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Background: A recent systematic review recommends against the use of any of the current COVID-19 prediction models in clinical practice. To enable clinicians to appropriately profile and treat suspected COVID-19 patients at the emergency department (ED), externally validated models that predict poor outcome are desperately needed., Objective: Our aims were to identify predictors of poor outcome, defined as mortality or ICU admission within 30 days, in patients presenting to the ED with a clinical suspicion of COVID-19, and to develop and externally validate a prediction model for poor outcome., Methods: In this prospective, multi-center study, we enrolled suspected COVID-19 patients presenting at the EDs of two hospitals in the Netherlands. We used backward logistic regression to develop a prediction model. We used the area under the curve (AUC), Brier score and pseudo-R2 to assess model performance. The model was externally validated in an Italian cohort., Results: We included 1193 patients between March 12 and May 27 2020, of whom 196 (16.4%) had a poor outcome. We identified 10 predictors of poor outcome: current malignancy (OR 2.774; 95%CI 1.682-4.576), systolic blood pressure (OR 0.981; 95%CI 0.964-0.998), heart rate (OR 1.001; 95%CI 0.97-1.028), respiratory rate (OR 1.078; 95%CI 1.046-1.111), oxygen saturation (OR 0.899; 95%CI 0.850-0.952), body temperature (OR 0.505; 95%CI 0.359-0.710), serum urea (OR 1.404; 95%CI 1.198-1.645), C-reactive protein (OR 1.013; 95%CI 1.001-1.024), lactate dehydrogenase (OR 1.007; 95%CI 1.002-1.013) and SARS-CoV-2 PCR result (OR 2.456; 95%CI 1.526-3.953). The AUC was 0.86 (95%CI 0.83-0.89), with a Brier score of 0.32 and, and R2 of 0.41. The AUC in the external validation in 500 patients was 0.70 (95%CI 0.65-0.75)., Conclusion: The COVERED risk score showed excellent discriminatory ability, also in an external validation. It may aid clinical decision making, and improve triage at the ED in health care environments with high patient throughputs.

Background: The systemic inflammatory response seen after surgery seems to be related to postoperative complications. A reduction of the inflammatory response through minimally invasive surgery might therefore be the mechanism via which postoperative outcome could be improved. The aim of this study was to investigate if postoperative inflammatory markers differed between laparoscopic (LPD) and open pancreatoduodenectomy (OPD) and if there was a relationship between inflammatory markers and the occurrence of postoperative complications., Methods: A side study of the multicenter randomized controlled LEOPARD-2 trial comparing LPD to OPD was performed. Area under the curve (AUC) for plasma inflammatory markers, including interleukin (IL-) 6, IL-8 and C reactive protein (CRP) levels, were determined during the first 96 postoperative hours and compared between LPD and OPD, Clavien-Dindo ≥ III complications, and postoperative pancreatic fistula (POPF) grade B/C., Results: Overall, 38 patients were included (18 LPD and 20 OPD). The median AUC of IL-6 was 627 (195-1378) after LPD vs. 338 (175-694)pg/mL after OPD, (p = 0.114). The AUC of IL-8 and CRP were comparable. IL-6 levels were higher in patients with a Clavien-Dindo ≥ III complication (634[309-1489] vs. 297 [171-680], p = 0.034) and POPF grade B/C (994 [534-3265] vs. 334 [173-704], p = 0.003). In patients with a POPF grade B/C, IL-6 levels tended to be higher after LPD, as compared to OPD (3533[IQR 1133-3533] vs. 715[IQR 39-1658], p = 0.053)., Conclusion: LPD, as compared to OPD, did not reduce the postoperative inflammatory response. IL-6 levels were associated with postoperative complications and pancreatic fistula., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Laparoscopic pancreatoduodenectomy with open reconstruction (LPD-OR) has been suggested to lower the rate of postoperative pancreatic fistula reported after laparoscopic pancreatoduodenectomy with laparoscopic reconstruction (LPD). Propensity score matched studies are, lacking., Methods: This is a multicenter prospective cohort study including patients from 7 Dutch centers between 2014-2018. Patients undergoing