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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 With the acceptance from the next of kin and their wish for organ donation, life support was withdrawn and cardiac arrest observed.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 2 ( P = 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., Competing Interests: The authors declare no funding or conflicts of interest.

Purpose: The incidence of intraoperative arterial injury during pancreatectomy is not well described. This study aims to evaluate the incidence, management, and outcome of arterial injuries during pancreatectomy., Methods: This is a retrospective study of 1535 consecutive patients undergoing pancreatectomy between 2006 and 2016 at Oslo University Hospital. The type of arterial injury and potential contributing factors were analyzed. Short-term outcomes were compared between patients with arterial injury and patients undergoing a planned arterial resection due to tumor involvement., Results: Arterial injury was diagnosed in 14 patients (incidence 0.91%), while planned arterial resection was performed in 22 patients. The injuries were located in the superior mesenteric artery (n = 5), right hepatic artery (n = 5), common hepatic artery (n = 2), left hepatic artery (n = 1), and celiac trunk (n = 2). The artery was reconstructed in all except one patient. In 11 patients with injury, peripancreatic inflammation, aberrant arterial anatomy, close relationship between tumor and injured artery, or a combination of the three were found. Median estimated blood loss was 1100 ml in both groups. Rate of severe complications (≥ Clavien grade IIIa), comprehensive complication index, and 90-day mortality for patients with intraoperative arterial injury vs planned arterial resection were 43 vs 45% (p = 0.879), median 35.9 vs 21.8 (p = 0.287), and 14.3 vs 4.5% (p = 0.551), respectively., Conclusion: Arterial injury during pancreatectomy is an infrequent and manageable complication. Early recognition and primary repair in order to restore arterial liver perfusion may improve outcome. However, the morbidity is high and comparable to patients undergoing a planned arterial resection.

Background: Liver transplantation is considered the standard of care for patients with hepatocellular carcinoma (HCC) within the Milan criteria. Liver transplantation in patients with unresectable colorectal cancer with liver-only disease has been shown to be associated with a 5-year overall survival rate of 56 per cent, compared with 9 per cent in patients receiving standard palliative chemotherapy. The aim of the present study was to compare disease-free (DFS) and overall (OS) survival after liver transplantation in patients with HCC and those with colorectal metastases., Methods: Data were collected from the SEcondary CAncer (SECA) study database and an institutional (national) database of patients undergoing liver transplantation for HCC; all liver-transplanted patients were included. Patients with colorectal metastases treated by liver transplantation were divided into high- and low-risk groups for mortality based on carcinoembryonic antigen levels, response to chemotherapy, largest lesion at time of transplantation and time from primary surgery to transplantation., Results: Patients with colorectal metastases had a median of 8 lesions, compared with 1 in patients with HCC within the Milan criteria. DFS was shorter in both the high-risk and the low-risk colorectal cancer groups compared with that in patients with HCC. The 5-year OS rate in the low-risk colorectal cancer group was 75 per cent, compared with 76 per cent in patients with HCC within the Milan criteria. The 5-year OS rate in patients with HCC beyond the Milan criteria was 56 per cent., Conclusion: The low-risk group of patients with colorectal cancer and unresectable liver-only disease had a 5-year OS rate following liver transplantation similar to that of patients with HCC with lesions within the Milan criteria., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Objectives: The importance of case load for treatment of extrahepatic biliary atresia (BA) is debated. The aim of this study was to register results of BA treatment in a small volume centre., Methods: Retrospective chart review study of patients with BA treated from 2000 to 2017. The institutional review board approved the study., Results: Forty-five babies were identified of which 42 (93%) are alive. Forty-one patients had a Kasai portoenterostomy (PE), two had a hepaticojejunostomy and two had a primary liver transplantation. The age at PE/hepaticojejunostomy was median 63 (4-145 days). Seven surgeons performed the operations, and the median duration of the diagnostic work-up was 8 (3-24) days. Clearance of jaundice was achieved in 23/43 (53%) babies, and 3- and 5-year native liver survival was 47% and 40%, respectively. Clearance of jaundice post-PE/hepaticojejunostomy was a strong predictor of native liver survival (adjusted OR: 0.027; 95%; p = .009). Plasma level of conjugated bilirubin at time of referral was also a significant predictor of native liver survival (adjusted OR: 1.053; p = .017)., Conclusion: A small volume centre may achieve satisfactory results for BA patients. The study has, however, identified factors that may further improve results; earlier referral, optimizing diagnostic work-up and establishing one dedicated surgical team.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: We aimed to evaluate changes in health-related quality of life (HRQoL) in patients 65 years or older from time of kidney transplantation (KTx) until 1 year postengraftment., Methods: A single-center prospective study was conducted. HRQoL was measured pre-KTx and at 2, 6, and 12 months postengraftment using self-reported Kidney Disease and Quality of Life short-form version 1.3. Intraindividual scores before and after KTx were evaluated. Liu Comorbidity Index was registered at enlisting. short-form-36 scores were additionally compared with scores from an age-matched population., Results: From January 1, 2013, until November 30, 2016, a total of 289 waitlisted patients were included. By September 1, 2017, 134 had reached 1 year postengraftment, and valid questionnaires were available in 120 (90%) patients. Mean age at KTx was 71.6 years (±4.3 years), 71% were male. Living donor was used in 21%, and preemptive KTx was performed in 30% of the recipients. Median waiting time for KTx from deceased donor was 16 months (range, 0.6-50.5 months). A total of 79 (66%) recipients had a Liu Comorbidity Index score of 3 or less.All HRQoL scores except the domain social function improved at 2 months postengraftment and remained stable or continued to improve at 1 year.HRQoL scores 12 months postengraftment were similar to those described in an age-matched general population except for the domain social function which remained at a significantly lower level. Time in dialysis was the most important variable associated with impaired HRQoL postengraftment., Conclusions: HRQoL scores showed clinically significant improvement in older KTx recipients 1 year posttransplant., Competing Interests: The authors declare no conflict of interests.

