Obesity is associated with increased risk of at least 13 cancer types. Evidence from bariatric surgery cohorts and some behavioural intervention trials supports the notion that weight loss can prevent obesity-related cancers. The introduction of glucagon-like peptide (GLP)-1 agonist drugs has rapidly revolutionised pharmacotherapy options. A cancer prevention clinical trial would be complex, lengthy, and costly; therefore, we undertook an international expert consensus to assess the need for and design of a weight-loss intervention cancer prevention trial. We used a combination of two nominal group meetings, sandwiching 3 Delphi rounds. A panel of 54 international, multi-disciplinary researchers was established, informed by patient groups. Feedback was incorporated iteratively, and borderline statements, those that did not reach consensus, were addressed in a final meeting. Through the Delphi rounds, retention rates were high (98%, 85%, 88%). Consensus was achieved on 25 statements. Including: (i) there is a need for clinical trial evidence to inform obesity-related cancer prevention strategies; (ii) a trial should reflect high-risk populations; (iii) trials should prioritise GLP-1 agonists; and (iv) future research should explore mechanistic pathways and relevant cancer precursors. This consensus underscores the need for trial evidence to inform strategies for obesity-related cancer prevention.

Background Accurate staging of lymph node metastasis (LNM) is crucial for personalising rectal cancer treatment. Lymph nodes (LNs) are the most common sites of rectal cancer metastasis, and malignant LNs are typically treated with neo-adjuvant radiotherapy or chemoradiotherapy (CRT) to reduce the chance of recurrence and distant metastasis after surgery. Radiological staging criteria, based on LN size, shape, and texture, are known to be subjective, and radiologists have an average diagnostic performance of 73% sensitivity and 74% specificity.Methods This study develops a fully automatic and end-to-end pre-operative radiological staging model for rectal cancer LNM using artificial intelligence (AI) methods. The model combines automatic detection of lymph nodes on Magnetic Resonance Imaging (MRI) with multiple instance learning patient-level lymph node staging. Models were trained and evaluated on an in-house dataset provided by Leeds Teaching Hospitals NHS Trust (LTHT) including 458 patients with pre-operative MRI scans, patient clinical data, and post-operative pathological TNM staging. Accurate detection of the lymph nodes on MRI is achieved using nnU-Net, and the classification results compare different 3D feature encoders, investigating a trade-off between performance and interpretability.Results The results demonstrate state-of-the-art performance with cross-validated metrics of 0.828 AUC, 86.6% sensitivity, and 72.4% specificity. Clinical validation study results show that the AI staging model performance exceeded three expert radiologists in predicting post-operative pathology with a 9% higher F1 score.Conclusions This study provides strong evidence that an end-to-end AI model can significantly improve pre-operative staging of rectal cancer lymph node metastasis. The model outperformed expert radiologists and shows clear potential to enhance clinical decision making and improve patient outcomes.