LPD-OR were matched LPD patients in a 1:1 ratio based on propensity scores. Main outcomes were postoperative pancreatic fistulas (POPF) grade B/C and Clavien-Dindo grade ≥3 complications., Results: A total of 172 patients were included, involving the first procedure for all centers. All 56 patients after LPD-OR could be matched to a patient undergoing LPD. With LPD-OR, the unplanned conversion rate was 21% vs. 9% with LPD (P < 0.001). Median blood loss (300 vs. 400 mL, P = 0.85), operative time (401 vs. 378 min, P = 0.62) and hospital stay (10 vs. 12 days, P = 0.31) were comparable for LPD-OR vs. LPD, as were Clavien-Dindo grade ≥3 complications (38% vs. 52%, P = 0.13), POPF grade B/C (23% vs. 21%, P = 0.82), and 90-day mortality (4% vs. 4%, P > 0.99)., Conclusion: In this propensity matched cohort performed early in the learning curve, no benefit was found for LPD-OR, as compared to LPD., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Minimally invasive distal pancreatectomy decreases time to functional recovery compared with open distal pancreatectomy, but the cost-effectiveness and impact on disease-specific quality of life have yet to be established., Methods: The LEOPARD trial randomized patients to minimally invasive (robot-assisted or laparoscopic) or open distal pancreatectomy in 14 Dutch centres between April 2015 and March 2017. Use of hospital healthcare resources, complications and disease-specific quality of life were recorded up to 1 year after surgery. Unit costs of hospital healthcare resources were determined, and cost-effectiveness and cost-utility analyses were performed. Primary outcomes were the costs per day earlier functional recovery and per quality-adjusted life-year., Results: All 104 patients who had a distal pancreatectomy (48 minimally invasive and 56 open) in the trial were included in this study. Patients who underwent a robot-assisted procedure were excluded from the cost analysis. Total medical costs were comparable after laparoscopic and open distal pancreatectomy (mean difference €-427 (95 per cent bias-corrected and accelerated confidence interval €-4700 to 3613; P = 0·839). Laparoscopic distal pancreatectomy was shown to have a probability of at least 0·566 of being more cost-effective than the open approach at a willingness-to-pay threshold of €0 per day of earlier recovery, and a probability of 0·676 per additional quality-adjusted life-year at a willingness-to-pay threshold of €80 000. There were no significant differences in cosmetic satisfaction scores (median 9 (i.q.r. 5·75-10) versus 7 (4-8·75); P = 0·056) and disease-specific quality of life after minimally invasive (laparoscopic and robot-assisted procedures) versus open distal pancreatectomy., Conclusion: Laparoscopic distal pancreatectomy was at least as cost-effective as open distal pancreatectomy in terms of time to functional recovery and quality-adjusted life-years. Cosmesis and quality of life were similar in the two groups 1 year after surgery., (© 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: Laparoscopic pancreatoduodenectomy may improve postoperative recovery compared with open pancreatoduodenectomy. However, there are concerns that the extensive learning curve of this complex procedure could increase the risk of complications. We aimed to assess whether laparoscopic pancreatoduodenectomy could reduce time to functional recovery compared with open pancreatoduodenectomy., Methods: This multicentre, patient-blinded, parallel-group, randomised controlled phase 2/3 trial was performed in four centres in the Netherlands that each do 20 or more pancreatoduodenectomies annually; surgeons had to have completed a dedicated training programme for laparoscopic pancreatoduodenectomy and have done 20 or more laparoscopic pancreatoduodenectomies before trial participation. Patients with a benign, premalignant, or malignant indication for pancreatoduodenectomy, without signs of vascular involvement, were randomly assigned (1:1) to undergo either laparoscopic or open pancreatoduodenectomy using a central web-based system. Randomisation was stratified for annual case volume and preoperative estimated risk of pancreatic fistula. Patients were blinded to