Cholangiopathies are progressive disorders with largely unknown pathoetiology and limited treatment options. We aimed to develop a novel surgical technique with direct access to the bile ducts that would complement existing mouse models of cholestasis, biliary inflammation, and fibrosis and present a new route of administration for testing of potential treatment strategies. We developed a surgical technique to access the murine biliary tree by injection of different solvents through catheterization of the gall bladder with simultaneous clamping of the common bile duct. To demonstrate the applicability of the technique, we injected either phosphate-buffered saline or dimethyl sulfoxide in concentrations of 50 or 65% and compared these groups with sham-operated mice. The surgery was optimized to achieve a mortality rate close to 0. There were no significant changes in pain, activity level, or mortality from the day of the surgery until euthanization for any groups. Injection of phosphate-buffered saline or 50% dimethyl sulfoxide was generally well-tolerated, whereas 65% dimethyl sulfoxide led to higher weight loss, an increase of serum alanine transaminase, and histological portal inflammation. There were no signs of inflammation in the gut. We have developed a bile duct injection technique that is well-tolerated, easily reproducible, and that may complement existing models of cholangiopathies. Direct access to the bile ducts without causing harm to the hepatobiliary or intestinal tissue may be valuable in future studies of normal biliary physiology and different pathophysiological mechanisms of disease and to test novel therapeutic strategies. NEW & NOTEWORTHY To evaluate tolerability of the bile duct to injection of both polar and nonpolar compounds, we established a novel biliary injection technique. This technique is well-tolerated, easily reproducible, and with direct access to the bile ducts for studies of the murine biliary tree. The bile duct injection technique may complement existing animal models and be a valuable tool in future studies of normal biliary physiology or pathophysiology and to test novel therapeutic strategies.

Hepatocellular carcinoma (HCC) in childhood differs from adult HCC because it is often associated with inherited liver disease. It is, however, unclear whether liver transplantation (LT) for HCC in childhood with or without associated inherited disease has a comparable outcome to adult HCC. On the basis of data from the European Liver Transplant Registry (ELTR), we aimed to investigate if there are differences in patient and graft survival after LT for HCC between children and adults and between patients with underlying inherited versus noninherited liver disease, respectively. We included all 175 children who underwent LT for HCC and were enrolled in ELTR between 1985 and 2012. Of these, 38 had an associated inherited liver disease. Adult HCC patients with (n = 79) and without (n = 316, matched by age, sex, and LT date) inherited liver disease served as an adult comparison population. We used multivariable piecewise Cox regression models with shared frailty terms (for LT center) to compare patient and graft survival between the different HCC groups. Survival analyses demonstrated a superior longterm survival of children with inherited liver disease when compared with children with HCC without inherited liver disease (hazard ratio [HR], 0.29; 95% CI, 0.10-0.90; P = 0.03) and adults with HCC with inherited liver disease (HR, 0.27; 95% CI, 0.06-1.25; P = 0.09). There was no survival difference between adults with and without inherited disease (HR, 1.05; 95% CI, 0.66-1.66; P = 0.84). In conclusion, the potential survival advantage of children with an HCC based on inherited disease should be acknowledged when considering transplantation and prioritization for these patients. Further prospective studies accounting for tumor size and extension at LT are necessary to fully interpret our findings. Liver Transplantation 24 246-255 2018 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: The previously reported SECA study demonstrated a dramatic 5-year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM., Methods: Chest CT scans from 11 patients in the SECA study resected for 18 pulmonary metastases were reviewed retrospectively. Tumour diameter, volume and CT characteristics were registered and tumour volume doubling time was calculated. Findings in the SECA group were compared with those of a control group consisting of 12 patients with non-transplanted rectal cancer resected for 26 pulmonary metastases. Disease-free survival (DFS) and overall survival (OS) after first pulmonary resection were determined., Results: Median doubling time based on tumour diameter and volume in the SECA and control groups were 125 and 130 days (P = 0·658) and 110 and 129 days (P = 0·632) respectively. The metastases in both groups were distributed to all lung lobes and were mostly peripheral. Median DFS after LT in the SECA group and after primary pelvic surgery in the control group was 17 (range 6-42) and 18 (2-57) months respectively (P = 0·532). In the SECA group, estimated 5-year DFS and OS rates after first pulmonary resection were 39 and 51 per cent respectively., Conclusion: Patients treated by LT for unresectable CLM have a good prognosis following resection of pulmonary metastases. Doubling time did not appear to be worse with the immunosuppression used after LT., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Purpose: The main objective of this study was to evaluate the prognostic value of volumetric and metabolic information derivied from F-18 fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) in combination with computed tomography (CT) prior to liver transplantation (LT) in patients with nonresectable colorectal liver metastases (CLM). Due to scarcity of liver grafts, prognostic information enabling selection of candidates who will gain the highest survival after LT is of vital importance. 18 F-FDG PET/CT was a part of the preoperative study protocol. Patients without evidence of extrahepatic malignant disease on 18 F-FDG PET/CT who also fulfilled all the other inclusion criteria underwent LT., Methods: The preoperative 18 F-FDG PET/CT examinations of all patients included in the SECA (secondary cancer) study were retrospectively assessed. Maximum, mean and peak standardized uptake values (SUV max , SUV mean and SUV peak ), tumor to background (T/B) ratio, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured and calculated for all liver metastases. Total MTV and TLG were calculated for each patient. Cut-off values were determined for each of these parameters by using receiver operating characteristic (ROC) analysis dividing the patients into two groups. One, three and five-year overall survival (OS) and disease free survival (DFS) for patients over and under the cut-off value were compared by using the Kaplan-Meier method and log rank test., Results: Twenty-three patients underwent LT in the SECA study. Total MTV and TLG under the cut-off values were significantly correlated to improved OS at three and five years (p = 0.027 and 0.026) and DFS (p = 0.01). One, three and five-year OS and DFS were not significantly related to SUV max , SUV mean , SUV peak or T/B-ratio., Conclusion: Total MTV and TLG from 18 F FDG PET/CT prior to LT for nonresectable CLM were significantly correlated to improved three and five-year OS and DFS and can potentially improve the patient selection for LT.

