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Introduction: Cholangiocarcinoma during pregnancy is an extremely rare entity with poor prognosis. Limited data are available regarding the diagnosis, progression, and pregnancy-related outcomes. Case Presentation: We present a case of mid-to-distal cholangiocarcinoma diagnosed by endosonographically guided biopsy during pregnancy at 15 weeks of gestation. Pregnancy termination was considered but based on multidisciplinary team and shared decision-making, surgery was performed during pregnancy. The patient underwent pancreatoduodenectomy with radical resection at 17 weeks of gestation. The postoperative period was complicated by a grade B postoperative pancreatic fistula treated by antibiotics only. At 39 weeks of gestation, a cesarean section was performed and a healthy boy was delivered. Conclusion: Decision-making on whether to perform a pancreatoduodenectomy in pregnant patients is challenging. This case report is the first to report on successful pancreatoduodenectomy during pregnancy for extrahepatic cholangiocarcinoma. Moreover, this case highlights the second trimester as favorable period for surgical intervention and the importance of close follow-up and diagnostic assessment of pregnant patients with unexplained and persistent abnormal liver function tests.

Abstract Background Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial. Methods This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the “Trials within Cohorts” (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19–9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment. Discussion The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients’ quality of life will be obtained. Trial registration Clinicaltrials.gov, NCT04875325 . Registered on May 6, 2021.

Introduction Postoperative pancreatic fistula (POPF) occurs in 25% of patients undergoing a high-risk pancreatoduodenectomy (PD) and is a driving cause of major morbidity, mortality, prolonged hospital stay and increased costs after PD. There is a need for perioperative methods to decrease these risks. In recent studies, preoperative chemoradiotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) reduced the rate of POPF seemingly due to radiation-induced pancreatic fibrosis. However, patients with a high risk of POPF mostly have a non-pancreatic periampullary tumour and do not receive radiotherapy. Prospective studies using radiotherapy specifically to reduce the risk of POPF have not been performed. We aim to assess the safety, feasibility and preliminary efficacy of preoperative stereotactic radiotherapy on the future pancreatic neck transection margin to reduce the rate of POPF.Methods and analysis In this multicentre, single-arm, phase II trial, we aim to assess the feasibility and safety of a single fraction of preoperative stereotactic radiotherapy (12 Gy) to a 4 cm area around the future pancreatic neck transection margin in patients at high risk of developing POPF after PD aimed to reduce the risk of grade B/C POPF. Adult patients scheduled for PD for malignant and premalignant periampullary tumours, excluding PDAC, with a pancreatic duct diameter ≤3 mm will be included in centres participating in the Dutch Pancreatic Cancer Group. The primary outcome is the safety and feasibility of single-dose preoperative stereotactic radiotherapy before PD. The most relevant secondary outcomes are grade B/C POPF and the difference in the extent of fibrosis between the radiated and non-radiated (uncinate margin) pancreas. Evaluation of endpoints will be performed after inclusion of 33 eligible patients.Ethics and dissemination Ethical approval was obtained by the Amsterdam UMC’s accredited Medical Research Ethics Committee (METC). All included patients are required to have provided written informed consent. The results of this trial will be used to determine the need for a randomised controlled phase III trial and submitted to a high-impact peer-reviewed medical journal regardless of the study outcome.Trial registration number NL72913 (Central Committee on Research involving Human Subjects Registry) and NCT05641233 (ClinicalTrials).

Abstract Objective This study aimed to develop and evaluate an automatic model using artificial intelligence (AI) for quantifying vascular involvement and classifying tumor resectability stage in patients with pancreatic ductal adenocarcinoma (PDAC), primarily to support radiologists in referral centers. Resectability of PDAC is determined by the degree of vascular involvement on computed tomography scans (CTs), which is associated with considerable inter-observer variability. Methods We developed a semisupervised machine learning segmentation model to segment the PDAC and surrounding vasculature using 613 CTs of 467 patients with pancreatic tumors and 50 control patients. After segmenting the relevant structures, our model quantifies vascular involvement by measuring the degree of the vessel wall that is in contact with the tumor using AI-segmented CTs. Based on these measurements, the model classifies the resectability stage using the Dutch Pancreatic Cancer Group criteria as either resectable, borderline resectable, or locally advanced (LA). Results We evaluated the performance of the model using a test set containing 60 CTs from 60 patients, consisting of 20 resectable, 20 borderline resectable, and 20 locally advanced cases, by comparing the automated analysis obtained from the model to expert visual vascular involvement assessments. The model concurred with the radiologists on 227/300 (76%) vessels for determining vascular involvement. The model’s resectability classification agreed with the radiologists on 17/20 (85%) resectable, 16/20 (80%) for borderline resectable, and 15/20 (75%) for locally advanced cases. Conclusions This study demonstrates that an AI model may allow automatic quantification of vascular involvement and classification of resectability for PDAC. Relevance statement This AI model enables automated vascular involvement quantification and resectability classification for pancreatic cancer, aiding radiologists in treatment decisions, and potentially improving patient outcomes. Key points • High inter-observer variability exists in determining vascular involvement and resectability for PDAC. • Artificial intelligence accurately quantifies vascular involvement and classifies resectability for PDAC. • Artificial intelligence can aid radiologists by automating vascular involvement and resectability assessments. Graphical Abstract

