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.

The role of preoperative albumin-bilirubin grade for oncological risk stratification in liver transplant patients with hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Albumin-bilirubin (ALBI) score was shown to correlate with liver function and tumor recurrence after hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to assess the prognostic value of ALBI grade in liver transplantation (LT) patients with HCC. METHODS: Pre-LT available independent predictors of recurrence-free survival (RFS) and microvascular tumor invasion (MVI) were determined in 123 patients with HCC. RESULTS: Posttransplant HCC recurrence rates were 10.5%, 15.9%, and 68.2% in ALBI grade 1, 2, and 3, respectively (P < .001). Along with serum α-fetoprotein (AFP) and C-reactive protein (CRP) levels, ALBI grades 1 or 2 was identified as an independent predictor of RFS (hazard ratio, 3.52; 95% confidence interval [CI], 1.577-7.842; P = .002). Furthermore, ALBI grade 3 proved to be the strongest indicator of MVI (odds ratio, 11.59; 95% CI, 3.412-39.381; P < .001). A novel oncological risk score-based on AFP, CRP, and ALBI grade provided the best discriminative capacity (c-statistic 0.806) in selecting liver recipients with low oncological risk profile. CONCLUSION: Preoperative ALBI grade seems to be valuable for refinement of oncological risk stratification at LT for HCC.

Serological Risk Index Based on Alpha-Fetoprotein and C-Reactive Protein to Indicate Futile Liver Transplantation Among Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: The aim of this study was to establish a preoperatively available serological risk index using alpha-fetoprotein (AFP) and C-reactive protein (CRP) for predicting oncologically futile liver transplantation (LT) in hepatocellular carcinoma (HCC) patients. METHODS: A total of 119 liver transplant patients with HCC were retrospectively analyzed. The prognostic impact of clinical and histopathologic factors including pre-LT serum AFP and CRP values was determined. RESULTS: Apart from microvascular tumor invasion (MVI; odds ratio [OR] 15.77), pretransplant serum levels of AFP > 100 ng/ml (OR 13.31) and CRP > 0.8 mg/dl (OR 13.97) were identified as independent predictors of HCC recurrence. The cumulative risk of HCC relapse at 5 years post-LT was 2.3% in low serological tumor activity (STA) index (AFP ≤ 100 ng/ml + CRP ≤ 0.8 mg/dl), 17.1% in intermediate STA (AFP ≤ 100 ng/ml or CRP ≤ 0.8 mg/dl), and 91.6% in high STA index (AFP > 100 ng/ml + CRP > 0.8 mg/dl; p < 0.001), respectively. High STA index was identified as most powerful pre-LT available predictor of MVI (OR 15.31) and posttransplant HCC recurrence (OR 54.44). Five-year recurrence-free survival rate in Milan Out patients with high STA was 0%, compared to 91.7% and 83.6% in those with low or intermediate STA index (p < 0.001), respectively. CONCLUSION: Our proposed serological risk index based on pretransplant serum AFP and CRP values is able to predict oncologically futile LT among advanced HCC patients.

Combining 18F-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). 18F-fludeoxyglucose (18F-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- 18F-FDG-avid and 18F-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.

Prognostic Impact of Intraoperative Blood Loss in Liver Transplant Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: The aim of this retrospective study was to analyze the impact of intraoperative blood loss (IOBL) on outcome in liver transplant (LT) patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 108 LT patients with HCC were retrospectively analyzed. They were all clinically staged according to the Milan criteria and to 18F-fluoro-D-glucose (18F-FDG) uptake on positron-emission tomography (PET). RESULTS: Recurrence-free survival rates at 3 and 5 years post-LT were 91.9% and 91.9% among patients with low (≤1,500 ml) IOBL, and 43.9% and 37.1% in those with high (>1,500 ml) IOBL (log-rank p<0.001). Multivariate analysis demonstrated low IOBL to be an independent predictor of better recurrence-free survival in patients with HCC exceeding the Milan criteria (hazard ratio=3.66; p=0.029) and in those with PET-positive tumors (hazard ratio=4.13; p=0.007). CONCLUSION: Intraoperative bleeding is associated with increased likelihood of tumor recurrence following LT for HCC. Limiting IOBL should be considered for improving post-LT outcome, particularly in patients with HCC beyond standard criteria.

Postoperative peak serum C-reactive protein is a predictor of outcome following liver transplantation for hepatocellular carcinoma.

CONTEXT: C-reactive protein (CRP), a biomarker of inflammation, may correlate with prognosis in several malignancies. OBJECTIVE: To investigate the prognostic impact of early postoperative peak serum levels of CRP on tumor-specific outcome in 106 liver transplant patients with hepatocellular carcinoma (HCC). METHODS AND RESULTS: In multivariate Cox regression analysis, a posttransplant elevated peak CRP level (>versus ≤ 3.5 mg/dl) was identified as an independent predictor of poor recurrence-free survival (p = 0.01; HR = 4.04; CI = 1.399-11.640). CONCLUSION: Early postoperative serum CRP may serve as a useful inflammation-based biomarker of outcome in liver transplant patients with HCC.

Extended Ischemia Times Promote Risk of HCC Recurrence in Liver Transplant Patients.

