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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.To assess the efficacy and safety of the BIHAP in patients after total pancreatectomy.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.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.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.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.trialregister.nl Identifier: NL8871.

Contains fulltext : 251531.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To quantify the impact of individual complications on mortality, organ failure, hospital stay, and readmission after pancreatoduodenectomy. SUMMARY OF BACKGROUND DATA: An initial complication may provoke a sequence of adverse events potentially leading to mortality after pancreatoduodenectomy. This study was conducted to aid prioritization of quality improvement initiatives. METHODS: Data from consecutive patients undergoing pancreatoduodenectomy (2014-2017) were extracted from the Dutch Pancreatic Cancer Audit. Population attributable fractions (PAF) were calculated for the association of each complication (ie, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, wound infection, and pneumonia) with each unfavorable outcome [ie, in-hospital mortality, organ failure, prolonged hospital stay (>75th percentile), and unplanned readmission), whereas adjusting for confounders and other complications. The PAF represents the proportion of an outcome that could be prevented if a complication would be eliminated completely. RESULTS: Overall, 2620 patients were analyzed. In-hospital mortality occurred in 95 patients (3.6%), organ failure in 198 patients (7.6%), and readmission in 427 patients (16.2%). Postoperative pancreatic fistula and postpancreatectomy hemorrhage had the greatest independent impact on mortality [PAF 25.7% (95% CI 13.4-37.9) and 32.8% (21.9-43.8), respectively] and organ failure [PAF 21.8% (95% CI 12.9-30.6) and 22.1% (15.0-29.1), respectively]. Delayed gastric emptying had the greatest independent impact on prolonged hospital stay [PAF 27.6% (95% CI 23.5-31.8)]. The impact of individual complications on unplanned readmission was smaller than 11%. CONCLUSION: Interventions focusing on postoperative pancreatic fistula and postpancreatectomy hemorrhage may have the greatest impact on in-hospital mortality and organ failure. To prevent prolonged hospital stay, initiatives should in addition focus on delayed gastric emptying.

BACKGROUND: The aim of this study was to investigate the incidence and risk factors of primary and secondary liver failure after major liver resection for perihilar cholangiocarcinoma.METHODS: All patients who underwent a major liver resection for presumed perihilar cholangiocarcinoma between 2000 and 2020 at 2 tertiary-referral hospitals were included. Liver failure was defined according to the International Study Group for Liver Surgery criteria, and only grade B/C was considered clinically relevant. Primary liver failure was defined as failure without any underlying postoperative cause, and secondary liver failure was defined as liver failure with an onset after an underlying postoperative complication as a cause.RESULTS: The incidence of liver failure and 90-day mortality were 20.9% and 17.0% in the 253 included patients, respectively. The incidences of primary liver failure was 9.1% and secondary liver failure was 11.9%. Abdominal sepsis, portal vein thrombosis, and arterial thrombosis were the most frequent causes. The absence of preoperative remnant liver assessment and blood loss were independent risk factors for primary liver failure. Independent risk factors for secondary liver failure were Eastern Cooperative Oncology group performance status, percutaneous biliary drainage, and preoperative cholangitis.CONCLUSION: Liver failure after major liver resection for perihilar cholangiocarcinoma occurred in 1 of every 5 patients. The proposed subdivision into primary and secondary liver failure could help to understand differences in outcomes between centers and help to reduce liver failure.

Background: Total pancreatectomy has high morbidity and mortality and differences among countries are currently unknown. This study compared the use and postoperative outcomes of total pancreatec-tomy among 4 Western countries. Methods: Patients who underwent one-stage total pancreatectomy were included from registries in the United States, Germany, the Netherlands, and Sweden (2014-2018). Use of total pancreatectomy was assessed by calculating the ratio total pancreatectomy to pancreatoduodenectomy. Primary outcomes were major morbidity (Clavien Dindo >3) and in-hospital mortality. Predictors for the primary outcomes were assessed in multivariable logistic regression analyses. Sensitivity analysis assessed the impact of volume (low-volume 40 pancreatoduodenectomies annually; data available for the Netherlands and Germany). Results: In total, 1,579 patients underwent one-stage total pancreatectomy. The relative use of total pancreatectomy to pancreatoduodenectomy varied up to fivefold (United States 0.03, Germany 0.15, the Netherlands 0.03, and Sweden 0.15; P < .001). Both the indication and several baseline characteristics differed significantly among countries. Major morbidity occurred in 423 patients (26.8%) and differed (22.3%, 34.9%, 38.3%, and 15.9%, respectively; P < .001). In-hospital mortality occurred in 85 patients (5.4%) and also differed (1.8%, 10.2%, 10.8%, 1.9%, respectively; P < .001). Country, age >75, and vascular resection were predictors for in-hospital mortality. In-hospital mortality was lower in high-volume centers in the Netherlands (4.9% vs 23.1%; P = .002), but not in Germany (9.8% vs 10.6%; P = .733). Conclusion: Considerable differences in the use of total pancreatectomy, patient characteristics, and postoperative outcome were noted among 4 Western countries with better outcomes in the United States and Sweden. These large, yet unexplained, differences require further research to ultimately improve patient outcome. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

OBJECTIVE: This analysis aimed to compare failure to rescue (FTR) after pancreatoduodenectomy across the Atlantic. SUMMARY BACKGROUND DATA: FTR, or mortality after development of a major complication, is a quality metric originally created to compare hospital results. FTR has been studied in North American and Northern European patients undergoing pancreatoduodenectomy (PD). However, a direct comparison of FTR after PD between North America and Northern Europe has not been performed. METHODS: Patients who underwent PD in North America, the Netherlands, Sweden and Germany (GAPASURG dataset) were identified from their respective registries (2014-17). Patients who developed a major complication defined as Clavien-Dindo ≥3 or developed a grade B/C postoperative pancreatic fistula (POPF) were included. Preoperative, intraoperative, and postoperative variables were compared between patients with and without FTR. Variables significant on univariable analysis were entered into a logistic regression for FTR. RESULTS: Major complications occurred in 6188 of 22,983 patients (26.9%) after PD, and 504 (8.1%) patients had FTR. North American and Northern European patients with complications differed, and rates of FTR were lower in North America (5.4% vs 12%, P < 0.001). Fourteen factors from univariable analysis contributing to differences in patients who developed FTR were included in a logistic regression. On multivariable analysis, factors independently associated with FTR were age, American Society of Anesthesiology ≥3, Northern Europe, POPF, organ failure, life-threatening complication, nonradiologic intervention, and reoperation. CONCLUSIONS: Older patients with severe systemic diseases are more difficult to rescue. Failure to rescue is more common in Northern Europe than North America. In stable patients, management of complications by interventional radiology is preferred over reoperation.

