Cancer Biology or Ineffective Surveillance? A multicentre retrospective analysis of colitis-associated post-colonoscopy colorectal cancers.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is associated with high rates of post-colonoscopy colorectal cancer (PCCRC), but further in-depth qualitative analyses are required to determine whether they result from inadequate surveillance or aggressive IBD cancer evolution. METHODS: All IBD patients who had a colorectal cancer (CRC) diagnosed between January 2015 to July 2019 and a recent (<4 years) surveillance colonoscopy at one of four English hospital trusts underwent root cause analyses as recommended by the World Endoscopy Organisation to identify plausible PCCRC causative factors. RESULTS: 61% (n=22/36) of the included IBD CRCs were PCCRCs. They developed in patients with high cancer risk factors (77.8%; n=28/36) requiring annual surveillance, yet 57.1% (n=20/35) had inappropriately delayed surveillance. Most PCCRCs developed in situations where (i) an endoscopically unresectable lesion was detected (40.9%; n=9/22), (ii) there was a deviation from the planned management pathway (40.9%; n=9/22) e.g. service, clinician or patient-related delays in acting on a detected lesion, or (iii) lesions were potentially missed as they were typically located within areas of active inflammation or post-inflammatory change (36.4%; n=8/22). CONCLUSIONS: IBD PCCRC prevention will require more proactive strategies to reduce endoscopic inflammatory burden, improve lesion optical characterisation, adherence to recommended surveillance intervals and patient acceptance of prophylactic colectomy. However, the significant proportion appearing to originate from non-adenomatous-looking mucosa which fail to yield neoplasia on biopsy yet display aggressive cancer evolution highlight the limitations of current surveillance. Emerging molecular biomarkers may play a role in enhancing cancer risk stratification in future clinical practice.

Two-year real-world outcome data from a single tertiary centre shows reduced ustekinumab persistence in a non-bio-naïve Crohn's disease cohort with penetrating disease, -ostomies and sarcopenia.

Background: Ustekinumab was approved in 2016 for the treatment of moderate-severe Crohn's disease (CD). Clinical trials and real-world studies have suggested ustekinumab to be a safe and effective treatment; however, studies to date infrequently use imaging techniques to predict response to biologics in CD. Objectives: We assessed the 2-year real-world effectiveness and safety of ustekinumab in a tertiary CD cohort with the use of novel imaging techniques. Design: Retrospective cohort study. Methods: Retrospective data were collected between 2016 and 2021. Study end points included ustekinumab persistence, biological and/or clinical response and remission at 12, 18 and 24 months. Statistical analysis included demographic and inferential analyses. Results: In all, 131 CD patients [57.3% female, median age of 26.0 (21.0-37.0)] were included. Patients were non-bio naïve, and the majority received ustekinumab as third- or fourth-line treatment. At 24 months, 61.0% (80/131) persisted with ustekinumab [52.7% (69/131) steroid free]. Clinical response was reported in 55.2% (37/67), clinical remission in 85.7% (57/67), biological response in 46.8% (22/47) and biological remission in 31.9% (15/47) of patients at 24 months. The low outcome numbers were attributable to missing data. Improvements in routine disease markers, including C-reactive protein and Harvey-Bradshaw Index, were also reflected in magnetic resonance imaging-derived disease scores. The presence of penetrating CD, an -ostomy and sarcopenia were all predictors of poorer ustekinumab outcomes (p < 0.05). Conclusion: Ustekinumab is effective in non-bio-naïve CD patients with non-stricturing, non-penetrating disease with an unremarkable safety profile but may be less effective in those with penetrating disease, -ostomies and sarcopenia.

Identifying key mechanisms leading to visual recognition errors for missed colorectal polyps using eye-tracking technology.

