to measure the variation in care, highlighting the need to define the standards of excellence in IBD care. Through a consensus approach, we aimed to establish key performance indicators (KPIs), providing reliable benchmarks for IBD care delivery in UK. Methods: KPIs that measure critical aspects of a patient journey within an IBD service were identified though stakeholder meetings. A two-stage Delphi consensus was then conducted. The first involved a multidisciplinary team of IBD clinicians and patients to refine definitions and methodology. The second stage assessed feasibility and utility of the proposed QI process by surveying gastroenterology services across UK. Results: First, the four proposed KPIs were refined and included time from primary care referral to diagnosis in secondary care, time to treatment recommendation following a diagnosis, appropriate use of steroids and advanced therapies prescreening and assessment. Second, the Delphi consensus reported >85% agreement on the feasibility of local adoption of the QI process and >75% agreement on the utility of benchmarking of the KPIs. Conclusions: Through a structured approach, we propose quantifiable KPIs for benchmarking to improve and reduce the individual variation in IBD care across the UK.

Immune-related adverse events in checkpoint blockade: Observations from human tissue and therapeutic considerations.

Checkpoint inhibitors (CPIs) are monoclonal antibodies which, by disrupting interactions of immune checkpoint molecules with their ligands, block regulatory immune signals otherwise exploited by cancers. Despite revolutionary clinical benefits, CPI use is associated with an array of immune-related adverse events (irAEs) that mirror spontaneous autoreactivity. Severe irAEs necessitate pausing or stopping of CPI therapy and use of corticosteroids and/or other immunomodulatory interventions. Despite increasingly widespread CPI use, irAE pathobiology remains poorly understood; its elucidation may point to targeted mitigation strategies and uncover predictive biomarkers for irAE onset in patients, whilst casting new light on mechanisms of spontaneous immune-mediated disease. This review focuses on common CPI-induced irAEs of the gut, skin and synovial joints, and how these compare to immune-mediated diseases such as ulcerative colitis, vitiligo and inflammatory arthritis. We review current understanding of the immunological changes reported following CPI therapy at the level of peripheral blood and tissue. Many studies highlight dysregulation of cytokines in irAE-affected tissue, particularly IFNγ and TNF. IrAE-affected tissues are also predominantly infiltrated by T-cells, with low B-cell infiltration. Whilst there is variability between studies, patients treated with anti-programmed cell death-1 (PD-1)/PDL-1 therapies seem to exhibit CD8+ T-cell dominance, with CD4+ T-cells dominating in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy. Interestingly, CD8+CXCR3+ T-cells have been reported to be elevated in gastrointestinal, dermatological and musculoskeletal -irAE affected tissues. These findings may highlight potential opportunities for therapeutic development or re-deployment of existing therapies to prevent and/or improve the outcome of irAEs.

Genomic diagnosis and care co-ordination for monogenic inflammatory bowel disease in children and adults: consensus guideline on behalf of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition.

Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.

A treatment planning comparison of photon stereotactic ablative radiotherapy and proton beam therapy for the re-irradiation of pelvic cancer recurrence.

BACKGROUND: Patients who experience a pelvic cancer recurrence in or near a region that received initial radiotherapy, typically have few options for treatment. Organs at risk (OAR) have often reached their dose constraint limits leaving minimal dose remaining for standard re-irradiation (reRT). However, photon based stereotactic ablative radiotherapy (SABR) has been utilised for reRT with promising initial results although meeting OAR constraints can be challenging. Proton beam therapy (PBT) could offer an advantage. MATERIALS AND METHODS: SABR plans used for treatment for ten pelvic reRT patients were dosimetrically compared to PBT plans retrospectively planned using the same CT and contour data. PBT plans were created to match the CTV dose coverage of SABR treatment plans with V100% ≥95%. An 'as low as reasonably achievable' approach was taken to OAR tolerances with consideration of OAR dose from the initial radiation (using equivalent dose in 2 Gy fractions). RESULTS: Dosimetric comparison of relevant OAR statistics showed a decrease in OAR dose using PBT over SABR in all patients, with equivalent target coverage. The largest statistically significant reduction was seen for the colon D0.5 cm3 with a median reduction from 13.1 Gy to 5.9 Gy. There were statistically significant dose reductions in the median dose to small bowel, sacral plexus and cauda equina. CONCLUSION: PBT has the potential for significant dose reductions for OARs in the pelvic reRT setting compared to SABR. However, it remains unclear if the magnitude of these OAR dose reductions will translate into clinical benefit.