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 p 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.

Purpose To compare survival after CT-guided percutaneous irreversible electroporation (IRE) and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy versus FOLFIRINOX only in patients with locally advanced pancreatic cancer (LAPC). Materials and Methods A post hoc comparison was performed of data derived from a prospective IRE-FOLFIRINOX cohort and a retrospective FOLFIRINOX-only cohort. All patients received a minimum of 3 cycles of FOLFIRINOX for LAPC and were considered eligible for CT-guided percutaneous IRE. Endpoints included overall survival (OS), local and distant progression-free survival, and time to progression (TTP) and were compared using stratified Kaplan-Meier analysis. Patients who received > 8 cycles of FOLFIRINOX before IRE and who had tumors > 6 cm in the FOLFIRINOX-only group were excluded. Results Of 103 patients with a diagnosis of LAPC, 52 were deemed eligible (n = 30 IRE-FOLFIRINOX and n = 22 FOLFIRINOX-only). Patients in the FOLFIRINOX-only arm had larger tumors (53 mm ± 19 vs 38 mm ± 7, P = .340), had more locoregional lymph node metastases (23% vs 7%, P = .622), and more often received radiotherapy (7 patients vs 2 patients, P = .027); all other baseline characteristics were comparable. Median OS was 17.0 months (range, 5–35 mo; SD = 6) for IRE-FOLFIRINOX versus 12.4 months (range, 3–22 mo; SD = 6) for FOLFIRINOX-only (P = .038). After sensitivity analyses, median OS was 17.2 months (range, 6–27 mo; SD = 6) versus 12.4 months (range, 7–32 mo; SD = 10) (P = .05). Median TTP was longer in the IRE-FOLFIRINOX group: 14.2 months (range, 5–25 mo; SD = 4) versus 5.2 months (range, 2–22; SD = 6) (P = .0001). Conclusions In patients with LAPC after FOLFIRINOX chemotherapy, CT-guided percutaneous IRE may improve OS and TTP. This study may facilitate the design of randomized controlled trials to compare survival after IRE-FOLRINOX versus FOLFIRINOX-only.

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., In this report on the impact of waiting time to surgery in patients with pancreatic cancer and other periampullary malignancies, the main and most important finding was that the time interval to surgery did not affect survival. The study also found that, in a subgroup of patients with pancreatic ductal adenocarcinoma, waiting time did affect the resectability rate: patients with a longer interval to surgery had a lower resection rate. Sooner is not always better

Optimal surgical management of spine trauma will restore blood flow to the ischemic spinal cord. However, spine stabilization may also further exacerbate injury by inducing ischemia. Current electrophysiological technology is not capable of detecting acute changes in spinal cord blood flow or localizing ischemia. Further, alerts are delayed and unreliable. We developed an epidural optical device capable of directly measuring and immediately detecting changes in spinal cord blood flow using diffuse correlation spectroscopy (DCS). Herein we test the hypothesis that our device can continuously monitor blood flow during spine distraction. Additionally, we demonstrate the ability of our device to monitor multiple sites along the spinal cord and axially resolve changes in spinal cord blood flow. DCS-measured blood flow in the spinal cord was monitored at up to three spatial locations (cranial to, at, and caudal to the distraction site) during surgical distraction in a sheep model. Distraction was halted at 50% of baseline blood flow at the distraction site. We were able to monitor blood flow with DCS in multiple regions of the spinal cord simultaneously at ∼1 Hz. The distraction site had a greater decrement in flow than sites cranial to the injury (median −40 vs. −7%,). This pilot study demonstrated high temporal resolution and the capacity to axially resolve changes in spinal cord blood flow at and remote from the site of distraction. These early results suggest that this technology may assist in the surgical management of spine trauma and in corrective surgery of the spine.

Background: Outcomes for the four anatomical subtypes of biliary tract carcinoma (BTC) - intrahepatic, perihilar and distal cholangiocarcinoma (ICC, PHCC, DCC) and gallbladder carcinoma (GBC) - are often combined. However, large cohorts comparing short- and long-term outcomes for the anatomical subtypes of BTC are lacking. Methods: All patients who underwent resection for pathology proven ICC, PHCC, DCC or GBC (2000–2016) from a single Western high-volume center were retrospectively selected. Clinicopathological characteristics, short- and long-term outcomes were compared between the four anatomical subtypes. Results: Overall, 361 patients with resected BTC were included (33 ICC, 135 PHCC, 148 DCC, 45 GBC). Clavien-Dindo grade III or higher complications were 48%, 51%, 36% and 8% (p < 0.001) and 90-day mortality was 9%, 15%, 3%, 4% (p < 0.001), for ICC, PHCC, DCC, GBC. Median overall survival was 37, 42, 29 and 41 months (p = 0.722), for ICC, PHCC, DCC, GBC. Five-year survival ranged between 29% and 37%. Anatomical subtype was not an independent predictor for overall survival. Conclusion: In this large single-center cohort of resected BTC, major morbidity and 90-day mortality varied between the four anatomical subtypes of BTC, mainly due to differences in surgical approach However, a significant difference in overall survival was not detected.

