Publications by authors named "Thomas M van Gulik"

422 Publications

Debate: 'Right versus left liver resection for hilar cholangiocarcinoma' Extended Right-hemihepatectomy is Preferred.

Ann Surg 2021 Feb 18. Epub 2021 Feb 18.

Department of General, Visceral and Transplantation Surgery, University Medical Center Mainz, Germany Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, location AMC, University of Amsterdam, the Netherlands.

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http://dx.doi.org/10.1097/SLA.0000000000004821DOI Listing
February 2021

The Use of the Oxygenated AirdriveTM Machine Perfusion System in Kidney Graft Preservation: A Clinical Pilot Study.

Eur Surg Res 2021 Feb 18:1-10. Epub 2021 Feb 18.

Department of Surgery, Amsterdam University Medical Center, Location Academic Medical Center, Amsterdam, The Netherlands.

Background: The shortage of donor kidneys has led to the use of marginal donors, e.g., those whose kidneys are donated after circulatory death. Preservation of the graft by hypothermic machine perfusion (HMP) provides a viable solution to reduce warm ischemic damage. This pilot study was undertaken to assess the feasibility and patient safety of the AirdriveTM HMP system in clinical kidney transplantation.

Methods: Five deceased-donor kidneys were preserved using the oxygenated Airdrive HMP system between arrival at the recipient center (Amsterdam UMC) and implantation in the patient. The main study end-points were adverse effects due to the use of Airdrive HMP. Secondary end-points were clinical outcomes and perfusion parameters. All events occurring during the transplantation procedure or within 1 month of follow-up were monitored.

Results: Five patients were included in this pilot study. No technical failures were observed during the preservation period using the Airdrive HMP. Mean perfusion parameters were: duration 8.5 h (3-15 h), pressure 25 mm Hg (18-25 mm Hg), flow 49.77 mL/min (19-58 mL/min), resistance 0.57 mm Hg/min/mL (0.34-1.3 mm Hg/min/mL), and temperature 8.2 °C (2-13°C). Mean cold ischemia time (CIT) was 20.2 h (11-29.5 h). No adverse events or technical failures were observed during preservation and transplantation or during the 1-month follow-up.

Conclusions: This pilot study showed the feasibility of the use of the Airdrive HMP system with no adverse events in clinical kidney transplantation.
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http://dx.doi.org/10.1159/000513493DOI Listing
February 2021

Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid.

Biomolecules 2021 Feb 10;11(2). Epub 2021 Feb 10.

Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.
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http://dx.doi.org/10.3390/biom11020260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916678PMC
February 2021

Staging Laparoscopy in Patients with Intrahepatic Cholangiocarcinoma: Is It Still Useful?

Visc Med 2020 Dec 3;36(6):501-505. Epub 2020 Mar 3.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: The role of staging laparoscopy in patients with intrahepatic cholangiocarcinoma remains unclear. Despite extensive preoperative imaging, approximately 25% of patients are deemed unresectable at laparotomy due to metastasized disease. The aim of this study was to evaluate the frequency of unresectable disease found at staging laparoscopy and to identify predictors for detecting metastasized intrahepatic cholangiocarcinoma.

Methods: We retrospectively collected records of all patients with intrahepatic cholangiocarcinoma, presenting at our institution from 2008 to 2017. Staging laparoscopy was performed on the suspicion of distant metastases and on indication in larger tumors. The yield and sensitivity of staging laparoscopy was calculated. Reasons for unresectability at staging laparoscopy or laparotomy were recorded.

Results: Among a total of 80 patients with potentially resectable intrahepatic cholangiocarcinoma, 35 patients underwent staging laparoscopy on the suspicion of distant metastases. Unresectable disease was found at staging laparoscopy in 15 patients. Reasons for unresectability were liver metastasis ( = 6), peritoneal metastasis ( = 4), severe cirrhosis ( = 2), locally advanced tumor with satellite lesions ( = 1), and distant lymph node metastasis ( = 2). Considering optimal preoperative imaging, the true yield of staging laparoscopy was 20% (7/35). Two patients did not undergo laparotomy due to progression after staging laparoscopy. Of the remaining 18 patients who underwent laparotomy, 6 patients (30%) had unresectable disease, mostly because of distant metastasis ( = 4).

Conclusions: The role of staging laparoscopy to detect unresectable intrahepatic cholangiocarcinoma is highly dependent on the quality of preoperative imaging. Currently, no accurate selection criteria on imaging exist to select patients with intrahepatic cholangiocarcinoma who potentially benefit from staging laparoscopy.
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http://dx.doi.org/10.1159/000506297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768138PMC
December 2020

Occurrence of seeding metastases in resectable perihilar cholangiocarcinoma and the role of low-dose radiotherapy to prevent this.

World J Hepatol 2020 Nov;12(11):1089-1097

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 AZ, Netherlands.

Background: Preoperative biliary drainage in patients with presumed resectable perihilar cholangiocarcinoma (PHC) is hypothesized to promote the occurrence of seeding metastases. Seeding metastases can occur at the surgical scars or at the site of postoperative drains, and in case of percutaneous biliary drainage, at the catheter port-site. To prevent seeding metastases after resection, we routinely treated PHC patients with preoperative radiotherapy (RT) for over 25 years until January 2018.

Aim: To investigate the incidence of seeding metastases following resection of PHC.

Methods: All patients who underwent resection for pathology proven PHC between January 2000 and March 2019 were included in this retrospective study. Between 2000-January 2018, patients received preoperative RT (3 × 3.5 Gray). RT was omitted in patients treated after January 2018.