Targeting Leukocyte Trafficking in Inflammatory Bowel Disease.

In the last two decades, understanding of inflammatory bowel disease (IBD) immunopathogenesis has expanded considerably. Histopathological examination of the intestinal mucosa in IBD demonstrates the presence of a chronic inflammatory cell infiltrate. Research has focused on identifying mechanisms of immune cell trafficking to the gastrointestinal tract that may represent effective gut-selective targets for IBD therapy whilst avoiding systemic immunosuppression that may be associated with off-target adverse effects such as infection and malignancy. Integrins are cell surface receptors that can bind to cellular adhesion molecules to mediate both leukocyte homing and retention. In 2014, Vedolizumab (Entyvio®) was the first anti-integrin (anti-α4ß7 monoclonal antibody) treatment to be approved for use in IBD. Several other anti-integrin therapies are currently in advanced stages of development, including novel orally administered small-molecule drugs. Drugs targeting alternative trafficking mechanisms such as mucosal addressin cellular adhesion molecule-1 and sphingosine-1-phosphate receptors are also being evaluated. Here, we summarise key established and emerging therapies targeting leukocyte trafficking that may play an important role in realising the goal of stratified precision medicine in IBD care.

Gastrointestinal mucosal damage in patients with COVID-19 undergoing endoscopy: an international multicentre study.

BACKGROUND: Although evidence suggests frequent gastrointestinal (GI) involvement during coronavirus disease 2019 (COVID-19), endoscopic findings are scarcely reported. AIMS: We aimed at registering endoscopic abnormalities and potentially associated risk factors among patients with COVID-19. METHODS: All consecutive patients with COVID-19 undergoing endoscopy in 16 institutions from high-prevalence regions were enrolled. Mann-Whitney U, χ2 or Fisher's exact test were used to compare patients with major abnormalities to those with negative procedures, and multivariate logistic regression to identify independent predictors. RESULTS: Between February and May 2020, during the first pandemic outbreak with severely restricted endoscopy activity, 114 endoscopies on 106 patients with COVID-19 were performed in 16 institutions (men=70.8%, median age=68 (58-74); 33% admitted in intensive care unit; 44.4% reporting GI symptoms). 66.7% endoscopies were urgent, mainly for overt GI bleeding. 52 (45.6%) patients had major abnormalities, whereas 13 bled from previous conditions. The most prevalent upper GI abnormalities were ulcers (25.3%), erosive/ulcerative gastro-duodenopathy (16.1%) and petechial/haemorrhagic gastropathy (9.2%). Among lower GI endoscopies, 33.3% showed an ischaemic-like colitis.Receiver operating curve analysis identified D-dimers >1850 ng/mL as predicting major abnormalities. Only D-dimers >1850 ng/mL (OR=12.12 (1.69-86.87)) and presence of GI symptoms (OR=6.17 (1.13-33.67)) were independently associated with major abnormalities at multivariate analysis. CONCLUSION: In this highly selected cohort of hospitalised patients with COVID-19 requiring endoscopy, almost half showed acute mucosal injuries and more than one-third of lower GI endoscopies had features of ischaemic colitis. Among the hospitalisation-related and patient-related variables evaluated in this study, D-dimers above 1850 ng/mL was the most useful at predicting major mucosal abnormalities at endoscopy. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov (ID: NCT04318366).

Randomised clinical trial: combined impact and resistance training in adults with stable Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a predisposing factor for bone loss and muscle dysfunction, which could lead to osteoporotic fractures and physical disability, respectively. AIM: To assess the effect of 6 months of combined impact and resistance training on bone mineral density (BMD) and muscle function in adults with CD. METHODS: In this randomised controlled trial, 47 adults with stable CD were assigned to exercise (n = 23) or control (n = 24) groups and followed up for 6 months. The exercise group received usual care plus a 6-month combined impact and resistance training programme, involving three, 60-minute sessions per week and a gradual tapering of supervision to self-management. The control group received usual care alone. The primary outcomes were BMD (via dual energy X-ray absorptiometry) and muscle function (measures of upper and lower limb strength and endurance) at 6 months. RESULTS: At 6 months, BMD values were superior in the exercise group with statistical significance at lumbar spine (adjusted mean difference 0.036 g/cm2, 95% CI 0.024-0.048; P < 0.001), but not at femoral neck (0.018 g/cm2, 0.001-0.035; P = 0.059) or greater trochanter (0.013 g/cm2, -0.019 to 0.045; P = 0.415) after correcting for multiple outcomes. The exercise group also had superior values for all muscle function outcomes (P < 0.001; unadjusted mean differences ranging 22.6‒48.2%), and lower fatigue severity (P = 0.005). Three exercise-related adverse events were recorded: two instances of light-headedness and one of nausea. CONCLUSIONS: The intervention improved BMD and muscle function in adults with CD and appears as a suitable model of exercise for reducing future risk of osteoporotic fractures and disability. TRIAL REGISTRATION: ISRCTN11470370.

