Publications by authors named "Aksel Foss"

88 Publications

Liver transplantation as last-resort treatment for patients with bile duct injuries following cholecystectomy: a multicenter analysis.

Ann Gastroenterol 2021 2;34(1):111-118. Epub 2020 Oct 2.

2 Department of Propaedeutic Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece (Peter Tsaparas, Nikolaos Machairas, Ioannis D. Kostakis, Georgios C. Sotiropoulos).

Background: Liver transplantation (LT) has been used as a last resort in patients with end-stage liver disease due to bile duct injuries (BDI) following cholecystectomy. Our study aimed to identify and evaluate factors that cause or contribute to an extended liver disease that requires LT as ultimate solution, after BDI during cholecystectomy.

Methods: Data from 8 high-volume LT centers relating to patients who underwent LT after suffering BDI during cholecystectomy were prospectively collected and retrospectively analyzed.

Results: Thirty-four patients (16 men, 18 women) with a median age of 45 (range 22-69) years were included in this study. Thirty of them (88.2%) underwent LT because of liver failure, most commonly as a result of secondary biliary cirrhosis. The median time interval between BDI and LT was 63 (range 0-336) months. There were 23 cases (67.6%) of postoperative morbidity, 6 cases (17.6%) of post-transplant 30-day mortality, and 10 deaths (29.4%) in total after LT. There was a higher probability that patients with concomitant vascular injury (hazard ratio 10.69, P=0.039) would be referred sooner for LT. Overall survival following LT at 1, 3, 5 and 10 years was 82.4%, 76.5%, 73.5% and 70.6%, respectively.

Conclusion: LT for selected patients with otherwise unmanageable BDI following cholecystectomy yields acceptable long-term outcomes.
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http://dx.doi.org/10.20524/aog.2020.0541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774661PMC
October 2020

Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives.

Curr Pharm Des 2020 ;26(28):3389-3401

Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Norway.

Background: Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today's clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects.

Summary: Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.
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http://dx.doi.org/10.2174/1381612826666200610183608DOI Listing
January 2021

Microbubble contrast-enhanced ultrasound in the vascular evaluation after pancreas transplantation: a single-center experience.

Acta Radiol 2019 Oct 12;60(10):1224-1231. Epub 2019 Feb 12.

Surgical Department, Section of Transplant Surgery, Oslo University Hospital, Oslo, Norway.

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http://dx.doi.org/10.1177/0284185119828190DOI Listing
October 2019

Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation.

Transplantation 2019 03;103(3):630-637

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Background: When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR.

Methods: The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 ± 10 seconds and 50 ± 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant.

Results: Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 ± 5 days after the first transplant) between the 2 arms (1.33 ± 1.10 versus 1.56 ± 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups.

Conclusions: Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.
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http://dx.doi.org/10.1097/TP.0000000000002425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389380PMC
March 2019

First Scandinavian Protocol for Controlled Donation After Circulatory Death Using Normothermic Regional Perfusion.

Transplant Direct 2018 Jul 13;4(7):e366. Epub 2018 Jun 13.

Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Donation after circulatory death (DCD) can increase the pool of available organs for transplantation. This pilot study evaluates the implementation of a controlled DCD (cDCD) protocol using normothermic regional perfusion in Norway.

Methods: Patients aged 16 to 60 years that are in coma with documented devastating brain injury in need of mechanical ventilation, who would most likely attain cardiac arrest within 60 minutes after extubation, were eligible. With the acceptance from the next of kin and their wish for organ donation, life support was withdrawn and cardiac arrest observed. After a 5-minute no-touch period, extracorporeal membrane oxygenation for post mortem regional normothermic regional perfusion was established. Cerebral and cardiac reperfusion was prevented by an aortic occlusion catheter. Measured glomerular filtration rates 1 year postengraftment were compared between cDCD grafts and age-matched grafts donated after brain death (DBD).

Results: Eight cDCD were performed from 2014 to 2015. Circulation ceased median 12 (range, 6-24) minutes after withdrawal of life-sustaining treatment. Fourteen kidneys and 2 livers were retrieved and subsequently transplanted. Functional warm ischemic time was 26 (20-51) minutes. Regional perfusion was applied for 97 minutes (54-106 minutes). Measured glomerular filtration rate 1 year postengraftment was not significantly different between cDCD and donation after brain death organs, 75 (65-76) vs 60 (37-112) mL/min per 1.73 m ( = 0.23). No complications have been observed in the 2 cDCD livers.

Conclusion: A protocol for cDCD is successfully established in Norway. Excellent transplant outcomes have encouraged us to continue this work addressing the shortage of organs for transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000000802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056274PMC
July 2018

Human Adipose-Derived Mesenchymal Stem Cells Respond to Short-Term Hypoxia by Secreting Factors Beneficial for Human Islets In Vitro and Potentiate Antidiabetic Effect In Vivo.

Cell Med 2017 14;9(3):103-116. Epub 2017 Apr 14.

Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway.