Results: A total of 171 patients underwent resection for PHC between January 2000 and March 2019. Of 171 patients undergoing resection, 111 patients (65%) were treated with preoperative RT. Intraoperative bile cytology showed no difference in the presence of viable tumor cells in bile of patients undergoing preoperative RT or not. Overall, two patients (1.2%) with seeding metastases were identified, both in the laparotomy scar and both after preoperative RT (one patient with endoscopic and the other with percutaneous and endoscopic biliary drainage).

Conclusion: The incidence of seeding metastases in patients with resected PHC in our series was low (1.2%). This low incidence and the inability of providing evidence that preoperative low-dose RT prevents seeding metastases, has led us to discontinue preoperative RT in patients with resectable PHC in our center.
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http://dx.doi.org/10.4254/wjh.v12.i11.1089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701958PMC
November 2020

Lessons Learned From Two Prematurely Terminated, Randomized Trials on Biliary Drainage in Perihilar Cholangiocarcinoma.

Clin Gastroenterol Hepatol 2020 Nov 18. Epub 2020 Nov 18.

Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.cgh.2020.11.021DOI Listing
November 2020

HyCHEED System for Maintaining Stable Temperature Control during Preclinical Irreversible Electroporation Experiments at Clinically Relevant Temperature and Pulse Settings.

Sensors (Basel) 2020 Oct 31;20(21). Epub 2020 Oct 31.

Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Electric permeabilization of cell membranes is the main mechanism of irreversible electroporation (IRE), an ablation technique for treatment of unresectable cancers, but the pulses also induce a significant temperature increase in the treated volume. To investigate the therapeutically thermal contribution, a preclinical setup is required to apply IRE at desired temperatures while maintaining stable temperatures. This study's aim was to develop and test an electroporation device capable of maintaining a pre-specified stable and spatially homogeneous temperatures and electric field in a tumor cell suspension for several clinical-IRE-settings. A hydraulically controllable heat exchange electroporation device (HyCHEED) was developed and validated at 37 °C and 46 °C. Through plate electrodes, HyCHEED achieved both a homogeneous electric field and homogenous-stable temperatures; IRE heat was removed through hydraulic cooling. IRE was applied to 300 μL of pancreatic carcinoma cell suspension (Mia PaCa-2), after which cell viability and specific conductivity were determined. HyCHEED maintained stable temperatures within ±1.5 °C with respect to the target temperature for multiple IRE-settings at the selected temperature levels. An increase of cell death and specific conductivity, including post-treatment, was found to depend on electric-field strength and temperature. HyCHEED is capable of maintaining stable temperatures during IRE-experiments. This provides an excellent basis to assess the contribution of thermal effects to IRE and other bio-electromagnetic techniques.
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http://dx.doi.org/10.3390/s20216227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662544PMC
October 2020

International multicenter propensity score matched study on laparoscopic versus open left lateral sectionectomy.

HPB (Oxford) 2020 Oct 7. Epub 2020 Oct 7.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Background: Despite a lack of high-level evidence, current guidelines recommend laparoscopic left lateral sectionectomy (LLLS) as the routine approach over open LLS (OLLS). Randomized studies and propensity score matched studies on LLLS vs OLLS for all indications, including malignancy, are lacking.

Methods: This international multicenter propensity score matched retrospective cohort study included consecutive patients undergoing LLLS or OLLS in six centers from three European countries (January 2000-December 2016). Propensity scores were calculated based on nine preoperative variables and LLLS and OLLS were matched in a 1:1 ratio. Short-term operative outcomes were compared using paired tests.

Results: A total of 560 patients were included. Out of 200 LLLS, 139 could be matched to 139 OLLS. After matching, baseline characteristics were well balanced. LLLS was associated with shorter operative time (144 (110-200) vs 199 (138-283) minutes, P < 0.001), less blood loss (100 (50-300) vs 350 (100-750) mL, P = 0.005) and a 3-day shorter postoperative hospital stay (4 (3-7) vs 7 (5-9) days, P < 0.001).

Conclusion: This international multicenter propensity score matched study confirms the superiority of LLLS over OLLS based on shorter postoperative hospital stay, operative time, and less blood loss thus validating current guideline advice.
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http://dx.doi.org/10.1016/j.hpb.2020.09.006DOI Listing
October 2020

Choledochoduodenostomy versus hepaticojejunostomy - a matched case-control analysis.

HPB (Oxford) 2020 Sep 13. Epub 2020 Sep 13.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands.

Background: Choledochoduodenostomy (CD) is believed to cause certain long-term complications, such as sump syndrome and reflux gastritis. Therefore, CD is considered inferior to a Roux-and-Y hepaticojejunostomy (HJ). The aim of this study was to compare short- and long-term outcomes following CD and HJ for benign biliary diseases.

Methods: This was a retrospective, matched case-control study of patients undergoing biliary-digestive anastomosis for benign diseases between 2000 and 2016 in a tertiary centre. Patients undergoing CD and HJ were matched 1:1 based on age, sex, ASA-classification, indication, history of abdominal surgery or acute cholecystitis/pancreatitis. Short- and long-term outcomes were compared.

Results: Of 336 patients undergoing biliary-digestive anastomoses, 27 patients underwent CD. Matching resulted in two comparable groups of 26 patients each. Overall morbidity after HJ and CD was comparable: 30.8% versus 26.9% (p>0.999). Long-term complications occurred in 23.1% after HJ, and in 50% after CD (p=0.118). After CD, 2 patients (7.7%) developed sump syndrome. Both patients with an anastomotic stricture after HJ could be managed by endoscopic/radiological re-intervention, whilst all six patients with a stricture after CD required surgical re-intervention (p=0.016).