BACKGROUND:Anastomotic leak is a serious complication in colorectal surgery. Indocyanine green fluorescence angiography (ICGFA) is an adjunctive digital method of assessing bowel perfusion intraoperatively. We assessed whether ICGFA use during surgery reduces postoperative anastomotic leak exclusively using data from randomised controlled trials (RCTs). METHODS:In this systematic review and meta-analysis, we searched PubMed, ScienceDirect, Scopus, Web of Science, Embase, and the Cochrane Collaboration databases from inception to July 19, 2025, for English-language RCTs comparing additive intraoperative ICGFA with standard surgeon perfusion assessment alone in patients undergoing colorectal resection with primary anastomosis according to prespecified criteria and PRISMA guidelines. Summary-level data were extracted by two reviewers. The primary outcome was overall anastomotic leak rate. The Jadad scale (Oxford quality scoring system) was used to assess trial quality, the Cochrane Risk of Bias (RoB 2) tool for RCTs was used to assess risk of bias, and GRADE was used to assess strength of evidence. Meta-regression and trial sequential analyses were performed. This study is registered with PROSPERO, CRD420250652639. FINDINGS:719 records were initially identified, with 387 remaining after screening and 184 sought for full eligibility screening, of which nine were eligible RCTs (with 4754 patients) for analysis. ICGFA significantly reduced overall anastomotic leak (risk ratio 0·66 [95% CI 0·56-0·78], p<0·0001; number needed to treat [NNT]=24), with trial sequential analysis showing that the required information size (2183) was exceeded overall. ICGFA reduced both anastomotic leak requiring intervention (risk ratio 0·73 [95% CI 0·60-0·89], p=0·0020; NNT=39) and anastomotic leak not requiring intervention (0·48 [0·31-0·72], p=0·0004, NNT=35). Significant benefit was observed for left-sided resections (risk ratio 0·62 [95% CI 0·51-0·74], p<0·0001; NNT=19), rectal resections (0·62 [0·51-0·76], p<0·0001; NNT=19), and low anterior resections (0·62 [0·48-0·79], p<0·0001; NNT=13), in which the required information size was also exceeded, but not for right-sided resections. In the meta-regression analysis, among all tested covariates, only patient BMI significantly modified the ICGFA treatment effect, with an increasing protective effect with increasing BMI (coefficient -0·0153 [95% CI -0·0251 to -0·0056], p=0·0020). Evidence was graded as high certainty for overall, left-sided, rectal, asymptomatic, and 30-day anastomotic leaks, and moderate certainty for clinically significant anastomotic leak. INTERPRETATION:Intraoperative use of ICGFA reduces anastomotic leak rates in left-sided and rectal colorectal resections. Given the evidence available now, further general efficacy trials are no longer required and research should shift to implementation and defined targeted subgroup ICGFA role definition (ie, in non-rectal left-sided resections). FUNDING:None.

Background Anastomotic leak is the most feared complication of rectal cancer surgery, being reported in 10–15% of patients. Indocyanine green near-infrared angiography has been introduced to evaluate anastomotic blood supply and reduce anastomotic leak, with promising results. Objective and main outcome measure The primary objective was to evaluate the efficacy and mechanism of indocyanine green near infrared angiography in reducing the anastomotic leak rate in rectal cancer surgery. The primary end point was clinical anastomotic leak rate within 90 days of operation. The key secondary end point was the rate of all anastomotic leaks within 90 days of operation. Design and methods A prospective, unblinded, parallel-group, non-Clinical Trial of an Investigational Medicinal Product, randomised controlled trial comparing surgery with indocyanine green near infrared angiography against standard care (white light laparoscopy) to determine the effect on anastomotic leak in patients undergoing elective rectal cancer resection. Participants were randomised 1 : 1 using minimisation with a random element. Analyses were intention-to-treat. Setting Twenty-eight European hospitals. Participants Adult patients ≥ 18 years with a diagnosis of rectal cancer, suitable for curative resection by high or low anterior resection with anastomosis. Interventions Surgery with indocyanine green near infrared angiography or standard of care. Results Between 10 January 2018 and 15 August 2023, 766 participants were randomised; 698 (91.1%) participants were included in the primary analysis. The overall rates of clinical and all anastomotic leaks were 90/698 (12.9%) and 121/698 (17.3%), respectively. In the primary analysis, clinical anastomotic leaks occurred in 36/343 (10.5%) and 54/355 (15.2%) in the indocyanine green near-infrared angiography and standard care groups, respectively; the primary model estimated an adjusted odds ratio of 0.667 (95% confidence interval 0.419 to 1.060; p = 0.0868). Key secondary analysis, including all anastomotic leaks, observed 47/343 (13.7%) and 74/355 (20.8%) leaks in indocyanine green near-infrared angiography and standard care groups, respectively, with the key secondary model estimated an adjusted odds ratio of 0.607 (95% confidence interval 0.403 to 0.915; p = 0.0172) in favour of indocyanine green near infrared. In the economic analysis, indocyanine green near infrared angiography had a 62% chance of being cost-effective and led to a per-patient cost saving of £97.34 (95% confidence interval £91.32 to £103.00). Limitations Surgeons or data collectors were unable to be blinded. The trial population largely consisted of White ethnic groups, and so some ethnic groups are likely under-represented. Conclusions The use of indocyanine green near infrared angiography reduces the rate of clinical and all anastomotic leaks following rectal cancer resection, but only reached statistical significance for all leaks. It is safe, easy to use and cost-effective. Taken in context with other clinical trials, our results suggest that indocyanine green near infrared angiography should be considered as the future standard of care in rectal cancer surgery. Future work The microbiome substudy has shown important shifts in the microbiome profile across the rectal cancer treatment pathway that warrant further investigation regarding a causal role in anastomotic leak and other postoperative complications. Further work is required to standardise and quantify indocyanine green near infrared angiography as a means of real-time assessment of tissue perfusion. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 14/150/62. Plain language summary Why did we do this trial? Bowel (colon and rectal) cancer is one of the most common cancers in the United Kingdom, causing 16,000 deaths each year. Surgery is required to remove the piece of bowel that contains the cancer, and then the two open ends of the bowel are joined together. One of the most serious complications is an anastomotic leak which happens when the join in the bowel does not heal properly. This can cause leaks that are obvious when patients become very unwell, but some leaks are found by chance and still result in a bad outcome for the patient. Ensuring good blood supply to the bowel that is being joined can reduce the risk of an anastomotic leak. There is a new technology to assist surgeons called indocyanine green near infra-red. During the operation, a dye is injected into the blood which glows and shows the blood supply to help the surgeons make decisions. We wanted to find out if using indocyanine green near infra-red reduces the number of anastomotic leaks. What did we do? Between 2017 and 2023, 766 patients who needed an operation for rectal cancer agreed to take part in the Intraoperative Fluorescence Angiography to Prevent Anastomotic Leak in Rectal Cancer Surgery trial. To allow a fair comparison of treatments, half the patients were randomised to have a standard operation (surgery without indocyanine green near infra-red), and the other half were randomised to have their operation with indocyanine green near infra-red. What did we find and what does this mean? The Intraoperative Fluorescence Angiography to Prevent Anastomotic Leak in Rectal Cancer Surgery trial has shown that the use of indocyanine green near infra-red during surgery reduces the rate of most types of anastomotic leaks, but did not change how often the worst leaks occurred. Using indocyanine green near infra-red helped surgeons to better choose which parts of the bowel to join, which helped prevent anastomotic leaks from happening. Reducing the risk of anastomotic leaks means that less patients will become unwell after having an operation for rectal cancer and overall cancer outcomes will improve.

