Whole-body MRI compared with standard pathways for staging metastatic disease in lung and colorectal cancer: the Streamline diagnostic accuracy studies.

BACKGROUND: Whole-body magnetic resonance imaging is advocated as an alternative to standard pathways for staging cancer. OBJECTIVES: The objectives were to compare diagnostic accuracy, efficiency, patient acceptability, observer variability and cost-effectiveness of whole-body magnetic resonance imaging and standard pathways in staging newly diagnosed non-small-cell lung cancer (Streamline L) and colorectal cancer (Streamline C). DESIGN: The design was a prospective multicentre cohort study. SETTING: The setting was 16 NHS hospitals. PARTICIPANTS: Consecutive patients aged ≥ 18 years with histologically proven or suspected colorectal (Streamline C) or non-small-cell lung cancer (Streamline L). INTERVENTIONS: Whole-body magnetic resonance imaging. Standard staging investigations (e.g. computed tomography and positron emission tomography-computed tomography). REFERENCE STANDARD: Consensus panel decision using 12-month follow-up data. MAIN OUTCOME MEASURES: The primary outcome was per-patient sensitivity difference between whole-body magnetic resonance imaging and standard staging pathways for metastasis. Secondary outcomes included differences in specificity, the nature of the first major treatment decision, time and number of tests to complete staging, patient experience and cost-effectiveness. RESULTS: Streamline C - 299 participants were included. Per-patient sensitivity for metastatic disease was 67% (95% confidence interval 56% to 78%) and 63% (95% confidence interval 51% to 74%) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference in sensitivity of 4% (95% confidence interval -5% to 13%; p = 0.51). Specificity was 95% (95% confidence interval 92% to 97%) and 93% (95% confidence interval 90% to 96%) respectively, a difference of 2% (95% confidence interval -2% to 6%). Pathway treatment decisions agreed with the multidisciplinary team treatment decision in 96% and 95% of cases, respectively, a difference of 1% (95% confidence interval -2% to 4%). Time for staging was 8 days (95% confidence interval 6 to 9 days) and 13 days (95% confidence interval 11 to 15 days) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference of 5 days (95% confidence interval 3 to 7 days). The whole-body magnetic resonance imaging pathway was cheaper than the standard staging pathway: £216 (95% confidence interval £211 to £221) versus £285 (95% confidence interval £260 to £310). Streamline L - 187 participants were included. Per-patient sensitivity for metastatic disease was 50% (95% confidence interval 37% to 63%) and 54% (95% confidence interval 41% to 67%) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference in sensitivity of 4% (95% confidence interval -7% to 15%; p = 0.73). Specificity was 93% (95% confidence interval 88% to 96%) and 95% (95% confidence interval 91% to 98%), respectively, a difference of 2% (95% confidence interval -2% to 7%). Pathway treatment decisions agreed with the multidisciplinary team treatment decision in 98% and 99% of cases, respectively, a difference of 1% (95% confidence interval -2% to 4%). Time for staging was 13 days (95% confidence interval 12 to 14 days) and 19 days (95% confidence interval 17 to 21 days) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference of 6 days (95% confidence interval 4 to 8 days). The whole-body magnetic resonance imaging pathway was cheaper than the standard staging pathway: £317 (95% confidence interval £273 to £361) versus £620 (95% confidence interval £574 to £666). Participants generally found whole-body magnetic resonance imaging more burdensome than standard imaging but most participants preferred the whole-body magnetic resonance imaging staging pathway if it reduced time to staging and/or number of tests. LIMITATIONS: Whole-body magnetic resonance imaging was interpreted by practitioners blinded to other clinical data, which may not fully reflect how it is used in clinical practice. CONCLUSIONS: In colorectal and non-small-cell lung cancer, the whole-body magnetic resonance imaging staging pathway has similar accuracy to standard staging pathways, is generally preferred by patients, improves staging efficiency and has lower staging costs. Future work should address the utility of whole-body magnetic resonance imaging for treatment response assessment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43958015 and ISRCTN50436483. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 66. See the NIHR Journals Library website for further project information.

