Arno Kornberg

Long‐term Combination of Interferon Alfa‐2b and Ribavirin for Hepatitis C Recurrence in Liver Transplant Patients

The purpose of this study was to evaluate the feasibility, tolerability and efficacy of long‐term combination therapy with interferon‐alfa 2b (IFNα‐2b) and ribavirin (Rb) for recurrent hepatitis C after liver transplantation. Fifteen patients with histologically confirmed hepatitis C after liver transplantation were treated. After a basic course of 12 months (IFNα‐2b 3 MU/3 times a week; Rb 3 × 200 mg/day), patients achieving clearance of viremia underwent maintenance therapy with ribavirin (3 × 200 mg/day). Patients without virological response continuously received combination therapy. Levels of HCV RNA, aminotransferases and bilirubin were followed. Therapy led to a significant decline of transaminases and bilirubin in all patients (p < 0.05). Sixty‐four per cent of patients had clearance of viremia after 12 months. Sustained virological response was 88%. In patients without virological response, continuation of combination therapy prevented another biochemical relapse of hepatitis. Treatment was accompanied by severe hematological side‐effects, requiring medical support in a majority of patients. In two patients (13.5%), therapy finally had to be withdrawn because of major hematological disorders. These results indicate that long‐term combination therapy with IFNα‐2b and Rb is effective in the treatment of recurrent hepatitis C and in preventing further relapse of disease after liver transplantation, but side‐effects may require cessation of therapy.

Hepatic Venous Outflow Reconstruction in Right Lobe Living‐Donor Liver Graft Using Recipient's Superficial Femoral Vein

Venous congestion of a liver graft from a life donor is a disastrous complication with a high risk of graft failure. For safety reasons, the middle hepatic vein (MHV) is currently unanimously left with the donor. As this vessel provides major venous draining of the right anterior sector, reconstruction of significant MHV tributaries is controversial. We describe here successful venous outflow reconstruction in adult‐to‐adult right lobe living‐donor liver transplantation (RL‐LDLT) using the recipients superficial femoral vein (SFV). Six months after transplantation, graft function and perfusion are excellent, and the patient is free of venous morbidity related to the harvest of the SFV.

Sustained clearance of serum hepatitis C virus-RNA independently predicts long-term survival in liver transplant patients with recurrent hepatitis C.

The aim of this study was to analyze the impact of virological response to long-term antiviral therapy using interferon plus ribavirin on survival of 30 liver transplant patients with recurrent hepatitis C. Mean treatment duration is currently 46 months (range: 3–144 months). Sustained clearance of serum hepatitis C virus RNA was achieved in 18 patients (60%). Allograft biopsies demonstrated fibrosis progression in seven virological nonresponders (66.6%), and none of the recipients with viral elimination (0%; P<0.001). Univariately, low pretransplant viral loads, the absence of cytomegalovirus infection, as well as biochemical and virological response to antiviral therapy indicated a positive impact on outcome (P<0.05). Only antiviral treatment induced clearance of viremia, however, was identified as independent predictor of long-term survival (P=0.02). Our data indicate that an antiviral combination should aim at viral eradication in liver transplant patients with recurrent hepatitis C, because it improves survival.

Differentiated therapy with prostaglandin E1 (alprostadil) after orthotopic liver transplantation: the usefulness of procalcitonin (PCT) and hepatic artery resistive index (RI) for the evaluation of early graft function and clinical course.

