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Background: Patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) are regularly treated with FOLFIRINOX, a chemotherapy regimen based on 5-fluorouracil, irinotecan and oxaliplatin, which is associated with high toxicity. Dosing of FOLFIRINOX is based on body surface area, risking under- or overdosing caused by altered pharmacokinetics due to interindividual differences in body composition. This study aimed to investigate the relationship between body composition and treatment toxicity in advanced stage PDAC patients treated with FOLFIRINOX., Methods: Data from patients treated at the Maastricht University Medical Centre + between 2012 and 2020 were collected retrospectively (n = 65). Skeletal muscle-, visceral adipose tissue, subcutaneous adipose tissue-, (SM-Index, VAT-Index, SAT-Index resp.) and Skeletal Muscle Radiation Attenuation (SM-RA) were calculated after segmentation of computed tomography (CT) images at the third lumbar level using a validated deep learning method. Lean body mass (LBM) was estimated using SM-Index. Toxicities were scored and grade 3-4 adverse events were considered dose-limiting toxicities (DLTs)., Results: Sixty-seven DLTs were reported during the median follow-up of 51.4 (95%CI 39.2-63.7) weeks. Patients who experienced at least one DLT had significantly higher dose intensity per LBM for all separate cytotoxics of FOLFIRINOX. Independent prognostic factors for the number of DLTs per cycle were: sarcopenia (β = 0.292; 95%CI 0.013 to 0.065; p = 0.013), SM-Index change (% per 30 days, β = -0.045; 95%CI -0.079 to -0.011; p = 0.011), VAT-Index change (% per 30 days, β = -0.006; 95%CI -0.012 to 0.000; p = 0.040) between diagnosis and the first follow-up CT scan, and cumulative relative dose intensity >80 % (β = -0.315; 95 % CI -0.543 to -0.087; p = 0.008)., Conclusion: Sarcopenia and early muscle and fat wasting during FOLFIRINOX treatment were associated with treatment-related toxicity, warranting exploration of body composition guided personalized dosing of chemotherapeutics to limit DLTs., Competing Interests: Declaration of competing interest Judith de Vos-Geelen has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, and has received institutional research funding from Servier. All outside the submitted work. All other authors did not have any conflicts to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: International guidelines recommend monitoring the use and outcome of minimally invasive pancreatic surgery (MIPS). However, data from prospective international audits on minimally invasive distal pancreatectomy (MIDP) are lacking. This study examined the use and outcome of robot-assisted (RDP) and laparoscopic (LDP) distal pancreatectomy in the E-MIPS registry., Patients and Methods: Post-hoc analysis in a prospective audit on MIPS, including consecutive patients undergoing MIDP in 83 centers from 19 European countries (01-01-2019/31-12-2021). Primary outcomes included intraoperative events (grade 1: excessive blood loss, grade 2: conversion/change in operation, grade 3: intraoperative death), major morbidity, and in-hospital/30-day mortality. Multivariable logistic regression analyses identified high-risk groups for intraoperative events. RDP and LDP were compared in the total cohort and high-risk groups., Results: Overall, 1672 patients undergoing MIDP were included; 606 (36.2%) RDP and 1066 (63.8%) LDP. The annual use of RDP increased from 30.5% to 42.6% ( P <0.001). RDP was associated with fewer grade 2 intraoperative events compared with LDP (9.6% vs. 16.8%, P <0.001), with longer operating time (238 vs. 201 min, P <0.001). No significant differences were observed between RDP and LDP regarding major morbidity (23.4% vs. 25.9%, P =0.264) and in-hospital/30-day mortality (0.3% vs. 0.8%, P =0.344). Three high-risk groups were identified; BMI greater than 25 kg/m 2 , previous abdominal surgery, and vascular involvement. In each group, RDP was associated with fewer conversions and longer operative