Adipose-derived mesenchymal stem cells (ASCs) release factors beneficial for islets in vitro and protect against hyperglycemia in rodent models of diabetes. Oxygen tension has been shown to induce metabolic changes and alter ASCs' release of soluble factors. The effects of hypoxia on the antidiabetic properties of ASCs have not been explored. To investigate this, we incubated human ASCs for 48 h in 21% (normoxia) or 1% O (hypoxia) and compared viability, cell growth, surface markers, differentiation capability, and soluble factors in the conditioned media (CM). Human islets were exposed to CM from ASCs incubated in either normoxia or hypoxia, and islet function and apoptosis after culture with or without proinflammatory cytokines were measured. To test hypoxic preconditioned ASCs' islet protective effects in vivo, ASCs were incubated for 48 h in normoxia or hypoxia before being injected into Balb/c Rag 1 immunodeficient mice with streptozotocin-induced insulitis. Progression of diabetes and insulin content of pancreas were measured. We found that incubation in hypoxia was well tolerated by ASCs and that levels of VEGF-A, FGF-2, and bNGF were elevated in CM from ASCs incubated in hypoxia compared to normoxia, while levels of HGF, IL-8, and CXCL1 were reduced. CM from ASCs incubated in hypoxia significantly improved human islet function and reduced apoptosis after culture, and reduced cytokine-induced apoptosis. In our mouse model, pancreas insulin content was higher in both groups receiving ASCs compared to control, but the mice receiving preconditioned ASCs had lower random and fasting blood glucose, as well as improved oral glucose tolerance compared to untreated mice. In conclusion, our in vitro results indicate that the islet protective potential of ASCs improves in hypoxia, and we give insight into factors involved in this. Finally we show that hypoxic preconditioning potentiates ASCs' antidiabetic effect in vivo.
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http://dx.doi.org/10.3727/215517917X693401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509020PMC
April 2017

Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis.

Sci Rep 2017 05 8;7(1):1575. Epub 2017 May 8.

Section for Transplant Surgery, Oslo University Hospital, Oslo, Norway.

One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin:insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1α and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre-treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1α and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.
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http://dx.doi.org/10.1038/s41598-017-01805-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431546PMC
May 2017

Hepatic Epithelioid Hemangioendothelioma and Adult Liver Transplantation: Proposal for a Prognostic Score Based on the Analysis of the ELTR-ELITA Registry.

Transplantation 2017 03;101(3):555-564

1 Starzl Abdominal Transplant Unit, University Hospitals St. Luc, Université catholique Louvain, Brussels, Belgium. 2 Centre Hépatobiliaire Paul Brousse, Paris, France. 3 Medizinsche Hochschule Hannover, Hannover, Germany. 4 Transplancenter IKEM, Prague, Czech Republic. 5 Istituto Nazionale Tumori, Milano, Italy. 6 Charité Campus Virchow Klinikum, Berlin, Germany. 7 Department of General Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland. 8 UCJ Helsingfors, Helsinki, Finland. 9 Department Abdominal transplantation Surgery, Universitaire Ziekenhuizen Gasthuisberg KULeuven, Belgium. 10 Rikshospitalet, Oslo Universitetssykehus, Oslo, Norway. 11 Karolinska University Hospital, Huddinge, Stockholm, Sweden. 12 University Medical Centre Ljubljana, Ljubljana, Slovenia.

Background: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor which has an intermediate aggressive behavior. Although the value of liver transplantation (LT) is well established, its place in the management of HEHE is still unclear. The aim of this study is to confirm, based on a very large patient cohort, the value of LT in the management of HEHE and to identify risk factors for post-LT recurrence.

Methods: The outcome of 149 transplant recipients with HEHE recorded in the European Liver Transplant Registry during the period November 1984 to May 2014 was analyzed. Median post-LT follow-up was 7.6 years (interquartile range, 2.8-14.4).

Results: Cox regression analysis showed that macrovascular invasion (hazard ratio [HR], 4.8; P < 0.001), pre-LT waiting time of 120 days or less (HR, 2.6; P = 0.01) and hilar lymph node invasion (HR = 2.2; P = 0.03), but not pre-LT extrahepatic disease, were significant risk factors for recurrence. These findings, which were also confirmed in a propensity score analysis, allowed the development of a HEHE-LT score enabling stratification of patients in relation to their risk of tumor recurrence. Patients with a score of 2 or less had a much better 5-year disease-free survival compared to those having a score of 6 or higher (93.9% vs 38.5%; P < 0.001).

Conclusions: The analysis of this (largest in the world) HEHE adult liver recipient cohort clearly confirms the value of LT in the treatment of this rare disorder and also permits identification of patients at risk of posttransplant recurrence. Posttransplant follow-up should take the HEHE-LT score into account. Extrahepatic disease localization is reconfirmed not to be a contraindication for LT.
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http://dx.doi.org/10.1097/TP.0000000000001603DOI Listing
March 2017

Cost and clinical outcome of islet transplantation in Norway 2010-2015.

Clin Transplant 2017 01 9;31(1). Epub 2016 Dec 9.

Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.

Islet transplantation is a minimally invasive β-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L , and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.
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http://dx.doi.org/10.1111/ctr.12871DOI Listing
January 2017

Liver Transplantation for Hepatic Trauma: A Study From the European Liver Transplant Registry.