Liver resection is the only potentially curative treatment option in patients with liver metastases from colorectal cancer, but only about 20% of the patients are resectable. Liver transplantation of patients with unresectable liver metastases was attempted in the early era but it was abandoned due to poor survival. During the last decade, several case reports, a controlled pilot study, and a retrospective cohort study indicated that prolonged disease-free survival and overall survival can be obtained in a proportion of these patients. Strict selection criteria have not yet been well defined, but tumor load, response to chemotherapy, pretransplant carcinoembryonic antigen level, and time interval from resection of the primary tumor to transplant are all factors related to outcome. Carefully selected patients may obtain 5-year overall survival that approaches conventional indications for liver transplant. The scarcity of liver grafts is a significant problem, but this can possibly to some extent be addressed by use of extended criteria grafts and novel surgical techniques. There is an increasing interest in liver transplantation in these patients in the transplant community, and currently 4 clinical trials are active and are recruiting.

Objective: Superior mesenteric vein/portal vein (SMV/PV) resection and reconstruction during pancreatic surgery are increasingly common. Several reconstruction techniques exist. The aim of this study was to evaluate characteristics of patients and clinical outcomes for SMV/PV reconstruction using interposed cold-stored cadaveric venous allograft (AG+) or primary end-to-end anastomosis (AG-) after segmental vein resections during pancreatic surgery., Methods: All patients undergoing pancreatic surgery with SMV/PV resection and reconstruction from 2006 to 2015 were identified. Clinical and histopathologic outcomes as well as preoperative and postoperative radiologic findings were assessed., Results: A total of 171 patients were identified. The study included 42 and 71 patients reconstructed with AG+ and AG-, respectively. Patients in the AG+ group had longer mean operative time (506 minutes [standard deviation, 83 minutes] for AG+ vs 420 minutes [standard deviation, 91 minutes] for AG-; P < .01) and more intraoperative bleeding (median, 1000 mL [interquartile range (IQR), 650-2200 mL] for AG+ vs 600 mL [IQR, 300-1000 mL] for AG-; P < .01). Neoadjuvant therapy was administered more frequently for patients in the AG+ group (23.8% vs 8.5%; P = .02). Patients with AG+ had a longer length of tumor-vein involvement (median, 2.4 cm [IQR, 1.6-3.0 cm] for AG+ vs 1.8 cm [IQR, 1.2-2.4 cm] for AG-; P = .01), and a higher number of patients had a tumor-vein interface >180 degrees (35.7% for AG+ vs 21.1% for AG-; P = .02). There was no difference in number of patients with major complications (42.9% for AG+ vs 36.6% for AG-; P = .51) or early failure at the reconstruction site (9.5% for AG+ vs 8.5% for AG-; P = 1). A subgroup analysis of 10 patients in the AG+ group revealed the presence of donor-specific antibodies in all patients., Conclusions: The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis. Graft rejection could be a contributing factor to severe stenosis in patients reconstructed with allograft., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The underlying mechanism of liver regeneration after Associating Liver Partition and Portal vein ligation (PVL) for Staged hepatectomy (ALPPS) is still unclear. The aim of this study was to evaluate the relationship between future liver remnant (FLR) volume, liver regeneration characteristics and restoration of function in an experimental model of ALPPS., Methods: An ALPPS model in rats was developed with selective PVL, parenchymal transection and partial hepatectomy (step 1), followed by resection of the liver (step 2). Three different ALPPS groups with FLR sizes of 30, 20 and 10 per cent of total liver volume were compared with sham-operated controls and animals undergoing resection of left lateral lobe and 90 per cent PVL with respect to morbidity, mortality, liver regeneration and function., Results: Three of 15 animals that had ALPPS with 10 per cent FLR (ALPPS10) died after step 1. Ascites developed in two of five rats that had ALPPS with 20 per cent FLR and in three of four animals in the ALPPS10 group after step 2. Although the relative increments in FLR size and growth rates were highest in the ALPPS groups, small FLR size was associated with a sustained increase in levels of serum aminotransferases and bilirubin, a lower albumin concentration, severe sinusoidal injury, increased expression of proliferation markers and increased activation of hepatic progenitor cells after step 2., Conclusion: There is discordance between FLR volume increase and functional restoration after the ALPPS procedure.

