The cost-effectiveness of wound-edge protection devices compared to standard care in reducing surgical site infection after laparotomy: an economic evaluation alongside the ROSSINI trial.

BACKGROUND: Wound-edge protection devices (WEPDs) have been used in surgery for more than 40 years to reduce surgical site infection (SSI). No economic evaluation of WEPDs against any comparator has ever been conducted. The aim of the paper was to assess whether WEPDs are cost-effective in reducing SSI compared to standard care alone in the United Kingdom. METHODS AND FINDINGS: An economic evaluation was conducted alongside the ROSSINI trial. The study perspective was that of the UK National Health Service and the time horizon was 30 days post-operatively. The study was conducted in 21 UK hospitals. 760 patients undergoing laparotomy were randomised to either WEPD or standard care and 735 were included in the primary analysis. The main economic outcome was cost-effectiveness based on incremental cost (£) per quality adjusted life year (QALY) gained. Patients in the WEPD arm accessed health care worth £5,420 on average and gained 0.02131 QALYs, compared to £5,130 and 0.02133 QALYs gained in the standard care arm. The WEPD strategy was more costly and equally effective compared to standard care, but there was significant uncertainty around incremental costs and QALYs. The findings were robust to a range of sensitivity analyses. CONCLUSIONS: There is no evidence to suggest that WEPDs can be considered a cost effective device to reduce SSI. Their continued use is a waste of limited health care resources

Discovery and Validation of Methylation Biomarkers for Ulcerative Colitis Associated Neoplasia

Abstract Background and aims Ulcerative colitis (UC) is associated with a higher background risk of dysplasia and/or neoplasia due to chronic inflammation. There exist few biomarkers for identification of patients with dysplasia, and targeted biopsies in this group of patients are inaccurate in reliably identifying dysplasia. We aimed to examine the epigenome of UC dysplasia and to identify and validate potential biomarkers Methods Colonic samples from patients with UC-associated dysplasia or neoplasia underwent epigenome-wide analysis on the Illumina 450K methylation array. Markers were validated by bisulphite pyrosequencing on a secondary validation cohort and accuracy calculated using logistic regression and receiver-operator curves. Results Twelve samples from 4 patients underwent methylation array analysis and 6 markers (GNG7, VAV3, KIF5C, PIK3R5, TUBB6, and ZNF583) were taken forward for secondary validation on a cohort of 71 colonic biopsy samples consisting of normal uninflamed mucosa from control patients, acute and chronic colitis, “field” mucosa in patients with dysplasia/neoplasia, dysplasia, and neoplasia. Methylation in the beta-tubulin TUBB6 correlated with the presence of dysplasia (P &amp;lt; 0.0001) and accurately discriminated between dysplasia and nondysplastic tissue, even in the apparently normal field mucosa downstream from dysplastic lesions (AUC 0.84, 95% CI 0.81–0.87). Conclusions Methylation in TUBB6 is a potential biomarker for UC- associated dysplasia. Further validation is needed and is ongoing as part of the ENDCAP-C study. </jats:sec

Impact of wound edge protection devices on surgical site infection after laparotomy: multicentre randomised controlled trial (ROSSINI Trial).

OBJECTIVE: To determine the clinical effectiveness of wound edge protection devices in reducing surgical site infection after abdominal surgery. DESIGN: Multicentre observer blinded randomised controlled trial. PARTICIPANTS: Patients undergoing laparotomy at 21 UK hospitals. INTERVENTIONS: Standard care or the use of a wound edge protection device during surgery. MAIN OUTCOME MEASURES: Surgical site infection within 30 days of surgery, assessed by blinded clinicians at seven and 30 days and by patient's self report for the intervening period. Secondary outcomes included quality of life, duration of stay in hospital, and the effect of characteristics of the patient and operation on the efficacy of the device. RESULTS: 760 patients were enrolled with 382 patients assigned to the device group and 378 to the control group. Six patients in the device group and five in the control group did not undergo laparotomy. Fourteen patients, seven in each group, were lost to follow-up. A total of 184 patients experienced surgical site infection within 30 days of surgery, 91/369 (24.7%) in the device group and 93/366 (25.4%) in the control group (odds ratio 0.97, 95% confidence interval 0.69 to 1.36; P=0.85). This lack of benefit was consistent across wound assessments performed by clinicians and those reported by patients and across all secondary outcomes. In the secondary analyses no subgroup could be identified in which there was evidence of clinical benefit associated with use of the device. CONCLUSIONS: Wound edge protection devices do not reduce the rate of surgical site infection in patients undergoing laparotomy, and therefore their routine use for this role cannot be recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 40402832

Design of a multicentre randomized trial to evaluate CT colonography versus colonoscopy or barium enema for diagnosis of colonic cancer in older symptomatic patients: The SIGGAR study