IMPORTANCE:. Patients admitted with cerebral hemorrhage or cerebral edema often undergo external ventricular drain (EVD) placement to monitor and manage intracranial pressure (ICP). A strain gauge transducer accompanies the EVD to convert a pressure signal to an electrical waveform and assign a numeric value to the ICP. OBJECTIVES:. This study explored ICP accuracy in the presence of blood and other viscous fluid contaminates in the transducer. DESIGN:. Preclinical comparative design study. SETTING:. Laboratory setting using two Natus EVDs, two strain gauge transducers, and a sealed pressure chamber. PARTICIPANTS:. No human subjects or animal models were used. INTERVENTIONS:. A control transducer primed with saline was compared with an investigational transducer primed with blood or with saline/glycerol mixtures in mass:mass ratios of 25%, 50%, 75%, and 100% glycerol. Volume in a sealed chamber was manipulated to reflect changes in ICP to explore the impact of contaminates on pressure measurement. MEASUREMENTS AND MAIN RESULTS:. From 90 paired observations, ICP readings were statistically significantly different between the control (saline) and experimental (glycerol or blood) transducers. The time to a stable pressure reading was significantly different for saline vs. 25% glycerol (< 0.0005), 50% glycerol (< 0.005), 75% glycerol (< 0.0001), 100% glycerol (< 0.0005), and blood (< 0.0005). A difference in resting stable pressure was observed for saline vs. blood primed transducers (0.041). CONCLUSIONS AND RELEVANCE:. There are statistically significant and clinically relevant differences in time to a stable pressure reading when contaminates are introduced into a closed drainage system. Changing a transducer based on the presence of blood contaminate should be considered to improve accuracy but must be weighed against the risk of introducing infection.

Abstract Background Minimally invasive pancreatoduodenectomy (MIPD) aims to reduce the negative impact of surgery as compared to open pancreatoduodenectomy (OPD) and is increasingly becoming part of clinical practice for selected patients worldwide. However, the safety of MIPD remains a topic of debate and the potential shorter time to functional recovery needs to be confirmed. To guide safe implementation of MIPD, large-scale international randomized trials comparing MIPD and OPD in experienced high-volume centers are needed. We hypothesize that MIPD is non-inferior in terms of overall complications, but superior regarding time to functional recovery, as compared to OPD. Methods/design The DIPLOMA-2 trial is an international randomized controlled, patient-blinded, non-inferiority trial performed in 14 high-volume pancreatic centers in Europe with a minimum annual volume of 30 MIPD and 30 OPD. A total of 288 patients with an indication for elective pancreatoduodenectomy for pre-malignant and malignant disease, eligible for both open and minimally invasive approach, are randomly allocated for MIPD or OPD in a 2:1 ratio. Centers perform either laparoscopic or robot-assisted MIPD based on their surgical expertise. The primary outcome is the Comprehensive Complication Index (CCI®), measuring all complications graded according to the Clavien-Dindo classification up to 90 days after surgery. The sample size is calculated with the following assumptions: 2.5% one-sided significance level (α), 80% power (1-β), expected difference of the mean CCI® score of 0 points between MIPD and OPD, and a non-inferiority margin of 7.5 points. The main secondary outcome is time to functional recovery, which will be analyzed for superiority. Other secondary outcomes include post-operative 90-day Fitbit™ measured activity, operative outcomes (e.g., blood loss, operative time, conversion to open surgery, surgeon-reported outcomes), oncological findings in case of malignancy (e.g., R0-resection rate, time to adjuvant treatment, survival), postoperative outcomes (e.g., clinically relevant complications), healthcare resource utilization (length of stay, readmissions, intensive care stay), quality of life, and costs. Postoperative follow-up is up to 36 months. Discussion The DIPLOMA-2 trial aims to establish the safety of MIPD as the new standard of care for this selected patient population undergoing pancreatoduodenectomy in high-volume centers, ultimately aiming for superior patient recovery. Trial registration ISRCTN27483786. Registered on August 2, 2023

Abstract Background The genomes of present-day non-Africans are composed of 1–3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50–60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. Results The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19–1.54, P = 3.59 × 10–6), with a P-value close to a threshold that takes into account multiple testing. Conclusions Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Abstract Background Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. Methods This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. Discussion The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Trial registration Clinical Trials: NCT04927780. Registered June 16, 2021.