Transplantation 2016 11;100(11):2372-2381

1 Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.2 Hepato-Biliary Center, AP-HP Paul Brousse Hospital, University Paris-Sud, Villejuif, France.3 Division of Hepatopancreatobiliary and Transplantation Surgery, Department of Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.4 Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany.5 Department of General Surgery and Transplantation, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.6 Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Department of Surgery and Transplantation, University of Modena and Reggio Emilia, Modena, Italy.7 Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy.8 Department of General and Visceral Surgery, University Hospital of Muenster, Muenster, Germany.9 Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.10 Unit of Surgery and Liver Transplantation, Hospital Universitario Reina Sofia, Córdoba, Spain.11 Transplant Institute, Sahlgrenska University Hospital, Sahlgrenska Academy, Gothenburg, Sweden.12 Department of Abdominal, Visceral and Transplantation Surgery, Charité Universitätsmedizin, Campus Virchow, Berlin, Germany.13 Department of General and Transplant Surgery, University Hospital Essen, Essen, Germany.14 Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany.15 Unità Operativa Chirurgia Generale e Trapianti di Fegato, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.16 Liver Transplant Center, General Surgery Unit, A.O. Città della Salute e della Scienza, Molinette Hospital, University of Turin, Turin, Italy.17 Liver Transplant Unit, Hospital Juan Canalejo, La Coruna, Spain.18 Abdominal Trasplant Unit, Universitary Clinical Hospital, Santiago de Compostela, Spain.19 Hepatic-Biliary-Pancreatic Surgery and Liver Transplant Unit, University Hospital Virgen del Rocío of Seville, Seville, Spain.20 Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium.21 Department of Abdominal Surgery and Transplantation, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium.22 Department of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland.23 Center of Cardiovascular Surgery and Transplantations, Brno, Czech Republic.24 Department of General and Visceral Surgery, Goethe University Hospital and Clinics, Frankfurt, Germany.25 Department of Visceral, Transplant, Vascular and Thoracic Surgery, University Hospital of Leipzig, Leipzig, Germany.26 Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.27 Service de Chirurgie Digestive et Transplantation, University Lille Nord de France, Centre Hospitalier Universitaire Lille, Lille, France.28 The Liver Unit, Queen Elizabeth Hospital Birmingham Edgbaston, Birmingham, United Kingdom.29 Institute of General Surgery and Liver Transplantation, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.30 Department of Surgery, Pope John XXIII Hospital, Bergamo, Italy.31 Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, Rome, Italy.32 Division of Transplantation, Department of Surgery, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.33 Department of Surgery and Organ Transplantation, Porto, Portugal.34 Department of HBP Surgery and Transplant, Hospital Universitari Vall d'Hebro'n, Autonomous University of Barcelona, Barcelona, Spain.35 Service of General and Digestive Surgery and Abdominal Organ Transplantation, "Doce de Octubre", University Hospital, Madrid, Spain.36 Liver Unit, Gregorio Marañón University Hospital, Madrid, Spain.37 Unidad de Trasplante Hepatico, Hospital Universitarro Puerta de Hierro, Madrid, Spain.38 Hepatobiliopancreatic Surgery and Transplantation Unit, La Fe University Hospital, Valencia, Spain.39 Inonu University, Liver Transplantation Institute, Malatya, Turkey.

Background: Liver transplantation is the most extreme form of surgical management of patients with hepatic trauma, with very limited literature data supporting its use. The aim of this study was to assess the results of liver transplantation for hepatic trauma.

Methods: This retrospective analysis based on European Liver Transplant Registry comprised data of 73 recipients of liver transplantation for hepatic trauma performed in 37 centers in the period between 1987 and 2013. Mortality and graft loss rates at 90 days were set as primary and secondary outcome measures, respectively.

Results: Mortality and graft loss rates at 90 days were 42.5% and 46.6%, respectively. Regarding general variables, cross-clamping without extracorporeal veno-venous bypass was the only independent risk factor for both mortality (P = 0.031) and graft loss (P = 0.034). Regarding more detailed factors, grade of liver trauma exceeding IV increased the risk of mortality (P = 0.005) and graft loss (P = 0.018). Moreover, a tendency above the level of significance was observed for the negative impact of injury severity score (ISS) on mortality (P = 0.071). The optimal cut-off for ISS was 33, with sensitivity of 60.0%, specificity of 80.0%, positive predictive value of 75.0%, and negative predictive value of 66.7%.

Conclusions: Liver transplantation seems to be justified in selected patients with otherwise fatal severe liver injuries, particularly in whom cross-clamping without extracorporeal bypass can be omitted. The ISS cutoff less than 33 may be useful in the selection process.
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http://dx.doi.org/10.1097/TP.0000000000001398DOI Listing
November 2016

Indications and Outcomes in Liver Transplantation in Patients With Primary Sclerosing Cholangitis in Norway.

Transplant Direct 2015 Oct 19;1(9):e39. Epub 2015 Oct 19.

Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Section of Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Primary sclerosing cholangitis (PSC) is 1 of the leading causes of liver transplantation (LTX) in Scandinavia, and an increasing number of PSC patients have been transplanted in Norway during the last 2 decades. This trend is partly attributable to the recently established practice in Norway of offering LTX to PSC patients with cholangiocellular dysplasia. Based on the controversy associated with this practice, we herein aimed to report the main features and outcomes of our LTX program in PSC.

Methods: The primary indication for LTX (quality of life/end-stage liver disease or suspected neoplasia) was retrospectively determined for 222 patients undergoing LTX for PSC or other autoimmune liver diseases (primary biliary cirrhosis/autoimmune hepatitis) with at least 5 years of follow-up.

Results: In PSC patients impaired quality of life (43.5%) and end-stage liver disease (38.4%) were the most frequent indications for LTX, whereas suspected neoplasia accounted for 18.1%. The proportion of PSC patients with manifest encephalopathy, variceal bleeding, or ascites declined over time. In patients with suspected neoplasia as the primary indication for LTX (n = 25), neoplasia was confirmed in the explanted liver in 20 patients (80%). Five-year survival rates for PSC patients transplanted between 2001 and 2009 were 91.9% for patients receiving LTX due to impaired quality of life or end-stage liver disease and 83.3% for suspected neoplasia.

Conclusions: The PSC patients are increasingly listed for LTX at an earlier stage of their liver disease. In patients with suspected neoplasia before LTX, 5-year survival was acceptable, despite confirmation of neoplasia in 80% of the liver explants.
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http://dx.doi.org/10.1097/TXD.0000000000000548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946487PMC
October 2015

Evaluation of Perfluorohexyloctane/Polydimethylsiloxane for Pancreas Preservation for Clinical Islet Isolation and Transplantation.

Cell Transplant 2016 12 27;25(12):2269-2276. Epub 2016 May 27.

This study aimed to evaluate a 50:50 mix of perfluorohexyloctane/polydimethylsiloxane 5 (F6H8S5) preservation of pancreases in a clinical setting compared with standard solutions for 1) cold ischemia time (CIT) 10 h and 2) an extended CIT 20 h. Procured clinical-grade pancreases were shipped in either F6H8S5 or in standard preservation solutions, that is, University of Wisconsin (UW) or Custodiol. F6H5S5 was preoxygenated for at least 15 min. Included clinical-grade pancreases were procured in UW or Custodiol. Upon arrival at the islet isolation laboratory, the duodenum was removed followed by rough trimming while F6H8S5 was oxygenated for 1520 min. Trimmed pancreases were immersed into oxygenated F6H8S5 and stored at 4C overnight followed by subsequent islet isolation. Pancreas preservation using F6H8S5 proved as effective as UW and Custadiol when used within CIT up to 10 h, in terms of both isolation outcome and islet functionality. Preservation in F6H8S5 of pancreases with extended CIT gave results similar to controls with CIT 10 h for both isolated islet functionality and isolation outcome. This study of clinically obtained pancreases indicates a clear benefit of using F6H8S5 on pancreases with extended CIT as it seems to allow extended cold ischemic time without affecting islet function and islet numbers.
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http://dx.doi.org/10.3727/096368916X691709DOI Listing
December 2016

Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human Islets In Vitro Compared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids.

J Diabetes Res 2016 18;2016:4196460. Epub 2016 Jan 18.

Department of Transplant Medicine, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.

Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.
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http://dx.doi.org/10.1155/2016/4196460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739465PMC
December 2016

Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets in vitro.

Transpl Int 2015 Oct 23;28(10):1152-61. Epub 2015 Jun 23.

Department of Transplantation Medicine, Oslo University Hospital, Norway.

Main Problem: Islet transplantation has become a promising treatment for type 1 diabetes. However, immunosuppressive drugs used today cause islet deterioration and modification strategies are necessary. But little is known about pharmacokinetics interactions and intracellular concentrations of immunosuppressive drugs in human islets.

Methods: We determined the pharmacokinetics of tacrolimus and sirolimus in islets by measuring intracellular concentration after exposure alone or in combination at two different doses up to 48 h. A quantification technique established in our laboratory using a Micromass Quattro micro API MS/MS-instrument with electrospray ionization was used. Islets function was measured by oxygen consumption rates. Presence of drug transporters OATP1B1 and ABCB1 and metabolizing enzyme CYP3A4 in islets were quantified using real-time quantitative PCR.

Results: Islets incubated with tacrolimus and sirolimus had a significant decrease in intracellular concentration of sirolimus compared to sirolimus alone. Reduced intracellular sirolimus concentration was followed by increased p70S6k phosphorylation suggesting preservation of the mTOR-signaling pathway. Drug transporters OATP1B1 and ABCB1 and enzyme CYP3A4 were expressed in human islets, but were not involved in the reduced sirolimus concentration by tacrolimus.

Conclusion: These findings provide new knowledge of the drug interaction between tacrolimus and sirolimus, suggesting that tacrolimus has an inhibitory effect on the intracellular concentration of sirolimus in human islets.
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http://dx.doi.org/10.1111/tri.12617DOI Listing
October 2015

Clostripain, the Missing Link in the Enzyme Blend for Efficient Human Islet Isolation.