BACKGROUND AND AIM: Lack of visual recognition of colorectal polyps may lead to interval cancers. The mechanisms contributing to perceptual variation, particularly for subtle and advanced colorectal neoplasia, have scarcely been investigated. We aimed to evaluate visual recognition errors and provide novel mechanistic insights. METHODS: Eleven participants (seven trainees and four medical students) evaluated images from the UCL polyp perception dataset, containing 25 polyps, using eye-tracking equipment. Gaze errors were defined as those where the lesion was not observed according to eye-tracking technology. Cognitive errors occurred when lesions were observed but not recognized as polyps by participants. A video study was also performed including 39 subtle polyps, where polyp recognition performance was compared with a convolutional neural network. RESULTS: Cognitive errors occurred more frequently than gaze errors overall (65.6%), with a significantly higher proportion in trainees (P = 0.0264). In the video validation, the convolutional neural network detected significantly more polyps than trainees and medical students, with per-polyp sensitivities of 79.5%, 30.0%, and 15.4%, respectively. CONCLUSIONS: Cognitive errors were the most common reason for visual recognition errors. The impact of interventions such as artificial intelligence, particularly on different types of perceptual errors, needs further investigation including potential effects on learning curves. To facilitate future research, a publicly accessible visual perception colonoscopy polyp database was created.

Polyp characterization using deep learning and a publicly accessible polyp video database.

OBJECTIVES: Convolutional neural networks (CNN) for computer-aided diagnosis of polyps are often trained using high-quality still images in a single chromoendoscopy imaging modality with sessile serrated lesions (SSLs) often excluded. This study developed a CNN from videos to classify polyps as adenomatous or nonadenomatous using standard narrow-band imaging (NBI) and NBI-near focus (NBI-NF) and created a publicly accessible polyp video database. METHODS: We trained a CNN with 16,832 high and moderate quality frames from 229 polyp videos (56 SSLs). It was evaluated with 222 polyp videos (36 SSLs) across two test-sets. Test-set I consists of 14,320 frames (157 polyps, 111 diminutive). Test-set II, which is publicly accessible, 3317 video frames (65 polyps, 41 diminutive), which was benchmarked with three expert and three nonexpert endoscopists. RESULTS: Sensitivity for adenoma characterization was 91.6% in test-set I and 89.7% in test-set II. Specificity was 91.9% and 88.5%. Sensitivity for diminutive polyps was 89.9% and 87.5%; specificity 90.5% and 88.2%. In NBI-NF, sensitivity was 89.4% and 89.5%, with a specificity of 94.7% and 83.3%. In NBI, sensitivity was 85.3% and 91.7%, with a specificity of 87.5% and 90.0%, respectively. The CNN achieved preservation and incorporation of valuable endoscopic innovations (PIVI)-1 and PIVI-2 thresholds for each test-set. In the benchmarking of test-set II, the CNN was significantly more accurate than nonexperts (13.8% difference [95% confidence interval 3.2-23.6], P = 0.01) with no significant difference with experts. CONCLUSIONS: A single CNN can differentiate adenomas from SSLs and hyperplastic polyps in both NBI and NBI-NF. A publicly accessible NBI polyp video database was created and benchmarked.

METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn's disease-protocol for a multicentre, non-randomised, single-arm, prospective study.

INTRODUCTION: Crohn's disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis. METHODS AND ANALYSIS: We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis. ETHICS AND DISSEMINATION: This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London-Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN76899103.

Comparative effectiveness of a second-line biologic in patients with ulcerative colitis: vedolizumab followed by an anti-TNF versus anti-TNF followed by vedolizumab.

Background: Sequential drug treatment with biological agents in ulcerative colitis (UC) is becoming increasingly complex. There are few studies comparing head-to-head outcomes in second-line treatments. The study assesses whether using anti-tumour necrosis factor (anti-TNF)-α therapy following the α4ß7 integrin blocker vedolizumab (VDZ) or VDZ after an anti-TNF has more favourable clinical outcomes in UC in a real-world outpatient setting. Methods: Patients with UC who were exposed to first-line anti-TNF (adalimumab or infliximab) or VDZ who subsequently switched to the alternate class between May 2013 and August 2020 were identified by reviewing patient databases at 10 hospitals. Data were collected retrospectively using patient records. Baseline demographics, disease activity indices, biochemical markers, endoscopic Mayo score, colectomy rates, treatment persistence and urgent hospital utilisation composite endpoint (UHUC) rates were examined over a 52-week period. Results: Second-line week 52 treatment persistence was higher in the VDZ group (71/81, 89%) versus the anti-TNF group (15/34, 44%; p=0.0001), as were week 52 colectomy-free survival (VDZ: 77/80, 96%, vs anti-TNF: 26/32, 81%; p=0.009), week 52 UHUC survival (VDZ: 68/84, 81%, vs anti-TNF: 20/34, 59%; p=0.002) and week 52 corticosteroid-free clinical remission (CFCR) rates (VDZ: 22/34, 65%, vs anti-TNF: 4/20, 20%; p=0.001). Conclusion: Compared with second-line anti TNF usage, the VDZ second-line cohort had significantly higher 52-week treatment persistence, UHUC survival, higher colectomy-free survival rates and higher week 52 CFCR. These data suggest that VDZ is an effective biologic in UC as a second-line therapy after anti-TNF exposure. It highlights the effect of biological order on clinically important outcomes.