Background:. A potential downside of robotic pancreatoduodenectomy (RPD) is the lack of tactile feedback when tying sutures, which could be especially perilous during pancreatic anastomosis. Near-infrared fluorescence imaging with indocyanine green (NIRF-ICG) could detect transpancreatic-suture-induced hypoperfusion of the pancreatic stump during RPD, which may be related to postoperative pancreatic fistula (POPF) grade B/C, but studies are lacking. Methods:. This prospective study included 37 patients undergoing RPD to assess the relation between pancreatic stump hypoperfusion as objectified with NIRF-ICG using Firefly and the rate of POPF grade B/C. In 27 patients, NIRF-ICG was performed after tying down the transpancreatic U-sutures. In 10 ‘negative control’ patients, NIRF-ICG was performed before tying these sutures. Results:. Pancreatic stump hypoperfusion was detected using NIRF-ICG in 9/27 patients (33%) during RPD. Hypoperfusion was associated with POPF grade B/C (67% [6/9 patients] versus 17% [3/18 patients], P = 0.026). No hypoperfusion was objectified in 10 ‘negative controls’. Conclusions:. Transpancreatic-suture-induced pancreatic stump hypoperfusion can be detected using NIRF-ICG during RPD and was associated with POPF grade B/C. Surgeons could use NIRF-ICG to adapt their suturing approach during robotic pancreatico-jejunostomy. Further larger prospective studies are needed to validate the association between transpancreatic-suture-induced hypoperfusion and POPF.

Abstract Transitions from the liquid to the solid state of matter are omnipresent. They form a crucial step in the industrial solidification of metallic alloy melts and are greatly influenced by the thermophysical properties of the melt. Knowledge of the thermophysical properties of liquid metallic alloys is necessary in order to gain a tight control over the solidification pathway, and over the obtained material structure of the solid. Measurements of thermophysical properties on ground are often difficult, or even impossible, since liquids are strongly influenced by earth’s gravity. Another problem is the reactivity of melts with container materials, especially at high temperature. Finally, deep undercooling, necessary to understand nucleus formation and equilibrium as well as non-equilibrium solidification, can only be achieved in a containerless environment. Containerless experiments in microgravity allow precise benchmark measurements of thermophysical properties. The electromagnetic levitator ISS-EML on the International Space Station (ISS) offers perfect conditions for such experiments. This way, data for process simulations is obtained, and a deeper understanding of nucleation, crystal growth, microstructural evolution, and other details of the transformation from liquid to solid can be gained. Here, we address the scientific questions in detail, show highlights of recent achievements, and give an outlook on future work.

Abstract Background Pancreatic panniculitis is characterized by subcutaneous fat necrosis and is a rare presentation of an underlying pancreatic disease, appearing in approximately 2–3% of all patients with a pancreatic disease. The nodules usually involve the lower extremities. Pancreatic panniculitis is commonly associated with acute or chronic pancreatitis, and occasionally with pancreatic cancer, especially acinar cell carcinoma. Case presentation A 77-year-old Caucasian woman with no significant medical history was referred to our center with multiple painful, itchy, and warm red/blue cutaneous nodules on the left lower leg. These skin lesions were consistent with the clinical diagnosis of panniculitis. The skin biopsy obtained showed a predominantly lobular panniculitis with fat necrosis of which the aspect was highly suspicious for pancreatic panniculitis. Further analysis revealed high lipase serum of > 3000 U/L (normal range

Abstract Background Disease recurrence is the main cause of mortality after resection of pancreatic ductal adenocarcinoma (PDAC). In 20–30% of resected patients, isolated local PDAC recurrence occurs. Retrospective studies have suggested that stereotactic body radiation therapy (SBRT) might lead to improved local control in these patients, potentially having a beneficial effect on both survival and quality of life. The “nationwide randomized controlled trial on additional treatment for isolated local pancreatic cancer recurrence using stereotactic body radiation therapy” (ARCADE) will investigate the value of SBRT in addition to standard of care in patients with isolated local PDAC recurrence compared to standard of care alone, regarding both survival and quality of life outcomes. Methods The ARCADE trial is nested within a prospective cohort (Dutch Pancreatic Cancer Project; PACAP) according to the ‘Trials within Cohorts’ design. All PACAP participants with isolated local PDAC recurrence after primary resection who provided informed consent for being randomized in future studies are eligible. Patients will be randomized for local therapy (5 fractions of 8 Gy SBRT) in addition to standard of care or standard of care alone. In total, 174 patients will be included. The main study endpoint is survival after recurrence. The most important secondary endpoint is quality of life. Discussion It is hypothesized that additional SBRT, compared to standard of care alone, improves survival and quality of life in patients with isolated local recurrence after PDAC resection. Trial registration ClinicalTrials.gov registration NCT04881487 . Registered on May 11, 2021.

