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In childhood, developmental changes and environmental interactions highly affect orally dosed drug disposition across the age range. To optimize dosing regimens and ensure safe use of drugs in pediatric patients, understanding this age-dependent biology is necessary. In this proof-of-concept study, we aimed to culture age-specific enteroids from infant tissue which represent its original donor material, specifically for drug transport and metabolism. Enteroid lines from fresh infant tissues (n= 8, age range: 0.3–45 postnatal weeks) and adult tissues (n= 3) were established and expanded to 3D self-organizing enteroids. The gene expression of drug transporters P-gp (ABCB1), BCRP (ABCG2), MRP2 (ABCC2), and PEPT1 (SLC15A1) and drug metabolizing enzymes CYP3A4, CYP2C18, and UGT1A1 was determined with RT-qPCR in fresh tissue and its derivative differentiated enteroids. Expression levels of P-gp, BCRP, MRP2, and CYP3A4 were similar between tissues and enteroids. PEPT1 and CYP2C18 expression was lower in enteroids compared to that in the tissue. The expression of UGT1A1 in the tissue was lower than that in enteroids. The gene expression did not change with the enteroid passage number for all genes studied. Similar maturational patterns in tissues and enteroids were visually observed for P-gp, PEPT1, MRP2, CYP3A4, CYP2C18, and VIL1. In this explorative study, interpatient variability was high, likely due to the diverse patient characteristics of the sampled population (e.g., disease, age, and treatment). To summarize, maturational patterns of clinically relevant ADME genes in tissue were maintained in enteroids. These findings are an important step toward the potential use of pediatric enteroids in pediatric drug development, which in the future may lead to improved pediatric safety predictions during drug development. We reason that such an approach can contribute to a potential age-specific platform to study and predict drug exposure and intestinal safety in pediatrics.

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.

IMPORTANCE: Understanding the learning curve of a new complex surgical technique helps to reduce potential patient harm. Current series on the learning curve of minimally invasive distal pancreatectomy (MIDP) are mostly small, single-center series, thus providing limited data. OBJECTIVE: To evaluate the length of pooled learning curves of MIDP in experienced centers. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study included MIDP procedures performed from January 1, 2006, through June 30, 2019, in 26 European centers from 8 countries that each performed more than 15 distal pancreatectomies annually, with an overall experience exceeding 50 MIDP procedures. Consecutive patients who underwent elective laparoscopic or robotic distal pancreatectomy for all indications were included. Data were analyzed between September 1, 2021, and May 1, 2022. EXPOSURES: The learning curve for MIDP was estimated by pooling data from all centers. MAIN OUTCOMES AND MEASURES: The learning curve was assessed for the primary textbook outcome (TBO), which is a composite measure that reflects optimal outcome, and for surgical mastery. Generalized additive models and a 2-piece linear model with a break point were used to estimate the learning curve length of MIDP. Case mix–expected probabilities were plotted and compared with observed outcomes to assess the association of changing case mix with outcomes. The learning curve also was assessed for the secondary outcomes of operation time, intraoperative blood loss, conversion to open rate, and postoperative pancreatic fistula grade B/C. RESULTS: From a total of 2610 MIDP procedures, the learning curve analysis was conducted on 2041 procedures (mean [SD] patient age, 58 [15.3] years; among 2040 with reported sex, 1249 were female [61.2%] and 791 male [38.8%]). The 2-piece model showed an increase and eventually a break point for TBO at 85 procedures (95% CI, 13-157 procedures), with a plateau TBO rate at 70%. The learning-associated loss of TBO rate was estimated at 3.3%. For conversion, a break point was estimated at 40 procedures (95% CI, 11-68 procedures); for operation time, at 56 procedures (95% CI, 35-77 procedures); and for intraoperative blood loss, at 71 procedures (95% CI, 28-114 procedures). For postoperative pancreatic fistula, no break point could be estimated. CONCLUSION AND RELEVANCE: In experienced international centers, the learning curve length of MIDP for TBO was considerable with 85 procedures. These findings suggest that although learning curves for conversion, operation time, and intraoperative blood loss are completed earlier, extensive experience may be needed to master the learning curve of MIDP.