Conclusion: Although short-term complications were comparable, the number of anastomotic strictures was higher in patients undergoing CD. We therefore conclude that HJ is the biliary bypass of choice while CD should be performed in selected patients only.
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http://dx.doi.org/10.1016/j.hpb.2020.08.014DOI Listing
September 2020

Eligibility for Liver Transplantation in Patients with Perihilar Cholangiocarcinoma.

Ann Surg Oncol 2021 Mar 8;28(3):1483-1492. Epub 2020 Sep 8.

Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: Liver transplantation (LT) has been performed in a select group of patients presenting with unresectable or primary sclerosing cholangitis (PSC)-associated perihilar cholangiocarcinoma (pCCA) in the Mayo Clinic with a reported 5-year overall survival (OS) of 53% on intention-to-treat analysis. The objective of this study was to estimate eligibility for LT in a cohort of pCCA patients in two tertiary referral centers.

Methods: Patients diagnosed with pCCA between 2002 and 2014 were included from two tertiary referral centers in the Netherlands. The selection criteria used by the Mayo Clinic were retrospectively applied to determine the proportion of patients that would have been eligible for LT.

Results: A total of 732 consecutive patients with pCCA were identified, of whom 24 (4%) had PSC-associated pCCA. Overall, 154 patients had resectable disease on imaging and 335 patients were ineligible for LT because of lymph node or distant metastases. An age limit of 70 years led to the exclusion of 50 patients who would otherwise be eligible for LT. After applying the Mayo Clinic criteria, only 34 patients (5%) were potentially eligible for LT. Median survival from diagnosis for these 34 patients was 13 months (95% CI 3-23).

Conclusion: Only 5% of all patients presenting with pCCA were potentially eligible for LT under the Mayo criteria. Without transplantation, a median OS of about 1 year was observed.
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http://dx.doi.org/10.1245/s10434-020-09001-8DOI Listing
March 2021

Systematic review on percutaneous aspiration and sclerotherapy versus surgery in symptomatic simple hepatic cysts.

HPB (Oxford) 2021 Jan 20;23(1):11-24. Epub 2020 Aug 20.

Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, the Netherlands. Electronic address:

Background: Simple hepatic cysts (SHC) may cause pain and bloating and thus impair quality of life. Whereas current guidelines recommend laparoscopic cyst deroofing, percutaneous aspiration and sclerotherapy (PAS) may be used as a less invasive alternative. This review aimed to assess the efficacy of PAS and surgical management in patients with symptomatic SHC.

Methods: A systematic search in PubMed and Embase was performed according to PRISMA-guidelines. Studies reporting symptoms were included. Methodological quality was assessed by the MINORS-tool. Primary outcomes were symptom relief, symptomatic recurrence and quality of life, for which a meta-analysis of proportions was performed.

Results: In total, 736 patients from 34 studies were included of whom 265 (36%) underwent PAS, 348 (47%) laparoscopic cyst deroofing, and 123 (17%) open surgical management. During weighted mean follow-up of 26.1, 38.2 and 21.3 months, symptoms persisted in 3.5%, 2.1%, 4.2%, for PAS, laparoscopic and open surgical management, respectively. Major complication rates were 0.8%, 1.7%, and 2.4% and cyst recurrence rates were 0.0%, 5.6%, and 7.7%, respectively.

Conclusion: Outcomes of PAS for symptomatic SHC appear to be excellent. Studies including a step-up approach which reserves laparoscopic cyst deroofing for symptomatic recurrence after one or two PAS procedures are needed.
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http://dx.doi.org/10.1016/j.hpb.2020.07.005DOI Listing
January 2021

Intraoperative Imaging Techniques to Visualize Hepatic (Micro)Perfusion: An Overview.

Eur Surg Res 2020 13;61(1):2-13. Epub 2020 Jul 13.

Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

The microcirculation plays a crucial role in the distribution of perfusion to organs. Studies have shown that microcirculatory dysfunction is an independent predictor of morbidity and mortality. Hence, assessment of liver perfusion offers valuable information on the (patho)physiological state of the liver. The current review explores techniques in perfusion imaging that can be used intraoperatively. Available modalities include dynamic contrast-enhanced ultrasound, handheld vital microscopes, indocyanine green fluorescence angiography, and laser contrast speckle imaging. Dynamic contrast-enhanced ultrasound relays information on deep tissue perfusion and is a commonly used technique to assess tumor perfusion. Handheld vital microscopes provide direct visualization of the sinusoidal architectural structure of the liver, which is a unique feature of this technique. Intraoperative fluorescence imaging uses indocyanine green, a dye that is administered intravenously to visualize microvascular perfusion when excited using near-infrared light. Laser speckle contrast imaging produces non-contact large surface-based tissue perfusion imaging free from movement- or pressure-related artefacts. In this review, we discuss the intrinsic advantages and disadvantages of these techniques and their clinical and/or scientific applications.
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http://dx.doi.org/10.1159/000508348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592948PMC
July 2020

The utility of 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT/CT for selective internal radiation therapy in hepatocellular carcinoma.

Nucl Med Commun 2020 Aug;41(8):740-749

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centres, University of Amsterdam, Meibergdreef 9.

Background: Studies assessing the impact of selective internal radiation therapy (SIRT) on the regional liver function in patients with hepatocellular carcinoma (HCC) are sparse. This study assessed the changes in total and regional liver function using hepatobiliary scintigraphy (HBS) and investigated the utility of HBS to predict post-SIRT liver dysfunction.