Abstract Background Prophylactic abdominal drainage is current standard practice after distal pancreatectomy (DP), with the aim to divert pancreatic fluid in case of a postoperative pancreatic fistula (POPF) aimed to prevent further complications as bleeding. Whereas POPF after pancreatoduodenectomy, by definition, involves infection due to anastomotic dehiscence, a POPF after DP is essentially sterile since the bowel is not opened and no anastomoses are created. Routine drainage after DP could potentially be omitted and this could even be beneficial because of the hypothetical prevention of drain-induced infections (Fisher, 2018). Abdominal drainage, moreover, should only be performed if it provides additional safety or comfort to the patient. In clinical practice, drains cause clear discomfort. One multicenter randomized controlled trial confirmed the safety of omitting abdominal drainage but did not stratify patients according to their risk of POPF and did not describe a standardized strategy for pancreatic transection. Therefore, a large pragmatic multicenter randomized controlled trial is required, with prespecified POPF risk groups and a homogeneous method of stump closure. The objective of the PANDORINA trial is to evaluate the non-inferiority of omitting routine intra-abdominal drainage after DP on postoperative morbidity (Clavien-Dindo score ≥ 3), and, secondarily, POPF grade B/C. Methods/design Binational multicenter randomized controlled non-inferiority trial, stratifying patients to high and low risk for POPF grade B/C and incorporating a standardized strategy for pancreatic transection. Two groups of 141 patients (282 in total) undergoing elective DP (either open or minimally invasive, with or without splenectomy). Primary outcome is postoperative rate of morbidity (Clavien-Dindo score ≥ 3), and the most relevant secondary outcome is grade B/C POPF. Other secondary outcomes include surgical reintervention, percutaneous catheter drainage, endoscopic catheter drainage, abdominal collections (not requiring drainage), wound infection, delayed gastric emptying, postpancreatectomy hemorrhage as defined by the international study group for pancreatic surgery (ISGPS) (Wente et al., 2007), length of stay (LOS), readmission within 90 days, in-hospital mortality, and 90-day mortality. Discussion PANDORINA is the first binational, multicenter, randomized controlled non-inferiority trial with the primary objective to evaluate the hypothesis that omitting prophylactic abdominal drainage after DP does not worsen the risk of postoperative severe complications (Wente et al., 2007; Bassi et al., 2017). Most of the published studies on drain placement after pancreatectomy focus on both pancreatoduodenectomy and DP, but these two entities present are associated with different complications and therefore deserve separate evaluation (McMillan et al., 2016; Pratt et al., 2006). The PANDORINA trial is innovative since it takes the preoperative risk on POPF into account based on the D-FRS and it warrants homogenous stump closing by using the same graded compression technique and same stapling device (de Pastena et al., 2022; Asbun and Stauffer, 2011).

Summary: 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.

Background:. Intraductal papillary mucinous neoplasm (IPMN) with involvement of the main pancreatic duct usually requires surgical resection. Consensus is lacking whether to partially or completely resect the pancreatic portion with a dilated main pancreatic duct. Intraoperative pancreatoscopy may be useful to determine the extent of IPMN to tailor surgical resection and was recently studied in a large prospective international study. IPMN is increasingly utilized using a robotic approach. Studies describing the technical approach to intraoperative pancreatoscopy in robotic pancreatoduodenectomy and robotic distal pancreatectomy are lacking. Methods:. During robotic pancreatoduodenectomy, pancreatoscopy is performed once the pancreas neck is transected. The scope is advanced via a laparoscopic port into the left and right-sided pancreatic duct, guided by robotic graspers. During robotic distal pancreatectomy, pancreatoscopy is performed before complete parenchymal transection. The scope is advanced through an anterior ductotomy to examine the duct and guide the pancreatic transection line. Tips and tricks how to perform the procedure efficiently without complications are detailed. Results:. In total, 28 robot-assisted pancreatoscopies were performed during robotic pancreatoduodenectomy and robotic distal pancreatectomy. No intraoperative complications resulting from the intraoperative pancreatoscopy were noted. In the 2 described procedures, the added time required to perform the pancreatoscopy was 6 and 17 minutes, respectively. Both patients recovered without complication and were discharged on postoperative day 5 for the robotic pancreatoduodenectomy and day 6 for the robotic distal pancreatectomy. Conclusions:. Intraoperative pancreatoscopy can be safely performed during both robotic pancreatoduodenectomy and robotic distal pancreatectomy for IPMN with the involvement of the main pancreatic duct. An international prospective study has recently been completed with this technique.

Hyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied, but causal links remain enigmatic. Obese individuals with or without T2D were included from two independent Dutch cohorts. Human data were translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice. Flagellin is part of the bacterial locomotor appendage flagellum, present in gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response is associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice. We postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta-cell failure in time and represents a novel therapeutic target.

Abstract Background COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvascular reactivity in peripheral skeletal muscle of severe COVID-19 patients. Methods This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypoxemia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a three-minute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). Results Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not differ between the two groups. Dynamic VOT-derived parameters were significantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-flow nasal cannula support (32%). Patients on MV were also receiving sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were significant differences in baseline StO2 and ReO2 among the different ARDS groups according to SF ratio, but not among different respiratory support therapies. Conclusion Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determine whether these observations have prognostic implications. These results represent interim findings of the ongoing HEMOCOVID-19 trial. Trial registration ClinicalTrials.gov NCT04689477 . Retrospectively registered 30 December 2020.

Abstract Background The cortical microvascular cerebral blood flow response (CBF) to different changes in head-of-bed (HOB) position has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS) technique. However, the relationship between these relative ΔCBF changes and associated systemic blood pressure changes has not been studied, even though blood pressure is a major driver of cerebral blood flow. Methods Transcranial DCS data from four studies measuring bilateral frontal microvascular cerebral blood flow in healthy controls (n = 15), patients with asymptomatic severe internal carotid artery stenosis (ICA, n = 27), and patients with acute ischemic stroke (AIS, n = 72) were aggregated. DCS-measured CBF was measured in response to a short head-of-bed (HOB) position manipulation protocol (supine/elevated/supine, 5 min at each position). In a sub-group (AIS, n = 26; ICA, n = 14; control, n = 15), mean arterial pressure (MAP) was measured dynamically during the protocol. Results After elevated positioning, DCS CBF returned to baseline supine values in controls (p = 0.890) but not in patients with AIS (9.6% [6.0,13.3], mean 95% CI, p

Abstract Background Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26–34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. Methods The “Pancreatic Locally Advanced Unresectable Cancer Ablation” (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. Discussion The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. Trial registration Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018

BackgroundBiological sex, gender and age have an impact on the incidence and outcome in patients with metastatic pancreatic cancer. The aim of this study is to investigate whether biological sex, gender and age are associated with treatment allocation and overall survival (OS) of patients with metastatic pancreatic cancer in a nationwide cohort.MethodsPatients with synchronous metastatic pancreatic cancer diagnosed between 2015 and 2019 were selected from the Netherlands Cancer Registry (NCR). The association between biological sex and the probability of receiving systemic treatment were examined with multivariable logistic regression analyses. Kaplan Meier analyses with log-rank test were used to describe OS.ResultsA total of 7470 patients with metastatic pancreatic cancer were included in this study. Fourty-eight percent of patients were women. Women received less often systemic treatment (26% vs. 28%, P=0.03), as compared to men. Multivariable logistic regression analyses with adjustment for confounders showed that women ≤55 years of age, received more often systemic treatment (OR 1.82, 95% CI 1.24-2.68) compared to men of the same age group. In contrast, women at >55 years of age had a comparable probability to receive systemic treatment compared to men of the same age groups. After adjustment for confounders, women had longer OS compared to men (HR 0.89, 95% CI 0.84-0.93).ConclusionThis study found that women in general had a lower probability of receiving systemic treatment compared to men, but this can mainly be explained by age differences. Women had better OS compared to men after adjustment for confounders.