BACKGROUND:Data are mixed on whether indocyanine green (ICG) fluorescence angiography can reduce the high rate of anastomotic leaks in patients undergoing surgery for rectal cancer. Therefore, we aimed to investigate the safety and efficacy of ICG fluorescence angiography in reducing the rate of clinical anastomotic leaks in these patients. METHODS:IntAct was an unblinded randomised controlled trial conducted at 28 specialist rectal cancer centres across eight European countries. Adults (≥18 years) with rectal cancer (lower margin of cancer ≤15 cm from the anal verge) medically fit for elective, curative, laparoscopic or robotic high or low anterior resection were eligible. Patients not undergoing colorectal or anal anastomosis and those with synchronous colonic tumours or recurrent or locally advanced rectal cancer requiring extended or multi-visceral excision were excluded. Eligible participants were randomly assigned (1:1) by use of minimisation with a random element to undergo surgery with or without ICG (standard care). Resections and anastomoses were done per surgeon preference. In the ICG group, surgeons first marked proximal transection levels via standard white-light laparoscopy and then administered an intravenous bolus of 0·1 mg/kg of ICG for perfusion assessment. A second 0·1 mg/kg ICG assessment was done following anastomosis. In the standard care group, only a white-light assessment of bowel perfusion was performed. The primary endpoint was the rate of clinical anastomotic leak (grades B or C, per the International Study Group of Rectal Cancer) within 90 postoperative days. Analyses were done in the intention-to-treat population for complete cases. This trial is registered with the ISRCTN registry (ISRCTN13334746) and is now complete. FINDINGS:Between Oct 20, 2017, and Aug 15, 2023, 2534 patients were assessed for eligibility and 766 participants were randomly assigned (383 to the ICG group and 383 to the standard care group). 501 (65%) of 766 participants were male, 726 (95%) were of White ethnicity, and the median age was 64·0 years (IQR 56·0-72·0). 343 patients in the ICG group and 355 in the standard care group were included in the intention-to-treat analysis. The rates of anastomotic leak were 11 (3%) of 343 in the ICG group and 20 (6%) in the standard care group for grade A, 11 (3%) and 31 (9%) for grade B, and 25 (7%) and 23 (6%) for grade C. Within 90 days, a clinical anastomotic leak occurred in 90 (13%) of 698 participants: 36 (10%) of 343 in the ICG group and 54 (15%) of 355 in the standard care group (adjusted odds ratio 0·667 [95% CI 0·419-1·060]; p=0·087). There were no serious adverse events related to ICG. INTERPRETATION:Although IntAct did not show a significant benefit for ICG fluorescence angiography, a signal towards a reduction in clinical anastomotic leak rate was observed. The benefit of ICG could be in preventing grade A or B leaks, given similar rates of grade C leaks between groups. Future research is needed to standardise ICG fluorescence assessment and understand its relevance to anastomotic leak. FUNDING:National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Effective treatment for rectal cancer relies on accurate lymph node metastasis (LNM) staging. However, radiological criteria based on lymph node (LN) size, shape and texture morphology have limited diagnostic accuracy. In this work, we investigate applying a Variational Autoencoder (VAE) as a feature encoder model to replace the large pre-trained Convolutional Neural Network (CNN) used in existing approaches. The motivation for using a VAE is that the generative model aims to reconstruct the images, so it directly encodes visual features and meaningful patterns across the data. This leads to a disentangled and structured latent space which can be more interpretable than a CNN. Models are deployed on an in-house MRI dataset with 168 patients who did not undergo neo-adjuvant treatment. The post-operative pathological N stage was used as the ground truth to evaluate model predictions. Our proposed model 'VAE-MLP' achieved state-of-the-art performance on the MRI dataset, with cross-validated metrics of AUC 0.86 +/- 0.05, Sensitivity 0.79 +/- 0.06, and Specificity 0.85 +/- 0.05. Code is available at: https://github.com/benkeel/Lymph_Node_Classification_MIUA.