Background: This study sought to assess patient satisfaction and quality of life (QoL) before and after treatment of pancreatic and periampullary cancer. Methods: We conducted a prospective multicenter study of patients treated for pancreatic and periampullary cancer. General patient satisfaction was measured using the EORTC satisfaction with care questionnaire (IN-PATSAT32) at baseline and 3 months after treatment initiation, with a 10-point change on the Likert scale considered clinically meaningful. QoL was measured using the EORTC Core Quality of Life Questionnaire (QLQ-C30). The influence of treatment (curative and palliative) on patient satisfaction and QoL was determined. Results: Of 100 patients, 71 completed follow-up questionnaires. General satisfaction with care decreased from 74.3 before treatment to 61.9 after treatment (PP=.39). Clinically meaningful reductions were also observed for the reported interpersonal skills of doctors (from 73.4 to 63.3) and exchange of information within the care team (from 63.5 to 52.5). Satisfaction scores were lower for patients treated with curative intent than for those treated with palliative intent regarding interpersonal skills of doctors (P=.01), information provision by doctors (P=.004), information provision by nurses (P=.02), availability of nurses (P=.004), exchange of information within the care team (P=.01), and hospital access (P=.02). In multivariable analysis, clinicopathologic or QoL factors were not independently associated with general patient satisfaction. Conclusions: Satisfaction with care, but not QoL, decreased after pancreatic cancer treatment. Improvements in communication and interpersonal skills are needed to maintain patient satisfaction after treatment.

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 K trans and v e, ADC, and IVIM D correlated with collagen fraction. DCE k ep 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 k ep 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, Patient stratification based on biological variation in pancreatic ductal adenocarcinoma subtypes could help to improve clinical outcome. In this study, quantitative magnetic resonance imaging (MRI) parameters were directly correlated to immunohistochemistry‐derived tissue characteristics. Furthermore, based on MRI parameters a subgroup of patients with significantly better prognosis could be identified, indicating that patient stratification based on MRI parameters is feasible.

OBJECTIVE: The aim of this study was to evaluate whether neoadjuvant therapy (NAT) critically influenced microscopically complete resection (R0) rates and long-term outcomes for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy (PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-volume centers. SUMMARY OF BACKGROUND DATA: Limited size studies suggest that NAT improves R0 rates and overall survival compared to upfront surgery in R/BR-PDAC patients. METHODS: This multicenter study analyzed consecutive patients with R/BR-PDAC who underwent PD with PVR in 23 high-volume centers from 2009 to 2018. RESULTS: Data from 1192 patients with PD and PVR were collected and analyzed. The median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186 (15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and neoadjuvant chemoradiotherapy, respectively. The R0/R1/R2 rates were 57%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in patients who did not, respectively (P =0.004). The 1-, 3-, and 5-year OS in patients receiving NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%, respectively (P

Contains fulltext : 239076.pdf (Publisher’s version ) (Closed access) OBJECTIVE: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection). BACKGROUND: Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking. METHODS: Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015-December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS. RESULTS: Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222-0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01). CONCLUSIONS: Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only.

Background: In this retrospective cohort study, the potential of gemcitabine (gem)/cisplatin (cis) chemotherapy as future preoperative therapy for patients with unresectable locally advanced or borderline resectable intrahepatic, perihilar, and mid-cholangiocarcinoma was investigated. Methods: All patients with intrahepatic, perihilar, and mid-cholangiocarcinoma presented at Amsterdam UMC between January 2016 and October 2019 were included. The radiologic response after 3 and/or 6 cycles of gem/cis chemotherapy in patients with unresectable locally advanced or borderline resectable disease was derived from the original radiologic reports and subsequently re-evaluated for surgical exploration by consensus reading of 2 HPB surgeons and 1 radiologist. Results: Overall, 65 of 364 patients had a locally advanced or borderline resectable disease. Twenty-eight patients were treated with palliative chemotherapy, including 25 (89.3%) patients who received more than 3 cycles. Twenty-two patients (88.0%) and 13 patients (46.4%) showed RECIST stable disease or partial response after 3 and 6 cycles of chemotherapy, respectively. Three patients experienced grade 3 adverse events. Consensus reading concluded that exploration could have been reconsidered in 7 of 28 patients (25.0%). Conclusion: Gem/cis may be a safe and feasible preoperative treatment in initially unresectable locally advanced or borderline resectable cholangiocarcinoma. In addition, the findings of this study support to always rediscuss patients with stable or responsive disease in multidisciplinary team meetings to reconsider resection. Besides, prospective studies are needed to investigate this effect further and, based on these preliminary data, seem feasible in this setting.

Contains fulltext : 239059.pdf (Publisher’s version ) (Closed access) BACKGROUND AND OBJECTIVES: Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC. METHODS: From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated. RESULTS: A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index ≤1, and CA 19.9 1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein ≥ 270° were independent factors decreasing the probability of resection (c-index: 0.79). CONCLUSIONS: Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients.

Background: Over the years, high-volume pancreatic centers expanded their indications for pancreatoduodenectomy (PD) but with unknown impact on surgical and oncological outcome. Methods: All consecutive PDs performed between 1992–2017 in a single pancreatic center were identified from a prospectively maintained database and analyzed according to three time periods. Results: In total, 1434 patients underwent PD. Over time, more elderly patients underwent PD (P < 0.001) with increased use of vascular resection (10.4 to 16.0%, P < 0.001). In patients with cancer (n = 1049, 74.8%), the proportion pT3/T4 tumors increased from 54.3% to 70.6% over time (P < 0.001). The postoperative pancreatic fistula (16.0%), postpancreatectomy hemorrhage (8.0%) and delayed gastric emptying (31.0%) rate did not reduce over time, whereas median length of stay decreased from 16 to 12 days (P < 0.001). The overall failure-to-rescue rate (6.9%) and in-hospital mortality (2.2%) remained stable (P = 0.89 and P = 0.45). In 523 patients with pancreatic cancer (36.5%), the use of both adjuvant and neoadjuvant chemotherapy increased over time (both p

OBJECTIVE: To establish an international core set of patient-reported outcomes (PROs) selected by both patients and healthcare providers (HCPs) from the United States (US), Europe, and Asia. SUMMARY BACKGROUND DATA: PROs are increasingly recognized in pancreatic cancer studies. There is no consensus on which of the many available PROs are most important. METHODS: A multicenter Delphi study among patients with pancreatic cancer (curative- and palliative-setting) and HCPs in 6 pancreatic centers in the US (Baltimore, Boston), Europe (Amsterdam, Verona), and Asia (Mumbai, Seoul) was performed. In round 1, participants rated the importance of 56 PROs on a 1 to 9 Likert scale. PROs rated as very important (scores 7-9) by the majority (≥80%) of curative- and/or palliative-patients as well as HCPs were included in the core set. PROs not fulfilling these criteria were presented again in round 2, together with feedback on individual and group ratings. Remaining PROs were ranked based on the importance ratings. RESULTS: In total 731 patients and HCPs were invited, 501 completed round 1, and 420 completed both rounds. This included 204 patients in curative-setting, 74 patients in palliative-setting, and 142 HCPs. After 2 rounds, 8 PROs were included in the core set: general quality of life, general health, physical ability, ability to work/do usual activities, fear of recurrence, satisfaction with services/care organization, abdominal complaints, and relationship with partner/family. CONCLUSIONS: This international Delphi study among patients and HCPs established a core set of PROs in pancreatic cancer, which should facilitate the design of future pancreatic cancer trials and outcomes research.