Background Major bile duct injury (BDI) after cholecystectomy generally requires surgical reconstruction by means of hepaticojejunostomy. However, there is controversy regarding the optimal timing of surgical reconstruction. Methods A systematic review was performed by searching PubMed, Embase and Cochrane databases for studies published between 1990 and 2018 reporting on the timing of hepaticojejunostomy for BDI (PROSPERO registration CRD42018106611). The main outcomes were postoperative morbidity, postoperative mortality and anastomotic stricture. When individual patient data were available, time intervals of these studies were attuned to render these comparable with other studies. Data for comparable time intervals were pooled using a random‐effects model. In addition, data for all included studies were pooled using a generalized linear model. Results Some 21 studies were included, representing 2484 patients. In these studies, 15 different time intervals were used. Eight studies used the time intervals of less than 14 days (early), 14 days to 6 weeks (intermediate) and more than 6 weeks (delayed). Meta‐analysis revealed a higher risk of postoperative morbidity in the intermediate interval (early versus intermediate: risk ratio (RR) 0·73, 95 per cent c.i. 0·54 to 0·98; intermediate versus delayed: RR 1·50, 1·16 to 1·93). Stricture rate was lowest in the delayed interval group (intermediate versus delayed: RR 1·53, 1·07 to 2·20). Postoperative mortality did not differ within time intervals. The additional analysis demonstrated increased odds of postoperative morbidity for reconstruction between 2 and 6 weeks, and decreased odds of anastomotic stricture for delayed reconstruction. Conclusion This meta‐analysis found that surgical reconstruction of BDI between 2 and 6 weeks should be avoided as this was associated with higher risk of postoperative morbidity and hepaticojejunostomy stricture.

Background Dutch guidelines indicate that treatment of pancreatic head and periampullary malignancies should be started within 3 weeks of the multidisciplinary team (MDT) meeting. This study aimed to assess the impact of time to surgery on oncological outcomes. Methods This was a retrospective population‐based cohort study of patients with pancreatic head and periampullary malignancies included in the Netherlands Cancer Registry. Patients scheduled for pancreatoduodenectomy and who were discussed in an MDT meeting from May 2012 to December 2016 were eligible. Time to surgery was defined as days between the final preoperative MDT meeting and surgery, categorized in tertiles (short interval, 18 days or less; intermediate, 19–32 days; long, 33 days or more). Oncological outcomes included overall survival, resection rate and R0 resection rate. Results A total of 2027 patients were included, of whom 677, 665 and 685 had a short, intermediate and long time interval to surgery respectively. Median time to surgery was 25 (i.q.r. 14–36) days. Longer time to surgery was not associated with overall survival (hazard ratio 0·99, 95 per cent c.i. 0·87 to 1·13; P = 0·929), resection rate (relative risk (RR) 0·96, 95 per cent c.i. 0·91 to 1·01; P = 0·091) or R0 resection rate (RR 1·01, 0·94 to 1·09; P = 0·733). Patients with pancreatic ductal adenocarcinoma and a long time interval had a lower resection rate (RR 0·92, 0·85 to 0·99; P = 0·029). Discussion A longer time interval between the last MDT meeting and pancreatoduodenectomy did not decrease overall survival.

Patient stratification based on biological variation in pancreatic ductal adenocarcinoma (PDAC) subtypes could help to improve clinical outcome. However, noninvasive assessment of the entire tumor microenvironment remains challenging. In this study, we investigate the biological basis of dynamic contrast‐enhanced (DCE), intravoxel incoherent motion (IVIM), and R2*‐derived magnetic resonance imaging (MRI) parameters for the noninvasive characterization of the PDAC tumor microenvironment and evaluate their prognostic potential in PDAC patients. Patients diagnosed with treatment‐naïve resectable PDAC underwent MRI. After resection, a whole‐mount tumor slice was analyzed for collagen fraction, vessel density, and hypoxia and matched to the MRI parameter maps. MRI parameters were correlated to immunohistochemistry‐derived tissue characteristics and evaluated for prognostic potential. Thirty patients were included of whom 21 underwent resection with whole‐mount histology available in 15 patients. DCE Ktrans and ve, ADC, and IVIM D correlated with collagen fraction. DCE kep and IVIM f correlated with vessel density and R2* with tissue hypoxia. Based on MRI, two main PDAC phenotypes could be distinguished; a stroma‐high phenotype demonstrating high vessel density and high collagen fraction and a stroma‐low phenotype demonstrating low vessel density and low collagen fraction. Patients with the stroma‐high phenotype (high kep and high IVIM D, n = 8) showed longer overall survival (not reached vs. 14 months, P = 0.001, HR = 9.1, P = 0.004) and disease‐free survival (not reached vs. 2 months, P

