Performance and evaluation in computed tomographic colonography screening: protocol for a cluster randomised trial

Background: Colorectal cancer (CRC) is a common, important healthcare priority and improving patient outcome relies on early diagnosis. Colonoscopy and computed tomographic colonography (CTC) are commonly-used diagnostic tests. Although colonoscopists are highly regulated and must be accredited, no analogous process exists for CTC. There are currently no universally accepted radiologist performance indicators for CTC, and lack of regulatory oversight may lead to variability in quality and lower neoplasia detection rates. This study aims to determine whether a structured educational training and feedback programme can improve radiologist interpretation accuracy. / Methods: NHS England CTC reporting radiologists will be cluster randomised to either an intervention (one-day individualised training and assessment with feedback) or control (assessment with no training or feedback) arm. Each cluster represents radiologists reporting CTC in a single NHS site. Both the intervention and control arm will undertake four CTC assessments at baseline, 1-month (after training; intervention arm or enrolment; control arm), 6- and 12 months to assess their detection of colorectal cancer (CRC) and 6mm+ polyps. The primary outcome will be difference in sensitivity at the 1-month test between arms. Secondary outcomes will include sensitivity at 6 and 12 months and radiologist characteristics associated with improved performance. Multilevel logistic regression will be used to analyse per-polyp and per-case sensitivity. Local ethical and Health Research Authority approval have been obtained. / Discussion: Lack of infrastructure to ensure that CTC radiologists can report adequately and lack of consensus regarding appropriate quality metrics may lead to variability in performance. Our provision of a structured education programme with feedback will evaluate the impact of individualised training and identify the factors related to improved radiologist performance in CTC reporting. An improvement in performance could lead to increased neoplasia detection and better patient outcome. / Registration: Clinical Trials (ClinicalTrials.gov Identifier: NCT02892721); available from: https://clinicaltrials.gov/ct2/show/NCT02892721. NIHR Clinical Research Network (CPMS ID 32293)

Post-imaging colorectal cancer or interval cancer rates after computed tomographic colonography: A systematic review and meta-analysis

Background: CT colonography (CTC) is highly sensitive for colorectal cancer, but “interval” or postimaging colorectal cancer (PICRC) rates (diagnosis of cancer after initial negative CTC) are unknown, as are their underlying causes. Methods: We conducted a systematic review and meta-analysis of post-CTC PICRC rates and causes by searching MEDLINE, EMBASE and the Cochrane Register. We included randomised, cohort, cross-sectional or case-control studies published Jan 1994-Feb 2017, using CTC performed according to international consensus standards with aim of detecting cancer or polyps, and reporting PICRC rates or sufficient data to allow their calculation. Two independent reviewers extracted data from the study reports. We used random-effects meta-analysis to estimate pooled PICRC rates, expressed using (a) total number of cancers and (b) total number of CTC scans as denominators, and (c) per 1000 person-years. Primary study authors provided details of retrospective CTC image review and causes for each PICRC. The study is registered (PROSPERO:CRD42016046838). Findings: 2977 articles were screened and 12 analysed. These reported 19,867 patients (18-96 years; of 11,590 with sex data available, 6532 (56·4%) female) from March 2002-May 2015. At mean 34 months’ follow-up (range: 3 to 128·4 months), CTC detected 643 cancers and 29 PICRCs were diagnosed. The pooled PICRC rate was 4·42 PICRCs/100 cancers detected; 95%CI 3·03-6·42, corresponding to 1·61 PICRCs/1000 CTCs (95%CI 1·11-2·33) or 0·64 PICRCs/1000 person-years (95%CI 0·44-0·92). Heterogeneity was low (I2 =0%). Over half (17/28, 61%) of PICRCs were due to perceptual error and visible in retrospect. Interpretation: The 3-year PICRC rate post-CTC is 4·4%, or 0·64 per 1000 person-years, towards the lower end of range reported for colonoscopy. Most arise from perceptual errors. Radiologist training and quality assurance may help reduce PICRC rates. Funding: St Mark’s Hospital Foundation and the UCL/UCLH Biomedical Research Centre

Diagnostic accuracy for the extent and activity of newly diagnosed and relapsed Crohn’s disease: a multicentre prospective comparison of magnetic resonance enterography and small bowel ultrasound –The METRIC Trial