Probiotic Bacillus amyloliquefaciens H57 ameliorates subclinical necrotic enteritis in broiler chicks by maintaining intestinal mucosal integrity and improving feed efficiency.

Subclinical necrotic enteritis (NE) was induced in broiler chicks using a high dose of Eimeria spp. vaccine in the drinking water on day 9, and Clostridium perfringens (Cp) culture mixed in the feed on days 14 and 15. The aim was to evaluate the effects of probiotic Bacillus amyloliquefaciens strain H57 (H57) in preventing NE in chicks. Day-old Ross 308, male broilers were weighed and randomly assigned to 6 treatment groups (6 replicate cages/treatment and 8 birds/cage). Birds in group 1 (control) were fed the basal wheat-soybean diet without H57 or NE infection; in group 2 (Eimeria) were treated with Eimeria alone; in group 3 (Cp) were treated with Cp alone; in group 4 (NE) received both Eimeria and Cp; in group 5 (NE-H57) received NE infection and H57; and group 6 (H57) received H57. The basal diet of chicks in groups 5 and 6 was supplemented with H57 at a density of 2 × 108 spores/g feed from 1 D of age. On day 21, there were no significant treatment effects on BW and feed intake between control and H57 birds. However, on day 21, the feed conversion ratio of NE-H57 birds was significantly improved when compared with NE birds (1.28 vs. 1.36; P < 0.001). Birds challenged with NE had a higher occurrence of pasty vent than birds infected with either Eimeria, Cp, or NE-H57 (41 vs. 27 vs. 29 vs. 19%, respectively; P < 0.001). Intestinal lesion scores of NE birds were also higher than those of Eimeria, Cp, and NE-H57 birds (5.67 vs. 2.56 vs. 2.78 vs. 2.10, respectively; P < 0.001) and correlated with pasty vent (Pearson's r = 0.56; P < 0.001). Microscopic evaluation showed mucosal damage and necrosis in NE birds. In contrast, villi from NE-H57 birds were normal, with no damage or infiltration with Eimeria or Cp. H57 appears to be effective in challenged birds, as it maintained epithelial barrier integrity and improved feed efficiency.

Immunosuppression-induced clonal T-cell lymphoproliferative disease causing severe diarrhoea mimicking coeliac disease following renal transplantation: a case report.

BACKGROUND: Post-transplant lymphoproliferative disease is a recognized complication following solid organ transplantation. This is usually a B cell disease and frequently associated with Epstein Barr virus infection, although T cell PTLD can occur. T cell PTLD is usually a monomorphic, lymphomatous disease associated with an adverse prognosis. CASE REPORT: We report a 52 year old male pre-emptive renal transplant recipient who developed severe diarrhea with weight loss following intensification of his immunosuppression due to antibody mediated rejection 3 years after transplantation. Duodenal biopsy demonstrated monoclonal CD8+ T cell duodenitis leading to increased intraepithlieal lymphocytes and sub-total villous atrophy mimicking coeliac disease. Coeliac disease was excluded by negative anti-tissue transglutaminase antibody, HLA-DQ2 and HLA-DQ8 testing. There was no evidence of lymphoma either on biopsy or CT enterography and no FDG avid disease on PET. Symptoms did not improve with reduction of immunosuppression, but resolved fully on complete withdrawal of treatment. The transplant failed and he was established on dialysis. The diagnosis was early PTLD. CONCLUSIONS: Oesophagogastroduodenoscopy with small bowel biopsies is a useful investigation for determining the cause of diarrhoea in renal transplant patients when more common causes have been excluded. This is the first report that we are aware of clonal T cell PTLD mimicking coeliac disease which only resolved after complete withdrawal of immunosuppression. As treatments for lymphoma are aggressive they are only initiated in the malignant phase and management of early stage PTLD is to minimise risk of progression by reducing immunosuppression. Any plans to retransplant will have to take into consideration the possibility that PTLD will recur.