Transplant Direct 2015 Jun 24;1(5):e19. Epub 2015 Jun 24.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Unlabelled: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential as they synergize with collagenase for effective pancreas digestion. The presence of tryptic-like activity has been implicated in efficient enzyme blends and the present study aimed to evaluate if addition of clostripain, an enzyme with tryptic-like activity, could improve efficacy of the islet isolation procedure.

Methods: Clostripain was added to the enzyme blend just before pancreas perfusion. Islets were isolated per standard method and numerous isolation parameters, islet quality control, and the number of isolations fulfilling standard transplantation criteria were evaluated. Two control organs per clostripain organ were chosen by blindly matching against body mass index, cold ischemia time, hemoglobin A1c, donor sex, and donor age.

Results: There were no differences in pancreas weight, dissection time, digestion time, harvest time, percent digested pancreas, or total pellet volume before islet purification between control or clostripain pancreases. Glucose-stimulated insulin release results were similar between groups. Total isolation islet equivalents, purified tissue volume and islet equivalents/g pancreas as well as fulfillment of transplantation criteria favored clostripain processed pancreases.

Conclusions: The addition of clostripain to the enzyme blend soundly improved islet yields and transplantation rates. It gently aided pancreas digestion and maintained proper islet functionality. The addition of clostripain to the enzyme blend has now been implemented into standard isolation protocols at the isolation centers in Uppsala and in Oslo.
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http://dx.doi.org/10.1097/TXD.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946465PMC
June 2015

Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.

Scand J Gastroenterol 2015 Jun;50(6):797-808

Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital , Oslo , Norway.

Aim And Background: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013.

Materials And Methods: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report.

Results: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively.

Conclusion: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).
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http://dx.doi.org/10.3109/00365521.2015.1036359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487534PMC
June 2015

Transplantation With Livers From Deceased Donors Older Than 75 Years.

Transplantation 2015 Dec;99(12):2534-42

1 Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital, Oslo, Norway. 2 Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway. 3 Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway. 4 Department of Transplantation, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden. 5 Division of Transplantation Surgery, Karolinska University Hospital Huddinge, Solna, Sweden. 6 Department of Surgical Sciences, Upper Abdominal Surgery, Uppsala Academic Hospital, Uppsala, Sweden. 7 Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland. 8 Department of Surgical Gastroenterology and Transplantation, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 9 Division of Cancer medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 10 Institute for Clinical Medicine, University of Oslo, Oslo, Norway.

Background: The availability of donor organs limits the number of patients in need who are offered liver transplantation. Measures to expand the donor pool are crucial to prevent on-list mortality. The aim of this study was to evaluate the use of livers from deceased donors who were older than 75 years.

Methods: Fifty-four patients who received a first liver transplant (D75 group) from 2001 to 2011 were included. Donor and recipient data were collected from the Nordic Liver Transplant Registry and medical records. The outcome was compared with a control group of 54 patients who received a liver graft from donors aged 20 to 49 years (D20-49 group). Median donor age was 77 years (range, 75-86 years) in the D75 group and 41 years (range, 20-49 years) in the D20-49 group. Median recipient age was 59 years (range, 31-73 years) in the D75 group and 58 years (range, 31-74 years) in the D20-49 group.

Results: The 1-, 3-, and 5-year patient/graft survival values were 87/87%, 81/81%, and 71/67% for the D75 group and 88/87%, 75/73%, and 75/73% for the D20-49 group, respectively. Patient (P = 0.89) and graft (P = 0.79) survival did not differ between groups. The frequency of biliary complications was higher in the D75 group (29.6/13%, P = 0.03).

Conclusions: Selected livers from donors over age 75 years should not be excluded based on age, which does not compromise patient or graft survival despite a higher frequency of biliary complications.
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http://dx.doi.org/10.1097/TP.0000000000000728DOI Listing
December 2015

Graft function 1 year after pregnancy in an islet-transplanted patient.

Transpl Int 2015 Oct 11;28(10):1235-9. Epub 2015 May 11.

Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway.

Pancreatic islet transplantation is a treatment option for patients with type 1 diabetes (T1D), but pregnancy has generally not been advised for women after receiving an islet allograft. We hereby describe what is to our knowledge the first successful pregnancy and persistent graft function in a woman 4 years after her initial islet transplantation. A 37-year-old woman with brittle type 1 diabetes was transplanted with two separate islet graft infusions, eventually becoming insulin independent. Ten months after her second transplantation, her immunosuppression was switched from tacrolimus and sirolimus to tacrolimus, azathioprine, and prednisolone, due to her wish to become pregnant. She became pregnant one year later, and after 38 weeks of uncomplicated pregnancy, she gave birth to a healthy child by C-section. The current report suggests that pregnancy and childbirth can be accomplished after islet transplantation without loss of islet graft function.
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http://dx.doi.org/10.1111/tri.12596DOI Listing
October 2015

Continuous molecular adsorbent recirculating system treatment in 69 patients listed for liver transplantation.

Scand J Gastroenterol 2015 11;50(9):1127-34. Epub 2015 Apr 11.