Background Magnetic resonance enterography (MRE) and ultrasound (US) are used to image Crohn’s disease, but comparative accuracy for disease extent and activity is not known with certainty. We undertook a prospective multicentre cohort trial to address this Methods We recruited from 8 UK hospitals. Eligible patients were 16 years or older, newly diagnosed with Crohn’s disease, or had established disease with suspected relapse. Consecutive patients underwent MRE and US in addition to standard investigations. Discrepancy between MRE and US for small bowel (SB) disease presence triggered an additional investigation, if not already available. The primary outcome was difference in per patient sensitivity for SB disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). Accuracy for SB and colonic disease presence and activity were secondary outcomes. The trial is completed (ISRCTN03982913). Findings 284 patients completed the trial (133 new diagnosis, 151 relapse). MRE sensitivity (n=233) for SB disease extent (80% [95%CI 72 to 86]) and presence (97% [91 to 99]) were significantly greater than US (70% [62 to 78], 92% [84 to 96]); a 10% (1 to 18; p=0.027), and 5% (1 to 9), difference respectively. MRE specificity for SB disease extent (95% [85 to 98]) was significantly greater than US (81% [64 to 91]). Sensitivity for active SB disease was significantly greater for MRE than US (96% [92 to 99] vs. 90% [82 to 95]), difference 6% (2 to 11). Overall, there were no significant accuracy differences for colonic disease presence. Accuracy in newly diagnosed and relapse patients was similar, although US had significantly greater sensitivity for colonic disease than MRE in newly diagnosed patients (67% [49 to 81) vs. 47% [31 to 64]), difference 20% (1 to 39). There were no serious adverse events. Interpretation MRE has higher diagnostic accuracy for the extent and activity of SB Crohn’s disease than US when tested in a prospective multi centre cohort trial setting

Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn's disease (METRIC): a multicentre trial

Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue. We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed. 284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72-86]) and presence (97% [91-99]) were significantly greater than that of ultrasound (70% [62-78] for disease extent, 92% [84-96] for disease presence); a 10% (95% CI 1-18; p=0·027) difference for extent, and 5% (1-9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85-98]) was significantly greater than that of ultrasound (81% [64-91]); a difference of 14% (1-27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86-99) with MRE and 84% (65-94) with ultrasound (difference 12% [0-25]; p=0·054). There were no serious adverse events. Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly. National Institute of Health and Research Health Technology Assessment. [Abstract copyright: Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Magnetic resonance enterography compared with ultrasonography in newly diagnosed and relapsing Crohn's disease patients: the METRIC diagnostic accuracy study

Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared. To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease. Prospective multicentre cohort study. Eight NHS hospitals. Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse. Magnetic resonance enterography and ultrasonography. The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness. Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%;  = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests. Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice. Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease. Current Controlled Trials ISRCTN03982913. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 42. See the NIHR Journals Library website for further project information

Extrinsic Fluorescent Dyes as Tools for Protein Characterization

Noncovalent, extrinsic fluorescent dyes are applied in various fields of protein analysis, e.g. to characterize folding intermediates, measure surface hydrophobicity, and detect aggregation or fibrillation. The main underlying mechanisms, which explain the fluorescence properties of many extrinsic dyes, are solvent relaxation processes and (twisted) intramolecular charge transfer reactions, which are affected by the environment and by interactions of the dyes with proteins. In recent time, the use of extrinsic fluorescent dyes such as ANS, Bis-ANS, Nile Red, Thioflavin T and others has increased, because of their versatility, sensitivity and suitability for high-throughput screening. The intention of this review is to give an overview of available extrinsic dyes, explain their spectral properties, and show illustrative examples of their various applications in protein characterization

Prevalence and risk factors for post-investigation colorectal cancer (“interval cancer”) after computed tomographic colonography: protocol for a systematic review

Background Colorectal cancer (CRC) is a common and important disease. There are different tests for diagnosis, one of which is computed tomographic colonography (CTC). No test is perfect, and patients with normal CTC may subsequently develop CRC (either because it was overlooked originally, or because it has developed in the interim). This is termed post-investigation colorectal cancer (PICRC) or “interval cancer”. How frequently this occurs after CTC is not known. The purpose of this systematic review and meta-analysis is to use the primary literature to estimate the PICRC rate after CTC, and explore associated factors. Methods Primary studies reporting post-investigation colorectal cancer (PICRC) rates after CTC will be identified from PubMed, Embase and Cochrane Register of Controlled Trials databases. Peer-reviewed studies published after 1994 (the year CTC was introduced) will be included and the rate of PICRC within 36 months of CTC recorded. Data will be extracted from selected studies for a random effects meta-analysis. Heterogeneity, risk of bias and publication bias will be assessed, and exploratory analysis will examine factors associated with higher PICRC rates in the literature. Conclusion PICRC rates are the ultimate benchmark of diagnostic quality for colonic investigations. This systematic review and meta-analysis will identify and synthesise evidence to determine PICRC rates after CTC and explore factors that may contribute to higher rates