Colorectal and lung cancer are the leading causes of cancer-related deaths in the UK. Optimal treatment depends on accurately defining (or 'staging') the extent of disease, particularly if it has spread to other parts of the body such as the liver. Current staging pathways are complex and rely on a variety of tests that use X-rays, such as computed tomography and positron emission tomography­computed tomography scans. Patients often undergo multiple tests before starting treatment. Alternatively, it is possible to scan the whole body using magnetic resonance imaging without X-rays, and this may be more accurate and reduce the time and number of tests needed before treatment can start. We compared the ability to detect cancer spread, efficiency, patient experience and cost-effectiveness of staging based on whole-body magnetic resonance imaging with the standard NHS pathways in participants newly diagnosed with either lung (187 participants) or colorectal (299 participants) cancer. We found that the whole-body magnetic resonance imaging pathway was as accurate as standard staging pathways and resulted in very similar treatment decisions made by the clinical teams. The whole-body magnetic resonance imaging pathway detected 67% and 50% of participants with cancer spread in colorectal and lung cancer, respectively, compared with 63% and 54%, respectively, for standard staging. However, staging was quicker using whole-body magnetic resonance imaging (by 5 days for colorectal cancer and 6 days for lung cancer) and needed on average one less test to stage colorectal cancer. The whole-body magnetic resonance imaging pathway was also cheaper (costing on average £216 and £317 for colorectal and lung cancer, respectively, compared with £285 and £620, respectively, for standard pathways). Participants generally found whole-body magnetic resonance imaging more burdensome than standard imaging but most preferred the whole-body magnetic resonance imaging pathway if it reduced the time to staging and/or the number of tests. Agreement between different radiology doctors interpreting the same whole-body magnetic resonance imaging scan was moderate for colon cancer and low for lung cancer, emphasising the need for training.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Institute of Health and Research Health Technology Assessment.

Early use of Antibiotics for at Risk CHildren with InfluEnza (ARCHIE): protocol for a double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Influenza and influenza-like illness (ILI) create considerable burden on healthcare resources each winter. Children with pre-existing conditions such as asthma, diabetes mellitus and cerebral palsy are among those at greatest risk of clinical deterioration from influenza/ILI. The Antibiotics for at Risk CHildren with InfluEnza (ARCHIE) trial aims to determine whether early oral treatment with the antibiotic co-amoxiclav reduces the likelihood of reconsultation due to clinical deterioration in these 'at risk' children. METHODS AND ANALYSIS: The ARCHIE trial is a double-blind, parallel, randomised, placebo-controlled trial. 'At risk' children aged 6 months to 12 years inclusive who present within the first 5 days of an ILI episode will be randomised to receive a 5-day course of oral co-amoxiclav 400/57 twice daily or placebo. Randomisation will use a non-deterministic minimisation algorithm to balance age and seasonal influenza vaccination status.To detect respiratory virus infections, a nasal swab will be obtained from each participant before commencing study medication. To identify carriage of potential bacterial respiratory pathogens, we will also obtain a throat swab where possible.The primary outcome is reconsultation in any healthcare setting due to clinical deterioration within 28 days of randomisation. We will analyse this outcome using log-binomial regression model adjusted for region, age and seasonal influenza vaccination status.Secondary outcomes include duration of fever, duration of symptoms and adverse events. Continuous outcomes will be compared using regression analysis (or equivalent non-parametric method for non-normal data) adjusting for minimisation variables. Binary outcomes will be compared using χ2/Fisher's exact test and log-binomial regression. ETHICS: The ARCHIE trial has been reviewed and approved by the North West-Liverpool East Research Ethics Committee, Health Research Authority and Medicines and Healthcare Products Regulatory Agency. Our findings will be published in peer-reviewed journals and disseminated via our study website (www.archiestudy.com) and links with relevant charities. TRIAL REGISTRATION NUMBERS: ISRCTN 70714783; Pre-results. EudraCT 2013-002822-21; Pre-results.