Methods: Patients treated with SIRT for HCC between 2011 and 2019, underwent Tc-mebrofenin HBS with single-photon emission computed tomography/computed tomography (SPECT/CT) before and 6 weeks after SIRT. The corrected mebrofenin uptake rate (cMUR) and corresponding volume was measured in the total liver, and in treated and nontreated liver regions. Patients with and without post-SIRT liver dysfunction were compared.

Results: A total of 29 patients, all Child-Pugh-A and mostly intermediate (72%) stage HCC were included in this study. Due to SIRT, the cMURtotal declined from 5.8 to 4.5%/min/m (P < 0.001). Twenty-two patients underwent a lobar SIRT, which induced a decline in cMUR (2.9-1.7%/min/m, P < 0.001) and volume (1228-1101, P = 0.002) of the treated liver region, without a change in cMUR (2.4-2.0%/min/m, P = 0.808) or volume (632-644 mL, P = 0.661) of the contralateral nontreated lobe. There were no significant pre-SIRT differences in total or regional cMUR or volume between patients with and without post-SIRT liver dysfunction.

Conclusion: In patients treated with SIRT for HCC, HBS accurately identified changes in total and regional liver function and may have a complementary role to personalize lobar or selective SIRT. In this pilot study, there were no pre-SIRT differences in cMUR or volume to aid in predicting post-SIRT liver dysfunction.
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http://dx.doi.org/10.1097/MNM.0000000000001224DOI Listing
August 2020

Thermodynamic profiling during irreversible electroporation in porcine liver and pancreas: a case study series.

J Clin Transl Res 2020 Apr 12;5(3):109-132. Epub 2020 Mar 12.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Aims: First, the aim of the study was to determine whether irreversible electroporation (IRE) is associated with heat generation in the liver and pancreas at clinical (≤1,500 V/cm) and supraclinical (>1,500 V/cm) electroporation settings; second, to assess the risk of thermal tissue damage in and adjacent to the treated volume in highly perfused versus moderately perfused parts of both organs; third, to investigate the influence of perfusion and of the presence and the orientation of a metal stent on the maximal thermal elevation (ΔT) in the tissue during an IRE session at fixed IRE settings, and finally, to determine whether the maximum temperature elevation within the IRE-subjected organ during an IRE treatment (single or multiple sessions) is reflected in the organ's surface temperature.

Methods: The aims were investigated in 12 case studies conducted in five female Landrace pigs. Several IRE settings were applied for lateral (2), triangular (3), and rectangular (4) electrode configurations in the liver hilum, liver periphery, pancreas head, and pancreas tail. IRE series of 10-90 pulses were applied with pulse durations that varied from 70 μs to 90 μs and electric field strengths between 1,200 V/cm and 3,000 V/cm. In select cases, a metal stent was positioned in the bile duct at the level of the liver hilum. Temperatures were measured before, during, and after IRE in and adjacent to the treatment volumes using fiber optical temperature probes (temperature at the nucleation centers) and digital thermography (surface temperature). The occurrence of thermal damage was assumed to be at temperatures above 50 °C (ΔT ≥ 13 °C relative to body temperature of 37 °C). The temperature fluctuations at the organ surface (ΔT) were compared to the maximum temperature elevation during an IRE treatment in the electroporation zone. In select cases, IRE was applied to tissue volumes encompassing the portal vein (PV) and a constricted and patent superior mesenteric vein (SMV) to determine the influence of the heatsink effect of PV and SMV on ΔT.

Results: The median baseline temperature was 31.6 °C-36.3 °C. ΔT ranged from -1.7 °C to 25.5 °C in moderately perfused parts of the liver and pancreas, and from 0.0 °C to 5.8 °C in highly perfused parts. The median ΔT of the liver and pancreas was 1.0 °C and 10.3 °C, respectively. Constricting the SMV in the pancreas head yielded a 0.8 °C higher ΔT. The presence of a metal stent in the liver hilum resulted in a ΔT of 19.8 °C. Stents parallel to the electrodes caused a ΔT difference of 4.2 °C relative to the perpendicular orientation.

Conclusions: Depending on IRE settings and tissue type, IRE is capable of inducing considerable heating in the liver and pancreas that is sufficient to cause thermal tissue damage. More significant temperature elevations are positively correlated with increasing number of electrode pairs, electric field strength, and pulse number. Temperature elevations can be further exacerbated by the presence and orientation of metal stents. Temperature elevations at the nucleation centers are not always reflected in the organ's surface temperature. Heat sink effects caused by large vessels were minimal in some instances, possibly due to reduced blood flow caused by anesthesia.

Relevance For Patients: Appropriate IRE settings must be chosen based on the tissue type and the presence of stents to avoid thermal damage in healthy peritumoral tissue and to protect anatomical structures [Table: see text].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326268PMC
April 2020

Transthoracic Versus Transhiatal Esophagectomy for Esophageal Cancer: A Nationwide Propensity Score-Matched Cohort Analysis.

Ann Surg Oncol 2021 Jan 30;28(1):175-183. Epub 2020 Jun 30.

Amsterdam UMC, Department of Surgery, Cancer Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.

Background: Chemoradiation followed by resection has been the standard therapy for resectable (cT1-4aN0-3M0) esophageal carcinoma in the Netherlands since 2010. The optimal surgical approach remains a matter of debate. Therefore, the purpose of this study was to compare the transhiatal and the transthoracic approach concerning morbidity, mortality and oncological quality.

Methods: Data was acquired from the Dutch Upper GI Cancer Audit. Patients who underwent esophagectomy with curative intent and gastric tube reconstruction for mid/distal esophageal or esophagogastric junction carcinoma (cT1-4aN0-3M0) from 2011 to 2016 were included. Patients who underwent a transthoracic and transhiatal esophagectomy were compared after propensity score matching.