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.

Performance of artificial intelligence for detection of subtle and advanced colorectal neoplasia.

OBJECTIVES: There is uncertainty regarding the efficacy of artificial intelligence (AI) software to detect advanced subtle neoplasia, particularly flat lesions and sessile serrated lesions (SSLs), due to low prevalence in testing datasets and prospective trials. This has been highlighted as a top research priority for the field. METHODS: An AI algorithm was evaluated on four video test datasets containing 173 polyps (35,114 polyp-positive frames and 634,988 polyp-negative frames) specifically enriched with flat lesions and SSLs, including a challenging dataset containing subtle advanced neoplasia. The challenging dataset was also evaluated by eight endoscopists (four independent, four trainees, according to the Joint Advisory Group on gastrointestinal endoscopy [JAG] standards in the UK). RESULTS: In the first two video datasets, the algorithm achieved per-polyp sensitivities of 100% and 98.9%. Per-frame sensitivities were 84.1% and 85.2%. In the subtle dataset, the algorithm detected a significantly higher number of polyps (P < 0.0001), compared to JAG-independent and trainee endoscopists, achieving per-polyp sensitivities of 79.5%, 37.2% and 11.5%, respectively. Furthermore, when considering subtle polyps detected by both the algorithm and at least one endoscopist, the AI detected polyps significantly faster on average. CONCLUSIONS: The AI based algorithm achieved high per-polyp sensitivities for advanced colorectal neoplasia, including flat lesions and SSLs, outperforming both JAG independent and trainees on a very challenging dataset containing subtle lesions that could have been overlooked easily and contribute to interval colorectal cancer. Further prospective trials should evaluate AI to detect subtle advanced neoplasia in higher risk populations for colorectal cancer.

Multicentre randomised controlled trial comparing standard and high resolution optical technologies in colorectal cancer screening.

BACKGROUND AND OBJECTIVES: The UK bowel cancer screening programme (BCSP) has been established for the early detection of colorectal cancer offering colonoscopy to patients screened positive by faecal occult blood tests. In this multisite, prospective, randomised controlled trial, we aimed to compare the performance of Standard Definition Olympus Lucera (SD-OL) with Scope Guide and the High Definition Pentax HiLine (HD-PHL). PATIENTS AND METHODS: Subjects undergoing a colonoscopy as part of the UK National BCSP at four UK sites were randomised to an endoscopy list run using either SD-OL or HD-PHL. Primary endpoints were polyp and adenoma detection rate (PDR and ADR, respectively) as well as polyp size, morphology and histology characteristics. RESULTS: 262 subjects (168 males, mean age 66.3±4.3 years) were colonoscoped (133 patients with HD-PHL while 129 with SD-OL). PDR and ADR were comparable within the two optical systems. The HD-PHL group resulted in a PDR 55.6% and ADR 43.6%; the SD-OL group had PDR 56.6% and ADR 45.7%. HD-PHL was significantly superior to SD-OL in detection of flat adenomas (18.6% vs 5.2%, p<0.001), but not detection of pedunculated or sessile polyps. Patient comfort, use of sedation and endoscopist perception of procedural difficulty resulted similar despite the use of Scope Guide with SD-OL. CONCLUSION: PDR and ADR were not significantly different between devices. The high-resolution colonoscopy system HD-PHL may improve polyp detection as compared with standard resolution technology in detecting flat adenomas. This advantage may have clinically significant implications for missed lesion rates and post-colonoscopy interval colorectal cancer rates.