Access to safe, timely and affordable surgical care is lacking globally. Less than 6

Anastomotic leakage (AL) following resection for rectal cancer has a significant negative impact on patients and represents a substantial economic burden. Intraoperative fluorescence angiography using indocyanine green (ICG+) is a potential strategy to reduce ALs. Findings from recent randomized controlled trials were positive; however, no full economic evaluations of ICG+ have been conducted to date. We conducted a cost-utility analysis of the ICG+ vs standard surgeon assessment (ICG-) using the IntAct trial data. We took the perspective of the UK NHS over a 90-day post procedure horizon. EQ-5D-5L and resource use data were collected at baseline, 30 and 90 days in the UK trial sub-sample to enable estimation of quality-adjusted life years (QALYs) and costs. Incremental cost-effectiveness ratios (ICERs) were estimated using generalised linear regression models. We analysed data from n=345 UK patients finding negligible adjusted differences in QALYs (−0.001 in the primary multiply imputed analysis) at 90 days but modest cost savings (£73 [95% CI −£78, −£67] for the primary and £140 [95% CI −£150, −£129] for the secondary complete case analyses) per patient for ICG+. The ICER primary analysis indicated ICG+ was cost effective. Simulations indicated ICG+ had a 60% chance of being the optimal strategy in the primary analysis. This research represents a novel contribution on the value of ICG+ for preventing ALs. Results indicate that ICG+ leads to modest cost savings. Together with the clinical effectiveness results, and the potential positive budget impact, the current results indicate ICG+ is likely to provide net health benefit.

BackgroundMental rehearsal (MR), the deliberate practice of skills specific to a procedure, has been successfully used in sports and music training for decades, but has not been adopted in surgery. This narrative review explores MR's role in surgical training and clinical practice, evaluating its effectiveness in motor skill acquisition, technical and non-technical skill development, and real world clinical implementation. Our aim was to assess MR's impact on both surgical education and clinical performance, while identifying the barriers to its routine adoption in surgical training.MethodsWe searched for relevant studies on the topic and impacts of MR in surgery using the Medline database up to December 2024. A range of studies were included covering mental rehearsal, surgical education, surgical training, and surgical outcomes. The primary outcomes were to provide insights into the mechanisms and implementation of MR in surgery and to assess the potential impact of MR on surgical outcomes.ResultsThe narrative review provides scientific insights into the mechanisms of MR in surgery and describes in detail the implementation methodology. The majority of evidence demonstrates that MR is beneficial when used as an adjunct approach to other forms of training. Moreover, there is evidence to support MR as a low-cost and valuable learning technique. Many questions remain regarding training schedules including the optimal duration and nature of the MR sessions, accommodating the surgeon's prior experience, optimal number of repetitions, and addressing the abilities of the participants to perform mental imagery. Most studies have heterogenous methods, diffuse aims and poor descriptions of the specific intervention components. Several studies applied MR in demanding real-life surgical environments and demonstrated feasibility in surgery.ConclusionsThe preliminary findings suggest that MR may improve the performance of operators and operating teams as an efficient adjuvant to traditional surgical skills training methods. More work is needed to better understand how MR interventions can best be implemented to improve training, practice, and outcomes in routine surgical practice.