times., Conclusion: This European registry-based study demonstrated favorable outcomes for MIDP, with mortality rates below 1%. LDP remains the predominant approach, whereas the use of RDP is increasing. RDP was associated with fewer conversions and longer operative time, including in high-risk subgroups. Future randomized trials should confirm these findings and assess cost differences., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Prophylactic passive abdominal drainage is standard practice after distal pancreatectomy. This approach aims to mitigate the consequences of postoperative pancreatic fistula (POPF) but its added value, especially in patients at low risk of POPF, is currently being debated. We aimed to assess the non-inferiority of a no-drain policy in patients after distal pancreatectomy., Methods: In this international, multicentre, open-label, randomised controlled, non-inferiority trial, we recruited patients aged 18 years or older undergoing open or minimally invasive elective distal pancreatectomy for all indications in 12 centres in the Netherlands and Italy. We excluded patients with an American Society of Anesthesiology (ASA) physical status of 4-5 or WHO performance status of 3-4, added by amendment following the death of a patient with ASA 4 due to a pre-existing cardiac condition. Patients were randomly assigned (1:1) intraoperatively by permuted blocks (size four to eight) to either no drain or prophylactic passive drain placement, stratified by annual centre volume (<40 or ≥40 distal pancreatectomies) and low risk or high risk of grade B or C POPF. High-risk was defined as a pancreatic duct of more than 3 mm in diameter, a pancreatic thickness at the neck of more than 19 mm, or both, based on the Distal Pancreatectomy Fistula Risk Score. Other patients were considered low-risk. The primary outcome was the rate of major morbidity (Clavien-Dindo score ≥III), and the most relevant secondary outcome was grade B or C POPF, grading per the International Study Group for Pancreatic Surgery. Outcomes were assessed up to 90 days postoperatively and analysed in the intention-to-treat population and per-protocol population, which only included patients who received the allocated treatment. A prespecified non-inferiority margin of 8% was compared with the upper limit of the two-sided 95% CI (Wald) of unadjusted risk difference to assess non-inferiority. This trial is closed and registered in the Netherlands Trial Registry, NL9116., Findings: Between Oct 3, 2020, and April 28, 2023, 376 patients were screened for eligibility and 282 patients were randomly assigned to the no-drain group (n=138; 75 [54%] women and 63 [46%] men) or the drain group (n=144; 73 [51%] women and 71 [49%] men). Seven patients in the no-drain group received a drain intraoperatively; consequently, the per-protocol population included 131 patients in the no-drain group and 144 patients in the drain group. The rate of major morbidity was non-inferior in the no-drain group compared with the drain group in the intention-to-treat analysis (21 [15%] vs 29 [20%]; risk difference -4·9 percentage points [95% CI -13·8 to 4·0]; p non-inferiority =0·0022) and the per-protocol analysis (21 [16%] vs 29 [20%]; risk difference -4·1 percentage points [-13·2 to 5·0]; p non-inferiority =0·0045). Grade B or C POPF was observed in 16 (12%) patients in the no-drain group and in 39 (27%) patients in the drain group (risk difference -15·5 percentage points [95% CI -24·5 to -6·5]; p non-inferiority <0·0001) in the intention-to-treat analysis. Three patients in the no-drain group died within 90 days; the cause of death in two was not considered related to the trial. The third death was a patient with an ASA score of 4 who died after sepsis and a watershed cerebral infarction at second admission, leading to multiple organ failure. No patients in the drain group died within 90 days., Interpretation: A no-drain policy is safe in terms of major morbidity and reduced the detection of grade B or C POPF, and should be the new standard approach in