Results: After propensity score matching, 1532 of 4143 patients were included for analysis. The transthoracic approach yielded more lymph nodes (transthoracic median 19, transhiatal median 14; p < 0.001). There was no difference in the number of positive lymph nodes, however, the median (y)pN-stage was higher in the transthoracic group (p = 0.044). The transthoracic group experienced more chyle leakage (9.7% vs. 2.7%, p < 0.001), more pulmonary complications (35.5% vs. 26.1%, p < 0.001), and more cardiac complications (15.4% vs. 10.3%, p = 0.003). The transthoracic group required a longer hospital stay (median 14 vs. 11 days, p < 0.001), ICU stay (median 3 vs. 1 day, p < 0.001), and had a higher 30-day/in-hospital mortality rate (4.0% vs. 1.7%, p = 0.009).

Conclusions: In a propensity score-matched cohort, the transthoracic esophagectomy provided a more extensive lymph node dissection, which resulted in a higher lymph node yield, at the cost of increased morbidity and short-term mortality.
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http://dx.doi.org/10.1245/s10434-020-08760-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752871PMC
January 2021

Choledochal malformations in adults in the Netherlands: Results from a nationwide retrospective cohort study.

Liver Int 2020 10 3;40(10):2469-2475. Epub 2020 Aug 3.

Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: Patients with a choledochal malformation, formerly described as cysts, are at increased risk of developing a cholangiocarcinoma and resection is recommended. Given the low incidence of choledochal malformation (CM) in Western countries, the incidence in these countries is unclear. Our aim was to assess the incidence of malignancy in CM patients and to assess postoperative outcome.

Methods: In a nationwide, retrospective study, all adult patients who underwent surgery for CM between 1990 and 2016 were included. Patients were identified through the Dutch Pathology Registry and local patient records and were analysed to determine the incidence of malignancy, as well as postoperative mortality and morbidity.

Results: A total of 123 patients with a CM were included in the study (Todani Type I, n = 71; Type II, n = 10; Type III, n = 3; Type IV, n = 27; unknown, n = 12). Median age was 40 years (range 18-70) and 81% were female. The majority of patients (99/123) underwent extrahepatic bile duct resection, with additional liver parenchyma resections in eight patients, only exploration in two, and a local cyst resection in eight patients. Postoperative 30-day mortality was 2% (2/123) and limited to patients who underwent liver resection. Severe morbidity occurred in 24%. In 14 of the 123 patients (11%), a malignancy was found in the resected specimen. One patient developed a periampullary malignancy 7 years later.

Conclusions: In a large Western series of CM patients, 11% were found to have a malignancy. This justifies resection in these patients, despite the risk of morbidity (24%) and mortality (2%).
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http://dx.doi.org/10.1111/liv.14568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540385PMC
October 2020

Interpatient heterogeneity in hepatic microvascular blood flow during vascular inflow occlusion (Pringle manoeuvre).

Hepatobiliary Surg Nutr 2020 Jun;9(3):271-283

Department of Surgery, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Vascular inflow occlusion (VIO) during liver resections (Pringle manoeuvre) can be applied to reduce blood loss, however may at the same time, give rise to ischemia-reperfusion injury (IRI). The aim of this study was to assess the characteristics of hepatic microvascular perfusion during VIO in patients undergoing major liver resection.

Methods: Assessment of hepatic microcirculation was performed using a handheld vital microscope (HVM) at the beginning of surgery, end of VIO (20 minutes) and during reperfusion after the termination of VIO. The microcirculatory parameters assessed were: functional capillary density (FCD), microvascular flow index (MFI) and sinusoidal diameter (SinD).

Results: A total of 15 patients underwent VIO; 8 patients showed hepatic microvascular perfusion despite VIO (partial responders) and 7 patients showed complete cessation of hepatic microvascular perfusion (full responders). Functional microvascular parameters and blood flow levels were significantly higher in the partial responders when compared to the full responders during VIO (FCD: 0.84±0.88 . 0.00±0.00 mm/mm, P<0.03, respectively, and MFI: 0.69-0.22 . 0.00±0.00, P<0.01, respectively).

Conclusions: An interpatient heterogeneous response in hepatic microvascular blood flow was observed upon VIO. This may explain why clinical strategies to protect the liver against IRI lacked consistency.
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http://dx.doi.org/10.21037/hbsn.2020.02.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262621PMC
June 2020

Subzero non-frozen preservation of human livers in the supercooled state.

Nat Protoc 2020 06 20;15(6):2024-2040. Epub 2020 May 20.

Center for Engineering in Medicine, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA.

Preservation of human organs at subzero temperatures has been an elusive goal for decades. The major complication hindering successful subzero preservation is the formation of ice at temperatures below freezing. Supercooling, or subzero non-freezing, preservation completely avoids ice formation at subzero temperatures. We previously showed that rat livers can be viably preserved three times longer by supercooling as compared to hypothermic preservation at +4 °C. Scalability of supercooling preservation to human organs was intrinsically limited because of volume-dependent stochastic ice formation at subzero temperatures. However, we recently adapted the rat preservation approach so it could be applied to larger organs. Here, we describe a supercooling protocol that averts freezing of human livers by minimizing air-liquid interfaces as favorable sites of ice nucleation and uses preconditioning with cryoprotective agents to depress the freezing point of the liver tissue. Human livers are homogeneously preconditioned during multiple machine perfusion stages at different temperatures. Including preparation, the protocol takes 31 h to complete. Using this protocol, human livers can be stored free of ice at -4 °C, which substantially extends the ex vivo life of the organ. To our knowledge, this is the first detailed protocol describing how to perform subzero preservation of human organs.
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http://dx.doi.org/10.1038/s41596-020-0319-3DOI Listing
June 2020

Mathematical modeling of the thermal effects of irreversible electroporation for , , and clinical use: a systematic review.