IMPORTANCE: Glucose control in patients after total pancreatectomy is problematic because of the complete absence of α- and β-cells, leading to impaired quality of life. A novel, bihormonal artificial pancreas (BIHAP), using both insulin and glucagon, may improve glucose control, but studies in this setting are lacking. OBJECTIVE: To assess the efficacy and safety of the BIHAP in patients after total pancreatectomy. DESIGN, SETTING, AND PARTICIPANTS: This randomized crossover clinical trial compared the fully closed-loop BIHAP with current diabetes care (ie, insulin pump or pen therapy) in 12 adult outpatients after total pancreatectomy. Patients were recruited between August 21 and November 16, 2020. This first-in-patient study began with a feasibility phase in 2 patients. Subsequently, 12 patients were randomly assigned to 7-day treatment with the BIHAP (preceded by a 5-day training period) followed by 7-day treatment with current diabetes care, or the same treatments in reverse order. Statistical analysis was by Wilcoxon signed rank and Mann-Whitney U tests, with significance set at a 2-sided P < .05. MAIN OUTCOMES AND MEASURES: The primary outcome was the percentage of time spent in euglycemia (70-180 mg/dL [3.9-10 mmol/L]) as assessed by continuous glucose monitoring. RESULTS: In total, 12 patients (7 men and 3 women; median [IQR] age, 62.5 [43.1-74.0] years) were randomly assigned, of whom 3 did not complete the BIHAP phase and 1 was replaced. The time spent in euglycemia was significantly higher during treatment with the BIHAP (median, 78.30%; IQR, 71.05%-82.61%) than current diabetes care (median, 57.38%; IQR, 52.38%-81.35%; P = .03). In addition, the time spent in hypoglycemia (<70 mg/dL [3.9 mmol/L]) was lower with the BIHAP (median, 0.00% [IQR, 0.00%-0.07%] vs 1.61% [IQR, 0.80%-3.81%]; P = .004). No serious adverse events occurred. CONCLUSIONS AND RELEVANCE: Patients using the BIHAP after total pancreatectomy experienced an increased percentage of time in euglycemia and a reduced percentage of time in hypoglycemia compared with current diabetes care, without apparent safety risks. Larger randomized trials, including longer periods of treatment and an assessment of quality of life, should confirm these findings. TRIAL REGISTRATION: trialregister.nl Identifier: NL8871

Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection.

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ObjectiveFollowing an episode of acute biliary pancreatitis, cholecystectomy is advised to prevent recurrent biliary events. There is limited evidence regarding the optimal timing and safety of cholecystectomy in patients with necrotising biliary pancreatitis.DesignA post hoc analysis of a multicentre prospective cohort. Patients with biliary pancreatitis and a CT severity score of three or more were included in 27 Dutch hospitals between 2005 and 2014. Primary outcome was the optimal timing of cholecystectomy in patients with necrotising biliary pancreatitis, defined as: the optimal point in time with the lowest risk of recurrent biliary events and the lowest risk of complications of cholecystectomy. Secondary outcomes were the number of recurrent biliary events, periprocedural complications of cholecystectomy and the protective value of endoscopic sphincterotomy for the recurrence of biliary events.ResultsOverall, 248 patients were included in the analysis. Cholecystectomy was performed in 191 patients (77%) at a median of 103 days (P25–P75: 46–222) after discharge. Infected necrosis after cholecystectomy occurred in four (2%) patients with persistent peripancreatic collections. Before cholecystectomy, 66 patients (27%) developed biliary events. The risk of overall recurrent biliary events prior to cholecystectomy was significantly lower before 10 weeks after discharge (risk ratio 0.49 (95% CI 0.27 to 0.90); p=0.02). The risk of recurrent pancreatitis before cholecystectomy was significantly lower before 8 weeks after discharge (risk ratio 0.14 (95% CI 0.02 to 1.0); p=0.02). The complication rate of cholecystectomy did not decrease over time. Endoscopic sphincterotomy did not reduce the risk of recurrent biliary events (OR 1.40 (95% CI 0.74 to 2.83)).ConclusionThe optimal timing of cholecystectomy after necrotising biliary pancreatitis, in the absence of peripancreatic collections, is within 8 weeks after discharge.

