Katharina Thrum

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.

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‐α2b and ribavirin 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

Abstract: 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.

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.

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

Abstract 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.

Combining 18 F-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.

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.

Langzeitüberleben nach Lebertransplantation beim hepatozellulären Karzinom — Ist die Erweiterung der Indikationskriterien gerechtfertigt?

Background: Against the background of an increasing donor organ shortage and new therapeutical options, there must be a re-evaluation of critical indications for liver transplantation (LT). The aim of this study was to analyse recurrence rate and long-term survival of patients after LT for hepatocellular carcinoma (HCC), and moreover, to asses the impact of clinical and histopathological parameters. Patients and methods: A total of 45 patients after LT for HCC were included in this study. The Milan criteria were used for classification of »extended« and »non-extended« HCC. All patients received initially a calcineurin-inhibitor-based immunosuppressive regimen post-LT. In the case of recurrent HCC, a curative treatment concept (surgery, sirolimus) was performed, if possible. The influence of several clinical and histopathological variables on recurrence rate was analysed using Cox regression analysis. Long-term survival was calculated according Kaplan-Meier. Results: The current posttransplant follow-up ranges between 2 and 194 months (median: 74 mo). The overall 5-year survival accounts for 79,9 %. Despite a significantly higher HCC recurrence rate in the »extended group« (37,5 % versus 4,7 %, P = 0,01), patients of this cohort demonstrated a 5-year survival (n = 24, 79,1 %), which was comparable to patients of the »non-extended« population (n = 21, 80,9 %). The AFP-level, size, grading and stage of tumor, microvascular tumor invasion and Milan criteria revealed a significant impact on HCC recurrence rate (P < 0,05). The 5-year survival post-recurrence was 56 %. Only the immunaugmentation with rapamycine and surgical therapy had a beneficial influence on survival of these patients (P < 0,05). Conclusion: Expanding selection criteria for indicating LT in patients with HCC will lead to an increased tumor recurrence rate, but without automatically resulting in inferior patients’ outcome. Aggressive surgical intervention in combination with immunmodulation by rapamycine with its anti-tumor capabilities could improve patients’ prognosis. If confirmed in the future, this might justify a careful extension of selection criteria in this special set-up.