Background Portal vein embolization (PVE) is performed to reduce the risk of liver failure and subsequent mortality after major liver resection. Although a cut‐off value of 2·7 per cent per min per m2 has been used with hepatobiliary scintigraphy (HBS) for future remnant liver function (FRLF), patients with perihilar cholangiocarcinoma (PHC) potentially benefit from an additional cut‐off of 8·5 per cent/min (not corrected for body surface area). Since January 2016 a more liberal approach to PVE has been adopted, including this additional cut‐off for HBS of 8·5 per cent/min. The aim of this study was to assess the effect of this approach on liver failure and mortality. Methods This was a single‐centre retrospective study in which consecutive patients undergoing liver resection under suspicion of PHC in 2000–2015 were compared with patients treated in 2016–2019, after implementation of the more liberal approach. Primary outcomes were postoperative liver failure (International Study Group of Liver Surgery grade B/C) and 90‐day mortality. Results Some 191 patients with PHC underwent liver resection. PVE was performed in 6·4 per cent (9 of 141) of the patients treated in 2000–2015 and in 32 per cent (16 of 50) of those treated in 2016–2019. The 90‐day mortality rate decreased from 16·3 per cent (23 of 141) to 2 per cent (1 of 50) (P = 0·009), together with a decrease in the rate of liver failure from 19·9 per cent (28 of 141) to 4 per cent (2 of 50) (P = 0·008). In 2016–2019, 24 patients had a FRLF greater than 8·5 per cent/min and no liver failure or death occurred, suggesting that 8·5 per cent/min is a reliable cut‐off for patients with suspected PHC. Conclusion The major decrease in liver failure and mortality rates in recent years and the simultaneous increased use of PVE suggests an important role for PVE in reducing adverse outcomes after surgery for PHC.

Abstract Background Pancreatic resection is a major abdominal operation with 50% risk of postoperative complications. A common complication is pancreatic fistula, which may have severe clinical consequences such as postoperative bleeding, organ failure and death. The objective of this study is to investigate whether implementation of an algorithm for early detection and minimally invasive management of pancreatic fistula may improve outcomes after pancreatic resection. Methods This is a nationwide stepped-wedge, cluster-randomized, superiority trial, designed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. During a period of 22 months, all Dutch centers performing pancreatic surgery will cross over in a randomized order from current practice to best practice according to the algorithm. This evidence-based and consensus-based algorithm will provide daily multilevel advice on the management of patients after pancreatic resection (i.e. indication for abdominal imaging, antibiotic treatment, percutaneous drainage and removal of abdominal drains). The algorithm is designed to aid early detection and minimally invasive step-up management of postoperative pancreatic fistula. Outcomes of current practice will be compared with outcomes after implementation of the algorithm. The primary outcome is a composite of major complications (i.e. post-pancreatectomy bleeding, new-onset organ failure and death) and will be measured in a sample size of at least 1600 patients undergoing pancreatic resection. Secondary endpoints include the individual components of the primary endpoint and other clinical outcomes, healthcare resource utilization and costs analysis. Follow up will be up to 90 days after pancreatic resection. Discussion It is hypothesized that a structured nationwide implementation of a dedicated algorithm for early detection and minimally invasive step-up management of postoperative pancreatic fistula will reduce the risk of major complications and death after pancreatic resection, as compared to current practice. Trial registration Netherlands Trial Register: NL 6671 . Registered on 16 December 2017.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Diffusive correlation spectroscopy (DCS) is an emerging optical technique that measures blood perfusion in deep tissue. In a DCS measurement, temporal changes in the interference pattern of light, which has passed through tissue, are quantified by an autocorrelation function. This autocorrelation function is further parameterized through a non-linear curve fit to a solution to the diffusion equation for coherence transport. The computational load for this non-linear curve fitting is a barrier for deployment of DCS for clinical use, where real-time results, as well as instrument size and simplicity, are important considerations. We have mitigated this computational bottleneck through development of a hardware analyzer for DCS. This analyzer implements the DCS curving fitting algorithm on digital logic circuit using Field Programmable Gate Array (FPGA) technology. The FPGA analyzer is more efficient than a typical software analysis solution. The analyzer module can be easily duplicated for processing multiple channels of DCS data in real-time. We have demonstrated the utility of this analyzer in pre-clinical large animal studies of spinal cord ischemia. In combination with previously described FPGA implementations of auto-correlators, this hardware analyzer can provide a complete device-on-a-chip solution for DCS signal processing. Such a component will enable new DCS applications demanding mobility and real-time processing.