Introduction Anastomotic leak (AL) represents a significant complication following gastrointestinal (GI) surgery, contributing to increased morbidity and mortality. pH monitoring has emerged as a potential diagnostic tool for the early detection of AL, but its effectiveness and clinical utility remain to be fully elucidated. This review aims to summarise the evidence regarding perianastomotic pH monitoring for AL detection. Methods A systematic search of relevant databases was conducted to identify pre-clinical and clinical studies investigating pH monitoring for AL detection following GI surgery. Studies were screened by two independent reviewers based on predefined inclusion and exclusion criteria. Data were extracted and presented as a narrative synthesis. Results A total of 10 studies were included in the review, comprising animal studies (n = 2), and human studies in upper GI (n = 3) and colorectal (n = 5) patients. Consistent findings of lower pH values in patients with AL across various postoperative time points were demonstrated. There was diversity in the pH detection method, in addition to variable frequency and timing of pH monitoring. Four studies reported a shorter time for AL detection with pH monitoring vs conventional methods, although no statistical comparisons were used. No standard pH cut-off value for AL detection was identified. Conclusion pH monitoring shows potential as a diagnostic tool for the early detection of AL following GI surgery. While the existing evidence supports its potential utility, further research is required to establish standardised protocols and assess its clinical impact.

Introduction As a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low anterior resection syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on quality of life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options.Methods and analysis The objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of transanal irrigation (TAI) or sacral neuromodulation (SNM) compared with optimised conservative management (OCM) for people with major LARS.POLARiS is a prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort design, with internal pilot phase, qualitative sub-study, process evaluation and economic evaluation. Approximately 1500 adult participants from UK hospitals and 500 from Australian hospitals who have undergone a high or low anterior resection for colorectal cancer in the last 10 years will be recruited into the cohort. Six-hundred participants from the UK and 200 participants from Australia, with major LARS symptoms, defined as a LARS score of ≥30, will be recruited to the randomised controlled trial (RCT) element. Participants entering the RCT will be randomised between OCM, TAI or SNM, all with equal allocation ratios.Cohort and RCT participants will be followed up for a 24-month period, completing a series of questionnaires measuring LARS symptoms and QoL, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted.The primary outcome measure of the POLARiS cohort and RCT is the LARS score up to 24 months post-registration/randomisation. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI versus OCM and SNM versus OCM. Secondary outcomes include health-related QoL, adverse events, treatment compliance and cost-effectiveness (up to 24 months post-registration/randomisation).Ethics and dissemination Ethical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants on request and published on completion of the trial in a peer-reviewed journal and at international conferences.Trial registration number ISRCTN12834598; ACTRN12623001166662.

Background:Postoperative pain following abdominal surgery is a significant obstacle to patient recovery, often necessitating high analgesic doses associated with adverse effects like cognitive impairment and cardiorespiratory depression. Reliable animal models are crucial for understanding the pathophysiology of post surgical pain and developing more effective pain-relieving strategies. Methods:We developed a mouse model to replicate peritoneal trauma induced by abdominal surgery. 30 C57BL/6 mice underwent laparotomy, with half undergoing standardised peritoneal abrasion and the rest serving as controls. Mouse recovery was assessed using two validated scoring systems of surgical recovery: Post surgery Severity Assessment (PSSA) and Mouse Grimace Score (MGS). Blood samples were taken for cytokine analysis. Adhesions were evaluated on day 6, and peritoneal tissue was examined for healing markers. Results:After laparotomy, all mice exhibited expected pain profiles. Mice with peritoneal abrasion had significantly higher PSSA (7.2 ± 1.2 vs 4.68 ± 0.82, p ≤ 0.001) and MGS scores (3.62 ± 0.74 vs 0.82 ± 0.40, p ≤ 0.05) with slower recovery. Serum inflammatory cytokine levels were significantly elevated in the abraded group, and adhesion formation was higher in this group. Immunohistochemical analysis showed significantly increased expression of α-SMA, CD31, CD68, and F4/80 in peritoneal tissue in the abraded group. Discussion:A mouse model involving laparotomy and standardised peritoneal abrasion replicates the expected pathophysiological changes following abdominal surgery. It will be a useful model for better understanding the mechanisms of post surgical pain and developing improved pain-relief strategies. It also has utility for the study of intra-abdominal adhesion formation. Key message:To understand the intricate relationship between peritoneal trauma-induced pain, cytokine response, and post-operative adhesion formation in mouse models for advancing therapeutic interventions and enhancing post-operative recovery outcomes.

