Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of a Chronic Total Coronary Occlusion on the Incidence of Appropriate Implantable Cardioverter-Defibrillator Shocks and Mortality: A Substudy of the Dutch Outcome in ICD Therapy (DO-IT)) Registry.

BACKGROUND: Chronic total coronary occlusions (CTO) substantially increase the risk for sudden cardiac death. Among patients with chronic ischemic heart disease at risk for sudden cardiac death, an implantable cardioverter defibrillator (ICD) is the favored therapy for primary prevention of sudden cardiac death. This study sought to investigate the impact of CTOs on the risk for appropriate ICD shocks and mortality within a nationwide prospective cohort. METHODS AND RESULTS: This is a subanalysis of the nationwide Dutch-Outcome in ICD Therapy (DO-IT) registry of primary prevention ICD recipients in The Netherlands between September 2014 and June 2016 (n=1442). We identified patients with chronic ischemic heart disease (n=663) and assessed available coronary angiograms for CTO presence (n=415). Patients with revascularized CTOs were excluded (n=79). The primary end point was the composite of all-cause mortality and appropriate ICD shocks. Clinical follow-up was conducted for at least 2 years. A total of 336 patients were included, with an average age of 67±9 years, and 20.5% was female (n=69). An unrevascularized CTO was identified in 110 patients (32.7%). During a median follow-up period of 27 months (interquartile range, 24-32), the primary end point occurred in 21.1% of patients with CTO (n=23) compared with 11.9% in patients without CTO (n=27; P=0.034). Corrected for baseline characteristics including left ventricular ejection fraction, and the presence of a CTO was an independent predictor for the primary end point (hazard ratio, 1.82 [95% CI, 1.03-3.22]; P=0.038). CONCLUSIONS: Within this nationwide prospective registry of primary prevention ICD recipients, the presence of an unrevascularized CTO was an independent predictor for the composite outcome of all-cause mortality and appropriate ICD shocks.

Development and Validation of the Scoring System of Appendicitis Severity 2.0.

Importance: When considering nonoperative treatment in a patient with acute appendicitis, it is crucial to accurately rule out complicated appendicitis. The Atema score, also referred to as the Scoring System of Appendicitis Severity (SAS), has been designed to differentiate between uncomplicated and complicated appendicitis but has not been prospectively externally validated. Objective: To externally validate the SAS and, in case of failure, to develop an improved SAS (2.0) for estimating the probability of complicated appendicitis. Design, Setting, and Participants: This prospective study included adult patients who underwent operations for suspected acute appendicitis at 11 hospitals in the Netherlands between January 2020 and August 2021. Main Outcomes and Measures: Appendicitis severity was predicted according to the SAS in 795 patients and its sensitivity and negative predictive value (NPV) for complicated appendicitis were calculated. Since the predefined targets of 95% for both were not met, the SAS 2.0 was developed using the same cohort. This clinical prediction model was developed with multivariable regression using clinical, biochemical, and imaging findings. The SAS 2.0 was externally validated in a temporal validation cohort consisting of 565 patients. Results: In total, 1360 patients were included, 463 of whom (34.5%) had complicated appendicitis. Validation of the SAS resulted in a sensitivity of 83.6% (95% CI, 78.8-87.6) and an NPV of 85.0% (95% CI, 80.6-88.8), meaning that the predefined targets were not achieved. Therefore, the SAS 2.0 was developed, internally validated (C statistic, 0.87; 95% CI, 0.84-0.89), and subsequently externally validated (C statistic, 0.86; 95% CI, 0.82-0.89). The SAS 2.0 was designed to calculate a patient's individual probability of having complicated appendicitis along with a 95% CI. Conclusions and Relevance: In this study, external validation of the SAS fell short in accurately distinguishing complicated from uncomplicated appendicitis. The newly developed and externally validated SAS 2.0 was able to assess an individual patient's probability of having complicated appendicitis with high accuracy in patients with acute appendicitis. Use of this patient-specific risk assessment tool can be helpful when considering and discussing nonoperative treatment of acute appendicitis with patients.

Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial.

BACKGROUND: The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial. DESIGN AND METHODS: The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life. DISCUSSION: The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients. TRIAL REGISTRATION: Dutch Trial Register (NTR) NTR2883 . Registered May 3, 2011. ISRCTN, ISRCTN60945764 . Registered August 12, 2019.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial.

BACKGROUND: Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. METHODS: We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. FINDINGS: Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). INTERPRETATION: Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. FUNDING: The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Digital consults to optimize guideline-directed therapy: design of a pragmatic multicenter randomized controlled trial.

AIMS: Many heart failure (HF) patients do not receive optimal guideline-directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator-initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open-label trial to evaluate efficacy and safety of DC in patients on HF treatment. METHODS AND RESULTS: Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home-measured vital signs), (ii) patient education via an e-learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. CONCLUSIONS: The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient- and clinician-targeted DC for GDMT optimization.

An integrated personalized assistive devices approach to reduce the risk of foot ulcer recurrence in diabetes (DIASSIST): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Preventing foot ulcers in people with diabetes can increase quality of life and reduce costs. Despite the availability of various interventions to prevent foot ulcers, recurrence rates remain high. We hypothesize that a multimodal treatment approach incorporating various footwear, self-management, and education interventions that matches an individual person's needs can reduce the risk of ulcer recurrence with beneficial cost-utility. The aim of this study is to assess the effect on foot ulcer recurrence, footwear adherence, and cost-utility of an integrated personalized assistive devices approach in high-risk people with diabetes. METHODS: In a parallel-group multicenter randomized controlled trial, 126 adult participants with diabetes mellitus type 1 or 2, loss of protective sensation based on the presence of peripheral neuropathy, a healed plantar foot ulcer in the preceding 4 years, and possession of any type of custom-made footwear will be included. Participants will be randomly assigned to either enhanced therapy or usual care. Enhanced therapy consists of usual care and additionally a personalized treatment approach including pressure-optimized custom-made footwear, pressure-optimized custom-made footwear for indoor use, at-home daily foot temperature monitoring, and structured education, which includes motivational interviewing and personalized feedback on adherence and self-care. Participants will be followed for 12 months. Assessments include barefoot and in-shoe plantar pressure measurements; questionnaires concerning quality of life, costs, disease, and self-care knowledge; physical activity and footwear use monitoring; and clinical monitoring for foot ulcer outcomes. The study is powered for 3 primary outcomes: foot ulcer recurrence, footwear adherence, and cost-utility, the primary clinical, patient-related, and health-economic outcome respectively. DISCUSSION: This is the first study to integrate multiple interventions for ulcer prevention into a personalized state-of-the-art treatment approach and assess their combined efficacy in a randomized controlled trial in people with diabetes at high ulcer risk. Proven effectiveness, usability, and cost-utility will facilitate implementation in healthcare, improve the quality of life of high-risk people with diabetes, and reduce treatment costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05236660. Registered on 11 February 2022.

Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy alone for Crohn's perianal fistulas (PISA-II): long-term outcomes of an international, multicentre patient preference, randomised controlled trial.