The aim of the study was to assess feasibility and outcomes of a multicenter training program in laparoscopic pancreatoduodenectomy (LPD). Whereas expert centers have reported promising outcomes of LPD, nationwide analyses have raised concerns on its safety, especially during the learning curve. Multicenter, structured LPD training programs reporting outcomes including the first procedures are lacking. No LPD had been performed in the Netherlands before this study. During 2014-2016, 8 surgeons from 4 high-volume centers completed the Longitudinal Assessment and Realization of Laparoscopic Pancreatic Surgery (LAELAPS-2) training program in LPD, including detailed technique description, video training, and proctoring. In all centers, LPD was performed by 2 surgeons with extensive experience in pancreatic and laparoscopic surgery. Outcomes of all LPDs were prospectively collected. In total, 114 patients underwent LPD. Median pancreatic duct diameter was 3 mm [interquartile range (IQR = 2-4)] and pancreatic texture was soft in 74% of patients. The conversion rate was 11% (n = 12), median blood loss 350 mL (IQR = 200-700), and operative time 375 minutes (IQR = 320-431). Grade B/C postoperative pancreatic fistula occurred in 34% of patients, requiring catheter drainage in 22% and re-operation in 2%. A Clavien-Dindo grade ≥ III complication occurred in 43% of patients. Median length of hospital stay was 15 days (IQR = 9-25). Overall, 30-day and 90-day mortality were both 3.5%. Outcomes were similar for the first and second part of procedures. This LPD training program was feasible and ensured acceptable outcomes during the learning curve in all centers. Future studies should determine whether such a training program is applicable in other settings and assess the added value of LPD

Background Hepatobiliary scintigraphy (HBS) is used to quantify total and regional liver function. Transient elastography (TE) provides a non-invasive alternative to percutaneous biopsy to assess liver fibrosis and cirrhosis. This study aims to determine the correlation between HBS and histopathology of liver parenchyma, and to compare these with TE in patients with resectable hepatocellular carcinoma (HCC). Methods Patients who underwent surgery for HCC between 2000 and 2016 after preoperative HBS were included. Non-tumorous liver tissue was evaluated for inflammation, steatosis, ballooning, siderosis and fibrosis. Correlation analysis was performed between HBS results and histopathological scoring. These were also compared with TE and surgical outcomes. Results 71 patients underwent preoperative HBS of whom 24 also had TE. HBS correlated with portal and lobular inflammation as well as fibrosis. TE correlated with portal and lobular inflammation, ballooning and fibrosis. A significant correlation was found between HBS and TE. No association was found with overall postoperative morbidity and mortality. Conclusion HBS and TE show a moderate to strong correlation. HBS and TE share discriminatory features of histopathological scoring and show a weak to moderate correlation with hepatic inflammation and fibrosis.

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

An optimal learning climate is crucial for the quality of residency training and may also improve residents' well-being and empathy. We investigated the associations of learning climate with residents' work-related well-being. A multicenter questionnaire study was performed among 271 surgery and gynaecology residents in 21 training programs from September 2012 to February 2013. Residents were asked to complete work-related well-being measurements: work engagement (Utrecht Work Engagement Scale), job and specialty satisfaction (measures from Physician Worklife Study), and physician empathy (Jefferson Scale of Physician Empathy). The Dutch Residency Educational Climate Test was used to evaluate learning climate. Multivariate adjusted linear regression analyses were used to estimate associations of learning climate with work-related well-being measures. Well-being measures were completed by 144 residents (53.1%). Learning climate was evaluated by 193 residents, yielding 9.2 evaluations per training program on average. Overall learning climate score was positively associated with work engagement [regression coefficient b = 0.58; 95% confidence interval (CI) 0.18-0.98; p = 0.004] and job satisfaction (b = 0.80; 95% CI 0.48-1.13; p

Autorregulació cerebral; Malaltia cerebrovascular; Òptica difusa Autorregulación cerebral; Enfermedad cerebrovascular; Óptica difusa Cerebral autoregulation; Cerebrovascular disease; Diffuse optics 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

Background: Registries of pancreatic surgery have become increasingly popular as they facilitate both quality improvement and clinical research. We aimed to compare registries for design, variables collected, patient characteristics, treatment strategies, clinical outcomes, and pathology. Methods: Registered variables and outcomes of pancreatoduodenectomy (2014–2017) in 4 nationwide or multicenter pancreatic surgery registries from the United States of America (American College of Surgeons National Surgical Quality Improvement Program), Germany (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie - Studien-, Dokumentations- und Qualitätszentrum), the Netherlands (Dutch Pancreatic Cancer Audit), and Sweden (Swedish National Pancreatic and Periampullary Cancer Registry) were compared. A core registry set of 55 parameters was identified and evaluated using relative and absolute largest differences between extremes (smallest versus largest). Results: Overall, 22,983 pancreatoduodenectomies were included (15,224, 3,558, 2,795, and 1,406 in the United States of America, Germany, the Netherlands, and Sweden). Design of the registries varied because 20 out of 55 (36.4%) core parameters were not available in 1 or more registries. Preoperative chemotherapy in patients with pancreatic ductal adenocarcinoma was administered in 27.6%, 4.9%, 7.0%, and 3.4% (relative largest difference 8.1, absolute largest difference 24.2%, P < .001). Minimally invasive surgery was performed in 7.8%, 4.5%, 13.5%, and unknown (relative largest difference 3.0, absolute largest difference 9.0%, P < .001). Median length of stay was 8.0, 16.0, 12.0, and 11.0 days (relative largest difference 2.0, absolute largest difference 8.0, P < .001). Reoperation was performed in 5.7%, 17.1%, 8.7%, and 11.2% (relative largest difference 3.0, absolute largest difference 11.4%, P < .001). In-hospital mortality was 1.3%, 4.7%, 3.6%, and 2.7% (relative largest difference 3.6, absolute largest difference 3.4%, P < .001). Conclusion: Considerable differences exist in the design, variables, patients, treatment strategies, and outcomes in 4 Western registries of pancreatic surgery. The absolute largest differences of 24.3% for the use of preoperative chemotherapy, 9.0% for minimally invasive surgery, 11.4% for reoperation rate, and 3.4% for in-hospital mortality require further study and improvement. This analysis provides 55 core parameters for pancreatic surgery registries.