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.

Artificial intelligence and computer-aided diagnosis in colonoscopy: current evidence and future directions.

Computer-aided diagnosis offers a promising solution to reduce variation in colonoscopy performance. Pooled miss rates for polyps are as high as 22%, and associated interval colorectal cancers after colonoscopy are of concern. Optical biopsy, whereby in-vivo classification of polyps based on enhanced imaging replaces histopathology, has not been incorporated into routine practice because it is limited by interobserver variability and generally only meets accepted standards in expert settings. Real-time decision-support software has been developed to detect and characterise polyps, and also to offer feedback on the technical quality of inspection. Some of the current algorithms, particularly with recent advances in artificial intelligence techniques, match human expert performance for optical biopsy. In this Review, we summarise the evidence for clinical applications of computer-aided diagnosis and artificial intelligence in colonoscopy.

Current Practices in Ileal Pouch Surveillance for Patients With Ulcerative Colitis: A Multinational, Retrospective Cohort Study.

BACKGROUND AND AIMS: There are no universally accepted guidelines regarding surveillance of ulcerative colitis [UC] patients after restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA]. There also exists a lack of validated quality assurance standards for performing pouchoscopy. To better understand IPAA surveillance practices in the face of this clinical equipoise, we carried out a retrospective cohort study at five inflammatory bowel disease [IBD] referral centres. METHODS: Records of patients who underwent IPAA for UC or IBD unclassified [IBDU] were reviewed, and patients with <1-year follow-up after restoration of intestinal continuity were excluded. Criteria for determining the risk of pouch dysplasia formation were collected as well as the use of pouchoscopy, biopsies, and completeness of reports. RESULTS: We included 272 patients. Median duration of pouch follow-up was 10.5 [3.3-23.6] years; 95/272 [35%] had never undergone pouchoscopy for any indication; 191/272 [70%] had never undergone pouchoscopy with surveillance as the specific indication; and 3/26 [12%] high-risk patients had never undergone pouchoscopy. Two cases of adenocarcinoma were identified, occurring in the rectal cuff of low-risk patients. Patients under the care of surgeons appeared more likely to undergo surveillance, but rates of incomplete reporting were higher among surgeons [78%] than gastroenterologists [54%, p = 0.002]. CONCLUSIONS: We observed wide variation in surveillance of UC/IBDU-IPAA patients. In addition, the rate of neoplasia formation among 'low-risk' patients was higher than may have been expected. We therefore concur with previous recommendations that pouchoscopy be performed at 1 year postoperatively, to refine risk-stratification based on clinical factors alone. Reports should document findings in all regions of the pouch and biopsies should be taken.

A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population.

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD) are particularly common among the Ashkenazi Jewish (AJ) population. Population-specific estimates of familial risk are important for counseling; however, relatively small cohorts of AJ IBD patients have been analyzed for familial risk to date. This study aimed to recruit a new cohort of AJ IBD patients, mainly from the UK, to determine the familial occurrence of disease. METHODS: A total of 864 AJ IBD patients were recruited through advertisements, hospital clinics, and primary care. Participants were interviewed about their Jewish ancestry, disease phenotype, age of diagnosis, and family history of disease. Case notes were reviewed. RESULTS: The 864 probands comprised 506 sporadic and 358 familial cases, the latter with a total of 625 affected relatives. Of the UK cases, 40% had a positive family history with 25% having at least one affected first-degree relative. These percentages were lower among those recruited through hospital clinics and primary care (33% for all relatives and 22% among first-degree relatives). Examining all probands, the relative risk of IBD for offspring, siblings, and parents was 10.5, 7.4, and 4, respectively. Age of diagnosis was significantly lower in familial versus sporadic patients with Crohn's disease. CONCLUSIONS: This study reports familial risk estimates for a significant proportion of the AJ IBD population in the UK. The high rate of a positive family history in this cohort may reflect the greater genetic burden for IBD among AJs. These data are of value in predicting the likelihood of future recurrence of IBD in AJ families.