Background: The PISA-II trial showed that short-term anti-tumour necrosis factor (anti-TNF) therapy followed by surgical closure induces radiological healing of perianal fistulas in patients with Crohn's disease more frequently than anti-TNF therapy alone after 18 months. This study aimed to compare long-term outcomes of both treatment arms. Methods: Follow-up data were collected from patients who participated in the PISA-II trial, an international patient preference randomised controlled trial. This multicentre trial was performed in nine hospitals in the Netherlands and one hospital in Italy. Patients with Crohn's disease above the age of 18 years with an active high perianal fistula and a single internal opening were asked to participate. Patients were allocated to anti-TNF therapy (intravenous infliximab, or subcutaneous adalimumab, at the discretion of the gastroenterologist) for one year, or surgical closure combined with 4-months anti-TNF therapy. Patients without a treatment preference were randomised (1:1) using random block randomisation (block sizes of six without stratification), and patients with a treatment preference were treated according to their preferred treatment arm. For the current follow-up study, data were collected until May 2022. Primary outcome was radiological healing on magnetic resonance imaging (MRI), including all participants with a MRI made less than 6 months ago at the time of data collection. Analysis was based on observed data. Findings: Between September 14, 2013, and December 7, 2019, 94 patients were enrolled in the trial. Long-term follow-up data were available in 91 patients (36/38 (95%) anti-TNF + surgical closure, 55/56 (98%) anti-TNF). A total of 14/36 (39%) patients in the surgical closure arm were randomly assigned, which was not significantly different in the anti-TNF treatment arm (16/55 (29%) randomly assigned). Median follow-up was 5.7 years (interquartile range (IQR) 5-7). Radiological healing occurred significantly more often after anti-TNF + surgical closure (15/36 = 42% versus 10/55 = 18%; P = 0.014). Clinical closure was comparable (26/36 = 72% versus 34/55 = 62%; P = 0.18) in both groups. However, clinical closure in the surgical group was achieved with less re-interventions 4/26 (= 15%) versus 18/34 (= 53%), including (redo-)surgical closure procedures. Recurrences occurred in 0/25 (0%) patients with radiological healing versus 27/76 (36%) patients with clinical closure, sometime during follow-up. Anti-TNF trough levels were higher in patients with long-term clinical closure in both groups (P = 0.031 and P = 0.014). In 6/11 (55%) patients in the anti-TNF group with available trough levels, recurrences were diagnosed within three months of a drop under 3.5ug/ml. 36 patients stopped anti-TNF, after which 0/14 (0%) patients with radiological healing developed a recurrence and 9/22 (41%) with clinical closure. Self-rated (in)continence was comparable between groups, and 79% (60/76) of patients indicated comparable/improved continence after treatment. Decision-regret analysis showed that all (30/30) anti-TNF + surgical closure patients agreed or strongly agreed that surgery was the right decision versus 78% (36/46) in the anti-TNF arm. All surgical closure patients would go for the same treatment again, whereas this was 89% (41/46) in the anti-TNF arm. Interpretation: This study confirmed that surgical closure should be considered in amenable patients with perianal fistulas and Crohn's disease as long-term outcomes were favourable, and that radiological healing should be the aim of treatment as recurrences only occurred in patients without radiological healing. In patients with complete MRI closure, anti-TNF could be safely stopped. Funding: None.

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial.

Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of -7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI -6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0-30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5-5.5] vs 5 [95% CI 4.7-5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67-1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson & Johnson Medical Limited, Dutch Gastroenterology Society.

Less bleeding by omitting aspirin in non-ST-segment elevation acute coronary syndrome patients: Rationale and design of the LEGACY study.

BACKGROUND: Early aspirin withdrawal, also known as P2Y12-inhibitor monotherapy, following percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) can reduce bleeding without a trade-off in efficacy. Still the average daily bleeding risk is highest during the first months and it remains unclear if aspirin can be omitted immediately following PCI. METHODS: The LEGACY study is an open-label, multicenter randomized controlled trial evaluating the safety and efficacy of immediate P2Y12-inhibitor monotherapy versus dual antiplatelet therapy (DAPT) for 12 months in 3,090 patients. Patients are randomized immediately following successful PCI for NSTE-ACS to 75-100 mg aspirin once daily versus no aspirin. The primary hypothesis is that immediately omitting aspirin is superior to DAPT with respect to major or minor bleeding defined as Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, while maintaining noninferiority for the composite of all-cause mortality, myocardial infarction and stroke compared to DAPT. CONCLUSIONS: The LEGACY study is the first randomized study that is specifically designed to evaluate the impact of immediately omitting aspirin, and thus treating patients with P2Y12-inhibitor monotherapy, as compared to DAPT for 12 months on bleeding and ischemic events within 12 months following PCI for NSTE-ACS.

Two decades of surgical randomized controlled trials: worldwide trends in volume and methodological quality.