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC.Materials and methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy.Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34).Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd.

Objective: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. Summary Background Data: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. Methods: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). Results: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. Conclusion: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.

Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin α

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.

Importance: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear.Objective: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment.Design, Setting, and Participants: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded.Exposures: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise.Results: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73).Conclusions and Relevance: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Background: The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer.Methods: We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement.Results: Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3 -year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001).Conclusions: This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www pancreascalculaior. corn may facilitate use in daily practice and future trials. (C) 2019 Elsevier Ltd, BASO The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1x10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset≤50, and 4142 controls from the PANDoRA consortium while in the in silico data we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15x10-4 ). In conclusion we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. This article is protected by copyright. All rights reserved.

Background Radical resection of advanced pancreatic cancer may occasionally require a simultaneous colon resection. The risks and benefits of this combined procedure are largely unknown. This systematic review aimed to assess short and long term outcome after pancreatoduodenectomy with colon resection (PD-colon) for pancreatic ductal adenocarcinoma (PDAC). Methods A systematic literature search was performed in PubMed, Embase, and the Cochrane Library for studies published between 1994 and 2017 concerning PD-colon for PDAC. Results After screening 2038 articles, 5 articles with a total of 181 patients undergoing PD-colon were eligible for inclusion. Included studies showed a relatively low risk of bias. The pooled complication rate was 73% (95% CI 61–84) including a pooled colonic anastomotic leak rate of 5.5%. Pooled mortality was 10% (95% CI 6–15). Pooled mean survival (data from 86 patients) was 18 months (95% CI 13–23) with pooled 3- and 5-year survival of 31% (95% CI 20–72) and 19% (95% CI 6–38). Conclusion Based on the available data, PD-colon for PDAC seems to be associated with an increased morbidity and mortality but with survival comparable with standard PD in selected patients. Future large series are needed to allow for better patient selection for PD-colon.

Background Nonresected, nonmetastatic (NR‐M0) pancreatic cancer involves both locally advanced pancreatic cancer and patients who did not undergo resection due to poor health status or patient preference. This study investigates nationwide trends of characteristics, treatment, and survival of patients with NR‐M0 pancreatic cancer. Methods From the Netherlands Cancer Registry, all patients diagnosed with pancreatic cancer between 2006 and 2014 were selected. Chemotherapy and overall survival (OS) of NR‐M0 patients were evaluated for 3‐year time periods and 2 age groups using chi‐square tests for trend and Cox proportional hazard regression analysis. Results Of 18 234 patients, 33% had NR‐M0 pancreatic cancer, which decreased over time (in consecutive 3‐year periods: 38%‐33%‐28%, P

Lateral pancreaticojejunostomy (LPJ) has shown good postoperative outcomes in patients with painful, morphine dependent, chronic pancreatitis (CP). The recent rise of robotic and laparoscopic pancreatic surgery has found benefits such as reduced time to functional recovery. Few studies have reported on the feasibility, technique and outcome of robotic LPJ, especially including transection of the gastroduodenal artery. The present study describes the main steps for robotic LPJ in a patient with painful chronic pancreatitis with a dilated main pancreatic duct. The patient underwent robotic LPJ. The LPJ anastomosis is performed using a running suture technique in a longitudinal side-to-side manner. Routinely, the gastroduodenal artery is transected to drain the entire length of the main pancreatic duct. The patient is in French position; 7 trocars are placed (4 robotic, 2 laparoscopic assistants, 1 liver-retractor). After docking of the robot system, the omental bursa is opened, and the right gastroepiploic artery and vein are ligated at their base at the lower border of the pancreas. Intraoperative ultrasonography is performed in order to determine trajectory of the dilated main pancreatic duct which is opened for its entire length after the gastroduodenal artery has been suture ligated both cranially and caudally from the main pancreatic duct. A Roux limb is created, and a latero-lateral PJ is fashioned using several 3-0 barbed sutures. A stapled jejuno-jejunostomy is created at sufficient distance from the pancreatic anastomosis, aided by a 50 cm suture. The described technique for robotic LPJ is a complex but feasible operation for patients with treatment refractory CP and a dilated main pancreatic duct. Due to its complexity, implementation in high volume centers with extensive experience with CP surgery may improve outcomes.

Pancreatoduodenectomy (PD) is increasingly performed in high-volume centers, which may compromise waiting times. The aim of this study was to evaluate patient flow and outcome of PD within a regional oncology network of two high-volume centers. A post hoc analysis of a partially retrospective and prospective database was performed of all patients who underwent PD for pancreatic or periampullary neoplasms in both centers of the Gastrointestinal Oncology Center Amsterdam, a collaboration between an academic center and affiliated general teaching hospital, from 2010 to 2014. Outcomes included waiting time to surgery and postoperative morbidity and mortality. A total of 525 PDs were performed, 329 in the academic center (annual volume 66) and 196 in the teaching hospital (annual volume 39). Neoadjuvant treatment was more often used in the academic center, other baseline characteristics were similar. Overall time to surgery was 26 days, which was significantly less in the teaching hospital. The major postoperative morbidity rate was 38.3% (n = 201), and the 30- and 90-day mortality was 2.3% and 3.6%. A regional oncology network between an academic center and a general teaching hospital for PD can be an attractive option to safeguard waiting times in selected patients, without compromising outcome.