Incidental finding - the discovery of a bronchopulmonary foregut malformation through investigations for Crohn's disease.

Pulmonary sequestration (PMS) is a rare bronchopulmonary malformation. It has an incidence of between 0.15% to 1.7%. Likewise, cystic adenomatoid malformation (CCAM) is another relatively rare category of a bronchopulmonary malformation with a reported incidence of between 1 in 25,000 to 1 in 35,000. Moreover, a bronchopulmonary malformation with features allied to both of these forms is considered an even rarer entity. In general, bronchopulmonary malformations present with a range of non-specific symptoms. Radiological features can be non-specific yet distinctive when related to clinical features. Ultimately, definitive diagnosis depends upon histological assessment of lung tissue. We present an adult female with radiological features of both pulmonary sequestration and cystic adenomatoid malformation. This was an incidental finding unrelated to the patients presenting complaint. This case highlights the importance of using a structured and systematic approach when interpreting medical imagery.

Monitoring Crohn's disease during anti-TNF-α therapy: validation of the magnetic resonance enterography global score (MEGS) against a combined clinical reference standard.

OBJECTIVES: To assess the ability of magnetic resonance enterography global score (MEGS) to characterise Crohn's disease (CD) response to anti-TNF-α therapy. METHODS: Thirty-six CD patients (median age 26 years, 20 males) commencing anti-TNF-α therapy with concomitant baseline MRI enterography (MRE) were identified retrospectively. Patients' clinical course was followed and correlated with subsequent MREs. Scan order was randomised and MEGS (a global activity score) was applied by two blinded radiologists. A physician's global assessment of the disease activity (remission, mild, moderate or severe) at the time of MRE was assigned. The cohort was divided into clinical responders and non-responders and MEGS compared according to activity status and treatment response. Interobserver agreement was assessed. RESULTS: Median MEGS decreased significantly between baseline and first follow-up in responders (28 versus 6, P < 0.001) but was unchanged in non-responders (26 versus 18, P = 0.28). The median MEGS was significantly lower in clinical remission (9) than in moderate (14) or severe (29) activity (P < 0.001). MEGS correlated significantly with clinical activity (r = 0.53; P < 0.001). Interobserver Bland-Altman limits of agreement (BA LoA) were -19.7 to 18.5. CONCLUSIONS: MEGS decreases significantly in clinical responders to anti-TNF-α therapy but not in non-responders, demonstrates good interobserver agreement and moderate correlation with clinical disease activity. KEY POINTS: • MRI scores of Crohn's activity are used increasingly in clinical practice and therapeutic trials. • Such scores have been advocated as biomarkers of therapeutic response. • MEGS reflects clinical response to anti-TNF-α therapy and the clinical classification of disease activity. • MEGS demonstrates good interobserver agreement.

Incidence and Severity of Prepouch Ileitis: A Distinct Disease Entity or a Manifestation of Refractory Pouchitis?

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the operation of choice for patients with treatment-refractory ulcerative colitis. However, after this intervention, up to 50% of patients develop pouchitis. Moreover, a subgroup will also develop inflammation in the afferent ileum proximal to the pouch, a condition named prepouch ileitis (PI). METHODS: Data on 546 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis were retrospectively collected from 3 tertiary inflammatory bowel disease referral centers in the Netherlands, Belgium, and England. PI was considered present if there was endoscopic and histological inflammation in the afferent limb proximal to the pouch. Crohn's disease was excluded by reviewing the histology of colectomy resection specimens. RESULTS: PI was present in 33/546 (6%) patients and all of these had concurrent pouchitis. One hundred forty-four (26%) patients had pouchitis without PI and 369 (68%) patients did not have inflammatory pouch disease. Of the 33 patients with PI, 6 (18%) received no specific treatment, 9 (27%) responded to antibiotics, and 18 (54%) required escalation in therapy to steroids/immunomodulators or anti-tumor necrosis factor agents. Potent immunosuppressive treatment was required more frequently in patients with PI than those with pouchitis alone. CONCLUSIONS: PI is less common and more treatment refractory than pouchitis alone. Once PI is diagnosed, clinicians should be aware that response to antibiotic therapy is less likely than in pouchitis alone. Immunomodulatory therapy and escalation to anti-tumor necrosis factor agents should be considered early in cases of nonresponse. The suggestion that PI represents misdiagnosed Crohn's disease could not be substantiated in our cohort.