BACKGROUND: RCTs are essential in guiding clinical decision-making but are difficult to perform, especially in surgery. This review assessed the trend in volume and methodological quality of published surgical RCTs over two decades. METHODS: PubMed was searched systematically for surgical RCTs published in 1999, 2009, and 2019. The primary outcomes were volume of trials and RCTs with a low risk of bias. Secondary outcomes were clinical, geographical, and funding characteristics. RESULTS: Some 1188 surgical RCTs were identified, of which 300 were published in 1999, 450 in 2009, and 438 in 2019. The most common subspecialty in 2019 was gastrointestinal surgery (50.7 per cent). The volume of surgical RCTs increased mostly in Asia (61, 159, and 199 trials), especially in China (7, 40, and 81). In 2019, countries with the highest relative volume of published surgical RCTs were Finland and the Netherlands. Between 2009 and 2019, the proportion of RCTs with a low risk of bias increased from 14.7 to 22.1 per cent (P = 0.004). In 2019, the proportion of trials with a low risk of bias was highest in Europe (30.5 per cent), with the UK and the Netherlands as leaders in this respect. CONCLUSION: The volume of published surgical RCTs worldwide remained stable in the past decade but their methodological quality improved. Considerable geographical shifts were observed, with Asia and especially China leading in terms of volume. Individual European countries are leading in their relative volume and methodological quality of surgical RCTs.

An RCT is a form of research in which patients are divided randomly into two or more treatment groups to allow a fair and unbiased comparison of both treatments. RCTs are essential in guiding clinical decision-making, but are difficult to perform, especially in surgery. This review assessed the trend in volume and quality of published surgical RCTs over two decades. Surgical RCTs published in 1999, 2009, and 2019 were identified. The main outcome measures were volume of RCTs and trials with a low risk of bias. Different forms of bias can occur when research results are influenced by external factors. Some 1188 surgical RCTs were identified, of which 300 were published in 1999, 450 in 2009, and 438 in 2019. The volume of surgical RCTs published in these years increased mostly in Asia (61, 159, and 199 RCTs), especially in China (7, 40, and 81). In 2019, the countries with highest relative volume of published surgical RCTs were Finland and the Netherlands. Between 2009 and 2019, the proportion of RCTs with a low risk of bias increased from 14.7 to 22.1 per cent (P = 0.004). In 2019, the proportion of trials with a low risk of bias was highest in Europe (30.5 per cent), with the UK and the Netherlands as leaders in this respect. The volume of published surgical RCTs worldwide remained stable in the past decade but their methodological quality improved. Considerable geographical shifts were observed, with Asia and especially China leading in terms of volume. Individual European countries are leading in their relative volume and methodological quality of surgical RCTs.

Costs of complications following distal pancreatectomy: a systematic review.

BACKGROUND: Postoperative complications following distal pancreatectomy (DP) are common, especially postoperative pancreatic fistula (POPF). In order to design adequate prophylactic strategies, it is of relevance to determine the costs of these complications. An overview of the literature on the costs of complications following DP is lacking. METHODS: A systematic literature search was performed in PubMed, Embase, and Cochrane Library (inception until 1 August 2022). The primary outcome was the costs (i.e. cost differential) of major morbidity, individual complications and prolonged hospital stay. Quality of non-RCTs were assessed using the Newcastle-Ottawa scale. Costs were compared with the use of Purchasing Power parity. This systematic review was registered with PROSPERO (CRD42021223019). RESULTS: Overall, seven studies were included with 854 patients after DP. The rate POPF grade B/C varied between 13% and 27% (based on five studies) with a corresponding cost differential of EUR 18,389 (based on two studies). The rate of severe morbidity varied between 13% and 38% (based on five studies) with a corresponding cost differential of EUR 19,281 (based on five studies). CONCLUSION: This systematic review reported considerable costs for POPF grade B/C and severe morbidity after DP. Prospective databases and studies should report on all complications in a uniform matter to better display the economic burden of complications of DP.

Budget impact of endovascular treatment for acute ischaemic stroke patients in the Netherlands for 2015-2021.

