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.
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.
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.
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.
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.
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.
IntroductionCrohn’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 analysisWe 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 disseminationThis 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 numberISRCTN76899103.
Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), especially in severe, steroid-refractory disease. However, its role in steroid-refractoriness remains unknown. Our goals ...were to evaluate the prevalence of CMV disease in UC, the best diagnostic strategy, and the influence of disease activity and/or treatment in its development.
Prospective, observational study including 114 subjects with active UC requiring intravenous steroids, steroid-refractory UC, inactive UC on mesalamine, inactive UC on azathioprine, and healthy controls. CMV antibodies, pp65-antigenemia, and rectal biopsies for hematoxylin and eosin staining, immunohistochemistry, and CMV-pp67 mRNA were performed. These procedures were repeated after medical treatment only in patients with active UC. CMV disease was defined by the presence of inclusion bodies and/or positive immunohistochemistry in colonic biopsies.
CMV disease was found in 6 steroid-refractory, CMV-IgG-positive UC patients but not among controls, inactive UC, or steroid-responding UC patients. In 5 out of the 6 patients, CMV disease was diagnosed after 7-10 days on cyclosporine.
CMV disease in UC only affects seropositive, steroid-refractory UC patients. Steroid/cyclosporine treatment together with disease activity may predispose to latent colonic CMV reactivation. The impact of antiviral therapy on the clinical outcome of these patients remains to be elucidated.
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).
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.
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).
DCE and DWI parameters change significantly in responders to TNF-α antagonists and are significantly different according to clinically defined disease activity status.
DCE and DWI parameters change significantly in responders to TNF-α antagonists in CD, suggesting an effect on bowel wall vascularity.
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