eligible patients undergoing distal pancreatectomy., Funding: Ethicon UK (Johnson & Johnson Medical, Edinburgh, UK)., Competing Interests: Declaration of interests MAH received grants for investigator-initiated studies from Ethicon, Medtronic, and Intuitive Surgical. MGB received grants for investigator-initiated studies from Ethicon, Medtronic, OncoSil, and Intuitive Surgical. DJL received a proctoring grant from Intuitive Surgical. GM received personal consulting fees for clinical trial design from OncoSil Medical and participates in the advisory board of OncoSil Medical. CHJvE received a consultancy grant from AIM ImmunoTech. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Importance: Unintended tumor-positive resection margins occur frequently during minimally invasive surgery for colorectal liver metastases and potentially negatively influence oncologic outcomes., Objective: To assess whether indocyanine green (ICG)-fluorescence-guided surgery is associated with achieving a higher radical resection rate in minimally invasive colorectal liver metastasis surgery and to assess the accuracy of ICG fluorescence for predicting the resection margin status., Design, Setting, and Participants: The MIMIC (Minimally Invasive, Indocyanine-Guided Metastasectomy in Patients With Colorectal Liver Metastases) trial was designed as a prospective single-arm multicenter cohort study in 8 Dutch liver surgery centers. Patients were scheduled to undergo minimally invasive (laparoscopic or robot-assisted) resections of colorectal liver metastases between September 1, 2018, and June 30, 2021., Exposures: All patients received a single intravenous bolus of 10 mg of ICG 24 hours prior to surgery. During surgery, ICG-fluorescence imaging was used as an adjunct to ultrasonography and regular laparoscopy to guide and assess the resection margin in real time. The ICG-fluorescence imaging was performed during and after liver parenchymal transection to enable real-time assessment of the tumor margin. Absence of ICG fluorescence was favorable both during transection and in the tumor bed directly after resection., Main Outcomes and Measures: The primary outcome measure was the radical (R0) resection rate, defined by the percentage of colorectal liver metastases resected with at least a 1 mm distance between the tumor and resection plane. Secondary outcomes were the accuracy of ICG fluorescence in detecting margin-positive (R1; <1 mm margin) resections and the change in surgical management., Results: In total, 225 patients were enrolled, of whom 201 (116 [57.7%] male; median age, 65 [IQR, 57-72] years) with 316 histologically proven colorectal liver metastases were included in the final analysis. The overall R0 resection rate was 92.4%. Re-resection of ICG-fluorescent tissue in the resection cavity was associated with a 5.0% increase in the R0 percentage (from 87.4% to 92.4%; P < .001). The sensitivity and specificity for real-time resection margin assessment were 60% and 90%, respectively (area under the receiver operating characteristic curve, 0.751; 95% CI, 0.668-0.833), with a positive predictive value of 54% and a negative predictive value of 92%. After training and proctoring of the first procedures, participating centers that were new to the technique had a comparable false-positive rate for predicting R1 resections during the first 10 procedures (odds ratio, 1.36; 95% CI, 0.44-4.24). The ICG-fluorescence imaging was associated with changes in intraoperative surgical management in 56 (27.9%) of the patients., Conclusions and Relevance: In this multicenter prospective cohort study, ICG-fluorescence imaging was associated with an increased rate of tumor margin-negative resection and changes in surgical management in more than one-quarter of the patients. The absence of ICG fluorescence during liver parenchymal transection predicted an R0 resection with 92% accuracy. These results suggest that use of ICG fluorescence may provide real-time feedback of the tumor margin and a higher rate of complete oncologic resection.