INTRODUCTION: Endovascular treatment (EVT) has been proven to be both effective and cost-effective for patients with acute ischaemic stroke. We investigated the budget impact of large-scale implementation of EVT for acute ischaemic stroke patients in the Netherlands for 2015-2021. METHODS: An analysis was performed from a healthcare perspective as a preplanned substudy of the Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). Estimated yearly costs during follow-up after stroke for patients who had or had not been treated with EVT as add-on to usual care were linked to numbers of new patients retrieved from 2 Dutch registries of EVT that started after the last inclusion in MR CLEAN (2014). Aggregated costs and costs per care sector were calculated based on prevalence using a population dynamic tool. RESULTS: From 2015, the yearly number of new acute ischaemic stroke patients receiving EVT increased almost threefold, from 812 in 2015 to 2,370 in 2021. The introduction of EVT plus usual care resulted in estimated net annual savings that increased from €â€¯2.9 million in 2015 to €â€¯58 million in 2021. CONCLUSION: Offering EVT as add-on to usual care for acute ischaemic stroke patients was increasingly cost saving from a national healthcare perspective but affected distinct healthcare sectors differently.

Limited Clinical Impact of Ultralow-Dose Computed Tomography in Suspected Community-Acquired Pneumonia.

Patients clinically suspected of community-acquired pneumonia (CAP) were randomized between ultralow-dose chest computed tomography ([ULDCT] 261 patients) and chest radiograph ([CXR] 231 patients). We did not find evidence that performing ULDCT instead of CXR affects antibiotic treatment policy or patient outcomes. However, in a subgroup of afebrile patients, there were more patients diagnosed with CAP in the ULDCT group (ULDCT, 106 of 608 patients; CXR, 71 of 654 patients; P = .001).

Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer: A Randomized Clinical Trial.

PURPOSE: Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking. METHODS: Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior < .0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality. RESULTS: Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior = .0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior = .0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P = .4940). CONCLUSION: On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.

Acute pain management after thoracoscopic lung resection: a systematic review and explorative meta-analysis.

OBJECTIVES: Pain after thoracoscopic surgery may increase the incidence of postoperative complications and impair recovery. Guidelines lack consensus regarding postoperative analgesia. We performed a systematic review and meta-analysis to determine the mean pain scores of different analgesic techniques (thoracic epidural analgesia, continuous or single-shot unilateral regional analgesia and only systemic analgesia) after thoracoscopic anatomical lung resection. METHODS: Medline, Embase and Cochrane databases were searched until 1 October 2022. Patients undergoing at least >70% anatomical resections through thoracoscopy reporting postoperative pain scores were included. Due to a high inter-study variability an explorative meta-analysis next to an analytic meta-analysis was performed. The quality of evidence has been evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: A total of 51 studies comprising 5573 patients were included. Mean 24, 48 and 72 h pain scores with 95% confidence interval on a 0-10 scale were calculated. Length of hospital stay, postoperative nausea and vomiting, additional opioids and the use of rescue analgesia were analysed as secondary outcomes. A common-effect size was estimated with an extreme high heterogeneity for which pooling of the studies was not appropriate. An exploratory meta-analysis demonstrated acceptable mean pain scores of Numeric Rating Scale <4 for all analgesic techniques. CONCLUSIONS: This extensive literature review and attempt to pool mean pain scores for meta-analysis demonstrates that unilateral regional analgesia is gaining popularity over thoracic epidural analgesia in thoracoscopic anatomical lung resection, despite great heterogeneity and limitations of current studies precluding such recommendations. PROSPERO REGISTRATION: ID number 205311.

Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

Oncological Safety and Potential Cost Savings of Routine vs Selective Histopathological Examination After Appendectomy: Results of the Multicenter, Prospective, Cross-Sectional FANCY Study.

OBJECTIVE: To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy. BACKGROUND: The necessity of routine histopathological examination after appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking. METHODS: In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination. RESULTS: Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were €725,400 per 10,000 patients. CONCLUSIONS: Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.