Post-imaging colorectal cancer or interval cancer rates after CT colonography: a systematic review and meta-analysis

Background CT colonography is highly sensitive for colorectal cancer, but interval or post-imaging colorectal cancer rates (diagnosis of cancer after initial negative CT colonography) are unknown, as are their underlying causes. We did a systematic review and meta-analysis of post-CT colonography and post-imaging colorectal cancer rates and causes to address this gap in understanding. Methods We systematically searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. We included randomised, cohort, cross-sectional, or case-control studies published between Jan 1, 1994, and Feb 28, 2017, using CT colonography done according to international consensus standards with the aim of detecting cancer or polyps, and reporting post-imaging colorectal cancer rates or sufficient data to allow their calculation. We excluded studies in which all CT colonographies were done because of incomplete colonoscopy or if CT colonography was done with knowledge of colonoscopy findings. We contacted authors of component studies for additional data where necessary for retrospective CT colonography image review and causes for each post-imaging colorectal cancer. Two independent reviewers extracted data from the study reports. Our primary outcome was prevalence of post-imaging colorectal cancer 36 months after CT colonography. We used random-effects meta-analysis to estimate pooled post-imaging colorectal cancer rates, expressed using the total number of cancers and total number of CT colonographies as denominators, and per 1000 person-years. This study is registered with PROSPERO, number CRD42016042437. Findings 2977 articles were screened and 12 studies were eligible for analysis. These studies reported data for 19 867 patients (aged 18–96 years; of 11 590 with sex data available, 6532 [56%] were female) between March, 2002, and May, 2015. At a mean of 34 months' follow-up (range 3–128·4 months), CT colonography detected 643 colorectal cancers. 29 post-imaging colorectal cancers were subsequently diagnosed. The pooled post-imaging colorectal cancer rate was 4·42 (95% CI 3·03–6·42) per 100 cancers detected, corresponding to 1·61 (1·11–2·33) post-imaging colorectal cancers per 1000 CT colonographies or 0·64 (0·44–0·92) post-imaging colorectal cancers per 1000 person-years. Heterogeneity was low (I2=0%). 17 (61%) of 28 post-imaging colorectal cancers were attributable to perceptual error and were visible in retrospect. Interpretation CT colonography does not lead to an excess of post-test cancers relative to colonoscopy within 3–5 years, and the low 5-year post-imaging colorectal cancer rate confirms that the recommended screening interval of 5 years is safe. Since most post-imaging colorectal cancers arise from perceptual errors, radiologist training and quality assurance could help to reduce post-imaging colorectal cancer rates

Potential risks associated with the use of ionizing radiation for imaging and treatment of colorectal cancer in Lynch syndrome patients

The aim of this review is to investigate the literature pertaining to the potential risks of low-dose ionizing radiation to Lynch syndrome patients by use of computed tomography (CT), either diagnostic CT colonography (CTC), standard staging CT or CT surveillance. Furthermore, this review explores the potential risks of using radiotherapy for treatment of rectal cancer in these patients. No data or longitudinal observational studies of the impact of radiation exposure on humans with Lynch syndrome were identified. Limited experimental studies utilizing cell lines and primary cells exposed to both low and high radiation doses have been carried out to help determine radio-sensitivity associated with DNA mismatch repair gene deficiency, the defining feature of Lynch syndrome. On balance, these studies suggest that mismatch repair deficient cells may be relatively radio-resistant (particularly for low dose rate exposures) with higher mutation rates, albeit no firm conclusions can be drawn. Mouse model studies, though, showed an increased risk of developing colorectal tumors in mismatch repair deficient mice exposed to radiation doses around 2 Gy. With appropriate ethical approval, further studies investigating radiation risks associated with CT imaging and radiotherapy relevant doses using cells/tissues derived from confirmed Lynch patients or genetically modified animal models are urgently required for future clinical guidance