Background: Pancreatoduodenectomy with superior mesenteric-portal vein resection has become a common procedure in pancreatic surgery. The aim of this study was to compare standard pancreatoduodenectomy with pancreatoduodenectomy plus venous resection at a high-volume centre, and to examine trends in management and outcome over a decade for the latter procedure., Methods: This retrospective observational study included all patients undergoing pancreatoduodenectomy with or without venous resection at Oslo University Hospital between January 2006 and December 2015. Trends were evaluated by assessing preoperative clinical and radiological characteristics, as well as perioperative outcomes in three time intervals (early, intermediate and late)., Results: A total of 784 patients had a pancreatoduodenectomy, of whom 127 (16·2 per cent) underwent venous resection. Venous resection resulted in a longer operating time (median 422 versus 312 min; P = 0·001) and greater estimated blood loss (EBL) (median 700 versus 500 ml; P = 0·004) than standard pancreatoduodenectomy. The rate of severe complications was significantly higher for pancreatoduodenectomy with venous resection (37·0 versus 26·3 per cent; P = 0·014). The overall burden of complications, evaluated using the Comprehensive Complication Index (CCI), did not differ (median score 8·7 versus 8·7; P = 0·175). Trends in venous resection over time showed a significant reduction in EBL (median 1050 versus 375 ml; P = 0·001) and duration of hospital stay (median 14 versus 9 days; P = 0·011) between the early and late periods. However, despite an improvement in the intermediate period, severe complication rates returned to baseline in the late period (18 of 43 versus 9 of 42 versus 20 of 42 patients in early, intermediate and late periods respectively; P = 0·032), as did CCI scores (median 20·9 versus 0 versus 20·9; P = 0·041)., Conclusion: Despite an initial improvement in severe complications for venous resection during pancreatoduodenectomy, this was not maintained over time. Every fourth patient with venous resection needed relaparotomy, most frequently for bleeding., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

EBV after pediatric LT is a risk factor for PTLD. We wanted to evaluate the effect of intravenous ganciclovir on EBV viremia and to identify risk factors for chronic EBV viremia. All pediatric patients who underwent LT in Norway from 2002 until 2015 were reviewed. Twenty-two of 38 patients with viremia were treated with intravenous ganciclovir for a median of 22 (21-38) days. Treated and untreated patients were not different with respect to EBV seroconversion prior to transplantation or age at transplantation, but treated patients had significantly earlier viremia after transplantation (P=.005). There was no difference in the proportion of patients with reduction in virus load in patients treated with ganciclovir compared to untreated patients at 8 weeks. After 1 year, five of 19 patients treated with ganciclovir and six of 14 untreated patients had reduced virus load compared to start of viremia (P=.27). In conclusion, treatment with intravenous ganciclovir did not change the proportion of patients with reduction in EBV load at 8 weeks and 1 year after viremia. Younger age at transplantation, short time from transplantation to viremia, and lack of EBV seroconversion prior to transplantation were significant predictors of chronic EBV viremia., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

BACKGROUND To estimate the prevalence, symptoms, causes and treatment of renovascular disease in children, and also to assess the degree of secondary organ damage to the heart, kidneys and eyes (end organ damage).MATERIAL AND METHOD Retrospective review of data for all children (0 - 16 years) who were examined for resistant hypertension in the period 1998 - 2013 at Oslo University Hospital Rikshospitalet.RESULTS A total of 21 children/adolescents (median age 8.5 years, 11 girls) were assessed and treated for resistant hypertension in the study period. Altogether had 38 % no symptoms at the time of diagnosis and 19 % had classical symptoms of hypertension. Fifteen patients received invasive treatment in the form of percutaneous transluminal renal angioplasty (PTRA) (n = 5), nephrectomy (n = 6), coiling (n = 1), autotransplantation (n = 1) or a combination of these (n = 2). Blood pressure improved following treatment in 10 of 14 patients for whom outcomes were recorded in the medical records. End organ damage to the heart and retina was observed in 60 % and 50 % of patients, respectively.INTERPRETATION Children with severely elevated blood pressure as a result of renovascular disease often have unspecific or no symptoms. Blood pressure improved following invasive treatment in 10 of 14 children and few complications were recorded. Invasive treatment may be considered in children and adolescents when standard treatment for hypertension is insufficient.

CD8 + T cells that express retinoic acid-related orphan receptor (ROR)γt (T C 17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8 + RORγt + T cells (T C 17 cells) was increased in peripheral blood. The CD8 + RORγt + T cells represented a highly activated subset and produced IL-17A in equal amount as CD4 + RORγt + T cells (T H 17 cells). Most CD8 + RORγt + T cells coexpressed T-bet, a lineage transcription factor for T H 1 and T C 1 development, suggesting that CD8 + RORγt + T cells undergo plasticity toward a T C 17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8 + RORγt - T cells, the CD8 + RORγt + T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8 + RORγt + T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8 + RORγt + T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Background: Age and number of recipients in need of kidney re-transplantation are increasing. Re-transplantation practices and outcomes in elderly recipients are not previously explored. We aimed to retrospectively evaluate the outcomes of recipients 65 years and older receiving their second deceased donor allograft., Methods: The study was designed as a retrospective registry based study. All recipients 65 years or older who received a deceased donor kidney transplant at Oslo University Hospital between 2000 and 2014 were included in the study. Survival outcomes were compared between recipients of first (TX1) and second (TX2) allograft. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazard models with patient survival, uncensored graft survival and death-censored graft survival as outcomes in the analyses., Results: Seven hundred and thirty-tree recipients > 65 years received a first (n = 687) or second (n = 46) deceased donor kidney transplant. Five years uncensored graft survival rates were 64% in TX 2 and 67% in TX 1 (P= 0.789). Estimated five years graft survival rates censored for death with functioning graft were 88% in TX2 and 90% in TX1 (P=0.475). Adjusted hazard ratio for uncensored graft loss (TX2 vs. TX1) was 1.24 (95% CI 0.77 - 2.00). Adjusted hazard ratio for graft loss censored for death with functioning graft (TX2 vs. TX1) was 1.70 (0.72-4.02)., Conclusions: Older recipients of second transplants have outcomes that are comparable to the outcomes of age-matched first transplant recipients, and far better than previously documented for older transplant candidates remaining on dialysis treatment. Advanced age by itself should not be a contraindication for re-transplantation. Best results are achieved with short time on dialysis before re-transplantation.