Int J Hyperthermia 2020 ;37(1):486-505

Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation. This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR). A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted. Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR. Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects.
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http://dx.doi.org/10.1080/02656736.2020.1753828DOI Listing
November 2020

Improving the Safety of Major Resection for Hepatobiliary Malignancy: Portal Vein Embolization and Recent Innovations in Liver Regeneration Strategies.

Curr Oncol Rep 2020 05 16;22(6):59. Epub 2020 May 16.

Department of Radiology, St-Eloi University Hospital-Montpellier, Montpellier, France.

Purpose Of Review: For three decades, portal vein embolization (PVE) has been the "gold-standard" strategy to hypertrophy the anticipated future liver remnant (FLR) in advance of major hepatectomy. During this time, CT volumetry was the most common method to preoperatively assess FLR quality and function and used to determine which patients are appropriate surgical candidates. This review provides the most up-to-date methods for preoperatively assessing the anticipated FLR and summarizes data from the currently available strategies used to induce FLR hypertrophy before surgery for hepatobiliary malignancy.

Recent Findings: Functional and physiological imaging is increasingly replacing standard CT volumetry as the method of choice for preoperative FLR assessment. PVE, associating liver partition and portal vein ligation, radiation lobectomy, and liver venous deprivation are all currently available techniques to hypertrophy the FLR. Each strategy has pros and cons based on tumor type, extent of resection, presence or absence of underlying liver disease, age, performance status, complication rates, and other factors. Numerous strategies can lead to FLR hypertrophy and improve the safety of major hepatectomy. Which is best has yet to be determined.
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http://dx.doi.org/10.1007/s11912-020-00922-xDOI Listing
May 2020

Comparison of functional and volumetric increase of the future remnant liver and postoperative outcomes after portal vein embolization and complete or partial associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).

Ann Transl Med 2020 Apr;8(7):436

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands.

Background: Portal vein embolization (PVE) is performed to induce hypertrophy of an insufficient future remnant liver (FRL) before major liver resection. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) aims to offer a more rapid and increased hypertrophy response. The first stage can be performed with complete or partial (laparoscopic) transection of the liver parenchyma. This study aimed to investigate the increase in FRL volume and function, as well as postoperative outcomes after PVE or complete- or partial-ALPPS1.

Methods: Patients with insufficient FRL undergoing either PVE or ALPPS underwent CT-volumetry and functional assessment using Tc-mebrofenin hepatobiliary scintigraphy (HBS). Severe complications and 90-day mortality were evaluated after liver resection.

Results: Seventy-two patients were included; 51 underwent PVE, 12 complete-ALPPS1 and 9 partial-ALPPS1 of which 7 laparoscopic. The median increase in FRL function was 1.5-, 1.7- and 1.3-fold higher, respectively, than the increase in volume; (P<0.01, P<0.01 and P=0.44). The target hypertrophy response did not differ between the groups, but was reached earlier in both ALPPS1 groups (8 and 10 days) compared to the PVE group (23 days). Of the resected patients, 18%, 30% and 17% had severe postoperative complications and the 90-day mortality was 2%, 25% and 0%, respectively.

Conclusions: Increase of FRL function exceeded increase of volume after both PVE and ALPPS1. The target hypertrophy response was reached earlier in ALPPS. Complete and partial-ALPPS1 showed comparable functional and volumetric hypertrophy responses. A (laparoscopic) partial-ALPPS1 is preferred considering lower morbidity and mortality rates after resection.
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http://dx.doi.org/10.21037/atm.2020.03.191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210209PMC
April 2020

Should jaundice preclude resection in patients with gallbladder cancer? Results from a nation-wide cohort study.

HPB (Oxford) 2020 Dec 25;22(12):1686-1694. Epub 2020 Apr 25.

Department of Surgery, Radboudumc, P.O. Box 9101, Internal Code 618, 6500 HB, Nijmegen, the Netherlands. Electronic address:

Background: It is controversial whether patients with gallbladder cancer (GBC) presenting with jaundice benefit from resection. This study re-evaluates the impact of jaundice on resectability and survival.

Methods: Data was collected on surgically explored GBC patients in all Dutch academic hospitals from 2000 to 2018. Survival and prognostic factors were assessed.

Results: In total 202 patients underwent exploration and 148 were resected; 124 non-jaundiced patients (104 resected) and 75 jaundiced patients (44 resected). Jaundiced patients had significantly (P < 0.05) more pT3/T4 tumors, extended (≥3 segments) liver- and organ resections, major post-operative complications and margin-positive resection. 90-day mortality was higher in jaundiced patients (14% vs. 0%, P < 0.001). Median overall survival (OS) was 7.7 months in jaundiced patients (2-year survival 17%) vs. 26.1 months in non-jaundiced patients (2-year survival 39%, P < 0.001). In multivariate analysis, jaundice (HR1.89) was a poor prognostic factor for OS in surgically explored but not in resected patients. Six jaundiced patients did not develop a recurrence; none had liver- or common bile duct (CBD) invasion on imaging.

Conclusion: Jaundice is associated with poor survival. However, jaundice is not an independent adverse prognostic factor in resected patients. Surgery should be considered in patients with limited disease and no CBD invasion on imaging.
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http://dx.doi.org/10.1016/j.hpb.2020.03.015DOI Listing
December 2020

Correction to: Portal Vein Embolization is Associated with Reduced Liver Failure and Mortality in High-Risk Resections for Perihilar Cholangiocarcinoma.