Identification and separation of rigid image registration error sources, demonstrated for MRI-only image guided radiotherapy.

PURPOSE: Rigid image registration (RIR) accuracy is crucial for image guided radiotherapy (IGRT). However, existing clinical image registration assessment methods cannot separate and quantify RIR error sources. Herein, we develop an extension of the 'full circle method' for RIR consistency. Paired registration circuits are used to isolate sources of RIR error caused by reference dataset substitution, from those inherent to the underlying RIR. This approach was demonstrated in the context of MRI-only IGRT, assessing substitution of MRI-derived synthetic-CT (sCT) for conventional CT, in a cohort of rectal cancer patients. MATERIALS AND METHODS: Planning CT, MRI-derived sCT, and two CBCTs from seven rectal cancer patients were retrospectively registered with global and soft tissue clipbox based RIR. Paired registration circuits were constructed using two moving (cone beam CT) images and two reference images (CT and sCT), per patient. Differences between inconsistencies in registration circuits containing CT and sCT were used to determine changes in registration accuracy due to substitution of sCT for CT. RESULTS: sCT was found to be equivalent to CT under global RIR, with median differences of 0.05 mm and 0.01°. Soft tissue clipbox based RIR with sCT exhibited gross misregistration (>5 mm or 3°) for 3 patients. Registration consistency was degraded compared to CT across the cohort, with median differences of 0.54 mm and 0.15°. CONCLUSION: A paired registration circuit methodology for assessing RIR accuracy without ground truth information was developed and demonstrated for MRI-only IGRT in rectal cancer. This highlighted a reduction in clipbox based RIR consistency when sCT was substituted for conventional CT. The developed method enabled separation of degraded registration accuracy, from other error sources within the overall registration inconsistency. This novel methodology is applicable to any RIR scenario and enables analysis of the change in RIR performance on modification of image data or process.

Postoperative (Chemo)Radiotherapy for Oral Cavity Squamous Cell Carcinomas: Outcomes and Patterns of Failure.

AIMS: To determine outcomes after adjuvant radiotherapy for squamous cell carcinoma of the oral cavity and to correlate locoregional recurrence patterns with radiotherapy target volumes. MATERIALS AND METHODS: All patients receiving adjuvant radiotherapy±chemotherapy after surgery with curative intent for oral cavity squamous cell carcinoma between 2007 and 2012 were retrospectively analysed. Locoregional recurrences were reconstructed on the planning computed tomography scan by both deformable image co-registration and by visual assessment. Recurrences were categorised as in-field, marginal or out-of-field if >95%, 20-95%, and <20% of the recurrence volume was encompassed by 95% of the prescription isodose, respectively. RESULTS: In total, 106 patients with a median follow-up of 42 months were included. Oral cavity subsites included oral tongue (54%) and floor of mouth (32%). Thirty (28%) patients received concurrent chemotherapy. Fifty-five (52%) patients received bilateral neck radiotherapy. Two year overall, disease-free, local disease-free, regional disease-free and distant metastases-free survival were 72, 83, 92, 89, 94%, respectively. On multivariate analysis, extracapsular nodal spread was the only factor significantly associated with inferior overall survival. Fourteen (13%) patients have experienced locoregional failure. Of the eight local recurrences at the primary tumour site, four, three and one were classified as in-field, marginal and out-of-field, respectively. Of 10 regional recurrences, one, one and eight were in-field, marginal and out-of-field. There were 7/21 (33%) contralateral regional recurrences in patients with pN2a/b disease who did not receive contralateral neck irradiation; there were 0/21 (0%) and 0/9 (0%) contralateral regional recurrences in patients with pN0 or pN1 disease, respectively, who did not receive contralateral neck irradiation. CONCLUSION: Marginal recurrences highlight the need for generous target volume delineation. Based upon rates of contralateral regional recurrences, a comprehensive approach to target volume selection should be advised for tumour subsites with bilateral lymphatic drainage in the presence of pN2a/b disease.