Abstract Pain, a complex and debilitating condition, necessitates innovative therapeutic strategies to alleviate suffering and enhance patients' quality of life. Vesicular systems hold the potential to enhance precision of drug localisation and release, prolong the duration of therapeutic action and mitigate adverse events associated with long-term pharmacotherapy. This review critically assesses the current state-of-the-art in vesicle-based formulations (liposomes, polymersomes, ethosomes, and niosomes) for pain management applications. We highlight formulation engineering strategies used to optimise drug pharmacokinetics, present preclinical findings of experimental delivery systems, and discuss the clinical evidence for the benefits of clinically approved formulations. We present the challenges and outlook for future improvements in long-acting anaesthetic and analgesic formulation development.

Introduction As a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low Anterior Resection Syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on Quality-of-Life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options. Methods and Analysis The objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of trans-anal irrigation (TAI) or sacral neural modulation (SNM) compared to optimised conservative management (OCM) for people with major LARS. All patients who have had an anterior resection in the last 10 years who meet the eligibility criteria will be invited to participate in the cohort. Patients identified as having a major LARS score (LARS score ≥30) and who meet the eligibility criteria will be invited to take part in the randomised controlled trial (RCT). Cohort and RCT participants will be followed up for a 24-month period, and will complete a series of questionnaires measuring LARS symptoms and quality-of-life, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted. The primary outcome measure of the POLARiS cohort and RCT is the LARS score at 24 months. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI vs OCM and SNM vs OCM. Ethics and Dissemination Ethical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants upon request and published on completion of the trial in a peer-reviewed journal and at international conferences Trial Registration NumberISRCTN12834598Registered 04/08/2023 ACTRN12623001166662 Registered 10/11/2023

Objectives: Current guidelines suggest treating poor-prognosis eosinophilic granulomatosis with polyangiitis (EGPA) with a combination of glucocorticoids (GCs) plus cyclophosphamide (CYC). However, there is little to support the need for the addition of CYC. The objective of this study was to compare GCs plus CYC to alone as induction therapy in poor-prognosis EGPA. Methods: We emulated a target trial using observational data from a European multicenter retrospective base. We included patients with newly diagnosed EGPA with a 1996 Five Factor Score (FFS) of at least 1, treated with GCs or GCs plus CYC between June 1985 and November 2018. Propensity score analysis was used to adjust for potential confounders. Primary outcome was relapse at 12months. Secondary outcomes included major relapse at 12months and GC-dependent asthma and/or ear nose and throat (ENT) manifestations at 24months. Results: A total of 209 patients were included: 47 % were male and the mean age at diagnosis was 52 (+/- 16 years); 26 % were treated with GCs alone and 74 % with GCs plus CYC. After adjustment, the risk of relapse (hazard ratio [HR]: 0.24, 95%CI [0.08-0.67], p = 0.007), major relapse (HR: 0.24, 95%CI [0.07-0.85], p = 0.026) and the proportion of GC-dependent asthma and/or ENT manifestations (odds ratio:0.30, 95%CI [0.14-0.66], p = 0.003) were lower in the GCs plus CYC group compared to the GCs alone group. Conclusion: This target trial emulation study shows that the addition of CYC to GCs reduces the risk of vasculitis relapse and the rate of GC-dependent asthma and/or ENT manifestations in patients with poor-prognosis EGPA.