Ann Surg Oncol 2020 Dec;27(Suppl 3):968

Department of Surgery, Amsterdam UMC (location AMC), University of Amsterdam, Amsterdam, The Netherlands.

In the original article Moritz Schmelzle's last name is spelled wrong. It is correct as reflected here.
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http://dx.doi.org/10.1245/s10434-020-08353-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852859PMC
December 2020

A multicentre retrospective analysis on growth of residual hepatocellular adenoma after resection.

Liver Int 2020 09 28;40(9):2272-2278. Epub 2020 Apr 28.

Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background & Aims: Hepatocellular adenoma (HCA) is a benign liver tumour that may require resection in select cases. The aim of this study was to the assess growth of residual HCA in the remnant liver and to advise on an evidence-based management strategy.

Method: This multicentre retrospective cohort study included all patients with HCA who underwent surgery of HCA and had residual HCA in the remnant liver. Growth was defined as an increase of >20% in transverse diameter (RECIST criteria). Data on patient and HCA characteristics, diagnostic work-up, treatment and follow-up were documented and analysed.

Results: A total of 134 patients were included, one male. At diagnosis, median age was 38yrs (IQR 30.0-44.0) and median BMI was 29.9 kg/m (IQR 24.6-33.3). After resection, median number of residual sites of HCA was 3 (IQR 2-6). Follow-up of residual HCA showed regression in 24.6%, stable HCA in 61.9% and growth of at least one lesion in 11.2%. Three patients (2.2%) developed new HCA that were not visible on imaging prior to surgery. Four patients (3%, one male) underwent an intervention as growth was progressive. No statistically significant differences in clinical characteristics were found between patients with growing residual or new HCA versus those with stable or regressing residual HCA.

Conclusion: In patients with multiple HCA who undergo resection, growth of residual HCA is not uncommon but interventions are rarely needed as most lesions stabilize and do not show progressive growth. Surveillance is indicated when residual HCA show growth after resection, enabling intervention in case of progressive growth.
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http://dx.doi.org/10.1111/liv.14467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497037PMC
September 2020

Systematic review of MARS treatment in post-hepatectomy liver failure.

HPB (Oxford) 2020 Jul 2;22(7):950-960. Epub 2020 Apr 2.

Department of Surgery, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: Post-hepatectomy liver failure (PHLF) remains a serious complication after major liver resection with severe 90-day mortality. Molecular adsorbent recirculating system (MARS) is a potential treatment option in PHLF. This systematic review sought to analyze the experiences and results of MARS in PHLF.

Methods: Following the PRISMA guidelines, a systematic literature review using PubMed and Embase was performed. Non-randomized trials were assessed by the MINORS criteria.

Results: 2884 records were screened and 22 studies were extracted (no RCT). They contained 809 patients including 82 patients with PHLF. Five studies (n = 34) specifically investigated the role of MARS in patients with PHLF. In these patients, overall 90-day survival was 47%. Patients with primary PHLF had significantly better 90-day survival compared to patients with secondary PHLF (60% vs 14%, p = 0.03) and treatment was started earlier (median POD 6 (range 2-21) vs median POD 30 (range 15-39); p < 0.001). Number of treatments differed non-significantly in these groups. Safety and feasibility of early MARS treatment following hepatectomy was demonstrated in one prospective study. No major adverse events have been reported.

Conclusion: Early MARS treatment is safe and feasible in patients with PHLF. Currently, MARS cannot be recommended as standard of care in these patients. Further prospective studies are warranted.
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http://dx.doi.org/10.1016/j.hpb.2020.03.013DOI Listing
July 2020

ASO Author Reflections: Essential to Reduce Adverse Outcomes in Perihilar Cholangiocarcinoma Surgery-Portal Vein Embolization.

Ann Surg Oncol 2020 Jul 9;27(7):2319-2320. Epub 2020 Mar 9.

Department of Surgery, Amsterdam UMC (Location AMC), University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1245/s10434-020-08333-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311505PMC
July 2020

Portal Vein Embolization is Associated with Reduced Liver Failure and Mortality in High-Risk Resections for Perihilar Cholangiocarcinoma.

Ann Surg Oncol 2020 Jul 26;27(7):2311-2318. Epub 2020 Feb 26.

Department of Surgery, Amsterdam UMC (location AMC), University of Amsterdam, Amsterdam, The Netherlands.

Background: Preoperative portal vein embolization (PVE) is frequently used to improve future liver remnant volume (FLRV) and to reduce the risk of liver failure after major liver resection.

Objective: This paper aimed to assess postoperative outcomes after PVE and resection for suspected perihilar cholangiocarcinoma (PHC) in an international, multicentric cohort.

Methods: Patients undergoing resection for suspected PHC across 20 centers worldwide, from the year 2000, were included. Liver failure, biliary leakage, and hemorrhage were classified according to the respective International Study Group of Liver Surgery criteria. Using propensity scoring, two equal cohorts were generated using matching parameters, i.e. age, sex, American Society of Anesthesiologists classification, jaundice, type of biliary drainage, baseline FLRV, resection type, and portal vein resection.