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Background: We tested the added value of 3D-vision on procedure time and surgical performance during robotic pancreatoduodenectomy anastomoses in biotissue. Robotic surgery has the advantage of articulating instruments and 3D-vision. Consensus is lacking on the added value of 3D-vision during laparoscopic surgery. Given the improved dexterity with robotic surgery, the added value of 3D-vision may be even less with robotic surgery. Methods: In this experimental randomized controlled cross-over trial, 20 surgeons and surgical residents from 5 countries performed robotic pancreaticojejunostomy and hepaticojejunostomy anastomoses in a biotissue organ model using the da Vinci® system and were randomized to start with either 3D- or 2D-vision. Primary endpoint was the time required to complete both anastomoses. Secondary endpoint was the objective structured assessment of technical skill (OSATS; range 12–60) rating; scored by two observers blinded to 3D/2D. Results: Robotic 3D-vision reduced the combined operative time from 78.1 to 57.3 min (24.6% reduction, p< 0.001; 20.8 min reduction, 95% confidence intervals 12.8–28.8 min). This reduction was consistent for both anastomoses and between surgeons and residents, p< 0.001. Robotic 3D-vision improved OSATS performance by 6.1 points (20.8% improvement, p= 0.003) compared to 2D (39.4 to 45.1 points, ± 5.5). Conclusion: 3D-vision has a considerable added value during robotic pancreatoduodenectomy anastomoses in biotissue in both time reduction and improved surgical performance as compared to 2D-vision.

Background: Adhesions are a major cause of long-term postsurgical complications in abdominal and pelvic surgery. Existing adhesion scores primarily measure morphological characteristics of adhesions that do not necessarily correlate with morbidity. The aim of this study was to develop a clinical adhesion score (CLAS) measuring overall clinical morbidity of adhesion-related complications in abdominal and pelvic surgery. Methods: An international Delphi study was performed to identify relevant score items for adhesion-related complications, including small bowel obstruction, female infertility, chronic abdominal or pelvic pain, and difficulties at reoperation. The CLAS includes clinical outcomes, related to morbidity of adhesions, and weight factors, to correct the outcome scores for the likelihood that symptoms are truly caused by adhesions. In a pilot study, two independent researchers retrospectively scored the CLAS in 51 patients to evaluate inter-observer reliability, by calculating the Intraclass correlation coefficient. During a feasibility assessment, we evaluated whether the CLAS completely covered different clinical scenarios of adhesion-related morbidity. Results: Three Delphi rounds were performed. 43 experts agreed to participate, 38(88%) completed the first round, and 32 (74%) the third round. Consensus was reached on 83.4% of items. Inter-observer reliability for the CLAS was 0.95 (95% CI 0.91–0.97). During feasibility assessment, six items were included. As a result, the CLAS includes 22 outcomes and 23 weight factors. Conclusion: The CLAS represents a promising scoring system to measure and monitor the clinical morbidity of adhesion-related complications. Further studies are needed to confirm its utility in clinical practice.

Background: Robotic surgery may improve surgical performance during minimally invasive pancreatoduodenectomy as compared to 3D- and 2D-laparoscopy but comparative studies are lacking. This study assessed the impact of robotic surgery versus 3D- and 2D-laparoscopy on surgical performance and operative time using a standardized biotissue model for pancreatico- and hepatico-jejunostomy using pooled data from two randomized controlled crossover trials (RCTs). Methods: Pooled analysis of data from two RCTs with 60 participants (36 surgeons, 24 residents) from 11 countries (December 2017–July 2019) was conducted. Each included participant completed two pancreatico- and two hepatico-jejunostomies in biotissue using 3D-robotic surgery, 3D-laparoscopy, or 2D-laparoscopy. Primary outcomes were the objective structured assessment of technical skills (OSATS: 12–60) rating, scored by observers blinded for 3D/2D and the operative time required to complete both anastomoses. Sensitivity analysis excluded participants with excess experience compared to others. Results: A total of 220 anastomoses were completed (robotic 80, 3D-laparoscopy 70, 2D­laparoscopy 70). Participants in the robotic group had less surgical experience [median 1 (0–2) versus 6 years (4–12), p< 0.001], as compared to the laparoscopic group. Robotic surgery resulted in higher OSATS ratings (50, 43, 39 points, p= .021 and p< .001) and shorter operative time (56.5, 65.0, 81.5 min, p= .055 and p< .001), as compared to 3D- and 2D­laparoscopy, respectively, which remained in the sensitivity analysis. Conclusion: In a pooled analysis of two RCTs in a biotissue model, robotic surgery resulted in better surgical performance scores and shorter operative time for biotissue pancreatic and biliary anastomoses, as compared to 3D- and 2D-laparoscopy.