Abstract Increasing demand for donor organs has led to new pharmacological concepts for reducing ischemiareperfusion injury (I/R) of the graft after liver transplantation to prevent primary non-functioning of the organ. Prostaglandins have proved to be cytoprotective in several experimental models of ischemia and transplantation. The prophylactic administration after orthotopic liver transplantation is still a subject of controversial discussion. The aim of our study was the evaluation of the post-transplant hepatic artery resistive index (RI) measured by color Doppler imaging, in combination with postoperative elevation of transaminases, as parameters indicating the need for a differentiated systemic therapy with prostaglandin E1 (PGE1) (alprostadil). In addition, the value of serum procalcitonin (PCT) as a postoperative parameter for the extent of I/R is investigated. In the case of post-transplant elevated hepatic artery RI (RI > 0.75), the administration of PGE1 led to a significant reduction of transaminases (p < 0.05) and a decline of the RI. In addition, postoperative PCT levels could be reduced significantly by PGE1 application. These results suggest that determination of RI is feasible for indicating a need for therapy with PGE1. Its targeted application reduces hepatocellular damage due to I/R after liver transplantation.

Combined en-bloc liver-pancreas transplantation in patients with liver cirrhosis and insulin-dependent type 2 diabetes mellitus.

We report about our experience with combined en-bloc liver-pancreas transplantation in 14 patients with liver cirrhosis and insulin dependent type 2 diabetes mellitus. Exocrine drainage was achieved by duodeno-duodenostomy. Median posttransplant follow-up is currently 92.5 months. All patients were rendered independent from insulin therapy shortly after transplantation. Levels of glycosylated hemoglobin normalized in all recipients. Mean fasting C-peptide values increased from pretransplant 7.0±1.7 ng/mL to 10.5±2.9 ng/mL 3 months posttransplantation (P<0.001). One recipient (7.1%) developed recurrent exogenous insulin dependence 7 years after transplantation. Pancreas allograft rejection was confirmed by endoscopic biopsy of donor duodenum mucosa in two patients (14.3%). Calculated 5- and 7-year survival is currently at 64.3% and 64.3%, respectively. Our results indicate that combined en-bloc liver-pancreas transplantation using duodeno-duodenostomy is technically feasible and leads to excellent long-term control of glucose metabolism in patients with liver cirrhosis and insulin-dependent type 2 diabetes.

Impact of Ig-Therasorb® immunoapheresis on stability of xenogeneic ex vivo porcine liver perfusion : Value of aminotransferases and flow rates for the assessment of metabolic graft viability

Abstract Due to growing shortage of donor organs, the concept of extracorporeal pig liver perfusion in the treatment of acute liver failure has been rediscovered. Immunomodulation, such as immunoapheresis or inhibition of complement, results in long-term perfusion without exact knowledge of the remaining metabolic graft viability. This study was aimed at the comparison of conventional parameters of graft stability such as perfusion rates and release of aminotransferases with parameters of metabolic graft function. Ig-Therasorb® immunoapheresis (IA) of the xenogeneic perfusate was performed to protect the discordant pig livers from hyperacute rejection, mediated by preformed naturally occurring human xenogeneic antibodies. The application of IA created stable autologous graft reperfusion after a short time of xenoperfusion, but it was not able to prevent the livers from severe synthetic and functional damage. In the future, improvement of xenogeneic graft function, rather than pure prolongation of perfusion, must be the principal aim.

Serological Tumor Viability Risk Index Comprising Alpha-Fetoprotein and C-reactive Protein Identifies Eligible Liver Transplant Patients with Hepatocellular Carcinoma beyond Milan and Up-to-Seven Criteria

