y These authors have contributed equally to this work.With excellent short-term survival in liver transplantation (LT), we now focus on long-term outcome and report the first European single-center 20-year survival data. Three hundred thirty-seven LT were performed in 313 patients (09/88-12/92). Impact on long-term outcome was studied and a comparison to life expectancy of matched normal population was performed. A detailed analysis of 20-years follow-up concerning overweight (HBMI), hypertension (HTN), diabetes (HGL), hyperlipidemia (HLIP) and moderately or severely impaired renal function (MIRF, SIRF) is presented. Patient and graft survival at 1, 10, 20 years were 88.4%, 72.7%, 52.5% and 83.7%, 64.7% and 46.6%, respectively. Excluding 1-year mortality, survival in the elderly LT recipients was similar to normal population. Primary indication (p < 0.001), age (p < 0.001), gender (p ¼ 0.017), impaired renal function at 6 months (p < 0.001) and retransplantation (p ¼ 0.034) had significant impact on patient survival. Recurrent disease (21.3%), infection (20.6%) and de novo malignancy (19.9%) were the most common causes of death. Prevalence of .2%, p < 0.001), p ¼ 0.01) and HBMI (33.2-45%, p ¼ 0.014) increased throughout follow-up, while prevalence of HLIP (78.0-47.6%, p < 0.001) declined. LT has conquered many barriers to achieve these outstanding long-term results. However, much work is needed to combat recurrent disease and side effects of immunosuppression (IS).

Cholangiocarcinoma (CCA) represents a rare form of primary liver cancer with increasing incidence but dismal prognosis. Surgical treatment has remained the only potentially curative treatment option, but it remains unclear which patients benefit most from liver surgery, highlighting the need for new preoperative stratification strategies. In clinical routine, CA19-9 represents the most widely used tumor marker in CCA patients. However, data on the prognostic value of CA19-9 in CCA patients are limited and often inconclusive, mostly due to small cohort sizes. Here, we investigated the prognostic value of CA19-9 in comparison with other standard laboratory markers in a large cohort of CCA patients that underwent tumor resection. Of note, while CA19-9 and CEA were able to discriminate between CCA and healthy controls, CEA showed a higher accuracy for the differentiation between CCA and patients with primary sclerosing cholangitis (PSC) compared to CA19-9. Furthermore, patients with elevated levels of C-reactive protein (CRP), CA19-9 or CEA showed a significantly impaired survival in Kaplan-Meier curve analysis, but surprisingly, only CEA but not CA19-9 represented an independent predictor of survival in multivariate Cox-regression analysis. Our data suggest that CEA might help to identify CCA patients with an unfavourable prognosis after tumor resection.

Background: Cyclosporine and/or sirolimus impair recovery of renal transplants. This study examines the changes in urine metabolite profiles as surrogate markers of renal cell metabolism and function after cyclosporine and/or sirolimus treatment employing a rat kidney transplantation model. Methods: Using inbred Lewis rats, kidneys were transplanted into bilaterally nephrectomized recipients followed by treatment with either CsA (cyclosporine) 10, Rapa (sirolimus) 1, CsA10/Rapa1 or CsA25/Rapa1 mg/kg/day for 7 days. On day 7, urine was analyzed by ¹H-NMR spectroscopy. Blood and kidney tissue drug concentrations, tissue high-energy compounds (including ATP, ADP) and oxidative stress markers (15-F_2t-isoprostanes) in urine were measured by HPLC mass spectrometry. Results: Changes in urine metabolites followed the order Rapa1 < CsA10 < CsA10/Rapa1 < CsA25/Rapa1. Compared with controls, CsA25/Rapa1 showed the greatest changes (creatinine –36%, succinate –57%, citrate –89%, α-ketoglutarate –75%, creatine +498%, trimethylamine +210% and taurine +370%). 15-F_2t-isoprostane concentrations in urine increased in the combined immunosuppressant-treated animals ([CsA25/Rapa1]: 795 ± 222, [CsA10/Rapa1]: 475 ± 233 pg/mg/creatinine) as compared with controls (165 ± 78 pg/mg creatinine). Rapa concentration in blood and tissues increased in the combined treatment (blood: 31 ± 8 ng/ml, tissue: 1.3 ± 0.4 ng/mg) as compared with monotherapy (blood: 14 ± 8 ng/ml, tissue: 0.35 ± 0.15 ng/mg). Drug blood concentrations correlated with isoprostane urine concentrations, which correlated negatively with citrate, α-ketoglutarate and creatinine concentrations in urine. Only CsA25/Rapa1 significantly reduced high-energy metabolite concentrations in transplant kidney tissue (ATP –55%, ADP –24%). Conclusion: Immunosuppressant drugs induce changes in urine metabolite patterns, suggesting that immunosuppressant-induced oxidative stress is an early event in the development of nephrotoxicity. Urine 15-F_2t-isoprostane concentrations and metabolite profiles may be sensitive markers of immunosuppressant-induced nephrotoxicity.

De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow-up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow-up. The median follow-up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3-81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A-treated compared with tacrolimus-treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow-up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404-1414 2017 AASLD.

The organ shortage has led to increased use of marginal organs. The Eurotransplant Donor-Risk-Index (ET-DRI) was established to estimate outcome after Liver Transplantation (LT). Currently, data on impact of ET-DRI on long-term outcome for different indications and recipient conditions are missing. Retrospective, single-center analysis of long-term graft survival (GS) of 1767 adult primary LTs according to indication, labMELDcategory (1: ≤18; 2: >18-25; 3: >25-35; 4: >35), and ET-DRI. Mean ET-DRI in our cohort was 1.63 (±0.43). One-, 10, and 15-yr GS was 83.5%, 63.3%, and 54.8%. Long-term GS was significantly influenced by ET-DRI. Accordingly, four ET-DRI categories were defined and analyzed with respect to underlying disease. Significant impact of these categories was observed for: Alcohol, cholestatic/autoimmune diseases (CD/AIH), and HCV, but not for HCC, HBV, cryptogenic cirrhosis, and acute liver failure. labMELD categories showed no significant influence on graft, but on patient survival. Matching ET-DRI categories with labMELD revealed significant differences in long-term GS for labMELDcategories 1, 2, and 3, but not 4. In multivariate analysis, HCV combined with ET-DRI > 2 and labMELDcategory 3 combined with ET-DRI > 2 emerged as negative predictors. To achieve excellent long-term graft survival, higher risk organs (ET-DRI > 1.4) should be used restrictively for patients with CD/AIH or HCV. Organs with ET-DRI > 2 should be avoided in patients with a labMELD of >25-35.