Adhesions are the most common driver of long-term morbidity after abdominal surgery. Although laparoscopy can reduce adhesion formation, the effect of minimally invasive surgery on long-term adhesion-related morbidity remains unknown. We aimed to assess the impact of laparoscopy on adhesion-related readmissions in a population-based cohort.

Introduction:The aim of this study was to review the effect of irreversible electroporation parameter settings on the size of the ablation zone and the occurrence of thermal effects. This insight would help to optimize treatment protocols and effectively ablate a tumor while controlling the occurrence of thermal effects. Methods:Various individual studies report the influence of variation in electroporation parameters on the ablation zone size or occurrence of thermal effects. However, no connections have yet been established between these studies. With the aim of closing the gap in the understanding of and personalizing irreversible electroporation parameter settings, a systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A quality assessment was performed using an in-house developed grading tool based on components of commonly used grading domains. Data on the electroporation parameters voltage, number of electrodes, inter-electrode distance, active needle length, pulse length/number/protocol/frequency, and pulse interval were extracted. Ablation zone size and temperature data were grouped per parameter. Spearman correlation and linear regression were used to define the correlation with outcome measures. Results:A total of 7661 articles were screened, of which 18 preclinical studies (animal and phantom studies) met the inclusion criteria. These studies were graded as moderate (4/18) and low (14/18) quality. Only the applied voltage appeared to be a significant linear predictor of ablation zone size: length, surface, and volume. The pulse number was moderately but nonlinearly correlated with the ablation zone length. Thermal effects were more likely to occur for higher voltages (≥2000 V), higher number of electrodes, and increased active needle length. Conclusion:Firm conclusions are limited since studies that investigated and precisely reported the influence of electroporation parameters on the ablation zone size and thermal effects were scarce and mostly graded low quality. High-quality studies are needed to improve the predictability of the combined effect of variation in parameter combinations and optimize irreversible electroporation treatment protocols.

Patients with pancreatic ductal adenocarcinoma (PDAC) have a dismal 5 year survival of 9%. One important limiting factor for treatment efficacy is the dense tumor-supporting stroma. The cancer-associated fibroblasts in this stroma deposit excessive amounts of extracellular matrix components and anti-inflammatory mediators, which hampers the efficacy of chemo- and immunotherapies. Systemic depletion of all activated fibroblasts is, however, not feasible nor desirable and therefore a local approach should be pursued. Here, we provide a proof-of-principle of using fibroblast activation protein (FAP)-targeted photodynamic therapy (tPDT) to treat PDAC. FAP-targeting antibody 28H1 and irrelevant control antibody DP47GS were conjugated to the photosensitizer IRDye700DX (700DX) and the chelator diethylenetriaminepentaacetic acid. In vitro binding and cytotoxicity were evaluated using the fibroblast cell-line NIH-3T3 stably transfected with FAP. Biodistribution of 111In-labeled antibody-700DX constructs was determined in mice carrying syngeneic tumors of the murine PDAC cell line PDAC299, and in a genetically engineered PDAC mouse model (CKP). Then, tPDT was performed by exposing the subcutaneous or the spontaneous PDAC tumors to 690 nm light. Induction of apoptosis after treatment was assessed using automated analyses of immunohistochemistry for cleaved caspase-3. 28H1-700DX effectively bound to 3T3-FAP cells and induced cytotoxicity upon exposure to 690 nm light, whereas no binding or cytotoxic effects were observed for DP47GS-700DX. Although both 28H1-700DX and DP47GS-700DX accumulated in subcutaneous PDAC299 tumors, autoradiography demonstrated that only 28H1-700DX reached the tumor core. On the contrary, control antibody DP47GS-700DX was only present at the tumor rim. In CKPmice, both antibodies accumulated in the tumor, but tumor-to-blood ratios of 28H1-700DX were higher than that of the control. Notably, in vivo FAP-tPDT caused upregulation of cleaved caspase-3 staining in both subcutaneous and in spontaneous tumors. In conclusion, we have shown that tPDT is a feasible approach for local depletion of FAP-expressing stromal cells in murine models for PDAC.

Formation of adhesions after peritoneal surgery results in high morbidity. Barriers to prevent adhesion are seldom applied, despite their ability to reduce the severity of adhesion formation. We evaluated the benefits and harms of four adhesion barriers that have been approved for clinical use.