A proposed framework for developing quality assessment tools.

BACKGROUND: Assessment of the quality of included studies is an essential component of any systematic review. A formal quality assessment is facilitated by using a structured tool. There are currently no guidelines available for researchers wanting to develop a new quality assessment tool. METHODS: This paper provides a framework for developing quality assessment tools based on our experiences of developing a variety of quality assessment tools for studies of differing designs over the last 14 years. We have also drawn on experience from the work of the EQUATOR Network in producing guidance for developing reporting guidelines. RESULTS: We do not recommend a single 'best' approach. Instead, we provide a general framework with suggestions as to how the different stages can be approached. Our proposed framework is based around three key stages: initial steps, tool development and dissemination. CONCLUSIONS: We recommend that anyone who would like to develop a new quality assessment tool follow the stages outlined in this paper. We hope that our proposed framework will increase the number of tools developed using robust methods.

Prognostic models in acute pulmonary embolism: a systematic review and meta-analysis.

OBJECTIVE: To review the evidence for existing prognostic models in acute pulmonary embolism (PE) and determine how valid and useful they are for predicting patient outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: OVID MEDLINE and EMBASE, and The Cochrane Library from inception to July 2014, and sources of grey literature. ELIGIBILITY CRITERIA: Studies aiming at constructing, validating, updating or studying the impact of prognostic models to predict all-cause death, PE-related death or venous thromboembolic events up to a 3-month follow-up in patients with an acute symptomatic PE. DATA EXTRACTION: Study characteristics and study quality using prognostic criteria. Studies were selected and data extracted by 2 reviewers. DATA ANALYSIS: Summary estimates (95% CI) for proportion of risk groups and event rates within risk groups, and accuracy. RESULTS: We included 71 studies (44,298 patients). Among them, 17 were model construction studies specific to PE prognosis. The most validated models were the PE Severity Index (PESI) and its simplified version (sPESI). The overall 30-day mortality rate was 2.3% (1.7% to 2.9%) in the low-risk group and 11.4% (9.9% to 13.1%) in the high-risk group for PESI (9 studies), and 1.5% (0.9% to 2.5%) in the low-risk group and 10.7% (8.8% to12.9%) in the high-risk group for sPESI (11 studies). PESI has proved clinically useful in an impact study. Shifting the cut-off or using novel and updated models specifically developed for normotensive PE improves the ability for identifying patients at lower risk for early death or adverse outcome (0.5-1%) and those at higher risk (up to 20-29% of event rate). CONCLUSIONS: We provide evidence-based information about the validity and utility of the existing prognostic models in acute PE that may be helpful for identifying patients at low risk. Novel models seem attractive for the high-risk normotensive PE but need to be externally validated then be assessed in impact studies.

Assessment of the Incremental Benefit of Computer-Aided Detection (CAD) for Interpretation of CT Colonography by Experienced and Inexperienced Readers.

OBJECTIVES: To quantify the incremental benefit of computer-assisted-detection (CAD) for polyps, for inexperienced readers versus experienced readers of CT colonography. METHODS: 10 inexperienced and 16 experienced radiologists interpreted 102 colonography studies unassisted and with CAD utilised in a concurrent paradigm. They indicated any polyps detected on a study sheet. Readers' interpretations were compared against a ground-truth reference standard: 46 studies were normal and 56 had at least one polyp (132 polyps in total). The primary study outcome was the difference in CAD net benefit (a combination of change in sensitivity and change in specificity with CAD, weighted towards sensitivity) for detection of patients with polyps. RESULTS: Inexperienced readers' per-patient sensitivity rose from 39.1% to 53.2% with CAD and specificity fell from 94.1% to 88.0%, both statistically significant. Experienced readers' sensitivity rose from 57.5% to 62.1% and specificity fell from 91.0% to 88.3%, both non-significant. Net benefit with CAD assistance was significant for inexperienced readers but not for experienced readers: 11.2% (95%CI 3.1% to 18.9%) versus 3.2% (95%CI -1.9% to 8.3%) respectively. CONCLUSIONS: Concurrent CAD resulted in a significant net benefit when used by inexperienced readers to identify patients with polyps by CT colonography. The net benefit was nearly four times the magnitude of that observed for experienced readers. Experienced readers did not benefit significantly from concurrent CAD.