BACKGROUND: There is increasing evidence that ischemia-reperfusion injury (IRI) promotes vasculogenesis and tumor outgrowth in the liver. Hepatic IRI is exaggerated by prolongation of ischemia times. AIMS: The aim of this retrospective analysis was to assess the impact of ischemia times on risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Subgroup analysis focused on patients with (18)F-fluoro-deoxy-glucose ((18)F-FDG)-avid HCC on pretransplant positron emission tomography (PET). METHODS: A total of 103 liver transplant patients with HCC were included in this study. The impact of cold (CIT), warm (WIT), and total ischemia times (TIT) along with other prognostic variables on posttransplant outcome was analyzed in uni- and multivariate analysis. RESULTS: Twenty-four patients (23.3 %) developed tumor relapse after LT. Mean durations of CIT (468.0 vs. 375.5 min; P = 0.001), WIT (58.4 vs. 45.7 min; P = 0.001), and TIT (525.8 vs. 422.0 min; P < 0.001) were significantly longer in patients with compared to those without HCC recurrence. In multivariate regression analysis, (18)F-FDG-avid HCC (odds ratio [OR] 73.4), WIT >50 min (OR 52.5), alpha-fetoprotein level >400 IU/ml (OR 11.1), and Milan Out status (OR 7.4) were identified as independent predictors of HCC recurrence. In the subgroup of patients with PET-positive HCC, WIT remained the only independent variable to predict HCC recurrence (OR 15.5). CONCLUSION: Prolongation of ischemia times promotes the risk of HCC recurrence after LT, especially in patients with unfavorable tumor biology on PET imaging.

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.

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.

Antiviral maintenance treatment with interferon and ribavirin for recurrent hepatitis C after liver transplantation: pilot study.

BACKGROUND: The aim of this pilot study was to evaluate efficacy of a long-term antiviral maintenance therapy (AMT) with interferon-alpha2b and ribavirin in liver transplant recipients with recurrent hepatitis C. METHODS: Twenty-one patients with recurrent hepatitis C after liver transplantation received AMT with interferon and ribavirin, following 12 months of a basic antiviral combination treatment. Allograft function, viremia loads and allograft morphology were evaluated continuously. RESULTS: After 12 months of basic antiviral therapy, 14 patients (66.6%) had achieved initial clearance of viremia levels, and 17 recipients (81%) demonstrated normalization of allograft function, respectively. Inflammation score declined significantly (6.0 vs 3.9; P = 0.002), while stage of fibrosis remained unchanged. In virological responders maintenance therapy led to further regression of inflammation score (4.0 at baseline vs 3.1 at 24 months AMT) and fibrosis score (1.6 at baseline vs 1.1 at 24 months AMT). Despite persistence of viremia levels, continued antiviral therapy prevented progression to severe allograft inflammation in virological non-responders. Hematologic adverse effects resulted in treatment discontinuation in seven patients (33.3%). CONCLUSION: Long-term AMT, if tolerable, might be an effective approach for preventing progression to severe allograft fibrosis and thereby improving long-term survival in liver transplant recipients with recurrent hepatitis C.

Antiviral treatment withdrawal in viremic HCV-positive liver transplant patients: impact on viral loads, allograft function and morphology.

BACKGROUND: The aim of this study was to evaluate the clinical long-term consequences of antiviral treatment discontinuation in viremic hepatitis C virus (HCV)-positive liver transplant recipients. METHODS: Twenty-five HCV-positive patients after liver transplantation were included in this study. After diagnosing recurrent hepatitis C, a combination therapy with interferon-alpha2b and ribavirin for a minimum of 12 months was initiated. Viremia levels and allograft function were monitored continuously. Allograft biopsies were performed yearly, analyzing grading of inflammation and staging of fibrosis. RESULTS: HCV recurrence rate was 100%. Up to 114 months post-transplantation, sustained virological response rate was 64%. Treatment discontinuation in virological nonresponders led subsequently to a significant increase of viral loads and deterioration of allograft function (P<0.05) within 1 month. In three patients, a fibrosing cholestatic syndrome developed, resulting in one patient death. Antiviral retherapy was maintained for a mean of 33 months, leading to a significant decline of aminotransferases (P<0.05) as well as decreasing serum levels of bilirubin and HCV-RNA within 6 months. In addition, development of severe allograft fibrosis was prevented despite persistent viral loads. CONCLUSION: Our study suggests that antiviral treatment withdrawal carries the risk of severe disease progression in persistently viremic HCV-positive liver transplant patients.

Clonal origin of multifocal renal cell carcinoma as determined by microsatellite analysis.

PURPOSE: The reported incidence of satellite tumor lesions in renal cell carcinoma (7% to 25%) suggests that there is a risk of local recurrence after nephron sparing surgery. It remains largely unknown whether small satellite tumors show malignant features and whether they are metastases from the primary tumor. Therefore, we determined the clonality of multifocal tumors by molecular genetic analysis. MATERIALS AND METHODS: A total of 19 multifocal clear cell renal cell carcinomas were investigated by microsatellite analysis using 6 markers for chromosome 3p, namely D3S1560, D3S1289, D3S1766, D3S1300, D3S1566 and D3S1663. Polymerase chain reaction was performed according to standard protocols, followed by gel electrophoresis and automated analysis using an automated DNA sequencer (Li-Cor, Lincoln, Nebraska). RESULTS: All primary clear cell tumors were characterized by loss of heterozygosity on 3p. Multifocal tumors showed identical microsatellite alterations with at least 1 marker in 17 of the 19 cases. In 2 cases different microsatellite patterns were detected in tumors from the same kidney. CONCLUSIONS: Identical loss of heterozygosity and shift patterns detected in different tumors in the same kidney strongly suggest that multifocal clear cell renal cell carcinomas have a common clonal origin in most cases. These findings indicate that satellite tumors are the result of intrarenal metastasis from the primary tumor. The clinical implications of these results must be correlated with the clinical disease course in patients with multifocal renal cell carcinoma.