Mini-laparoscopy is superior in detecting liver cirrhosis and metastases in liver cancer: an over 10-year experience in 1,788 cases.

BACKGROUND/AIMS: Mini-laparoscopy has, since its first description in 1998, proven to be a valuable diagnostic method in liver diseases. We re-evaluated the significance of mini-laparoscopy for diagnosis and staging of liver disease and primary liver and bile duct cancer. PATIENTS AND METHODS: 1,788 consecutive patients who received a diagnostic mini-laparoscopy between 10/1998 and 06/2011 were included in this retrospective cohort study. RESULTS: In chronic liver disease, cirrhosis was detected by mini-laparoscopy in 27% of cases. A comparison of microscopic versus macroscopic diagnosis of cirrhosis revealed a sampling error for histology alone of 21%. Macroscopic inspection of the liver surface contributed to the diagnosis of unknown liver diseases in approximately 38%. In patients with bile duct or liver cancer, mini-laparoscopy led to upstaging of the disease in 33 and 23%, respectively. Major complications (bowel perforation and delayed bleeding) occurred in 0.39% of cases. CONCLUSIONS: Mini-laparoscopy is a valuable procedure with significant diagnostic impact in known and unknown inflammatory and malignant liver diseases. It can be safely performed even in patients with acute liver failure and severe coagulopathy and the diagnostic value does not differ from diagnostic laparoscopy performed with standard instruments.

A combination of α-fetoprotein and des-γ-carboxy prothrombin is superior in detection of hepatocellular carcinoma.

BACKGROUND AND AIM: The incidence of hepatocellular carcinoma (HCC) is increasing in western countries. Despite its low sensitivity, the diagnosis of HCC still depends on detection of α-fetoprotein (AFP). Therefore, the aim of this study was to evaluate the combined analysis of AFP and des-γ-carboxy prothrombin (DCP) in a European cohort. METHODS: We performed a single-center study (164 HCC/422 controls), in which the serum concentrations of AFP and DCP were determined. RESULTS: AFP and DCP were elevated in HCC patients compared to controls (p < 0.0001). By combination of AFP and DCP, the sensitivity was improved from 28.7% for AFP (cutoff 400 ng/ml; AFP at cutoff 10 ng/ml: 54.9%) to 78.0% using cutoffs of 10 ng/ml for AFP and 5 ng/ml for DCP (DCP alone, cutoff 5 ng/ml: 63.4%). Among early-stage patients, the sensitivity increased from 20% for AFP (cutoff 400 ng/ml; AFP at cutoff 10 ng/ml: 38%) to 55% in combination (DCP alone, cutoff 5 ng/ml: 47%). The area under the curve (AUC) for AFP and DCP was similar (AFP: 0.88; DCP: 0.87; combined: 0.91). Among non-cirrhotic patients, DCP (AUC: 0.93) showed a better performance than AFP (AUC: 0.84). Especially patients with non-alcoholic steatohepatitis had a high percentage of DCP-positive tumors. CONCLUSION: The data suggest that AFP alone is not sufficient for the serological diagnosis of HCC in European patients, while a combination of AFP and DCP can increase the sensitivity even in early-stage patients.

Optimized endoscopic treatment of ischemic-type biliary lesions after liver transplantation.

BACKGROUND: Biliary strictures are the most common complication after liver transplantation. A particular problem is ischemic-type biliary lesions (ITBLs), which are often responsible for graft failure and early retransplantation. Although some encouraging results of successful endoscopic treatment have been reported, this has not yet resulted in a standardized therapeutic approach to date. OBJECTIVE: To evaluate an optimized algorithm for the endoscopic treatment of ITBLs. SETTING AND PATIENTS: All adult patients who underwent liver transplantation at the University of Essen between April 1998 and July 2006. DESIGN: Retrospective outcome analysis. MAIN OUTCOME MEASUREMENTS: Success or failure of 2 different therapeutic algorithms in terms of normalization of cholestasis parameters and graft survival. RESULTS: Forty-eight patients who had undergone liver transplantation and had an endoscopically determined diagnosis of ITBL were identified. The median interval between liver transplantation and first endoscopic intervention was 242.5 (range, 16-3677) days. Patients received a median of 6 treatment sessions (range 2-13) every 8 to 10 weeks. In 16 of 48 patients, a combination of balloon dilation (BD) and implantation of a plastic endoprosthesis (BD+EP) was performed; in the remaining 32 patients, BD alone was performed. Overall, endoscopic therapy was successful in 73%. BD+EP was successful in 5 of 16 (31%) and BD alone in 30 of 32 patients (91%; P = .0027). In the BD+EP group, severe cholangitis developed in 25% of patients, but only 12% of the BD group (P = .01). The median duration of therapy was 374 (range 11-808) days. Six of 48 patients underwent retransplantation because of chronic graft rejection at a median of 1288 (range 883-4204) days after the primary liver transplantation. Six of 48 patients underwent hepaticojejunostomy because of unsuccessful endoscopic therapy, and 1 patient underwent surgery because of portal vein thrombosis. LIMITATIONS: Retrospective design. CONCLUSIONS: An endoscopic treatment regimen for ITBLs, preferably BD alone, could prolong the time to or could completely avoid surgical revision and early retransplantation and seems to be superior to endoscopic stenting.

Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses.

BACKGROUND & AIMS: Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment. METHODS: Patients (n=602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha-fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle. RESULTS: Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively. CONCLUSIONS: These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy.

Selective and sequential transarterial chemoembolization: survival in patients with hepatocellular carcinoma.

PURPOSE: To assess the survival time of patients with HCC following transarterial chemoembolization performed in a highly selective and sequential way. PATIENTS AND METHODS: 124 HCC patients (102 male, 22 female; mean age 63±11 years) treated with selective and sequential chemoembolization at a single center were included. Selective chemoembolization was performed through a coaxially introduced microcatheter in a segmental or subsegmental hepatic artery. Treatment was stopped after complete stasis of the blood flow in the tumor-feeding vessel. The primary endpoint of the study was overall survival. RESULTS: The median overall survival of the entire patient population was 27.2 months (mo) (±8.9 mo, 95% CI 9.8 mo, 44.6 mo). When stratified according to liver function the median survival was 46.1 mo (±9.0 mo; 95% CI 28.5 mo, 63.7 mo) for Child-Pugh A and 11.1 mo (±4.3 mo; 95% CI 2.7 mo, 19.5 mo) for Child-Pugh B (p<.001). The median survival was 46.1 mo (±16.6 mo; 95% CI 13.5 mo, 78.7 mo) for BCLC stage A, 19.7 mo (±2.6 mo; 95% CI 14.6 mo, 24.8 mo) for BCLC stage B, and 14.4 mo (±5.0 mo; 95% CI 4.5 mo, 24.3 mo) for BCLC stage C (p<.01). CONCLUSION: Selective and sequential chemoembolization offers long survival times in patients with HCC. Those patients with preserved liver function benefit more than patients with limited liver reserve.

A novel type of macrothrombocytopenia associated with a defect in α2,3-sialylation.

We describe a novel type of human thrombocytopenia characterized by the appearance of giant platelets and variable neutropenia. Searching for the molecular defect, we found that neutrophils had strongly reduced sialyl-Lewis X and increased Lewis X surface expression, pointing to a deficiency in sialylation. We show that the glycosylation defect is restricted to α2,3-sialylation and can be detected in platelets, neutrophils, and monocytes. Platelets exhibited a distorted structure of the open canalicular system, indicating defective platelet generation. Importantly, patient platelets, but not normal platelets, bound to the asialoglycoprotein receptor (ASGP-R), a liver cell-surface protein that removes desialylated thrombocytes from the circulation in mice. Taken together, this is the first type of human thrombocytopenia in which a specific defect of α2,3-sialylation and an induction of platelet binding to the liver ASGP-R could be detected.

Low-molecular-weight heparin in patients with advanced cirrhosis.

BACKGROUND & AIMS: The use of low-molecular-weight heparins (LMWH) in patients with advanced liver diseases is frequently avoided because of the enhanced risk of bleeding complications. However, many patients with impaired liver function are at a high risk of thrombosis or have an indication for therapeutic anticoagulation. Therefore, the aim of this study was to evaluate the pharmacokinetics of LMWH in patients with cirrhosis. METHODS: Eighty-four consecutive patients with cirrhosis and a clinical indication for prophylactic or therapeutic anticoagulation were included. The LMWH doses were chosen according to current guidelines. Antifactor Xa activity (anti-Xa) was assessed on two consecutive days, 4 h after drug administration. The severity of liver disease was quantified using Child-Turcotte-Pugh score, the MELD score and clinical features and was correlated with the anti-Xa value and the occurrence of complications. RESULTS: Antifactor Xa activity was negatively correlated with the severity of the liver disease, and a positive correlation was observed between antithrombin-III (AT) levels and anti-Xa value. AT itself was negatively correlated with the severity of liver disease. Seven patients had an episode of variceal bleeding. No patient died during the observation interval and no thromboembolic events occurred. CONCLUSION: Prophylactic use of LMWH in patients with cirrhosis appears to be safe. A decreased anti-Xa value in cirrhotic patients and a negative correlation with liver function challenge the unconditional use of anti-Xa assays in LMWH monitoring in cirrhotic patients and reveals a potential limitation of anti-Xa analysis in these patients. Low levels of AT, because of reduced hepatic synthesis, are the most likely cause of this phenomenon.

Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.

UNLABELLED: Radioembolization has been demonstrated to allow locoregional therapy of patients with hepatocellular carcinoma not eligible for transarterial chemoembolization or other local therapies. The aim of this study was to validate evidence of the safety and efficacy of this treatment in a European sample of patients with advanced hepatocellular carcinoma (HCC). Therefore, 108 consecutive patients with advanced HCC and liver cirrhosis were included. Yttrium-90 (Y-90) microspheres were administered in a lobar fashion over the right or left branch of the hepatic artery. The response to treatment was evaluated by computed tomography (CT) imaging applying Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria with recent European Association for the Study of the Liver / National Cancer Institute (EASL/NCI) amendments. Time to progression (TTP) and overall survival were estimated by the Kaplan-Meier method. In all, 159 treatment sessions were performed ranging between one to three treatments per patient. The mean radiation dose per treatment was 120 (± 18) Gy. According to EASL criteria, complete responses were determined in 3% of patients, partial responses in 37%, stable disease 53%, and primary progression in 6% of patients. TTP was 10.0 months, whereas the median overall survival was 16.4 months. No lung or visceral toxicity was observed. The most frequently observed adverse events was a transient fatigue-syndrome. CONCLUSION: Radioembolization with Y-90 glass microspheres for patients with advanced HCC is a safe and effective treatment which can be utilized even in patients with compromised liver function. Because TTP and survival appear to be comparable to systemic therapy in selected patients with advanced HCC, randomized controlled trials in combination with systemic therapy are warranted.

Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare primary liver malignancy. Until now, outcomes and prognostic factors after liver resection for these tumors have not been well-documented. STUDY DESIGN: Between April 1998 and December 2006, a total of 158 patients underwent surgical exploration in our institution for intended liver resection of ICC. Prospectively collected data of patients undergoing liver resection (n = 83) were analyzed with regard to preoperative findings, operative details, perioperative morbidity and mortality, pathologic findings, outcomes measured by tumor recurrence and survival, and prognostic factors for outcomes. RESULTS: Tumors were solitary in 47 patients. R0 resections were achieved in 53 patients. Vascular infiltration and lymph node metastasis were detected in 41% and 34%, respectively. After resection, the calculated 1-, 3-, and 5-year-survival rates were 71%, 38%, and 21%, respectively, with corresponding rates of 83%, 50%, and 30% in R0 resections. For 14 variables evaluated, only gender (p = 0.008), Union Internationale Contre le Cancer stage (p = 0.014), and R classification (p = 0.001) showed predictive value in the multivariate Cox proportional hazard regression. CONCLUSIONS: Results presented outline that an R0 resection leads to substantially prolonged survival in ICC and represents the considerable input of the surgeon to the outcomes of these patients. Union Internationale Contre le Cancer stage remains an important factor.

Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma.

BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) inhibitors play a key role in regulating signal transduction by blocking the mTOR pathway and combining anticancer and immunosuppressive properties. This study was undertaken to determine the prevalence and clinicopathological relevance of phospho-p70S6 (p-p70S6) kinase in hepatocellular carcinoma (HCC) and to investigate the effects of rapamycin on HCC in vitro. METHODS: A total of 196 patients with HCCs were treated either with surgical resection (n=106) or liver transplantation (n=90). Tumour tissue was investigated for p-p70S6, phospho-AKT, Ki-67, Cyclin-D1 and apoptosis, and staining results were correlated with clinicopathologically relevant parameters. RESULTS: Overall, p-p70S6 was detected in 24.5% (48/196) of HCCs. In the resection group, 26.4% (28/106) of HCC were positive and 22.2% (20/90) in the transplant group. p-p70S6 was significantly associated with elevated Cyclin-D1 immunoexpression and was correlated with decreased overall survival (P=0.011) in patients resected with a clear margin. In multivariate COX regression analysis, p-p70S6 was identified as an independent prognostic parameter in patients resected with a clear margin. Rapamycin induced apoptosis and growth inhibition by G0/G1 cell cycle arrest in vitro. However, in HCC patients p-p70S6 kinase was not associated with proliferation or apoptosis. CONCLUSIONS: Activation of p70S6 kinase indicates aggressive tumour behaviour in patients with clear margin-resected HCC. Identification of p-p70S6 kinase in HCC selects high-risk patients who may benefit from drugs targeting the mTOR pathway.