Department of Emergencies and Critical Care, Oslo University Hospital , Oslo , Norway.

Objective: The molecular adsorbent recirculating system (MARS) is used to purify blood from albumin-bound toxins in patients with liver failure. However, the application of MARS has not demonstrated improved survival in randomized clinical trials and the clinical utility has not been finally established. In our department, the use of MARS is now restricted to the most critically ill patients with acute or acute on chronic liver failure.

Material And Methods: Since 2005, we have treated 69 patients (30 males/39 females with median age of 49 years ranging from 1 months to 70 years) listed for liver transplantation (LT) with MARS. Median model of end-stage liver disease score in patients older than 12 years of age (n = 56) was 33 (interquartile range 26-39). The flow rate was 35-40 mL/kg/h and treatment kits were changed every 8-12 h. The patients were treated for a median of 27 h (range 1-144 h).

Results: Fifty-six patients (81%) were transplanted. Nine died before they could be transplanted, and four patients recovered without transplantation. Forty-six (82%) of the transplanted patients were alive 30 days after transplantation. Ammonium decreased modestly from a median of 148 to 124 µM (p = 0.03) during MARS treatment. We detected worsening of coagulopathy with significant decreases in platelet count and fibrinogen concentrations, and increase in International Normalized Ratio. Phosphate and magnesium decreased significantly during MARS treatment.

Conclusion: Continuous MARS therapy may bridge liver failure patients to LT under close observation and treatment of coagulopathy and electrolyte disturbances.
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http://dx.doi.org/10.3109/00365521.2015.1027262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673540PMC
March 2016

The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model.

PLoS One 2015 20;10(3):e0121204. Epub 2015 Mar 20.

Institute for Surgical Research and Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.

Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20μg/kg/day) or high (200μg/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121204PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368803PMC
February 2016

Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications.

Transpl Int 2015 Jul;28(7):800-12

Transplant Institute, Sahlgrenska University Hospital, Sahlgrenska Academy, Gothenburg, Sweden.

ABO-incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO-compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13-75); 33 patients were transplanted on urgent indications, 13 had malignancy-related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10-86). Forty-four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty-four patients received induction with IL-2 antagonist or anti-CD20 antibody. Median follow-up time was 29 months (range 0-200). The 1-, 3-, 5-, and 10-year Kaplan-Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1-, 3-, 5-, and 10-year GS for A2 grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non-A2 grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A2 grafts is associated with acceptable graft survival and can be used safely in urgent cases.
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http://dx.doi.org/10.1111/tri.12552DOI Listing
July 2015

A Novel Concept for Partial Liver Transplantation in Nonresectable Colorectal Liver Metastases: The RAPID Concept.

Ann Surg 2015 Jul;262(1):e5-9

Departments of *Transplantation Medicine, †Radiology, and ‡Oncology, Oslo University Hospital, Oslo, Norway; and §Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Objective: Selected patients with nonresectable colorectal liver metastases benefit from liver transplantation and have acceptable 5-year survival rates. However, allocating full-sized grafts to this group of patients is difficult due to the scarcity of grafts. This could be improved by utilizing small partial grafts, which mandates effective strategies to overcome the problems regarding insufficient functional liver mass.

Methods: We have developed a protocol incorporating previously reported experiences from living donor transplantation and recent developments in liver surgery, facilitating transplantation of very small liver grafts. At the time of transplantation, segments 1 to 3 are resected in the recipient and orthotopically replaced by a segment 2 to 3 allograft. Portal inflow is modulated by redirecting the portal flow to the graft with concomitant focus on keeping the portal vein pressure below 20 mm Hg. A second-stage hepatectomy is performed as soon as the graft has regenerated to a sufficient volume.

Results: A graft weighing 330 g was transplanted to a 50-year-old man weighing 92 kg, and the portal vein to the right remnant liver was closed. The volume of the liver graft was doubled 2 weeks after the first procedure, and it increased further after the second procedure, with extended right hepatectomy performed at day 23 after transplantation. There were no signs of liver failure or small-for-size syndrome.

Conclusions: The current protocol and ongoing study could represent a possible strategy to increase the availability of liver transplantation to patients with nonresectable liver tumors such as hepatocellular carcinoma and colorectal liver metastases.
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http://dx.doi.org/10.1097/SLA.0000000000001165DOI Listing
July 2015

Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma.

Hepatology 2015 May 24;61(5):1651-9. Epub 2015 Feb 24.

Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.