Background The Milan criteria (MC) are current standard for indicating liver transplantation (LT) for hepatocellular carcinoma (HCC). However, many beyond MC patients may be rejected despite beneficial outcome. Routine serological parameters of tumor viability, such as alpha-fetoprotein (AFP) and C-reactive protein (CRP), were shown to describe tumor aggressiveness. However, they have not yet been implemented in patients’ selection process. The aim of this study was to assess the prognostic accuracy of combining AFP and CRP to predict posttransplant outcome beyond standard criteria. Patients and Methods 119 liver transplant patients with HCC were retrospectively analyzed. Tumors were clinically staged according the MC and the Up-to-seven (UTS) criteria. The most optimal cut-off values of AFP (100 ng/ml; Area under the curve [AUC] = 0.826; r = 0.042; 95% Confidence Interval [CI] 0.743 – 0.909) and CRP (0.8 mg/dl; AUC = 0.824; r = 0.039; 95%CI 0.747 – 0.901) for predicting tumor recurrence were determined by ROC analysis. The impact of pretransplant available radiographic and serological features on posttransplant outcome was analyzed by uni- and multivariate analysis. Results Median post-LT follow-up was 74 months (range: 5-184). Tumor recurrence rate was 24.4%. In multivariate analysis, only CRP < 0.8 mg/dl (Odds ratio [OR] = 36.2; p < 0.001) and AFP < 100 ng/ml (OR = 17.571; p < 0.001) were identified as independent prognosticators of HCC recurrence, whereas macromorphology features were not independently significant. Five year RFS rates were 97.7% in low CRP/AFP (n = 44) and 85.8% in low CRP or AFP (n = 50) patients, defining a low serological tumor viability risk index (STVI). In contrast, RFS was only 10% in high CRP/AFP patients (n = 25; high STVI; log rank < 0.001). RFS was not different between Milan In patients (n = 69; 86.8%) and Milan Out patients with low STVI (n = 32; 87.1%), and between UTS In patients (n = 88; 81.6%) and UTS Out patients with low STVI (n = 20; 89.2%). In contrast, it was 0% in both beyond Milan and beyond UTS patients yielding high STVI (log rank < 0.001), respectively. Application of STVI increased transplant eligibility between 23% and 46%. Conclusion We were able to demonstrate that a STVI implementing routinely determined AFP and CRP values selects suitable liver transplant patients beyond standard criteria. Patients with beyond Milan or UTS HCC and pre-LT elevated AFP and CRP levels should be rejected since they yield an extremely high recurrence risk.

CMV-Hyperimmunoglobulin Improves Early Outcome in Critically Ill Liver Transplant Patients by a Combination of Antiviral, Anti-Inflammatory and Positive Immunomodulatory Capabilities

Background Liver transplantation (LT) in critically ill high patients is characterized by septical complications and high mortality rates. In vitro set-ups recently suggested beneficial anti-inflammatory and immunomodulatory capabilities related to cytomegalovirus (CMV) hyperimmunoglobulin (Ig) treatment. Nonetheless, this has not yet been transferred to clinical approaches. We, therefore, performed a clinical trial assessing the impact of early posttransplant therapy with CMVIg on immunology and early outcome in a series of high model of end-stage (MELD) score LT patients. Material/Methods Forty liver transplant patients with a median MELD score of 27 (range: 7-40) at listing and 38 (30 – 40) at LT were included in the analysis. Based on donor/recipient CMV matching, 5000IE CMVIg (Cytotect, Biotest, Germany) was administered (D+ and/or R+) daily for a minimum of one week post-LT. All patients received a tacrolimus (Tac) based immunosuppression. The impact of CMVIg treatment on CMV infection, allograft rejection and serologic parameters of immunologic activation (C-reactive protein [CRP]; procalcitonin [PCT]; interleukin 6 [IL-6]) was assessed. Prognosticators of 3-months survival were assessed by uni- and multivariate analysis. Results At LT, 18 patients were under renal replacement therapy (45%), 24 patients had to be ventilated (47.2%), and 24 patients received catecholamines (60%). Fatal risk triad (ventilation + dialysis + catecholamines) was present in 14 patients (35%). 24 patients received CMVIg (60%) post-LT, whereas 16 patients did not. Post-LT rates of CMV viremia and biopsy proven allograft rejection were 0% in the CMVIg- but 37% in the non-CMVIg group (p=0.001), although peak Tac levels were comparable (11.1 vs. 12.3 &mgr;g/L). Posttransplant mean peak values of CRP (4.9 vs. 16.3 mg/dl; p < 0.001), PCT (10.5 vs. 71.2 ng/ml; p < 0.001) and Il-6 (91.7 vs. 333.1 pg/ml; p < 0.001) were significantly lower in the CMVIg subset. Neutropenia post-LT was evident in 5 CMVIg patients (20.8%) and in 11 patients without CMVIg (69%; p = 0.002). 3-months survival rates were 95.5% and 62.5% in the CMVIg- and non-CMVIg subsets, respectively (log rank < 0.001). Septical complications were the major reason for mortality. In multivariate analysis, only CMVIg treatment (HR=6.0; 95%CI 2.09 – 17.35; p = 0.001) and absence of MMF (HR=0.268; 95%CI 0.096 – 0.753; p = 0.012) were assessed as independent and significant predictors of beneficial survival. Conclusion Early posttransplant treatment of CMVIg reduces pro-inflammatory and immunologic activation in critically ill liver transplant patients. Thereby, risk of CMV infection, allograft rejection and septical complications seem to be reduced. Our data clearly suggest that CMVIg provides balancing immunoregulatory efficacies, which may be particularly beneficial in high MELD liver recipients.

Postinterventional Tumor Necrosis Predicts Recurrence-Free Long-Term Survival in Liver Transplant Patients with Advanced Hepatocellular Carcinoma on Clinical Staging: 1134

Background: There is some evidence that a subset of patients with advanced HCC on clinical staging may, nonetheless, benefit from liver transplantation. The role of pretransplant interventional bridging treatment (IBT) for identifying adequate liver transplant candidates with HCC beyond the Milan criteria is still undefined. The aim of this trial was, therefore, to evaluate the value of IBT induced tumor necrosis on recurrence-free long-term survival in liver transplant patients with advanced HCC. Furthermore, we aimed at identifying pretransplant available clinical parameters that may predict histopathological response to IBT, and thereby, be useful for selecting adequate liver transplant candidates. Patients and methods: A total of 93 patients with HCC were included in this trial. 18F-FDG positron emission tomography (PET) has been performed in all of them pre-LT, classifying patients in PET(no increased FDG tumor uptake on PET) and PET + (increased FDG tumor uptake on PET). If being eligible, patients underwent pretransplant IBT by transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Clinical response to IBT was assessed by repeat CT scans (RECIST criteria). Macromorphologic tumor staging was based on CT/ MRI. Explant livers were histopathologically examined to determine variables of macromorphology, vascular and lymphatic invasion invasion, grading and grade of post-IBT tumor necrosis. Patients with a 50%-100% tumor necrosis were defined to be histological responders, while tumor necrosis rate < 50% indicated histological non-response to IBT. The impact of clinical and histopathologic parameters on clinical outcome was evaluated in uniand multivariate analysis. Results: Current overall follow-up is ranging between 5 and 162 months posttransplantation (mean: 64.3 ± 44.2 months). Finally, 59 liver transplant patients (63.4%) have received IBT, predominantly TACE. Overall, 21 patients developed tumor recurrence post-LT (22.6%), 11 patients in the IBT-group (18.6%) and 10 patients in the non-IBTpopulation (29.4%). Histologic responders had a significantly better recurrence-free survival rate after 5 years than histologic non-responders (96% versus 21%; P < 0,001). Histologic response to IBT resulted in a 5-year recurrence-free survival of 80% in Milan Out patients, which was comparable to Milan In recipients (87%), but significantly better than in histologically non-responding Milan Out recipients (0%; P < 0,001). In multivariate analysis, histologic response to IBT was identified as the only independent predictor of recurrence-free long-term survival (hazard ratio 53.3; P < 0.001). In multivariate logistic regression, pretransplant PETstatus was assessed as the only independent clinical parameter predicting histologic response to IBT (odds ratio 12.4; P < 0.001). Conclusion: Data of our trial indicate that liver transplant patients with HCC should undergo pretransplant IBT, if being eligible, aiming at extended tumor necrosis. Patients with advanced HCC on clinical staging may, thereby, achieve excellent recurrence-free lomg-term survival. Pretransplant PET evaluation is useful for identifying those patients that may undergo successful IBT. This could be useful for a reasonable extension of liver transplant criteria. 863