Results: A total of 1667 patients were treated for suspected PHC during the study period. In 298 patients who underwent preoperative PVE, the overall incidence of liver failure and 90-day mortality was 27% and 18%, respectively, as opposed to 14% and 12%, respectively, in patients without PVE (p < 0.001 and p = 0.005). After propensity score matching, 98 patients were enrolled in each cohort, resulting in similar baseline and operative characteristics. Liver failure was lower in the PVE group (8% vs. 36%, p < 0.001), as was biliary leakage (10% vs. 35%, p < 0.01), intra-abdominal abscesses (19% vs. 34%, p = 0.01), and 90-day mortality (7% vs. 18%, p = 0.03).

Conclusion: PVE before major liver resection for PHC is associated with a lower incidence of liver failure, biliary leakage, abscess formation, and mortality. These results demonstrate the importance of PVE as an integral component in the surgical treatment of PHC.
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http://dx.doi.org/10.1245/s10434-020-08258-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311501PMC
July 2020

Poor perfusion of the microvasculature in peritoneal metastases of ovarian cancer.

Clin Exp Metastasis 2020 04 1;37(2):293-304. Epub 2020 Feb 1.

Center for Gynecologic Oncology Amsterdam, Department of Gynecologic Oncology, The Netherlands Cancer Institute/Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Most women with epithelial ovarian cancer (EOC) suffer from peritoneal carcinomatosis upon first clinical presentation. Extensive peritoneal carcinomatosis has a poor prognosis and its pathophysiology is not well understood. Although treatment with systemic intravenous chemotherapy is often initially successful, peritoneal recurrences occur regularly. We hypothesized that insufficient or poorly-perfused microvasculature may impair the therapeutic efficacy of systemic intravenous chemotherapy but may also limit expansive and invasive growth characteristic of peritoneal EOC metastases. In 23 patients with advanced EOC or suspicion thereof, we determined the angioarchitecture and perfusion of the microvasculature in peritoneum and in peritoneal metastases using incident dark field (IDF) imaging. Additionally, we performed immunohistochemical analysis and 3-dimensional (3D) whole tumor imaging using light sheet fluorescence microscopy of IDF-imaged tissue sites. In all metastases, microvasculature was present but the angioarchitecture was chaotic and the vessel density and perfusion of vessels was significantly lower than in unaffected peritoneum. Immunohistochemical analysis showed expression of vascular endothelial growth factor and hypoxia inducible factor 1α, and 3D imaging demonstrated vascular continuity between metastases and the vascular network of the peritoneum beneath the elastic lamina of the peritoneum. We conclude that perfusion of the microvasculature within metastases is limited, which may cause hypoxia, affect the behavior of EOC metastases on the peritoneum and limit the response of EOC metastases to systemic treatment.
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http://dx.doi.org/10.1007/s10585-020-10024-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138772PMC
April 2020

Cell release during perfusion reflects cold ischemic injury in rat livers.

Sci Rep 2020 01 24;10(1):1102. Epub 2020 Jan 24.

Center for Engineering in Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.

The global shortage of donor organs has made it crucial to deeply understand and better predict donor liver viability. However, biomarkers that effectively assess viability of marginal grafts for organ transplantation are currently lacking. Here, we showed that hepatocytes, sinusoidal endothelial, stellate, and liver-specific immune cells were released into perfusates from Lewis rat livers as a result of cold ischemia and machine perfusion. Perfusate comparison analysis of fresh livers and cold ischemic livers showed that the released cell profiles were significantly altered by the duration of cold ischemia. Our findings show for the first time that parenchymal cells are released from organs under non-proliferative pathological conditions, correlating with the degree of ischemic injury. Thus, perfusate cell profiles could serve as potential biomarkers of graft viability and indicators of specific injury mechanisms during organ handling and transplantation. Further, parenchymal cell release may have applications in other pathological conditions beyond organ transplantation.
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http://dx.doi.org/10.1038/s41598-020-57589-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981218PMC
January 2020

Efficacy and safety of FOLFIRINOX as salvage treatment in advanced biliary tract cancer: an open-label, single arm, phase 2 trial.

Br J Cancer 2020 03 10;122(5):634-639. Epub 2020 Jan 10.

Amsterdam UMC, Department of Medical Oncology, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Background: No standard treatment is available for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin (GEMCIS). The objective of this study was to evaluate safety and anti-tumour activity of fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) as salvage treatment in patients with previously treated advanced BTC.

Methods: In this two-stage phase 2 study, patients with advanced BTC who had disease progression or unacceptable toxicity after ≥3 cycles of GEMCIS were eligible. Primary endpoints were safety and efficacy (defined as objective response rate, ORR). In stage one, ten patients were treated with FOLFIRINOX every 2 weeks. In stage two, an additional 20 patients were enrolled at a starting dose as defined in stage one, provided that in stage ≥1 objective response or ≥2 stable diseases were observed and ≤3 patients had serious adverse events (SAEs) within the first 6 weeks of treatment. Secondary endpoints were progression-free survival (PFS) and overall survival (OS).

Results: Forty patients were screened for eligibility and 30 patients were enrolled. In stage one, one patient had a partial response and five patients had stable disease. One patient had a SAE during the first 6 weeks of treatment, and five patients required a dose reduction due to adverse events. The most common grade 3-4 adverse events in stage one were neutropaenia, mucositis and diarrhoea. Stage two was initiated with FOLFIRINOX in an adapted dose. In stage two, grade 3-4 neutropaenia, diarrhoea, nausea and vomiting were the most common adverse events. The ORR, median PFS and OS in all patients were 10%, 6.2 and 10.7 months, respectively.

Conclusions: In patients with advanced BTC who progressed after or were intolerant to GEMCIS, FOLFIRINOX can be administered safely and could be considered as an option for salvage treatment in these patients.

Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02456714.
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http://dx.doi.org/10.1038/s41416-019-0698-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054309PMC
March 2020