Background: Although several classifications of perihilar cholangiocarcinoma (PHC) include vascular involvement, its prognostic value has not been investigated. Our aim was to assess the prognostic value of unilateral and main/bilateral involvement of the portal vein (PV) and hepatic artery (HA) on imaging in patients with PHC. Methods: All patients with PHC between 2002 and 2014 were included regardless of stage or management. Vascular involvement was defined as apparent tumor contact of at least 180 degrees to the PV or HA on imaging. Kaplan-Meier method with log-rank test was used to compare overall survival (OS) between groups. Cox regression was used for multivariable analysis. Results: In total, 674 patients were included with a median OS of 12.2 (95% CI 10.6-13.7) months. Patients with unilateral PV involvement had a median OS of 13.3 (11.0-15.7) months, compared with 14.7 (11.7-17.6) in patients without PV involvement (p = 0.12). Patients with main/bilateral PV involvement had an inferior median OS of 8.0 (5.4-10.7, p

OBJECTIVES: Large biobanks with uniform collection of biomaterials and associated clinical data are essential for translational research. The Netherlands has traditionally been well organized in multicenter clinical research on pancreatic diseases, including the nationwide multidisciplinary Dutch Pancreatic Cancer Group and Dutch Pancreatitis Study Group. To enable high-quality translational research on pancreatic and periampullary diseases, these groups established the Dutch Pancreas Biobank.METHODS: The Dutch Pancreas Biobank is part of the Parelsnoer Institute and involves all 8 Dutch university medical centers and 5 nonacademic hospitals. Adult patients undergoing pancreatic surgery (all indications) are eligible for inclusion. Preoperative blood samples, tumor tissue from resected specimens, pancreatic cyst fluid, and follow-up blood samples are collected. Clinical parameters are collected in conjunction with the mandatory Dutch Pancreatic Cancer Audit.RESULTS: Between January 2015 and May 2017, 488 patients were included in the first 5 participating centers: 4 university medical centers and 1 nonacademic hospital. Over 2500 samples were collected: 1308 preoperative blood samples, 864 tissue samples, and 366 follow-up blood samples.CONCLUSIONS: Prospective collection of biomaterials and associated clinical data has started in the Dutch Pancreas Biobank. Subsequent translational research will aim to improve treatment decisions based on disease characteristics.

Contains fulltext : 245466.pdf (Publisher’s version ) (Open Access) BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) shortens time to functional recovery and improves 30-day quality of life (QoL), as compared with open distal pancreatectomy (ODP) for nonmalignant disease. The impact of MIDP on QoL, cosmetic satisfaction, and overall major complications beyond 1-year follow-up is currently unknown. STUDY DESIGN: The Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD) trial randomized 108 patients to MIDP (laparoscopic or robotic) or ODP in 14 Dutch centers (April 2015 to March 2017). The primary outcome measure of this study was quality-adjusted life years (QALYs), as assessed with the EQ-5D. QoL was assessed using subscales of the EORTC QLQ-C30, PAN-26, and a body image questionnaire. The latter included a cosmetic satisfaction score (range 3-24), and a body image score (range 5-20). Differences between MIDP and ODP for QALYs, generic, and disease-specific QoL and body image were analyzed. Missing QoL data were imputed using multiple imputation. RESULTS: In total, 84 patients were alive, with a median follow-up of 44 months; 62 of these patients (74%) completed the questionnaires (27 MIDP, 35 ODP). There was no significant difference in QALYs between the 2 groups (mean score 2.34 vs 2.46 years, p = 0.63), nor on the QoL subscales. Significant overall change in EQ-5D health utilities were found for both groups over time (p < 0.001). Patients in the MIDP group scored higher on cosmetic satisfaction (21 vs 14, p = 0.049). No differences between the 2 groups were observed for clinical outcomes such as major complications, readmissions, and incisional hernias. CONCLUSIONS: More than 3 years after distal pancreatectomy, no improvement in QALYs and overall QoL was seen after MIDP, whereas cosmetic satisfaction was higher after MIDP as compared with ODP.

Major liver resection for perihilar cholangiocarcinoma (PHC) is associated with a 22% to 33% postoperative liver failure incidence. The aim of this study was analyze the predictive value of future liver remnant (FLR) volume for postoperative liver failure after resection for PHC and to develop a risk score to improve patient selection for portal vein embolization. A consecutive series of 217 patients underwent major liver resection for PHC between 1997 and 2014 at 2 Western centers; FLR volumes were calculated with CT volumetry; other variables included jaundice at presentation, immediate preoperative bilirubin, and preoperative cholangitis. The FLR volume was categorized as 45%. A risk score for postoperative liver failure (grade B/C according to the International Study Group of Liver Surgery criteria) was developed using multivariable logistic regression with 5 predefined variables. Postoperative liver failure incidence was 24% and liver failure-related mortality was 12%. Risk factors for liver failure were FLR volume 50 μmol/L (>2.9 mg/dL) (odds ratio 4.3; 95% CI 1.7 to 10.7), and preoperative cholangitis (odds ratio 3.4; 95% CI 1.6 to 7.4) were risk factors for liver failure. These variables were included in a risk score that showed good discrimination (area under the curve 0.79; 95% CI 0.72 to 0.86) and ranking patients in 3 risk sub-groups with predicted liver failure incidence of 4%, 14%, and 44%. The selection of patients for portal vein embolization using only liver volume is insufficient, considering the other predictors of liver failure in PHC patients. The proposed risk score can be used for selection of patients for portal vein embolization, for adequate patient counseling, and identification of other modifiable risk factors besides liver volume

Background Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response. 99m Tc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. Methods Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre–portal vein embolization and post–portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre–portal vein embolization future remnant liver function was performed to identify patients who would meet the post–portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m 2 ). Results Mean pre–portal vein embolization future remnant liver function was 1.80% ± 0.45%/min/m 2 and increased to 2.89% ± 0.97%/min/m 2 post–portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre–portal vein embolization future remnant liver function of ≥1.72%/min/m 2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post–portal vein embolization future remnant liver function below the cutoff value for safe resection. Conclusion When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS.