METRIC (MREnterography or ulTRasound in Crohn's disease): a study protocol for a multicentre, non-randomised, single-arm, prospective comparison study of magnetic resonance enterography and small bowel ultrasound compared to a reference standard in those aged 16 and over.

BACKGROUND: Crohn's disease (CD) is a lifelong, relapsing and remitting inflammatory condition of the intestine. Medical imaging is crucial for diagnosis, phenotyping, activity assessment and detecting complications. Diverse small bowel imaging tests are available but a standard algorithm for deployment is lacking. Many hospitals employ tests that impart ionising radiation, of particular concern to this young patient population. Magnetic resonance enterography (MRE) and small bowel ultrasound (USS) are attractive options, as they do not use ionising radiation. However, their comparative diagnostic accuracy has not been compared in large head to head trials. METRIC aims to compare the diagnostic efficacy, therapeutic impact and cost effectiveness of MRE and USS in newly diagnosed and relapsing CD. METHODS: METRIC (ISRCTN03982913) is a multicentre, non-randomised, single-arm, prospective comparison study. Two patient cohorts will be recruited; those newly diagnosed with CD, and those with suspected relapse. Both will undergo MRE and USS in addition to other imaging tests performed as part of clinical care. Strict blinding protocols will be enforced for those interpreting MRE and USS. The Harvey Bradshaw index, C-reactive protein and faecal calprotectin will be collected at recruitment and 3 months, and patient experience will be assessed via questionnaires. A multidisciplinary consensus panel will assess all available clinical and imaging data up to 6 months after recruitment of each patient and will define the standard of reference for the presence, localisation and activity of disease against which the diagnostic accuracy of MRE and USS will be judged. Diagnostic impact of MRE and USS will be evaluated and cost effectiveness will be assessed. The primary outcome measure is the difference in per patient sensitivity between MRE and USS for the correct identification and localisation of small bowel CD. DISCUSSION: The trial is open at 5 centres with 46 patients recruited. We highlight the importance of stringent blinding protocols in order to delineate the true diagnostic accuracy of both imaging tests and discuss the difficulties of diagnostic accuracy studies in the absence of a single standard of reference, describing our approach utilising a consensus panel whilst minimising incorporation bias. TRIAL REGISTRATION: METRIC - ISRCTN03982913 - 05.11.13.

Resource implications of expanding the use of donation after circulatory determination of death in liver transplantation.

In the United Kingdom, liver transplantation using donation after circulatory determination of death (DCDD) organs has increased steadily over the last few years and now accounts for 20% of UK transplant activity. The procurement of DCDD livers is actively promoted as a means of increasing the donor pool and bridging the evolving disparity between the wait-list length and the number of transplants performed. The objective of this retrospective study of a cohort of patients who were matched for age, liver disease etiology, and Model for End-Stage Liver Disease score was to determine whether differences in perioperative costs and resource utilization are associated with the use of such organs. Our results showed an increased prevalence of reperfusion syndrome in the DCDD cohort (P < 0.001), a prolonged heparin effect (P = 0.01), a greater incidence of hyperfibrinolysis (P = 0.002), longer periods of postoperative ventilator use (P = 0.03) and vasopressor support (P = 0.002), and a prolonged length of stay in the intensive therapy unit (ITU; P = 0.02). The peak posttransplant aspartate aminotransferase level was higher in the DCDD group (P = 0.007), and there was significantly more graft failure at 12 months (P = 0.03). In conclusion, we have demonstrated different perioperative and early postoperative courses for DCDD and donation after brain death (DBD) liver transplants. The overall quality of DCDD grafts is poorer; as a result, the length of the ITU stay and the need for multiorgan support are increased, and this has significant financial and resource implications. We believe that these implications require a careful real-life consideration of benefits. It is essential for DCDD not to be seen as a like-for-like alternative to DBD and for every effort to be continued to be made to increase the number of donations from brain-dead patients as a first resort.

QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.

Human papillomavirus testing by self-sampling: assessment of accuracy in an unsupervised clinical setting.

OBJECTIVES: To compare the performance and acceptability of unsupervised self-sampling with clinician sampling for high-risk human papillomavirus (HPV) types for the first time in a UK screening setting. SETTING: Nine hundred and twenty women, from two demographically different centres, attending for routine cervical smear testing. METHODS: Women performed an unsupervised HPV self-test. Immediately afterwards, a doctor or nurse took an HPV test and cervical smear. Women with an abnormality on any test were offered colposcopy. RESULTS: Twenty-one high-grade and 39 low-grade cervical intraepithelial neoplasias (CINs) were detected. The sensitivity for high-grade disease (CIN2+) for the self HPV test was 81% (95% confidence interval [CI] 60-92), clinician HPV test 100% (95% CI 85-100), cytology 81% (95% CI 60-92). The sensitivity of both HPV tests to detect high- and low-grade cervical neoplasia was much higher than that of cytology (self-test 77% [95%CI 65-86], clinician test 80% [95% CI 68-88], cytology 48% [95% CI 36-61]). For both high-grade alone, and high and low grades together, the specificity was significantly higher for cytology (greater than 95%) than either HPV test (between 82% and 87%). The self-test proved highly acceptable to women and they reported that the instructions were easy to understand irrespective of educational level. CONCLUSIONS: Our results suggest that it would be reasonable to offer HPV self-testing to women who are reluctant to attend for cervical smears. This approach should now be directly evaluated among women who have been non-attenders in a cervical screening programme.

Computed tomographic colonography: assessment of radiologist performance with and without computer-aided detection.

BACKGROUND & AIMS: In isolation, computer-aided detection (CAD) for computed tomographic (CT) colonography is as effective as optical colonoscopy for detection of significant adenomas. However, the unavoidable interaction between CAD and the reader has not been addressed. METHODS: Ten readers trained in CT but without special expertise in colonography interpreted CT colonography images of 107 patients (60 with 142 polyps), first without CAD and then with CAD after temporal separation of 2 months. Per-patient and per-polyp detection were determined by comparing responses with known patient status. RESULTS: With CAD, 41 (68%; 95% confidence interval [CI], 55%-80%) of the 60 patients with polyps were identified more frequently by readers. Per-patient sensitivity increased significantly in 70% of readers, while specificity dropped significantly in only one. Polyp detection increased significantly with CAD; on average, 12 more polyps were detected by each reader (9.1%, 95% CI, 5.2%-12.8%). Small- (< or =5 mm) and medium-sized (6-9 mm) polyps were significantly more likely to be detected when prompted correctly by CAD. However, overall performance was relatively poor; even with CAD, on average readers detected only 10 polyps (51.0%) > or =10 mm and 24 (38.2%) > or =6 mm. Interpretation time was shortened significantly with CAD: by 1.9 minutes (95% CI, 1.4-2.4 minutes) for patients with polyps and by 2.9 minutes (95% CI, 2.5-3.3 minutes) for patients without. Overall, 9 readers (90%) benefited significantly from CAD, either by increased sensitivity and/or by reduced interpretation time. CONCLUSIONS: CAD for CT colonography significantly increases per-patient and per-polyp detection and significantly reduces interpretation times but cannot substitute for adequate training.