Novel bile acid therapeutics for the treatment of chronic liver diseases.

Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases.

Patterns of failure after intensity-modulated radiotherapy in head and neck squamous cell carcinoma using compartmental clinical target volume delineation.

AIMS: To determine the pattern of disease recurrence in non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) patients treated with radical intensity-modulated radiotherapy (IMRT) with or without chemotherapy, and to correlate the sites of locoregional recurrence with radiotherapy target volumes. MATERIALS AND METHODS: In total, 136 patients treated with radical IMRT with or without chemotherapy between 2008 and 2011 for non-nasopharyngeal HNSCC were retrospectively identified. A compartmental approach to clinical target volume (CTV) delineation was routinely utilised during this period and IMRT was delivered using a 5-7 angle step and shoot technique. Locoregional recurrences were reconstructed on the planning computed tomography scan by both deformable image coregistration and by visual assessment, and were analysed in relation to target volumes and dosimetry. RESULTS: The median follow-up was 31 (range 3-53) months. Two year local control, regional control, disease-free survival, distant metastasis-free survival and overall survival were 86, 93, 78, 89 and 79%, respectively. One hundred and twenty of 136 (88%) patients achieved a complete response to treatment and 7/120 (6%) have subsequently had a locoregional recurrence. Analysis of these recurrences revealed five to be infield; one to be marginal to the high-dose CTV; one to be out-of-field. Overall the marginal/out-of-field recurrence rate was 2/136 (1.5%). CONCLUSIONS: IMRT utilising a compartmental approach to CTV delineation was associated with a low rate of marginal/out-of-field recurrence.

Drug advances in inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) remains incompletely understood, but is thought to be a consequence of immune dysregulation, impaired mucosal integrity, enteric bacterial dysbiosis and genetic susceptibility factors. Recent drug advances in the treatment of IBD have clarified the role of existing medication, including 5-amino-salicylic acids (5-ASAs) and has seen a burgeoning use of treatment with biologicals. With recent advances in our understanding of these debilitating diseases, it is hoped that novel therapeutic targets can be identified.

1H and 13C solution- and solid-state NMR investigation into wax products from the Fischer-Tropsch process.

(1)H and (13)C solid- and solution-state NMR have been used to characterise waxes produced in the Fischer-Tropsch reaction, using Co-based catalysts either unpromoted or promoted with approximately 1 wt% of either cerium or rhenium. The aim was to measure average structural information at the submolecular level of the hydrocarbon waxes produced, along with identification of the minor products, such as oxygenates and olefins, which are typically observed in these waxes. A parameter of key interest is the average number of carbon atoms within the hydrocarbon chain (N(C)). A wax prepared using an unpromoted Co/Al(2)O(3) catalyst had N(C)∼20, whilst waxes made using rhenium- or cerium-promoted Co/Al(2)O(3) catalysts were found to have N(C)∼21. All three samples contained small amounts of oxygenates and alkenes. The subtle differences found in the waxes, in particular the minor species produced, demonstrate that the different promoters have different effects during the reaction, with the Re-promoted catalyst producing the fewest by-products. It is shown in (13)C solid-state NMR spectra that for that for longer chain (compared to the lengths of chain in previous studies) waxes that the lack of resolution and the complexities added by the differential cross-polarisation (CP) dynamics mean that it is difficult to accurately determine N(C) from this approach. However the N(C) determined by (13)C CP magic angle spinning NMR is broadly consistent with the more accurate solution approaches used and suggest that the wax characteristics do not change in solution. On this basis an alternative approach for determining N(C) is suggested based on (1)H solution state NMR that provides a higher degree of accuracy of the chain length as well as information on the minor constituents.

A (59)Co NMR study to observe the effects of ball milling on small ferromagnetic cobalt particles.

To demonstrate the potential of nuclear magnetic resonance (NMR) spectroscopy for investigating detailed structural properties in ferromagnetic materials, three different particle sized cobalt (Co) powders have been ball milled for 24h are accurately characterised by internal-field (59)Co NMR. The (59)Co NMR spectra show distinct resonance bands corresponding to the different Co sites, face-centred-cubic (fcc), hexagonal-close-packed (hcp) and stacking faults (sfs), in Co metal powders. The hcp+fcc-->hcp phase transition encouraged by ball-milling was observed and quantitative values for each Co environment were obtained.