Background Uncontrolled introduction of laparoscopic liver surgery (LLS) could compromise postoperative outcomes. A stepwise introduction of LLS combined with structured training is advised. This study aimed to evaluate the impact of such a stepwise introduction. Methods A retrospective, single-center case series assessing short term outcomes of all consecutive LLS in the period November 2006-January 2017. The technique was implemented in a stepwise fashion. To evaluate the impact of this stepwise approach combined with structured training, outcomes of LLS before and after a laparoscopic HPB fellowship were compared. Results A total of 135 laparoscopic resections were performed. Overall conversion rate was 4% (n = 5), clinically relevant complication rate 13% (n = 18) and mortality 0.7% (n = 1). A significant increase in patients with major LLS, multiple liver resections, previous abdominal surgery, malignancies and lesions located in posterior segments was observed after the fellowship as well as a decrease in the use of hand-assistance. Increasing complexity in the post fellowship period was reflected by an increase in operating times, but without comprising other surgical outcomes. Conclusion A stepwise introduction of LLS combined with structured training reduced the clinical impact of the learning curve, thereby confirming guideline recommendations.

Background: Determining the resectability of locally advanced pancreatic cancer (LAPC) after FOLFIRINOX chemotherapy is challenging because CT-scans cannot reliably assess vascular involvement. This study evaluates the added value of intra-operative ultrasound (IOUS) in LAPC following FOLFIRINOX induction chemotherapy. Methods: Prospective multicenter study in patients with LAPC who underwent explorative laparotomy with IOUS after FOLFIRINOX chemotherapy. Resectability was defined according to the National Comprehensive Cancer Network guidelines. IOUS findings were compared with preoperative CT-scans and pathology results. Results: CT-staging in 38 patients with LAPC after FOLFIRINOX chemotherapy defined 22 patients LAPC, 15 borderline resectable and one resectable. IOUS defined 19 patients LAPC, 13 borderline resectable and six resectable. In 12/38 patients, IOUS changed the resectability status including five patients from borderline resectable to resectable and five patients from LAPC to borderline resectable. Two patients were upstaged from borderline resectable to LAPC. Tumor diameters were significantly smaller upon IOUS (31.7 ± 9.5 mm versus 37.1 ± 10.0 mm, p = 0.001) and resectability varied significantly (p = 0.043). Ultimately, 20 patients underwent resection of whom 14 were evaluated as (borderline) resectable on CT-scan, and 17 on IOUS. Discussion: This prospective study demonstrates that IOUS may change the resectability status up to a third of patients with LAPC following FOLFIRINOX chemotherapy.

Background The rationale for total pancreatectomy in painful, treatment refractory, chronic pancreatitis is pain control. Concomitant islet cell autotransplantation can prevent the loss of islet cell function. This study aimed to systematically examine the impact of total pancreatectomy with islet cell autotransplantation on pain and quality of life. Methods This meta-analysis was conducted according the Meta-analyses of Observational Studies in Epidemiology guideline. The Cochrane Library, PubMed, and Embase were searched for the following terms (1990 through April 2018): total pancreatectomy and chronic pancreatitis. Studies were included when addressing total pancreatectomy with islet cell autotransplantation for chronic pancreatitis in adults. Studies that reported no data on pain, endocrine function, or quality of life were excluded. Quality was assessed using the Newcastle-Ottawa scale for evaluation of all studies. Results We included 15 observational studies evaluating 1,255 patients, of whom 28% had had endoscopic and 23% operative therapy. One year after total pancreatectomy with islet cell autotransplantation, the opioid-free rate had improved from between 0% and 15% to 63% (95% CI 46–77), and the insulin-free rate had decreased from between 89.5% and 100% to 30% (95% CI 20–43). An alcoholic etiology was associated with a lesser insulin-free rate after total pancreatectomy with islet cell autotransplantation. Quality of life improved statistically after total pancreatectomy with islet cell autotransplantation. Publication bias was present for both opioid and insulin outcomes. Conclusion In selected patients with painful, treatment refractory, chronic pancreatitis, evidence shows that total pancreatectomy with islet cell autotransplantation is effective for pain control in almost two-thirds of patients, whereas the insulin-free rate is relatively low.

Background: The Warshaw (WT) and the Kimura (KT) techniques are both used for open or minimally invasive (MI) spleen preserving distal pancreatectomy (SPDP). Multicenter studies on long-term outcome of WT and KT are lacking. Methods: Multicenter retrospective study with transversal follow-up moment, including patients who underwent SPDP from 2000 to 2017 at three high-volume centers in Italy and the Netherlands. Primary endpoint was the incidence of short and long term complications. Patients without regular follow-up were interviewed about symptoms and complications. Results: In total, 164 patients were enrolled, 55 WT (33.5%) and 109 kT (66.5%), of which 95 (57.9%) MI. There was no 30-day mortality (0%).The only significant difference in short-term outcome was more delayed gastric emptying (DGE) after WT (9.1% vs 1.8%, p = 0.043). MI-SPDP was associated with less blood loss (median 150 vs 250 ml, respectively, p < 0.001), less DGE (0% vs 10%, p = 0.002), less abdominal abscesses (8.4% vs 18.4%, p = 0.03) and less splenic infarctions (3.2% vs. 13%, p = 0.042), than open SPDP. Long-term follow-up (median 41 months) was available for 111 patients (67.7%) of whom 18 (16.2%) had an SPDP-related long-term sequela, mostly perigastric varices (n = 11, 9%) but without differences between WT and KT. Less long-term sequelae were reported after MI as compared to open SPDP (12.5% vs 21.2%, p = 0.032). Conclusions: In this international retrospective study, the WT and KT had comparable short- and long-term outcomes. If a KT does not seem feasible during SPDP, a WT is recommended, rather than performing a splenectomy. MI-SPDP was associated with less short- and long term complications as compared to an open SPDP.