Changes in dynamic contrast-enhanced pharmacokinetic and diffusion-weighted imaging parameters reflect response to anti-TNF therapy in Crohn's disease.

OBJECTIVE: To investigate the effect of tumour necrosis factor (TNF)-α antagonists on MRI dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) parameters in Crohn's disease (CD). METHODS: 42 patients with CD (median age 24 years; 22 females) commencing anti-TNF-α therapy with baseline and follow-up (median 51 weeks) 1.5-T MR enterography (MRE) were retrospectively identified. MRE included DCE (n = 20) and/or multi-b-value DWI (n = 17). Slope of enhancement (SoE), maximum enhancement (ME), area under the time-intensity curve (AUC), Ktrans (transfer constant), ve (fractional volume of the extravascular-extracellular space), apparent diffusion coefficient (ADC) and ADCfast/slow were derived from the most inflamed bowel segments. A physician global assessment of disease activity (remission, mild, moderate and severe) at the time of MRE was assigned, and the cohort was divided into responders and non-responders. Data were compared using Mann-Whitney U test and analysis of variance. RESULTS: Follow-up Ktrans, ME, SoE, AUC and ADCME changed significantly in clinical responders but not in non-responders, baseline {[median [interquartile range (IQR)]: 0.42 (0.38), 1.24 (0.52), 0.18 (0.17), 17.68 (4.70) and 1.56 mm(2) s(-1) (0.39 mm(2) s(-1)) vs follow-up [median (IQR): 0.15 (0.22), 0.50 (0.54), 0.07 (0.1), 14.73 (2.06) and 2.14 mm(2) s(-1) (0.62 mm(2) s(-1)), for responders, respectively, p = 0.006 to p = 0.037}. SoE was higher and ME and AUC lower for patients in remission than for those with severe activity [mean (standard deviation): 0.55 (0.46), 0.49 (0.28), 14.32 (1.32)] vs [0.32 (0.37), 2.21 (2.43) and 23.05 (13.66), respectively p = 0.017 to 0.033]. ADC was significantly higher for patients in remission [2.34 mm(2) s(-1) (0.67 mm(2) s(-1))] than for those with moderate [1.59 mm(2) s(-1) (0.26 mm(2) s(-1))] (p = 0.005) and severe disease [1.63 mm(2) s(-1) (0.21 mm(2) s(-1))] (p = 0.038). CONCLUSION: DCE and DWI parameters change significantly in responders to TNF-α antagonists and are significantly different according to clinically defined disease activity status. ADVANCES IN KNOWLEDGE: DCE and DWI parameters change significantly in responders to TNF-α antagonists in CD, suggesting an effect on bowel wall vascularity.

Mucosal transcriptomics implicates under expression of BRINP3 in the pathogenesis of ulcerative colitis.

BACKGROUND: Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls, taken from macroscopically noninflamed tissue from the terminal ileum and 3 colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. METHODS: Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 patients with UC, 26 healthy controls, and 14 patients with Crohn's disease. Differential gene expression analysis was performed at each tissue location separately, and results were then meta-analyzed. Significantly, differentially expressed genes were validated using quantitative polymerase chain reaction. The location of gene expression within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. RESULTS: Only 4 probes were abnormally expressed throughout the colon in patients with UC with Bone morphogenetic protein/Retinoic acid Inducible Neural-specific 3 (BRINP3) being the most significantly underexpressed. Attenuated expression of BRINP3 in UC was independent of current inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy an average of 22 months later. BRINP3 is localized to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. CONCLUSIONS: Genome-wide expression analysis of noninflamed mucosal biopsies from patients with UC identified BRINP3 as significantly underexpressed throughout the colon in a large subset of patients with UC. Low levels of this gene could predispose or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition.