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

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(R) 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

Prophylactic anti-cytomegalovirus hyperimmunoglobulin in critically ill liver transplant patients: impact on early immunology and survival

Background: Anti-cytomegalovirus hyperimmunoglobulin (CMVIg) was shown to provide beneficial immunodulatory properties beyond antiviral efficacies. The aim of this retrospective study was to assess the impact of prophylactic CMVIg treatment on early outcome following liver transplantation (LT) in critically ill patients. Methods: Forty-three cirrhotic patients requiring pre-LT intensive care due to multiorgan failure were analyzed. Twenty-eight patients with enhanced CMV risk (D+/R+; D+/R−; D−/R+) received prophylactic CMVIg for a minimum of 7 days, while 15 patients (D−/R−) did not. Results: Post-transplantation rates of intra-abdominal infections (28% vs. 61.1%; p = 0.03), Epstein–Barr virus infections (0% vs. 33.3%; p = 0.034), allograft rejections (0% vs. 22.2%; p = 0.013) and sepsis-related mortality (4% vs. 27.8%; p = 0.026) were significantly lower, whereas incidence of CMV infections (4% vs. 22.2%; p = 0.066) tended to be lower in the CMVIg subset. In multivariate analysis, only pretransplant elevated serum lactate level (hazard ratio = 34.63; p = 0.009) and absence of CMVIg therapy (hazard ratio = 21.76; p = 0.023) were identified as independent promoters of 3-month mortality. Conclusion: Prophylactic treatment with CMVIg reduces predisposition for severe immunological and septic events and, thereby, early mortality in critically ill liver recipients

Combining F-18-FDG positron emission tomography with Up-to-seven criteria for selecting suitable liver transplant patients with advanced hepatocellular carcinoma

The Up-to-seven (UTS) criteria (sum of tumor size and number not exceeding 7) for indicating liver transplantation (LT) in hepatocellular carcinoma (HCC) were originally based on explant pathology features and absence of microvascular invasion (MVI). F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET) was shown to indicate the risk of MVI and tumor recurrence. The aim of this study was to analyze the prognostic significance of the clinical UTS criteria when being combined with PET-status of the tumor. Data of 116 liver transplant patients were subject to retrospective analysis. Five-year recurrence-free survival (RFS) rates in patients meeting (n = 85) and exceeding (n = 21) the radiographic UTS criteria were 81% and 55.1%, respectively (p = 0.014). In the UTS In subset, RFS was significantly better in PET-negative (94.9%) than in PET-positive patients (48.3%;p < 0.001). In the UTS Out subset, 5-year RFS rates were 87.1% and 19% in patients with non-F-18-FDG-avid and F-18-FDG-avid tumors (p < 0.001), respectively. Positive PET-status was identified as the only independent clinical predictor of tumor recurrence in beyond UTS patients (Hazard ratio [HR] 19.25;p < 0.001). Combining radiographic UTS criteria with FDG-PET may safely expand the HCC selection criteria for LT

Liver transplantation for hepatocellular carcinoma - non-cancer factors and implications for improving outcome beyond standard tumor criteria

Liver transplantation (LT) is recognized as best treatment option in patients with early hepatocellular cancer (HCC) in underlying liver cirrhosis. Apart from tumor size and number implemented in the Milan criteria, which are current worldwide standards for patient selection, several biological tumor factors have been identified to affect cancer-specific outcome. In particular, grading and vascular tumor invasions were shown to correlate with aggressive biological tumor behavior and poor survival following LT. Identifying tumors with favorable biology is one important approach for expanding the pool of eligible liver recipients beyond the Milan burden limits. Improving the immunological state and condition for appropriate defense against circulating cancer cell attack may be another important prognostic aspect. Therefore, there is increasing interest in non-cancer factors related to the peritransplant period that may influence the oncological outcome by providing negative immunomodulatory actions. Considering and modulation of these non-HCC factors of prognosis might contribute in safely expanding the HCC LT selection criteria

Extended postinterventional tumor necrosis-implication for outcome in liver transplant patients with advanced HCC.

BACKGROUND: Locoregional interventional bridging therapy (IBT) is an accepted neoadjuvant approach in liver transplant candidates with hepatocellular carcinoma (HCC). However, the prognostic value of IBT in patients with advanced HCC is still undefined. AIM: The aim of this trial was to evaluate the impact of postinterventional tumor necrosis on recurrence-free long-term survival after liver transplantation (LT) in patients with HCC, especially focusing on those exceeding the Milan criteria on pretransplant radiographic imaging. PATIENTS AND METHODS: A total of 93 consecutive liver transplant candidates with HCC were included in this trial. In 36 patients, tumors were clinically staged beyond Milan criteria prior LT. Fifty-nine patients underwent IBT by transarterial chemoembolization or radiofrequency ablation pretransplantation. Postinterventional tumor necrosis rate as assessed at liver explant pathology was correlated with outcome post-LT. RESULTS: There was no significant difference in 5-year tumor-free survival rate between the IBT- and the non-IBT subpopulation (78% versus 68%, P=0.25). However, tumor response following IBT (≥ 50% tumor necrosis rate at explant pathology) resulted in a significantly better outcome 5 years post-LT (96%) than tumor non-response to IBT (<50% tumor necrosis rate at explant pathology; 21%; P<0.001). Five-year recurrence-free survival rate was 80% in Milan Out patients with extended post-IBT tumor necrosis versus 0% in Milan Out patients without tumor response to IBT (P<0.001). None of macromorphological HCC features, but only the absence of increased (18)F-fluoro-deoxy-glucose ((18)FDG) uptake on pretransplant positron emission tomography (PET) was identified as independent predictor of postinterventional tumor response (P<0.001). CONCLUSION: Our results implicate that extended postinterventional tumor necrosis promotes recurrence-free long-term survival in patients with HCC beyond standard criteria. Pretransplant PET assessment may identify those patients with advanced HCC that will benefit from post-IBT tumor response and may, thereby, achieve excellent posttransplant outcome

Univariate analysis of predictive parameters for posttransplant recurrence-free long-term-survival in the IBT group (n = 59).

*<p>based on clinical staging.</p><p>PET: positron emission tomography.</p><p>G: grading.</p><p>AFP: alpha-fetoprotein.</p><p>UCSF: University of California San Francisco.</p

There was no significant difference in 5-year recurrence-free survival rate between Milan In recipients (87%) and Milan Out patients demonstrating post-IBT tumor response (80%).

<p>In contrast, none of Milan Out recipients without tumor response to IBT have survived 5 years post-LT (<i>P</i><0.001).</p

This figure demonstrates the micrographs (HE, 50×; 70×) of a post-IBT tumor responder with near complete postinterventional tumor necrosis (a), and of a tumor non-responder to IBT with necrotic tumor areas next to pseudoglandular HCC nodules (b), respectively.

<p>This figure demonstrates the micrographs (HE, 50×; 70×) of a post-IBT tumor responder with near complete postinterventional tumor necrosis (a), and of a tumor non-responder to IBT with necrotic tumor areas next to pseudoglandular HCC nodules (b), respectively.</p