treatment allocation. Analysis was done according to the intention-to-treat principle. The main objective of the phase 2 part of the trial was to assess the safety of laparoscopic pancreatoduodenectomy (complications and mortality), and the primary outcome of phase 3 was time to functional recovery in days, defined as all of the following: adequate pain control with only oral analgesia; independent mobility; ability to maintain more than 50% of the daily required caloric intake; no need for intravenous fluid administration; and no signs of infection (temperature <38·5°C). This trial is registered with Trialregister.nl, number NTR5689., Findings: Between May 13 and Dec 20, 2016, 42 patients were randomised in the phase 2 part of the trial. Two patients did not receive surgery and were excluded from analyses in accordance with the study protocol. Three (15%) of 20 patients died within 90 days after laparoscopic pancreatoduodenectomy, compared with none of 20 patients after open pancreatoduodenectomy. Based on safety data from the phase 2 part of the trial, the data and safety monitoring board and protocol committee agreed to proceed with phase 3. Between Jan 31 and Nov 14, 2017, 63 additional patients were randomised in phase 3 of the trial. Four patients did not receive surgery and were excluded from analyses in accordance with the study protocol. After randomisation of 105 patients (combining patients from both phase 2 and phase 3), of whom 99 underwent surgery, the trial was prematurely terminated by the data and safety monitoring board because of a difference in 90-day complication-related mortality (five [10%] of 50 patients in the laparoscopic pancreatoduodenectomy group vs one [2%] of 49 in the open pancreatoduodenectomy group; risk ratio [RR] 4·90 [95% CI 0·59-40·44]; p=0·20). Median time to functional recovery was 10 days (95% CI 5-15) after laparoscopic pancreatoduodenectomy versus 8 days (95% CI 7-9) after open pancreatoduodenectomy (log-rank p=0·80). Clavien-Dindo grade III or higher complications (25 [50%] of 50 patients after laparoscopic pancreatoduodenectomy vs 19 [39%] of 49 after open pancreatoduodenectomy; RR 1·29 [95% CI 0·82-2·02]; p=0·26) and grade B/C postoperative pancreatic fistulas (14 [28%] vs 12 [24%]; RR 1·14 [95% CI 0·59-2·22]; p=0·69) were comparable between groups., Interpretation: Although not statistically significant, laparoscopic pancreatoduodenectomy was associated with more complication-related deaths than was open pancreatoduodenectomy, and there was no difference between groups in time to functional recovery. These safety concerns were unexpected and worrisome, especially in the setting of trained surgeons working in centres performing 20 or more pancreatoduodenectomies annually. Experience, learning curve, and annual volume might have influenced the outcomes; future research should focus on these issues., Funding: Grant for investigator-initiated studies by Johnson & Johnson Medical Limited., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In the mandatory nationwide Dutch Pancreatic Cancer Audit, rates of major complications and Failure to Rescue (FTR) after pancreatoduodenectomy between low- and high-mortality hospitals are compared, and independent predictors for FTR investigated., Methods: Patients undergoing pancreatoduodenectomy in 2014 and 2015 in The Netherlands were included. Hospitals were divided into quartiles based on mortality rates. The rate of major complications (Clavien-Dindo ≥3) and death after a major complication (FTR) were compared between these quartiles. Independent predictors for FTR were identified by multivariable logistic regression analysis., Results: Out of 1.342 patients, 391 (29%) developed a major complication and in-hospital mortality was 4.2%. FTR occurred in 56 (14.3%) patients. Mortality was 0.9% in the first hospital quartile (4 hospitals, 327 patients) and 8.1% in the fourth quartile (5 hospitals, 310 patients). The rate of major complications increased by 40% (25.7% vs 35.2%) between the first and fourth hospital quartile, whereas the FTR rate increased by 560% (3.6% vs 22.9%). Independent predictors of FTR were male sex (OR = 2.1, 95%CI 1.2-3.9), age >75 years (OR = 4.3, 