Background: Elderly patients are the fastest-growing group in need of renal transplantation. This study puts focus on renal transplant recipients in their 80th year or longer at time of engraftment. Is there evidence to support an absolute upper age limit for renal transplantation?, Methods: Recipients in their 80th year or longer, transplanted between 1983 and 2015, were included. Data were retrieved from the Norwegian Renal Registry in the end of October 2015. Graft and patient survivals were compared with recipients aged 70 to 79 years at transplantation., Results: Forty-seven patients older than 79 years were transplanted in the defined period. Median age 80.1 years, 81% were men. Median time on dialysis before transplantation was 18.5 months. All patients received an allograft from a deceased donor (median donor age, 61.8 years). In the death-censored graft survival model, there was no statistical difference between the groups. We found improved patient and graft survivals after introduction of mycophenolate mofetil and induction with basiliximab. Patients transplanted before 2000 had increased risk of death compared with those transplanted after 2000 (hazard ratio, 3.2; 95% confidence interval, 1.2-8.7). Median uncensored graft survival for patients transplanted after the year 2000 was 5.0 year (95% confidence interval, 2.4-7.6). Median patient survival was 5.0 years (3.1-6.9) and 5-year patient survival was 55%., Conclusions: Age by itself should not be an absolute contraindication against renal transplantation. An estimated 5-year survival rate of 55% post-engraftment for an 80-year-old patient is in our opinion more than acceptable., Competing Interests: The authors declare no conflicts of interest.

Background: SMV/PV resection has become common practice in pancreatic surgery. The aim of this study was to evaluate the technical feasibility and surgical outcome of using cold-stored cadaveric venous allografts (AG) for superior mesenteric vein (SMV) and portal vein (PV) reconstruction during pancreatectomy., Methods: Patients who underwent pancreatic resection with concomitant vascular resection and reconstruction with AG between January 2006 and December 2014 were identified from our institutional prospective database. Medical records and pre- and postoperative CT-images were reviewed., Results: Forty-five patients underwent SMV/PV reconstruction with AG interposition (n = 37) or AG patch (n = 8). The median operative time and blood loss were 488 min (IQR: 450-551) and 900 ml (IQR: 600-2000), respectively. Major morbidity (Clavien ≥ III) occurred in 16 patients. Four patients were reoperated (thrombosis n = 2, graft kinking/low flow n = 2) and in-hospital mortality occurred in two patients. On last available CT scan, 3 patients had thrombosis, all of whom also had local recurrence. Estimated cumulative patency rate (reduction in SMV/PV luminal diameter <70% and no thrombosis) at 12 months was 52%., Conclusion: Cold-stored cadaveric venous AG for SMV/PV reconstruction during pancreatic surgery is safe and associated with acceptable long-term patency., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Human CD4(+)CD25(hi)FOXP3(+) regulatory T cells maintain immunologic tolerance and prevent autoimmune and inflammatory immune responses. Regulatory T cells undergo a similar activation cycle as conventional CD4(+) T cells upon antigen stimulation. Here, we demonstrate that T cell receptors and costimulation are required to activate the regulatory T cell suppressive function. Regulatory T cells suppressed the T cell receptor signaling in effector T cells in a time-dependent manner that corresponded with inhibition of cytokine production and proliferation. Modulation of the activation level and thereby the suppressive capacity of regulatory T cells imposed distinct T cell receptor signaling signatures and hyporesponsiveness in suppressed and proliferating effector T cells and established a threshold for effector T cell proliferation. The immune suppression of effector T cells was completely reversible upon removal of regulatory T cells. However, the strength of prior immune suppression by regulatory T cells and corresponding T cell receptor signaling in effector T cells determined the susceptibility to suppression upon later reexposure to regulatory T cells. These findings demonstrate how the strength of the regulatory T cell suppressive function determines intracellular signaling, immune responsiveness, and the later susceptibility of effector T cells to immune suppression and contribute to unveiling the complex interactions between regulatory T cells and effector T cells., (© Society for Leukocyte Biology.)

Background. Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) indicates a poor prognosis. Surgery is considered the only curative option for selected patients with HCC recurrence following LT. Traditionally, the preference is given to the open approach. Methods. In this report, we present two cases of laparoscopic resections (LR) for recurrent HCC after LT, performed at Oslo University Hospital, Rikshospitalet. Results. Both procedures were executed without intraoperative and postoperative adverse events. Whereas one of the patients had a recurrence one year after LR, the other patient did not have any sign of disease during 3-year follow-up. Conclusions. We argue that, in selected cases, patients with HCC recurrence following LT may benefit from LR due to its limited tissue trauma and timely start of subsequent treatment if curative resection cannot be obtained. In patients with relatively favorable prognosis, LR facilitates postoperative recovery course and avoids unnecessary laparotomy.

Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4 + T cells that express RORγt and IL-17 (T H 17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T reg ) contribute to T H 17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T H 17 associated functional plasticity in T reg . In this study, we investigated the phenotype and functional properties of T reg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3 + T reg , which exclusively occurred within the FOXP3 + RORγt + T reg compartment. The FOXP3 + RORγt + T reg retained FOXP3 + T reg markers and represented an activated subset. The expression of RORγt in T reg may indicate a phenotypic switch toward T H 17 cells. However, the FOXP3 + RORγt + T reg produced both T H 17 and T H 2 associated pro-inflammatory cytokines, which corresponded with elevated T H 17 and T H 2 immune responses in PDAC patients. Both the FOXP3 + T reg and FOXP3 + RORγt + T reg from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3 + RORγt + T reg have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.

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.

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.

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.

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).

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.

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., (© 2014 by the American Association for the Study of Liver Diseases.)