Background: Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. Methods: This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30–59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. Findings: Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of −1·0 percentage point (SE 0·1; −11 mmol/mol [SE 0·8]) vs −0·2 percentage points (SE 0·1; −2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: −0·8 percentage points, 95% CI −1·0 to −0·6; p1c −1·1 percentage points (SE 0·1; −12 mmol/mol [SE 0·8] versus −0·1 percentage points (SE 0·1; −1 mmol/mol [SE 0·8]; ETD −1·0 percentage points, 95% CI −1·2 to −0·8; p

Intrathoracic pressure influences cardiac output and may affect cerebral blood flow (CBF). We aimed to quantify the cerebral hemodynamic response to intrathoracic pressure reduction in patients with acute ischemic stroke using a noninvasive respiratory impedance (RI) device. We assessed low-level (6 cm H(2)O) and high-level (12 cm H(2)O) RI in 17 spontaneously breathing patients within 72 h of anterior circulation acute ischemic stroke. Average age was 65 years, and 35% were female. Frontal lobe tissue perfusion and middle cerebral artery velocity (MCAv) were continuously monitored with optical diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. High-level RI resulted in a 7% increase in MCAv (p = 0.004). MCAv varied across all studied levels (baseline vs low-level vs high-level, p = 0.006), with a significant test of trend (p = 0.002). Changes were not seen in DCS measured tissue perfusion by nonparametric pairwise comparison. Mixed effects regression analysis identified a small increase in both MCAv (low-level RI: β 2.1, p

Rapid detection of ischemic conditions at the bedside can improve treatment of acute brain injury. In this observational study of 11 critically ill brain-injured adults, we employed a monitoring approach that interleaves time-resolved near-infrared spectroscopy (TR-NIRS) measurements of cerebral oxygen saturation and oxygen extraction fraction (OEF) with diffuse correlation spectroscopy (DCS) measurement of cerebral blood flow (CBF). Using this approach, we demonstrate the clinical promise of non-invasive, continuous optical monitoring of changes in CBF and cerebral metabolic rate of oxygen (CMRO2). In addition, the optical CBF and CMRO2 measures were compared to invasive brain tissue oxygen tension (PbtO2), thermal diffusion flowmetry CBF, and cerebral microdialysis measures obtained concurrently. The optical CBF and CMRO2 information successfully distinguished between ischemic, hypermetabolic, and hyperemic conditions that arose spontaneously during patient care. Moreover, CBF monitoring during pressor-induced changes of mean arterial blood pressure enabled assessment of cerebral autoregulation. In total, the findings suggest that this hybrid non-invasive neurometabolic optical monitor (NNOM) can facilitate clinical detection of adverse physiological changes in brain injured patients that are otherwise difficult to measure with conventional bedside monitoring techniques.

Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow‐up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell‐free DNA from plasma samples of 58 treatment‐naive mPDAC patients was isolated and sequenced using a custom‐made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross‐check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p, What's new? Circulating tumor DNA (ctDNA) attracts much interest as a possible prognostic tool for cancer. Here, the authors showed that the quantity of ctDNA correlated strongly with tumor volume in metastatic pancreatic ductal adenocarcinoma (mPDAC). They conducted a retrospective analysis using samples collected from 58 untreated mPDAC patients. For this study, the authors designed a pancreatobiliary NGS panel, which they used to test the patients’ cell‐free DNA, along with droplet digital PCR. Both ctDNA variant allele frequency and tumor volume predicted overall survival, they found.

Background: Diffuse correlation spectroscopy (DCS) noninvasively permits continuous, quantitative, bedside measurements of cerebral blood flow (CBF). To test whether optical monitoring (OM) can detect decrements in CBF producing cerebral hypoxia, we applied the OM technique continuously to probe brain-injured patients who also had invasive brain tissue oxygen (PbO 2 ) monitors. Methods: Comatose patients with a Glasgow Coma Score (GCS) < 8) were enrolled in an IRB-approved protocol after obtaining informed consent from the legally authorized representative. Patients underwent 6–8 h of daily monitoring. Brain PbO 2 was measured with a Clark electrode. Absolute CBF was monitored with DCS, calibrated by perfusion measurements based on intravenous indocyanine green bolus administration. Variation of optical CBF and mean arterial pressure (MAP) from baseline was measured during periods of brain hypoxia (defined as a drop in PbO 2 below 19 mmHg for more than 6 min from baseline (PbO 2 > 21 mmHg). In a secondary analysis, we compared optical CBF and MAP during randomly selected 12-min periods of “normal” (> 21 mmHg) and “low” (< 19 mmHg) PbO 2 . Receiver operator characteristic (ROC) and logistic regression analysis were employed to assess the utility of optical CBF, MAP, and the two-variable combination, for discrimination of brain hypoxia from normal brain oxygen tension. Results: Seven patients were enrolled and monitored for a total of 17 days. Baseline-normalized MAP and CBF significantly decreased during brain hypoxia events (p < 0.05). Through use of randomly selected, temporally sparse windows of low and high PbO 2 , we observed that both MAP and optical CBF discriminated between periods of brain hypoxia and normal brain oxygen tension (ROC AUC 0.761, 0.762, respectively). Further, combining these variables using logistic regression analysis markedly improved the ability to distinguish low- and high-PbO 2 epochs (AUC 0.876). Conclusions: The data suggest optical techniques may be able to provide continuous individualized CBF measurement to indicate occurrence of brain hypoxia and guide brain-directed therapy.

Item does not contain fulltext BACKGROUND: Laparoscopic pancreatoduodenectomy may improve postoperative recovery compared with open pancreatoduodenectomy. However, there are concerns that the extensive learning curve of this complex procedure could increase the risk of complications. We aimed to assess whether laparoscopic pancreatoduodenectomy could reduce time to functional recovery compared with open pancreatoduodenectomy. METHODS: This multicentre, patient-blinded, parallel-group, randomised controlled phase 2/3 trial was performed in four centres in the Netherlands that each do 20 or more pancreatoduodenectomies annually; surgeons had to have completed a dedicated training programme for laparoscopic pancreatoduodenectomy and have done 20 or more laparoscopic pancreatoduodenectomies before trial participation. Patients with a benign, premalignant, or malignant indication for pancreatoduodenectomy, without signs of vascular involvement, were randomly assigned (1:1) to undergo either laparoscopic or open pancreatoduodenectomy using a central web-based system. Randomisation was stratified for annual case volume and preoperative estimated risk of pancreatic fistula. Patients were blinded to treatment allocation. Analysis was done according to the intention-to-treat principle. The main objective of the phase 2 part of the trial was to assess the safety of laparoscopic pancreatoduodenectomy (complications and mortality), and the primary outcome of phase 3 was time to functional recovery in days, defined as all of the following: adequate pain control with only oral analgesia; independent mobility; ability to maintain more than 50% of the daily required caloric intake; no need for intravenous fluid administration; and no signs of infection (temperature