1.8-10.2), BMI ≥30 (OR = 2.9, 1.3-6.6), histopathological diagnosis of periampullary cancer (OR = 2.0, 1.1-3.7), and hospital volume <30 (OR = 3.9, 1.6-9.6)., Conclusions: Variations in mortality between hospitals after pancreatoduodenectomy were explained mainly by differences in FTR, rather than the incidence of major complications., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Data from observational studies suggest that minimally invasive pancreatoduodenectomy (MIPD) is superior to open pancreatoduodenectomy regarding intraoperative blood loss, postoperative morbidity, and length of hospital stay, without increasing total costs. However, several case-matched studies failed to demonstrate superiority of MIPD, and large registry studies from the USA even suggested increased mortality for MIPDs performed in low-volume (<10 MIPDs annually) centers. Randomized controlled multicenter trials are lacking but clearly required. We hypothesize that time to functional recovery is shorter after MIPD compared with open pancreatoduodenectomy, even in an enhanced recovery setting., Methods/design: LEOPARD-2 is a randomized controlled, parallel-group, patient-blinded, multicenter, phase 2/3, superiority trial in centers that completed the Dutch Pancreatic Cancer Group LAELAPS-2 training program for laparoscopic pancreatoduodenectomy or LAELAPS-3 training program for robot-assisted pancreatoduodenectomy and have performed ≥ 20 MIPDs. A total of 136 patients with symptomatic benign, premalignant, or malignant disease will be randomly assigned to undergo minimally invasive or open pancreatoduodenectomy in an enhanced recovery setting. After the first 40 patients (phase 2), the data safety monitoring board will assess safety outcomes (not blinded for treatment allocation) and decide on continuation to phase 3. Patients from phase 2 will then be included in phase 3. The primary outcome measure is time (days) to functional recovery. All patients will be blinded for the surgical approach, at least until postoperative day 5, but preferably until functional recovery has been attained. Secondary outcome measures are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life, and costs., Discussion: The LEOPARD-2 trial is designed to assess whether MIPD reduces time to functional recovery, as compared with open pancreatoduodenectomy in an enhanced recovery setting., Trial Registration: Netherlands Trial Register, NTR5689 . Registered on 2 March 2016.

Background: Cohort studies from expert centers suggest that laparoscopic distal pancreatectomy (LDP) is superior to open distal pancreatectomy (ODP) regarding postoperative morbidity and length of hospital stay. But the generalizability of these findings is unknown because nationwide data on LDP are lacking., Study Design: Adults who had undergone distal pancreatectomy in 17 centers between 2005 and 2013 were analyzed retrospectively. First, all LDPs were compared with all ODPs. Second, groups were matched using a propensity score. Third, the attitudes of pancreatic surgeons toward LDP were surveyed. The primary outcome was major complications (Clavien-Dindo grade ≥III)., Results: Among 633 included patients, 64 patients (10%) had undergone LDP and 569 patients (90%) had undergone ODP. Baseline characteristics were comparable, except for previous abdominal surgery and mean tumor size. In the full cohort, LDP was associated with fewer major complications (16% vs 29%; p = 0.02) and a shorter median [interquartile range, IQR] hospital stay (8 days [7-12 days] vs 10 days [8-14 days]; p = 0.03). Of all LDPs, 33% were converted to ODP. Matching succeeded for 63 LDP patients. After matching, the differences in major complications (9 patients [14%] vs 19 patients [30%]; p = 0.06) and median [IQR] length of hospital stay (8 days [7-12 days] vs 10 days [8-14 days]; p = 0.48) were not statistically significant. The survey demonstrated that 85% of surgeons welcomed LDP training., Conclusions: Despite nationwide underuse and an impact of selection bias, outcomes of LDP seemed to be at least noninferior to ODP. Specific training is welcomed and could improve both the use and outcomes of LDP., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)