Background and Aims: Curative treatment of hepatocellular carcinoma (HCC) is dependent on early diagnosis. Surveillance of patients at high risk for HCC is a key determinant to achieve this goal, but may be an underutilized tool. The aim of this study was to determine the rate of pre-diagnosis surveillance in patients with HCC in a large population-based cohort and to assess to what extent cirrhosis was known prior to the diagnosis of HCC., Methods: All patients diagnosed with HCC during 2000-2009 in The South-Eastern Regional Health Authority, representing 56% of the Norwegian population, were identified from The National Cancer Registry and the medical records were reviewed., Results: Fifteen out of 486 patients (3%) were diagnosed by surveillance. Potential curative treatment was offered to 58% of the patients who underwent surveillance as opposed to 15% in the non-surveillance group. Only age ≤ 65 years was an independent predictor of screening in a multivariate model. Almost two thirds of the patients with cirrhosis were unrecognized prior to the HCC diagnosis. Two hundred and fourteen patients (44%) were non-cirrhotics., Conclusion: Regular HCC surveillance in at-risk populations is virtually not applied in Norway and this may contribute to inferior overall survival. Failure to recognize cirrhosis and a high rate of HCC in non-cirrhotic patients will be limiting factors for the overall effectiveness of a potential surveillance program.

Liver regeneration after major surgery may activate occult micrometastases and facilitate tumor growth, leading to liver tumor recurrence. Molecular changes during liver regeneration can provide a microenvironment that stimulates intrahepatic tumor propagation through alterations in cellular signaling pathways, where activation and proliferation of mature hepatocytes, hepatic progenitor cells, non-parenchymal liver cells might favor both liver regeneration and tumor growth. This review highlights recent advances of tumor growth and development in the regenerating liver, possible mechanisms and clinical implications.

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

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.

Background: The development of biomarkers describing the individual responses to the immunosuppressant mycophenolic acid (MPA) has focused on the target enzyme activity [inosine 5'-monophosphate dehydrogenase (IMPDH)]. An extended strategy is to quantify the metabolic consequences of IMPDH inhibition. The aim of this study was to develop an assay for quantification of IMPDH activity and related purine bases and to provide preliminary data on the behavior of these biomarkers during clinical exposure to MPA., Methods: Liquid chromatography-mass spectrometry was used to determine xanthine (IMPDH activity in incubated cell lysate), hypoxanthine, guanine, and adenine derived from free nucleotides in lymphocytes. Analytical performance was assessed, and the biomarkers were examined in CD4⁺ cells from 2 groups: Healthy individuals in a single-dose MPA study (n = 5) and liver transplant recipients on MPA therapy (n = 15)., Results: Coefficients of variation between series were below 10% and 15% for measurement of the purines and IMPDH activity, respectively. Although IMPDH was inhibited, the purine levels increased in response to MPA in 3 of the 5 healthy individuals, and this positive response seemed to be associated with IMPDH1 c.579 + 119 G/G and c.580 - 106 G/G. In the liver transplant study, guanine was not reduced in response to the transient drop in IMPDH activity after MPA dosing. However, there were trends toward decrease in guanine and elevation of hypoxanthine during prolonged MPA therapy. The guanine/hypoxanthine ratio (median) was 37% lower and the adenine level was 21% lower at day 17 compared with day 4 after transplantation., Conclusions: The assay allows precise quantification of IMPDH activity, hypoxanthine, guanine, and adenine in lymphocytes. Some individuals may possess a counteracting purine response to the MPA-mediated inhibition of IMPDH. Reduction of the guanine/hypoxanthine ratio may be related to prolonged inhibition of IMPDH and seems as an intriguing pharmacodynamic biomarker for MPA.

Background: Mycophenolic acid (MPA) and tacrolimus play important roles in immunosuppressive therapy after solid organ transplantation (Tx) and show large intra- and interindividual pharmacokinetic (PK) variabilities. The purpose of this study was to describe the intra- and interindividual variabilities of MPA and tacrolimus PKs during the first 3 weeks after adult liver transplantation. Furthermore, inosine monophosphate dehydrogenase activity was investigated., Materials: This study describes PK and pharmacodynamic parameters of MPA and the PKs of tacrolimus in 16 liver transplant recipients, in 4 follow-up periods (I-IV)., Results: The area under the concentration-time curve (AUC(0-12 hours)) for tacrolimus was low early after Tx (eg, median 78.6 around day 4) and variable in all 4 periods ranging from 3.8 to 267 μg h/L, whereas the predose concentrations (C₀) were 0.0-17.9 μg/L. From periods I to IV, the tacrolimus dose was doubled and the median dose per body weight-adjusted AUC(0-12 hours) increased by 123% (P = 0.017). The AUC(0-12 hours) of MPA was in the range 8.6-57.4 mg h/L, with median values from 21.9 to 27.8 mg h/L, whereas C₀ was between 0.0 and 7.3 mg/L in the 4 periods (medians from 1.2 to 1.6 mg/L). The maximum inhibition of inosine monophosphate dehydrogenase within a dose interval ranged from 9.5% to 100%., Conclusions: This study confirmed the large variability in the PKs of tacrolimus and MPA in liver transplant recipients. In particular, the MPA AUC(0-12 hours) was consistently low in all 4 periods. We also observed a low tacrolimus exposure during the first days after transplant compared with the following weeks.