Unlabelled: Early detection of the highly aggressive malignancy cholangiocarcinoma (CCA) remains a challenge but has the potential to render the tumor curable by surgical removal. This study evaluates a biomarker panel for the diagnosis of CCA by DNA methylation analyses of biliary brush samples. The methylation status of 13 candidate genes (CDO1, CNRIP1, DCLK1, FBN1, INA, MAL, SEPT9, SFRP1, SNCA, SPG20, TMEFF2, VIM, and ZSCAN18) was investigated in 93 tissue samples (39 CCAs and 54 nonmalignant controls) using quantitative methylation-specific polymerase chain reaction. The 13 genes were further analyzed in a test series of biliary brush samples (15 CCAs and 20 nonmalignant primary sclerosing cholangitis controls), and the methylation status of the four best performing markers was validated (34 CCAs and 34 primary sclerosing cholangitis controls). Receiver operating characteristic curve analyses were used to evaluate the performance of individual biomarkers and the combination of biomarkers. The 13 candidate genes displayed a methylation frequency of 26%-82% in tissue samples. The four best-performing genes (CDO1, CNRIP1, SEPT9, and VIM) displayed individual methylation frequencies of 45%-77% in biliary brushes from CCA patients. Across the test and validation biliary brush series, this four-gene biomarker panel achieved a sensitivity of 85% and a specificity of 98%, with an area under the receiver operating characteristic curve of 0.944.

Conclusion: We report a straightforward biomarker assay with high sensitivity and specificity for CCA, outperforming standard brush cytology, and suggest that the biomarker panel, potentially in combination with cytological evaluation, may improve CCA detection, particularly among primary sclerosing cholangitis patients.
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http://dx.doi.org/10.1002/hep.27707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832263PMC
May 2015

Is Liver Transplantation an Option in Colorectal Cancer Patients with Nonresectable Liver Metastases and Progression on All Lines of Standard Chemotherapy?

Ann Surg Oncol 2015 Jul 9;22(7):2195-200. Epub 2014 Oct 9.

Department of Oncology, Oslo University Hospital, Oslo, Norway,

Background: About 50 % of patients with metastatic colorectal cancer (CRC) will develop metastatic disease with liver as primary metastatic site. The majority of CRC patients has nonresectable disease and receives palliative chemotherapy. Overall survival (OS) from time of progression on last line of chemotherapy in metastatic CRC is about 5 months. CLM have been considered a contraindication for liver transplantation. However, we have previously reported 5-year OS of 60 % after liver transplantation for nonresectable CLM. There were six patients who had progressive disease (PD) on last line of standard chemotherapy at the time of liver transplantation; here we report the outcome for these six patients.

Methods: Patients with nonresectable liver-only CLM received liver transplantation in the SECA study, a subgroup of six patients whose disease had progressed on all standard lines of chemotherapy.

Results: These patients with nonresectable disease and PD on the last line of standard chemotherapy at time of liver transplantation had 8-35 metastatic lesions in the liver with the largest diameter at 2.8-13.0 cm. All patients had a relapse within 2.1-12.4 months after liver transplantation. Some patients received treatment with curative intent at the time of relapse, and median OS after transplantation was 41 months with a Kaplan-Meier calculated 5-year OS of 44 %.

Conclusions: Liver transplantation in nonresectable CLM patients with extensive tumor load and PD on the last line of chemotherapy had extended OS compared with any other treatment option reported in the literature.
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http://dx.doi.org/10.1245/s10434-014-4137-0DOI Listing
July 2015

Differences in long-term survival among liver transplant recipients and the general population: a population-based Nordic study.

Hepatology 2015 Feb 5;61(2):668-77. Epub 2015 Jan 5.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland; Department of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.

Unlabelled: Dramatic improvement in first-year outcomes post-liver transplantation (LT) has shifted attention to long-term survival, where efforts are now needed to achieve improvement. Understanding the causes of premature death is a prerequisite for improving long-term outcome. Overall and cause-specific mortality of 3,299 Nordic LT patients (1985-2009) having survived 1 year post-LT were divided by expected rates in the general population, adjusted for age, sex, calendar date, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver-Transplant Registry and WHO mortality-indicator database. Stagnant patient survival rates >1 year post-LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95% confidence interval [CI] 5.4-6.3), with improvement from 1985-1999 to 2000-2010 in hepatitis C (HCV) (SMR change 23.1-9.2), hepatocellular carcinoma (HCC) (SMR 38.4-18.8), and primary sclerosing cholangitis (SMR 11.0-4.2), and deterioration in alcoholic liver disease (8.3-24.0) and acute liver failure (ALF) (5.9-7.6). SMRs for cancer and liver disease (recurrent or transplant-unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22-693) and kidney disease (SMR 13-45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant-specific events caused 16% of deaths.

Conclusion: standardized premature mortality provided an improved picture of long-term post-LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow-up and future research.
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http://dx.doi.org/10.1002/hep.27538DOI Listing
February 2015

Chemotherapy or liver transplantation for nonresectable liver metastases from colorectal cancer?

Ann Surg 2015 May;261(5):956-60

*Department of Oncology, Oslo University Hospital, Oslo, Norway †Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway ‡Institute of Clinical Medicine, University of Oslo, Oslo, Norway §Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden; and ¶Department of Oncology, Odense University Hospital, Odense, Denmark.

Objective: The primary objective was to compare overall survival (OS) in patients with colorectal cancer (CRC) with nonresectable liver-only metastases treated by liver transplantation or chemotherapy.

Background: CRC is the third most common cancer worldwide. About 50% of patients will develop metastatic disease primarily to the liver and the lung. The majority of patients with liver metastases receive palliative chemotherapy, with a median OS of trial patients of about 2 years, and less than 10% are alive at 5 years.