Background and Aims: The standard whole-colon tests used to investigate patients with symptoms of colorectal cancer are barium enema and colonoscopy. Colonoscopy is the reference test but is technically difficult, resource intensive, and associated with adverse events, especially in the elderly. Barium enema is safer but has reduced sensitivity for cancer. CT colonography ("virtual colonoscopy") is a newer alternative that may combine high sensitivity for cancer with safety and patient acceptability. The SIGGAR trial aims to determine the diagnostic efficacy, acceptability, and economic costs associated with this new technology.Methods: The SIGGAR trial is a multi-centre randomised comparison of CT colonography versus standard investigation ( barium enema or colonoscopy), the latter determined by individual clinician preference. Diagnostic efficacy for colorectal cancer and colonic polyps measuring 1 cm or larger will be determined, as will the physical and psychological morbidity associated with each diagnostic test, the latter via questionnaires developed from qualitative interviews. The economic costs of making or excluding a diagnosis will be determined for each diagnostic test and information from the trial and other data from the literature will be used to populate models framed to summarise the health effects and costs of alternative approaches to detection of significant colonic neoplasia in patients of different ages, prior risks and preferences. This analysis will focus particularly on the frequency, clinical relevance, costs, and psychological and physical morbidity associated with detection of extracolonic lesions by CT colonography.Results: Recruitment commenced in March 2004 and at the time of writing ( July 2007) 5025 patients have been randomised. A lower than expected prevalence of end-points in the barium enema sub-trial has caused an increase in sample size. In addition to the study protocol, we describe our approach to recruitment, notably the benefits of extensive piloting, the use of a sham-randomisation procedure, which was employed to determine whether centres interested in participating were likely to be effective in practice, and the provision of funding for dedicated sessions for a research nurse at each centre to devote specifically to this trial

Loss of Expression and Promoter Methylation of SLIT2 Are Associated with Sessile Serrated Adenoma Formation.

Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carry out a whole-genome loss of heterozygosity analysis, followed by targeted promoter methylation and expression analysis to identify potential pathways in serrated adenomas. An initial panel of 9 sessile serrated adenomas (SSA) and one TSA were analysed using Illumina Goldengate HumanLinkage panel arrays to ascertain regions of loss of heterozygosity. This was verified via molecular inversion probe analysis and microsatellite analysis of a further 32 samples. Methylation analysis of genes of interest was carried out using methylation specific PCR (verified by pyrosequencing) and immunohistochemistry used to correlate loss of expression of genes of interest. All experiments used adenoma samples and normal tissue samples as control. SSA samples were found on whole-genome analysis to have consistent loss of heterozygosity at 4p15.1–4p15.31, which was not found in the sole TSA, adenomas, or normal tissues. Genes of interest in this region were PDCH7 and SLIT2, and combined MSP/IHC analysis of these genes revealed significant loss of SLIT2 expression associated with promoter methylation of SLIT2. Loss of expression of SLIT2 by promoter hypermethylation and loss of heterozygosity events is significantly associated with serrated adenoma development, and SLIT2 may represent a epimutated tumour suppressor gene according to the Knudson “two hit” hypothesis

Fully transformer-based biomarker prediction from colorectal cancer histology: a large-scale multicentric study

Background: Deep learning (DL) can extract predictive and prognostic biomarkers from routine pathology slides in colorectal cancer. For example, a DL test for the diagnosis of microsatellite instability (MSI) in CRC has been approved in 2022. Current approaches rely on convolutional neural networks (CNNs). Transformer networks are outperforming CNNs and are replacing them in many applications, but have not been used for biomarker prediction in cancer at a large scale. In addition, most DL approaches have been trained on small patient cohorts, which limits their clinical utility. Methods: In this study, we developed a new fully transformer-based pipeline for end-to-end biomarker prediction from pathology slides. We combine a pre-trained transformer encoder and a transformer network for patch aggregation, capable of yielding single and multi-target prediction at patient level. We train our pipeline on over 9,000 patients from 10 colorectal cancer cohorts. Results: A fully transformer-based approach massively improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training on a large multicenter cohort, we achieve a sensitivity of 0.97 with a negative predictive value of 0.99 for MSI prediction on surgical resection specimens. We demonstrate for the first time that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem. Interpretation: A fully transformer-based end-to-end pipeline trained on thousands of pathology slides yields clinical-grade performance for biomarker prediction on surgical resections and biopsies. Our new methods are freely available under an open source license

Interventions in randomised controlled trials in surgery: issues to consider during trial design

Until recently, insufficient attention has been paid to the fact that surgical interventions are complex. This complexity has several implications, including the way in which surgical interventions are described and delivered in trials. In order for surgeons to adopt trial findings, interventions need to be described in sufficient detail to enable accurate replication; however, it may be permissible to allow some aspects to be delivered according to local practice. Accumulating work in this area has identified the need for general guidance on the design of surgical interventions in trial protocols and reports. Key issues to consider when designing surgical interventions include the identification of each surgical intervention and their components, who will deliver the interventions, and where and how the interventions will be standardised and monitored during the trial. The trial design (pragmatic and explanatory), comparator and stage of innovation may also influence the extent of detail required. Thoughtful consideration of surgical interventions in this way may help with the interpretation of trial results and the adoption of successful interventions into clinical practice

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study

Background: Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard “core” set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. Methods and Findings: The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). Conclusion: This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice