BACKGROUND:Despite an increase in the number of pancreas transplants in the Scandiatransplant region in the last decade, there continues to be a gap between demand and supply of transplantable organs. This imbalance has encouraged the transplant community to consider new sources of grafts, such as the reintroduction of donors after circulatory death (DCD) who were the standard donors in our center before 1988. MATERIAL AND METHODS:In this long-term follow-up study, we compare 44 consecutive, simultaneous pancreas kidney transplants performed at Karolinska University Hospital between 1986 and 1991: 21 patients received DCD grafts and 23 received grafts from donors after brain death. RESULTS:Both groups had similar donor and recipient characteristics, but cold ischemia times were significantly shorter in the DCD group. Warm ischemia times were very short compared with other studies on DCDs. Patient and graft survival rates were similar in both groups. CONCLUSION:This study suggests that controlled DCD pancreas and kidney grafts transplanted simultaneously can be a feasible option for reducing organ shortage without any negative impact on the long-term results.

Introduction The recently proposed benchmarks in liver transplantation have shown, despite excellent patient and graft survival, a not satisfactory postoperative course in terms of length of hospital stay (LOS) and high rates of complications. Enhanced recovery programs (ERP) are widely used across different surgical disciplines and have shown reduced LOS and morbidity. However, its feasibility in the field of liver transplantation has not been established. Herein, we conducted this study to investigate the potential benefits of ERP and whether its application can beat the current benchmarks in liver transplantation. Methods We retrospectively studied all adult liver transplanted patients (≥18 years old) that followed our ERP between January 2016 and June 2017. Patients were excluded from ERP due to following reasons: ICU before transplant, encephalopathy grade III-IV before transplant, complicated surgery, combined organ transplantations, ICU stay >2 days post-transplant and acute re-transplantation. Outcomes were compared with patients who followed a conventional postoperative care pathway meeting the benchmark criteria as defined in the study by Muller et al between January 2010 and December 2015. All patients had a minimum follow up time of 3 months. Endpoints were LOS, readmissions within 30 and 90 days, number and grade of post-transplant complications according to the Clavien-Dindo classification within 1-year, biliary complications within 1 year, patient survival and graft survival.Results 69 out of 115 (60%) patients followed ERP and were included to the study group. 222 out of 405 (55%) patients met the benchmark criteria and were included to the control group. Donor and recipient demographics did not differ between the two groups. The ERP group had lower incidence of post-transplant complications (69,0 % in ERP group vs 85,1 % in control group, P=0,011) and shorter median LOS (9 days in ERP group vs 13 days in control group, P<0,001). There were no differences in readmission rate within 30 and 90 days, postoperative complications, patient survival and graft survival. Conclusion Enhanced recovery programme can improve the postoperative course after liver transplantation by reducing post-transplant complication and length of hospital without having any adverse effects. These results may have important implications in refining the postoperative care and improve the current benchmarks in liver transplantation.

Introduction: Patients with limited hepatocellular carcinoma (HCC) and well-preserved liver function can be treated by liver transplantation, resection or ablation. Transplantation offers good long-term results, but with a relatively high post-operative morbidity and long-term complications. Liver resection is associated with a high risk of recurrent cancer. Liver ablation has increased lately, both as a single curative option and while waiting for transplantation, as complication rates are favorable. Our objectives were to compare outcome after liver transplantation, resection or ablation respectively, in relation to tumor stage, liver function and comorbidities. Methods: Prospectively collected data was retrieved from national Swedish Quality Registry (SweLiv) for HCC-patients, treated 2008-2016 in Sweden. Overall survival and cumulative incidence of tumor recurrences were analyzed for each treatment group. Preliminary results: During 2008 - 2016, 3590 patients were diagnosed with HCC; 31% by surveillance, while 11% were incidental radiologic findings. Curatively aiming treatments were given in 1253 patients (35%); transplantation in 273, resection in 544 and ablation in 436 patients. Median time from diagnosis to treatment was 223, 83 and 107 days respectively. Five year overall survival was 52% for patients who had resection, 76% for transplantation and 35% for ablation. After 2 years, the probabilities for recurrence and for death without recurrence were 9% and 5% respectively after transplantation, 36% and 12% after resection and 44 and 14 % respectively after ablation. Conclusion: Recurrences and deaths without recurrence were more common after resection/ablation than after liver transplantation. Adjusted subgroup analyses will be done.

Purpose of study: National guidelines in Sweden stipulate that transplantation is indicated in HCC with a tumor up to San Francisco (UCSF) criteria. However, studies and case-series report successful transplantation after down staging. Vascularised tumor diameter, as measured by mRECIST correlate to survival, and improvements in intervention (standardisation and selection of beads and increased dose administration of doxorubicin) increase response rate after chemoembolization. Hypothesis: Survival will be prolonged for HCC patients selected to be downsized (in comparison to historical registry data). Transplantation will be possible with a 50% 5-year survival. Patient selection: Patients are eligible for study irrespective of tumor burden in the liver, of there is no extra hepatic growth or vascular invasion, and if the performance and comorbidity or social situation does not contraindicate transplantation. Method: A nationwide multi centre study selecting HCC above UCSF without size-limit. Intervention: Chemoembolization until response or failure. Ablation is allowed. Response is measured as decrease in vascularised diameter (in accordance with mRECIST), as a decrease of at least 30% and with a sum of maximum tumor diameter 80 mm. Prognostic factors is registered. Study is ongoing since autumn 2015. This study is affiliated to the national liver tumor register (SweLiv), which will add the possibility to describe the selection among all HCC patients.

Introduction: This is a population-based report concerning hepatocellular carcinoma (HCC) in Sweden. A national register (SweLiv) has so far registered > 2400 HCC cases since 2009. The estimated coverage in comparison with that mandatory swedish cancer registry is >95%. Method: 5 year relative survival data for HCC in Sweden 2009–2014 is shown with confidence interval depending on stage and treatment. Stage and treatment specific recurrence rates are presented. Results: Associated liver disease was found among 70%. There is a male dominance (3:1). The relative 5-year survival rate was 24%, equal between gender. The relative 5-year survival rate correlate to T-status. The most common underlying liver disease was Hepatitis C (28%). In patients with associated liver disease, median tumor diameter was 40 mm compared to 80 mm without associated liver disease. Treatments aiming for cure were planned for 29%. The relative 5-year survival rate was 74% after transplantation (n = 172), 51% after resection (n = 334) and 37% after ablation (n = 307). Conclusion: Active treatment correlate to survival and increased use of curative treatment options might increase survival. At the meeting recurrence rate depending on treatment and stage will be presented. This analysis will be of interest analysing potential benefits of extending curative treatment options above BCLC guidelines and Milan criteria.

Aim of the study Hepatobiliary scintigraphy can detect post-liver transplantation (LTx) structural complications and provide information of graft function. Hepatic extraction fraction (HEF) is a measurement of the hepatic extraction efficiency and hepatic extraction rate. In this study, we compared the HEF with biochemical and histological parameters between the LTx patients receiving cyclosporin A (CSA) or tacrolimus (TAC). Methods Thirty-nine adult patients who underwent LTx due to HCV cirrhosis between March 2007 and May 2011 were evaluated. All patients underwent a three-month follow-up that included hepatobiliary scintigraphy and blood biochemistry tests (s-bilirubin, ALT, AST, ALP, and gamma-GT). The same tests were repeated at the one-year follow-up; in addition s-creatinine, Iohexol clearance and a liver biopsy were performed. These clinical parameters were compared between the two groups, TAC (n=15), and CSA (n=24). Results The average HEF was significantly lower in the CSA group compared to the TAC group both at 3-month and 1-year after transplantation (p<0.001). The liver biochemistry tests, average donor and recipient age, average cold ischemia time, and Iohexol clearance were comparable between the two groups. Histology showed that the TAC group had more inflammation than the CSA group. Moreover, three patients who converted from CSA to TAC for liver unrelated side effects between 3.7 and 6.3 months postoperatively all increased their HEF values (27 to 90%, 42 to 100%, and 13 to 26%). Conclusion CSA treated patients presented a lower HEF value on hepatobiliary scintigraphy in spite of comparable liver function by traditional measurements indicating a false decrease on HEF values by CSA. Our finding has significant clinical implications as it indicates that the assessment of the liver graft function may be misled due to the falsely low HEF values in CSA treated patients with otherwise good liver function.

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.

The role of adjuvant systemic chemotherapy in liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial. Here, we report the results of a Nordic prospective, randomized, multi-centre trial of systemic low-dose doxorubicin in patients with HCC. Between February 1996 and April 2004, 46 patients were randomized to receive either neoadjuvant doxorubicin in combination with LT (chemo group; n = 19) or LT alone (control group; n = 27). In the chemo group, doxorubicin was administered intravenously, 10 mg/m(2) weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m(2) was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m(2), depending on the clinical course, up to a cumulative dose of 400 mg/m(2). Actuarial, 3-year overall survival (OS) and disease-free survival (DFS) in the control group were 70% and 50%, respectively. In the chemo group, both OS and DFS were 63%. Freedom from recurrence at 3 years was 55% in the control group and 74% in the chemo group. None of the differences was statistically significant. Neoadjuvant treatment with systemic low-dose doxorubicin seems not to improve either survival or freedom from recurrence in patients with HCC undergoing LT.

Hepatitis C virus (HCV)-induced cirrhosis is the major indication for liver transplantation globally, and an increasing indication for liver transplantation in Sweden. We have retrospectively examined the 120 patients transplanted for HCV cirrhosis from 1987 through 2005, including 11 who received more than one graft. The 1-, 3-, and 5-year postoperative survivals for all patients transplanted for HCV with or without hepatocellular cancer (HCC) were 77%, 66%, and 53%, respectively. HCV patients without HCC had a 1-, 3-, and 5-year survivals of 78%, 73%, and 61%, compared with 84%, 79% and 74%, respectively, for patients transplanted with chronic liver diseases without cancer or HCV. The number of patients with HCV cirrhosis transplanted in our center is increasing. Compared with patients transplanted for other chronic liver diseases, we experienced inferior results among patients with HCV cirrhosis.

A 49-year old male patient with severe hemophilia A, coinfected with HIV and HCV, who underwent orthoptic liver transplantation because of hepatitis C cirrhosis is presented. We describe a strong interaction between nelfinavir and tacrolimus postoperatively, that caused a reduction of the dose of tacrolimus by a factor 70 compared with normal, to achieve therapeutic blood concentrations and to avoid toxic side effects. We suggest that nelfinavir inhibits the metabolism of tacrolimus because both compounds are well-known substrates for the cytochrome P450 isoenzyme CYP 3A4. The nelfinavir serum concentrations were not affected by the institution of tacrolimus. Although the interaction dramatically changed the tacrolimus dose-concentration relationship, the situation was manageable by frequent monitoring of blood concentrations of tacrolimus.

Adjuvant treatment with adriamycin has been suggested to improve results after liver transplantation for hepatocellular cancer. Here we have applied an animal model for evaluation of treatment with adriamycin and/or cyclosporine A on liver tumour growth. Three chemically induced rat liver tumours with various degree of differentiation were transferred to the spleens of syngenic rats. Each recipient group was divided into four subgroups, treated with adriamycin and/or cyclosporine A or none of the drugs. When the tumour was well differentiated no proliferation was found in any of the subgroups. When the tumour exhibited a more pronounced dysplasia, adriamycin stimulated tumour growth. This effect was further increased by cyclosporine. In the animals transplanted with the most aggressive tumour, adriamycin inhibited tumour growth. When given together with cyclosporine this inhibition was counteracted. These data suggest that adriamycin, especially when given together with cyclosporine, may have a stimulatory effect on liver tumour cell growth.

BACKGROUND:Survival after liver transplantation for fulminant hepatic failure has been reported to be less favorable than survival for patients with chronic liver diseases. METHODS:We have studied all patients (n=229) undergoing highly urgent liver transplantation from 1990 to 2001 in the Nordic countries. The impact of patient and donor characteristics, with emphasis on donor-recipient ABO matching (identical, compatible, incompatible), has been studied. RESULTS:One-year and 3-year patient survival rates were 73% and 70% for the total period and 86% and 78% for the last 4-year period. Patients receiving an ABO-compatible liver allograft had significantly lower patient survival rates than those receiving an ABO-identical donor organ (1-year patient survival rates 66% of vs. 79%, P=0.03). Graft survival rates varied less (1-year graft survival rates of 64% vs. 74%, P=0.09). Patients receiving an ABO-incompatible liver allograft had patient survival rates of 70% at 1 year and 60% at 3 years but low graft survival rates (40% and 30% at 1 and 3 years). In a multiple regression analysis, significant independent predictors of poor patient survival were early year of transplantation, ABO-compatible donor, high donor age, and waiting time more than 3 days and less than 9 days. CONCLUSION:Survival after highly urgent liver transplantation has improved and is comparable to that observed in patients receiving a liver allograft because of chronic liver disease. Patients receiving an ABO-identical donor organ had significantly higher patient survival rates compared with those receiving an ABO-compatible donor liver.

BACKGROUND:Tumor recurrence after orthotopic liver transplantation (OLT) in patients with advanced primary liver cancer is common. To achieve an adjuvant graft-versus-tumor effect, the authors investigated whether transplantation of allogeneic peripheral blood stem cells (PSCT) after OLT can induce sustained complete donor chimerism.METHODS:Five patients with advanced primary liver cancer were included in the trial. None of the patients had signs of extrahepatic tumor before OLT. However, overall, the extent of surgery, as judged by morphologic examination of the explanted liver, was considered inadequate. A nonmyeloablative preparative regimen of fludarabine combined with total-body irradiation or cyclophosphamide preceded the allogeneic PSCT, which was then performed 16 to 135 days after OLT with human leukocyte antigen-matched donors. Mixed chimerism was monitored weekly by polymerase chain reaction of variable number tandem repeats after PSCT.RESULTS:In two patients, no engraftment of donor cells was seen, whereas one rejected the cells 2 months after PSCT. In two of the patients, a stable mixed donor chimerism was established. A mild transient graft-versus-host reaction was also noted in two patients. Three of the patients died of progressive disease 7 to 9 months after OLT. The other two are presently alive without recurrence at a follow-up of 26 and 10 months, respectively.CONCLUSIONS:These data suggest that PSCT after OLT is feasible, with low transplant-related morbidity. The rate of nonengraftment or rejection of the transplanted stem cells in this group of patients was three of five. An augmented pretreatment to prevent donor T-cell rejection seems to be necessary in this setting.

BACKGROUND In histocompatibility mismatched experimental animals, a combination of T-cell-depleted autologous and allogeneic marrow may induce mixed chimerism and tolerance. Patients with large primary liver tumors have a poor outcome. We investigated whether it were possible to induce mixed chimerism and obtain an antitumor effect in a patient with a large primary liver cancer after combined liver and bone marrow transplantation (BMT). METHODS A 46-year-old female with a primary non resectable liver cancer received a liver transplant from a cadaveric donor. Subsequently, she was conditioned with 4x2 Gy of total lymphoid irradiation, 120 mg/kg cyclophosphamide, and 7.5 Gy total body irradiation. Twelve days after liver transplantation, she received T-cell-depleted autologous:cadaveric 5/6 antigen HLA-mismatched marrow in a proportion of CD34+ cells of 0.5:3.0x10(6)/kg. Chimerism status was determined with polymerase chain reaction amplification of variable number tandem repeats from DNA obtained from CD3+, CD19+, and CD45+ magnetic-bead-separated cells. RESULTS The early posttransplant period was uneventful; liver function was normal and the hematopoietic engraftment of donor and recipient origin was prompt. Alpha-fetoprotein levels dropped from 440 to 35 microg/l. One month after marrow transplantation, donor T-cells decreased markedly. Monoclonal antibody OKT-3 and 10(5)/kg donor T-cells were given. One month later, the patient developed diarrhea and abdominal pain. A colonoscopy showed moderate gastrointestinal acute graft-versus-host disease and a Cryptosporidium infection. Three months after BMT, she became a complete donor chimera. Chimera cells showed little, if any, reactivity in mixed lymphocyte cultures to recipient and donor cells, but reacted to third party. Five months after BMT, she developed progressive Aspergillus fumigatus pneumonia and died. No tumor was found at the autopsy. CONCLUSION We obtained mixed donor-recipient hematopoietic chimerism without severe acute graft-versus-host-disease, after combined T-cell depleted autologous and allogeneic BMT and a transplantation of a liver from an HLA-mismatched cadaveric donor. Additional donor T-cells enhanced donor bone marrow engraftment, but rejected the autograft. On the basis of this first attempt, further clinical studies are warranted.