Background: Differentiation between adenomas and carcinomas of the ampulla of Vater is crucial for therapy and prognosis. This was a systematic review of the literature on the accuracy of diagnostic modalities used to differentiate between benign and malignant ampullary tumours., Methods: A literature search was conducted in PubMed, Embase, CINAHL, and the Cochrane Library. Studies were included if they reported diagnostic test accuracy information among benign and malignant ampullary tumours, and used pathological diagnosis as the reference standard. Risk of bias was assessed using Quality Assessment on Diagnostic Accuracy Studies (QUADAS) 2 and QUADAS-C., Results: Ten studies comprising 397 patients were included. Frequently studied modalities were (CT; 2 studies), endoscopic ultrasonography (EUS; 3 studies), intraductal ultrasonography (IDUS; 2 studies), and endoscopic forceps biopsy (3 studies). For CT, the reported sensitivity for detecting ampullary carcinoma was 44 and 95%, and the specificity 58 and 60%. For EUS, the sensitivity ranged from 63 to 89% and the specificity between 50 and 100%. A sensitivity of 88 and 100% was reported for IDUS, with a specificity of 75 and 93%. For forceps biopsy, the sensitivity ranged from 20 to 91%, and the specificity from 75 to 86%. The overall risk of bias was scored as moderate to poor. Data were insufficient for meta-analysis., Conclusion: To differentiate benign from malignant ampullary tumours, EUS and IDUS seem to be the best diagnostic modalities. Sufficient high-quality evidence, however, is lacking., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Hepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of patients operated for HCAs < 50 mm compared to HCAs ≥ 50 mm. Changes in final postoperative diagnosis were assessed. We performed a retrospective study that included patients who underwent resection for (suspected) HCAs in the Netherlands from 2014 to 2019. Indication for resection was analyzed and stratified for small (<50 mm) and large (≥50 mm) tumors. Logistic regression analysis was performed on factors influencing change in tumor diagnosis. Out of 222 patients who underwent surgery, 44 (20%) patients had a tumor <50 mm. Median age was 46 (interquartile range [IQR], 33-56) years in patients with small tumors and 37 (IQR, 31-46) years in patients with large tumors ( p  = 0.016). Patients with small tumors were more frequently men (21% vs. 5%, p  = 0.002). Main indications for resection in patients with small tumors were suspicion of (pre)malignancy (55%), (previous) bleeding (14%), and male sex (11%). Patients with large tumors received operations because of tumor size >50 mm (52%), suspicion of (pre)malignancy (28%), and (previous) bleeding (5.1%). No difference was observed in HCA-subtype distribution between small and large tumors. Ninety-six (43%) patients had a postoperative change in diagnosis. Independent risk factors for change in diagnosis were tumor size <50 mm (adjusted odds ratio [aOR], 3.4; p  < 0.01), male sex (aOR, 3.7; p  = 0.03), and lack of hepatobiliary contrast-enhanced magnetic resonance imaging (CE-MRI) (aOR, 1.8; p  = 0.04). Resection for small (suspected) HCAs was mainly indicated by suspicion of (pre)malignancy, whereas for large (suspected) HCAs, tumor size was the most prevalent indication. Male sex, tumor size <50 mm, and lack of hepatobiliary CE-MRI were independent risk factors for postoperative change in tumor diagnosis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of the American Association for the Study of Liver Diseases.)

Introduction: Benign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma. Some BLTCs, for example, (large) hepatocellular adenoma, are at risk of complications. Incidence of malignant degeneration or haemorrhage is low in most other BLTCs. Nevertheless, the diagnosis BLTC may carry a substantial burden and patients may be symptomatic, necessitating treatment. The indications for interventions remain matter of debate. The primary study aim is to investigate patient-reported outcomes (PROs) of patients with BLTCs, with special regards to the influence of invasive treatment as compared with the natural course of the disease., Methods and Analysis: A nationwide observational cohort study of patients with BLTC will be performed between October 2021 and October 2026, the minimal follow-up will be 2 years. During surveillance, a questionnaire regarding symptoms and their impact will be sent to participants on a biannual basis and more often in case of invasive intervention. The questionnaire was previously developed based on PROs considered relevant to patients with BLTCs and their caregivers. Most questionnaires will be administered by computerised adaptive testing through the Patient-Reported Outcomes Measurement Information System. Data, such as treatment outcomes, will be extracted from electronic patient files. Multivariable analysis will be performed to identify patient and tumour characteristics associated with significant improvement in PROs or a complicated postoperative course., Ethics and Dissemination: The study was assessed by the Medical Ethics Committee of the University Medical Center Groningen and the Amsterdam UMC. Local consultants will provide information and informed consent will be asked of all patients. Results will be published in a peer-reviewed journal., Study Registration: NL8231-10 December 2019; Netherlands Trial Register., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study evaluates the effect of preoperative macrogol on gastrointestinal recovery and functional recovery after liver surgery combined with an enhanced recovery programme in a randomized controlled setting., Methods: Patients were randomized to either 1 sachet of macrogol a day, one week prior to surgery versus no preoperative laxatives. Postoperative management for all patients was within an enhanced recovery programme. The primary outcome was recovery of gastrointestinal function, defined as Time to First Defecation. Secondary outcomes included Time to Functional Recovery., Results: Between August 2012 and September 2016, 82 patients planned for liver resection were included in the study, 39 in the intervention group and 43 in the control group. Median Time to First Defecation was 4.0 days in the intervention group (IQR 2.8-5.0) and 4.0 days in the control group (IQR 2.9-5.0), P = 0.487. Median Time to Functional Recovery was day 6 (IQR 4.0-8.0) in the intervention group and day 5 (IQR 4.0-7.5) in the control group, P = 0.752. No significant differences were seen in complication rate, reinterventions or mortality., Conclusion: This randomized controlled trial showed no advantages of 1 sachet of macrogol preoperatively combined with an enhanced recovery programme, for patients undergoing liver surgery., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer cachexia and skeletal muscle wasting are related to poor survival. In this study, quantitative body composition measurements using computed tomography (CT) were investigated in relation to survival, post-operative complications, and surgical site infections in surgical patients with cancer of the head of the pancreas., Methods: A prospective cohort of 199 patients with cancer of the head of the pancreas was analysed by CT imaging at the L3 level to determine (i) muscle radiation attenuation (average Hounsfield units of total L3 skeletal muscle); (ii) visceral adipose tissue area; (iii) subcutaneous adipose tissue area; (iv) intermuscular adipose tissue area; and (v) skeletal muscle area. Sex-specific cut-offs were determined at the lower tertile for muscle radiation attenuation and skeletal muscle area and the higher tertile for adipose tissues. These variables of body composition were related to overall survival, severe post-operative complications (Dindo-Clavien ≥ 3), and surgical site infections (wounds inspected daily by an independent trial nurse) using Cox-regression analysis and multivariable logistic regression analysis, respectively., Results: Low muscle radiation attenuation was associated with shorter survival in comparison with moderate and high muscle radiation attenuation [median survival 10.8 (95% CI: 8.8-12.8) vs. 17.4 (95% CI: 14.7-20.1), and 18.5 (95% CI: 9.2-27.8) months, respectively; P < 0.008]. Patient subgroups with high muscle radiation attenuation combined with either low visceral adipose tissue or age <70 years had longer survival than other subgroups (P = 0.011 and P = 0.001, respectively). Muscle radiation attenuation was inversely correlated with intermuscular adipose tissue (r p  = -0.697, P < 0.001). High visceral adipose tissue was associated with an increased surgical site infection rate, OR: 2.4 (95% CI: 1.1-5.3; P = 0.027)., Conclusions: Low muscle radiation attenuation was associated with reduced survival, and high visceral adiposity was associated with an increase in surgical site infections. The strong correlation between muscle radiation attenuation and intermuscular adipose tissue suggests the presence of ectopic fat in muscle, warranting further investigation. CT image analysis could be implemented in pre-operative risk assessment to assist in treatment decision-making., (© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: An enhanced recovery after surgery (ERAS) program aims to reduce the stress response to surgery and thereby accelerate recovery. It is unclear whether these programs can be safely implemented for elderly patients, especially in highly complex surgery such as pancreaticoduodenectomy (PD). The objective of this study was to evaluate the feasibility of an ERAS program in elderly patients undergoing PD., Methods: Implementation of the ERAS protocol was studied prospectively in a consecutive series of patients undergoing PD between January 2009 and August 2013. Patients were divided into two groups: ≤ 65 years and ≥ 70 years. Endpoints were length of stay (LOS), readmissions, morbidity, mortality, and compliance with ERAS targets., Results: Of a total of 110 patients, 55 were ≤ 65 years (median 57) and 55 ≥ 70 years (median 77). Median LOS was 14 days in both groups. In patients without complications median LOS was 9 days. Both mortality and readmissions did not differ between groups (mortality n = 3 (5.5 %) in younger versus n = 6 (10.9 %) in older patients, p = 0.49, readmissions: n = 11 (20 %) versus n = 7 (12.7 %), p = 0.44). CT-drainage and relaparotomy-rates were not different between groups, nor was overall morbidity (n = 31 (56.3 %) in the older versus n = 35 (63.3 %) in the younger group, p = 0.44). There were no differences in compliance with elements of the ERAS protocol between groups., Conclusion: An ERAS program seems feasible and safe for patients ≥ 70 years of age undergoing PD.