Methods: Patients with nonresectable liver-only CRC metastases underwent liver transplantation in the SECA study (n = 21). Disease-free survival (DFS) and OS of patients included in the SECA study were compared with progression-free survival (PFS) and OS in a similar cohort of CRC patients with liver-only disease included in a first-line chemotherapy study, the NORDIC VII study (n = 47). PFS/DFS and OS were estimated by the Kaplan-Meier method.

Results: DFS/PFS in both groups were 8 to 10 months. However, a dramatic difference in OS was observed. The 5-year OS rate was 56% in patients undergoing liver transplantation compared with 9% in patients starting first-line chemotherapy. The reason for the large difference in OS despite similar DFS/PFS is likely different metastatic patterns at relapse/progression. Relapse in the liver transplantation group was often detected as small, slowly growing lung metastases, whereas progression of nonresectable liver metastases was observed in the chemotherapy group.

Conclusions: Compared with chemotherapy, liver transplantation resulted in a marked increased OS in CRC patients with nonresectable liver-only metastases.
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http://dx.doi.org/10.1097/SLA.0000000000000786DOI Listing
May 2015

Liver transplantation for metastatic liver malignancies.

Curr Opin Organ Transplant 2014 Jun;19(3):235-44

aSection for Transplantation Surgery, Oslo University Hospital Rikshospitalet bInstitute of Clinical Medicine, University of Oslo, Oslo, Norway cStarzl Unit of Abdominal Transplantation, Department of Abdominal and Transplantation Surgery, University Hospitals St Luc, Université catholique de Louvain (UCL), Brussels, Belgium.

Purpose Of Review: Liver transplantation is a validated treatment of primary hepatobiliary tumours. Over the last decade, a renewed interest for liver transplantation as a curative treatment of colorectal liver metastasis (CR-LM) and neuro-endocrine metastasis (NET-LM) has developed.

Recent Findings: The ELTR and UNOS analyses showed that liver transplantation may offer excellent disease-free survival (ranging from 30 to 77%) in case of NET-LM, on the condition that stringent selection criteria are implemented. The interest for liver transplantation in the treatment of CR-LM has been fostered by the Norwegian SECA study. Five-year A 5-year survival rate of 60% could be reached. Despite the high recurrence rate (90%), one-third of patients were disease free following pulmonary surgery for metastases.

Summary: Liver transplantation will take a more prominent place in the therapeutic algorithm of CR-LM and NET-LM. Larger experiences are necessary to improve knowledge about tumour biology and to refine selection criteria. A multimodal approach adding neo and adjuvant medical treatment to the transplant procedure will be key to bring this oncologic transplant project into the clinical arena. The preserved liver function in these patients will allow a more deliberate access to split liver and living donation for these indications.
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http://dx.doi.org/10.1097/MOT.0000000000000086DOI Listing
June 2014

HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation.

World J Gastroenterol 2014 Apr;20(14):3986-4000

Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.

Aim: To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX).

Methods: In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR.

Results: Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups.

Conclusion: We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.
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http://dx.doi.org/10.3748/wjg.v20.i14.3986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983454PMC
April 2014

Low incidence of hyperfibrinolysis and thromboembolism in 195 primary liver transplantations transfused with solvent/detergent-treated plasma.

Clin Med Res 2014 Sep 10;12(1-2):27-32. Epub 2014 Jan 10.

Faculty of Medicine, University of Oslo, Rikshospitalet, Box 4950 Nydalen, 0424 Oslo, Norway Dept. of Immunology, Oslo University Hospital, Rikshospitalet, Box 4950 Nydalen, 0424 Oslo, Norway.

Background: Liver transplantation regularly requires transfusion of red blood cells (RBCs), plasma, and platelets. Compared to fresh frozen plasma (FFP) from single blood donors, solvent/detergent-treated plasma (SD-plasma) pooled from several hundred blood donors has advantages with respect to pathogen reduction, standardized content of plasma proteins, and significantly reduced risk of transfusion related lung injury and allergic/immunologic adverse reactions. However, SD-plasma has been suspected to increase the incidence of hyperfibrinolysis and thromboembolic events.

Study Design And Methods: We investigated the transfusion practices, hyperfibrinolysis parameters, and thrombosis outcomes in 195 consecutive adult primary liver transplants in our center using SD-plasma (Octaplas) as the exclusive source of plasma.

Results: Perioperatively, median (interquartile range) 4 (1 to 9) RBC-units, 10 (4 to 18) plasma-bags, and 0 (0 to 2) platelet-units were transfused. Hyperfibrinolysis defined as LY30 ≤ 7.5% was detected in 12/138 thrombelastography-monitored patients (9%). These patients received significantly more RBCs, plasma, and platelets than did patients without hyperfibrinolysis. Thrombotic graft complications were observed in three patients (2%). Pulmonary embolism was not observed in any patient.

Conclusion: SD-plasma is a safe plasma product for liver transplant recipients, and the incidences of hyperfibrinolysis and thromboembolic events are not significantly different from those seen in centers using FFP.
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http://dx.doi.org/10.3121/cmr.2013.1168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453305PMC
September 2014
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