Objective: Liver regeneration following hepatectomy can stimulate the growth of hepatocellular carcinoma (HCC), and major hepatectomy can be associated with activation of hepatic progenitor cells (HPCs). The aim of this study was to evaluate how HPCs influence the malignant potential of tumor cells in vitro and HCC tumor growth after surgery in a rodent model., Material and Methods: Hepatoma cells (JM1) were cultured with conditioned medium (CM) from syngeneic HPCs (WB-F344). Growth rate, resistance to Adriamycin, and expression patterns for invasiveness and stemness were compared with naïve JM1. Microscopic HCC tumors from naïve JM1 or JM1 cultured with CM were inoculated in Fischer 344 rats undergoing 70% hepatectomy with or without simultaneous infusion of WB-F344. Tumor growth and invasiveness-related factors were compared. Buffalo rats were induced with Morris hepatoma cells. Liver tissue from both in vivo models was examined with regard to activation of cells with progenitor-like phenotype., Results: Co-culture with CM resulted in an increased resistance to Adriamycin and enhanced expressions of α-FP, MMP9, ABCG2, CD133, and SOX2, as well as the activation of ERK, AKT, WNT, and TGF-β1 pathways. Tumor size and metastases were significantly higher in groups with co-cultured cells or HPCs infusion. After 70% hepatectomy and tumor implantation, cells positive for α-FP, CK19, and CD133 were found, thus suggesting a progenitor-like phenotype in the setting of epithelial-mesenchymal transition., Conclusion: HPCs have a marked effect on HCC cells in vitro and appear to stimulate the growth and malignant potential of experimental HCC tumors.

Introduction: Pancreatic neuroendocrine tumors (PNET) are rare neoplasms with better prognosis than most pancreatic malignancies. Surgery of locally advanced PNET remains controversial, and the role of vascular reconstruction in this patient group has yet to be defined. The aim of this study was to evaluate the feasibility and outcome of pancreatic resections with vascular reconstruction in patients with locally advanced PNET., Methods: Retrospective analysis of patients who underwent pancreatic surgery with vascular reconstruction for locally advanced PNET at a single institution. Furthermore, a review of the relevant literature on the topic was performed., Results: Seven patients who had undergone vascular reconstruction for locally advanced PNET were identified. Four patients had liver metastases at time of surgery. Postoperative complications developed in four patients with no mortality. Median follow-up time of all patients was 21 (range, 3-58) months. Three patients had disease in remission after 58, 42 and 3 months, respectively. One patient died 35 months postoperatively due to progressive disease, whereas three patients had progression of disease after 21, 9, and 4 months postoperatively., Conclusion: Pancreatic surgery with vascular reconstruction in patients with locally advanced PNET is feasible with acceptable outcome.

Objective: The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs)., Background: Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5-year survival rate of about 50% after liver transplantation for CLMs could be anticipated., Methods: In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy., Results: Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8-60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors., Conclusions: OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453).

Abstract Objective. The first objective of the present study was to identify opportunities of improvement for clinical practice, assessed by local quality indicators, then to analyze possible reasons why we did not reach defined treatment quality measures. The second objective was to characterize patients, considered unresectable according to present criteria, for future arrangement of interventional studies with improved patient selection. Material and methods. Prospective observational cohort study from October 2008 to December 2010 of patients referred to the authors' institution with suspected pancreatic or periampullary neoplasm. Results. Of 330 patients, 135 underwent surgery, 195 did not, 129 due to unresectable malignancies. The rest had benign lesions. Perioperative morbidity rate was 32.6%, mortality 0.7%. Radical resection (R0) was obtained in 23 (41.8%) of 55 patients operated for pancreatic adenocarcinoma and 6.3% underwent reconstructive vascular surgery. Diagnostic failure/delay resulted in unresectable carcinoma, primarily misconceived as serous cystic adenoma in two patients. One resected lesion turned out to be focal autoimmune pancreatitis. One case with misdiagnosed cancer was revised to be a pseudoaneurysm. Palliative treatment was offered to 144 patients with malignant tumors, 62 due to locally advanced disease and all pancreatic adenocarcinomas. Conclusions. Quality improvement opportunities were identified for patient selection and surgical technique: Too few patients underwent reconstructive vascular surgery. The most important quality indicators are those securing resectional, radical (R0) surgery. Altogether 143 patients (57.9%) of those with malignant tumors were found unresectable, most of these patients are eligible for inclusion in future interventional studies with curative and/or palliative intention.

Background: Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration., Objective: To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model., Methods: Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers., Results: Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes., Conclusions: The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The pharmacokinetics of the immunosuppressant mycophenolic acid (MPA) demonstrates high inter- and intra-patient variability. Variation in the binding of MPA to albumin has been postulated to be an important factor in this variability, and monitoring of free MPA has been suggested to improve therapeutic drug monitoring (TDM) of MPA. Inosine monophosphate dehydrogenase (IMPDH) is the target enzyme for MPA, therefore the IMPDH activity in lymphocytes can serve as a marker of the MPA-specific response. This study aimed to explore how the albumin concentration influences the free concentration of MPA in liver transplant recipients and to assess whether alteration in the free MPA influences IMPDH activity in CD4 + cells., Methods: Blood samples were taken from 20 liver transplant recipients on two separate occasions (days 3-5 and 16-21). Total and free concentrations of MPA, and IMPDH activity were measured during the first 4 h of each dose interval., Results: Albumin levels correlated with the free fraction of MPA. However, the total MPA and free MPA were equal predictors of the immunosuppressive response as defined by IMPDH activity., Conclusion: Total and free MPA are equally good predictors of the immunosuppressive effect exerted by MPA as defined by IMPDH activity. IMPDH activity measurements represent a promising approach to TDM in patients treated with MPA.

Ischemic vascular complications and rejection occur more frequently with pediatric liver transplants versus adult liver transplants. Using intrahepatic microdialysis catheters, we measured lactate, pyruvate, glucose, and glycerol values at the bedside for a median of 10 days in 20 pediatric liver grafts. Ischemia (n = 6), which was defined as a lactate level > 3.0 mM and a lactate/pyruvate ratio > 20, was detected without a measurable time delay with 100% sensitivity and 86% specificity. Rejection (n = 8), which was defined as a lactate level > 2.0 mM and a lactate/pyruvate ratio < 20 lasting for 6 or more hours, was detected with 88% sensitivity and 45% specificity. With additional clinical criteria, the specificity was 83% without a decrease in the sensitivity. Rejection was detected at a median of 4 days (range = 1-7 days) before alanine aminotransferase increased (n = 5, P = 0.11), at a median of 4 days (range = 2-9 days) before total bilirubin increased 25% or more (n = 7, P = 0.04), and at a median of 6 days (range = 4-11 days) before biopsy was performed (n = 8, P = 0.05). In conclusion, microdialysis catheters can be used to detect episodes of ischemia and rejection before current standard methods in pediatric liver transplants with clinically acceptable levels of sensitivity and specificity. The catheters were well tolerated by the children, and no major complications related to the catheters were observed., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Hepatic artery (HA) occlusion and portal vein (PV) occlusion are the most common vascular complications after liver transplantation with an impact on mortality and retransplantation rates. The detection of severe hypoperfusion may be delayed with currently available diagnostic tools. Hypoperfusion and anaerobically produced lactic acid lead to increases in tissue carbon dioxide. We investigated whether the continuous assessment of the intrahepatic and intra-abdominal partial pressure of carbon dioxide (PCO(2) ) could be used to detect and distinguish HA and PV occlusions in real time. In 13 pigs, the HA and the PV were fully occluded (n = 7) or gradually occluded (n = 6). PCO(2) was monitored intrahepatically and between loops of small intestine. The hepatic and intestinal metabolism was assessed with microdialysis and PV as well as hepatic vein blood samples, and the results were compared to clinical parameters for the systemic circulation and blood gas analysis. Total HA occlusion led to significant increases in hepatic PCO(2) and lactate, and this was accompanied by significant decreases in the partial pressure of oxygen and glucose. PV occlusion induced a significant increase in intestinal PCO(2) (but not hepatic PCO(2) ) along with significant increases in intestinal lactate and glycerol. Gradual HA occlusion and PV occlusion caused steady hepatic and intestinal PCO(2) increases, respectively. Systemic clinical parameters such as the blood pressure, heart rate, and cardiac output were affected only by PV occlusion. In conclusion, even gradual HA occlusion affects liver metabolism and can be reliably identified with hepatic PCO(2) measurements. Intestinal PCO(2) increases only during PV occlusion. A combination of hepatic and intestinal PCO(2) measurements can reliably diagnose the affected vessel and depict the severity of the occlusion, and this may emerge as a potential real-time clinical monitoring tool for the postoperative course of liver transplantation and enable early interventions., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Rejection and ischemia are serious complications after liver transplantation. Early detection is mandatory, but specific markers are largely missing, particularly for rejection. The objective of this study was to explore the ability of microdialysis catheters inserted in liver grafts to detect and discriminate rejection and ischemia through postoperative measurements of inflammatory mediators. Microdialysis catheters with a 100-kDa pore size were inserted into 73 transplants after reperfusion. After the study's completion, complement activation product 5a (C5a), C-X-C motif chemokine 8 (CXCL8), CXCL10, interleukin-1 (IL-1) receptor antagonist, IL-6, IL-10, and macrophage inflammatory protein 1β were analyzed en bloc in all grafts with biopsy-confirmed rejection (n = 12), in grafts with vascular occlusion/ischemia (n = 4), and in reference grafts with a normal postoperative course of circulating transaminase and bilirubin levels (n = 17). The inflammatory mediators were elevated immediately after graft reperfusion and decreased toward low, stable values during the first 24 hours in nonischemic grafts. In grafts suffering from rejection, CXCL10 increased significantly (P = 0.008 versus the reference group and P = 0.002 versus the ischemia group) 2 to 5 days before increases in circulating alanine aminotransferase and bilirubin levels. The area under the receiver operating characteristic curve was 0.81. Grafts with ischemia displayed increased levels of C5a (P = 0.002 versus the reference group and P = 0.008 versus the rejection group). The area under the curve was 0.99. IL-6 and CXCL8 increased with both ischemia and rejection. In conclusion, CXCL10 and C5a were found to be selective markers for rejection and ischemia, respectively., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Glucocorticoids represent a cornerstone in the immunosuppressive therapy after solid organ transplantation. Interconversion between active and inactive states of glucocorticoids (ie, prednisolone and prednisone) is catalyzed by the enzymes 11β-hydroxysteroid dehydrogenases 1 and 2., Materials: This study investigated the pharmacokinetics of prednisolone and prednisone in 16 liver transplant recipients. Blood samples were collected in four 12-hour dosing intervals during the first 3 weeks posttransplant, including samples drawn at 13 time points., Results: Area under the time-concentration curve of prednisolone was 3-13 μg·h·mL·mg·kg with maximum concentrations (Cmax) between 0.37 and 2.5 μg·mL·mg·kg and trough concentrations (C0) between 0.13 and 1.1 μg·mL·mg·kg. The elimination half-lives were 1.9-10.3 hours. Apparent volume of distribution (VD/F) and apparent clearance (Cl/F) were 23-159 L and 4.7-28.7 L/h, respectively., Conclusions: This study demonstrated large intraindividual and interindividual variabilities in glucocorticoid pharmacokinetics. The results suggest that current prednisolone dosing early after liver transplantation might be too high, in particular when coadministered with methylprednisolone. These findings indicate a potential for improvement by personalized dosing of glucocorticoids in organ transplantation.