Spinal cord ischemia leads to iatrogenic injury in multiple surgical fields, and the ability to immediately identify onset and anatomic origin of ischemia is critical to its management. Current clinical monitoring, however, does not directly measure spinal cord blood flow, resulting in poor sensitivity/specificity, delayed alerts, and delayed intervention. We have developed an epidural device employing diffuse correlation spectroscopy (DCS) to monitor spinal cord ischemia continuously at multiple positions. We investigate the ability of this device to localize spinal cord ischemia in a porcine model and validate DCS versus Laser Doppler Flowmetry (LDF). Specifically, we demonstrate continuous (>0.1Hz) spatially resolved (3 locations) monitoring of spinal cord blood flow in a purely ischemic model with an epidural DCS probe. Changes in blood flow measured by DCS and LDF were highly correlated (r = 0.83). Spinal cord blood flow measured by DCS caudal to aortic occlusion decreased 62%. This monitor demonstrated a sensitivity of 0.87 and specificity of 0.91 for detection of a 25% decrease in flow. This technology may enable early identification and critically important localization of spinal cord ischemia.

Abstract 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 (

Despite the wide range of clinical and research applications, the reliability of the absolute oxygenation measurements of continuous wave near-infrared spectroscopy sensors is often questioned, partially due to issues of standardization. In this study, we have compared the performances of 13 units of a continuous wave near-infrared spectroscopy device (PortaMon, Artinis Medical Systems, NL) to test their suitability for being used in the HEMOCOVID-19 clinical trial in 10 medical centers around the world. Detailed phantom and in vivo tests were employed to measure the precision and reproducibility of measurements of local blood oxygen saturation and total hemoglobin concentration under different conditions: for different devices used, different operators, for probe repositioning over the same location, and over time (hours/days/months). We have detected systematic differences between devices when measuring phantoms (inter-device variability,

Abstract Background Observational cohort studies have suggested that minimally invasive distal pancreatectomy (MIDP) is associated with better short-term outcomes compared with open distal pancreatectomy (ODP), such as less intraoperative blood loss, lower morbidity, shorter length of hospital stay, and reduced total costs. Confounding by indication has probably influenced these findings, given that case-matched studies failed to confirm the superiority of MIDP. This accentuates the need for multicenter randomized controlled trials, which are currently lacking. We hypothesize that time to functional recovery is shorter after MIDP compared with ODP even in an enhanced recovery setting. Methods LEOPARD is a randomized controlled, parallel-group, patient-blinded, multicenter, superiority trial in all 17 centers of the Dutch Pancreatic Cancer Group. A total of 102 patients with symptomatic benign, premalignant or malignant disease will be randomly allocated to undergo MIDP or ODP in an enhanced recovery setting. The primary outcome is time (days) to functional recovery, defined as all of the following: independently mobile at the preoperative level, sufficient pain control with oral medication alone, ability to maintain sufficient (i.e. >50%) daily required caloric intake, no intravenous fluid administration and no signs of infection. Secondary outcomes are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life and costs. Discussion The LEOPARD trial is designed to investigate whether MIDP reduces the time to functional recovery compared with ODP in an enhanced recovery setting. Trial registration Dutch Trial Register, NTR5188 . Registered on 9 April 2015

Abstract Objective This study investigates the expression of mRNA encoding vasopressin in the hypothalamus of autopsy brains of individuals diagnosed with schizophrenia. Methods Ten brains of individuals with schizophrenia and 10 brains from individuals without any disease were examined during autopsy. The hypothalamic block was dissected and immersion fixed in paraformaldehyde, sucrose substituted, frozen, and cut into 20‐µm‐thick coronal cryostat sections. The sections were hybridized with an S‐35‐labeled DNA antisense oligo probe and after washing covered by an X‐ray film. The hybridization signals on the films were transferred to a computer and densitometrically quantified. Results The densitometry signals showed a statistically significant lower mRNA expression (53% decrease; p = 0.014) in the paraventricular nucleus of the individuals with schizophrenia compared to the controls. In the supraoptic nucleus, the decrease in the group with schizophrenia was 39% compared to the controls, but this decrease was not statistically significant (p = 0.194). Conclusions Our results show a low expression of mRNA encoding vasopressin in the paraventricular nucleus of the individuals with schizophrenia. We suggest that vasopressin is not directly involved in the pathogenesis of schizophrenia, but might influence schizophrenic symptoms via vasopressin receptors located in the social behavioral neural network in the forebrain.

A 73-year-old male presented with jaundice and severe muscle weakness. He was diagnosed with distal cholangiocarcinoma and paraneoplastic necrotizing autoimmune myopathy (NAM). Treatment of NAM consisted of dexamethasone pulse therapy, prednisone, and single-dose intravenous immunoglobulin. The distal cholangiocarcinoma was resected through a total laparoscopic pancreatoduodenectomy. After hospital discharge, muscle strength initially increased postoperatively; however, pneumonia resulted in the deterioration of his general condition and death 5 months after the diagnosis of paraneoplastic NAM.