Background: To warrant the adoption or rejection of health care interventions in daily practice, it is important to establish the point at which the available evidence is considered sufficiently conclusive. This process must avoid bias resulting from multiple testing and take account of heterogeneity across studies. The present paper addresses the issue of whether the available evidence may be considered sufficiently conclusive to continue or discontinue the current practice of postoperative abdominal drainage after pancreatic resection., Methods: A systematic review was conducted of randomized and non-randomized studies comparing outcomes after routine intra-abdominal drainage with those after no drainage after pancreatic resection. Studies were retrieved from the PubMed, Cochrane Central Trial Register and EMBASE databases and meta-analysed cumulatively, adjusting for multiple testing and heterogeneity using the iterated logarithm method., Results: Three reports, describing, respectively, one randomized and two non-randomized studies with a comparative design, met the inclusion criteria predefined for primary studies reporting on drain management and complications after pancreatic resection. These studies included 89, 179 and 226 patients, respectively. The absolute differences in rates of postoperative complications in these studies were -6.4%, -9.5% and -6.3%, respectively, in favour of the no-drain groups. The cumulative risk difference in major complications, adjusted for multiple testing and heterogeneity, was -7.8%, with a 95% confidence interval of -20.2% to 4.7% (P = 0.214)., Conclusions: The routine use of abdominal drains after pancreatic resection may result in a higher risk for major complications, but the evidence is inconclusive., (© 2012 International Hepato-Pancreato-Biliary Association.)

Objectives: Enhanced recovery after surgery (ERAS) or fast-track protocols have been implemented in different fields of surgery to attenuate the surgical stress response and accelerate recovery. The objective of this study was to systematically review the literature on outcomes of ERAS protocols applied in liver surgery., Methods: The MEDLINE, EMBASE, PubMed and Cochrane Library databases were searched for randomized controlled trials (RCTs), case-control studies and case series published between January 1966 and October 2011 comparing adult patients undergoing elective liver surgery in an ERAS programme with those treated in a conventional manner. The primary outcome measure was hospital length of stay (LoS). Secondary outcome measures were time to functional recovery, and complication, readmission and mortality rates., Results: A total of 307 articles were found, six of which were included in the review. These comprised two RCTs, three case-control studies and one retrospective case series. Median LoS ranged from 4 days in an ERAS group to 11 days in a control group. Morbidity, mortality and readmission rates did not differ significantly between the groups. Only two studies assessed time to functional recovery. Functional recovery in these studies was reached 2 days before discharge., Conclusions: This systematic review suggests that ERAS protocols can be successfully implemented in liver surgery. Length of stay is reduced without compromising morbidity, mortality or readmission rates., (© 2012 International Hepato-Pancreato-Biliary Association.)