Liver transplantation, liver resection, and transarterial chemoembolization for hepatocellular carcinoma in cirrhosis: which is the best oncological approach?

The aim of the study was to evaluate our institutional experience with monotherapies for hepatocellular carcinoma (HCC) in the setting of cirrhosis. A retrospective cohort study was carried out at the tertiary care academic referral center and involved 185 consecutive HCC patients with cirrhosis and no previous treatment who underwent resection (n = 61), transarterial chemoembolization (TACE) (n = 64), or liver transplantation (LT) (n = 60). Long-term survival and survival according to the Milan criteria were the main outcomes measured. Median survival after resection, TACE, and LT was 11, 14, and 23 months, respectively. Five-year cumulative survival after resection, TACE, and LT was 23, 10, and 59%, respectively (P = 0.001). Five-year cumulative disease-free survival after resection and LT was 15% and 77%, respectively (P = 0.002). The presence of complications in the resection group (P = 0.004), MELD score (P = 0.0003), and maximum tumor diameter (P = 0.05) in the TACE group, and tumor grade (P = 0.01) and complications (P = 0.004) in the LT group were found to be independent predictors of survival. Five-year survival for patients within the Milan criteria after resection, TACE, and LT was 26, 37, and 66%, respectively. Five-year survival for patients outside the Milan criteria for patients undergoing LT was 53%. The results suggest that LT represents the best oncological treatment option for patients with HCC in the setting of cirrhosis, even for those beyond the Milan criteria. Considering the scarcity of available organs, liver resection remains the best alternative option. TACE remains a potential therapy in patients within the Milan criteria, where it may be more beneficial than resection.

Successful photodynamic therapy for biliary papillomatosis: a case report.

Papillomatosis of the bile duct is a rare disease with a high risk of malignant transformation. Therapeutical options include partial hepatectomy and liver transplantation. A previously healthy 65-years old male developed jaundice and right upper abdominal quadrant pain in 1996. A villous adenoma of the distal bile duct was diagnosed. A Whipple procedure was performed. In 2002 the patient turned symptomatic again. Another adenoma was found in the right hepatic duct resulting in a right hepatectomy. Two years later the patient again developed cholestasis. After drainage of the left hepatic duct with a percutaneous transhepatic cholangial drainage (PTCD) catheter, a recurrent biliary adenomatosis was diagnosed by cholangioscopy. As there was no surgical option left, the patient received photodynamic therapy (PDT) for the recurrent biliary papillomatosis. Three mo after he received further photodynamic therapies, the bile duct epithelium appeared normal and the patient had no signs of adenomatosis, both macroscopically and histologically. The follow-up cholangioscopy in late 2005 revealed only a small papilloma without the need for intervention. In early 2006, the patient died of multi organ failure without signs of extrahepatic cholestasis or cholangitis at the age of 75, 10 years after the diagnosis of biliary papillomatosis was established. The patient exceeded the average life expectancy of patients with biliary papillomatosis by far. Thus, PDT might be a sufficient therapeutic option for recurrent papillomatosis patients with no significant side effects.

Sorafenib in advanced hepatocellular carcinoma.

BACKGROUND: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. RESULTS: At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. CONCLUSIONS: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)

Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon.

Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-alpha)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their 'loss' in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN-alpha treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN-alpha therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.

Toll-like receptor-stimulated non-parenchymal liver cells can regulate hepatitis C virus replication.

BACKGROUND/AIMS: The aim of this study was to further elucidate the role of the IFN and the Toll-like receptor (TLR) system in the control of HCV replication by non-parenchymal liver cells (NPC). METHODS: Murine HCV replicon bearing MH1 cells were incubated with supernatants from TLR1-9-stimulated murine NPC (Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC)) and bone marrow-derived myeloid dendritic cells (mDC). HCV replication and expression of IFN-stimulated genes (ISGs) as well as TLR1-9 mRNA were determined by real-time rtPCR. RESULTS: IFNs (-alpha, -beta, -gamma) and TLR3 ligands only (despite the expression of TLR1-7 and TLR9 mRNA) achieved direct suppression of HCV replication by about 80-90% or 60%, respectively. Supernatants from TLR3- and 4-stimulated NPC only, however, led to potent suppression of HCV replication through IFN-beta and induction of ISGs. By contrast, mDCs could be stimulated by TLR2, -3, -4, -7 and -9 to produce antiviral cytokines. CONCLUSIONS: TLR3- and TLR4-stimulated NPC are able to regulate HCV replication through production of IFN-beta. This can also, at least partly explain the high level of ISG expression in HCV infected livers. These novel findings are of particular relevance for the control of HCV replication by the innate immune system of the liver.

Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is almost universal, but the natural history of recurrent HCV in the allograft is highly variable. Our study had two aims: 1) to assess the impact of different pre- and postLT factors on graft and patient survival in HCV transplant recipients and 2) to create a model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT. METHODS: A total of 168 LTs were considered for this study. Univariate and multivariate Cox proportional hazards regression model was used, as well as logistic regression analysis to create a model of prediction of HCV cirrhosis within 5 years after LT. RESULTS: Predictive factors for both decreased graft and patient survival included patients recently transplanted (2000-2004), induction without azathioprine, short-term therapy with mycophenolate mofetil and prednisone (< or =6 months), presence of early cholestasis, histologically proven early recurrence of hepatitis C. Recipient human leukocyte antigen DR3 positivity, presence of early cholestasis, and donor age >50 years were identified as independent predictors of graft cirrhosis within 5 years. A predictive model was established in order to calculate at 6 months a risk score for graft HCV cirrhosis within 5 years postLT using a formula that included the identified independent predictors. The area under receiver operating characteristic curve was 0.83, indicating a good ability to predict medium-term HCV allograft cirrhosis. CONCLUSION: This model may be a useful tool for better identifying high-risk HCV patients who should be selected for early initiation of antiviral therapy.

Long-term production of major coagulation factors and inhibitors by primary human hepatocytes in vitro: perspectives for clinical application.

BACKGROUND/AIMS: Patients with coagulation factor disorders require lifelong symptomatic treatment. This is associated with limited efficacy and transmission risks. From a clinical point of view, hepatocyte transplantation offers a rational alternative but is currently being hampered by lack of functional stability of engrafted cells. It was the aim of our study to devise culture conditions providing stable cell polarity, attachment and growth factor stimulation to improve longevity and coagulation factor production. METHODS: Human hepatocytes (HC) were plated on different extracellular matrices, inside collagen gel or Matrigel. HC were grown inside growth factor-enriched serum-free medium (SFM) or exposed to media switching from differentiation (DM) to dedifferentiation (DeDM). RESULTS: Over more than 30 days in vitro human HC synthesized coagulation factors (factors VII, VIII, IX, fibrinogen) and coagulation inhibitors (antithrombin III, protein C). Protein synthesis was augmented when HC were grown inside a 3D collagen type I matrix, while Matrigel showed no additional benefit. Soluble growth factors improved coagulation factor production when applied in SFM or in sequential DM/DeDM. Coagulation factor levels ranged from 3% to 12% in the first week to 2.5-5% after 4 weeks, reaching biologically relevant levels. CONCLUSION: Preserved synthesis and secretion of coagulation factors in balanced proportion by human HC in this model may offer new perspectives for HC transplantation in coagulation defects of patients.

[Angiosarcoma of the liver as a rare cause of rapidly progressive liver failure]. / Angiosarkom der Leber als seltene Ursache eines rasch progredienten Leberversagens.

BACKGROUND: Angiosarcoma of the liver is a rare, highly malignant and sometimes diffusely infiltrating vessel tumor with rapid progression and poor prognosis. CASE REPORT: A 46-year-old male patient with rapidly progressive liver failure, initially regarded as decompensation of known alcoholic liver cirrhosis, is reported. The patient was referred to the authors' center for evaluation of liver transplantation, but a massive weight loss despite long absence of any alcohol intake raised the suspicion of a malignant disease. The abdominal ultrasound examination showed a massive hepatomegaly with an extremely inhomogeneous echo structure as well as moderate ascites. A following MRI demonstrated diffuse focal contrast enhancement in the entire liver parenchyma, confirming diffuse infiltration of the organ by a malignant tumor. In addition, MRI was suspicious of bone metastases. The usual tumor markers were normal. Sonographically guided percutaneous liver biopsy established the diagnosis of a malignant vascular tumor with diffuse infiltration of the liver parenchyma. 3 days later the patient died of uncontrollable bleeding from esophageal varices. Macroscopic examination of the liver during autopsy showed multiple lacunae filled with blood. Therefore, the differential diagnosis of a peliosis hepatis was raised. However, histology confirmed the diagnosis of a malignant angiosarcoma with diffuse osseous metastases. CONCLUSION: A diffuse infiltration of the liver by an angiosarcoma in the absence of any definite lesions may lead to a substantial delay of the diagnosis. The only relevant differential diagnosis in this case is the equally rare peliosis hepatis.