Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance.

BACKGROUND: Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). METHODS: OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs. RESULTS: Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression.In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC. CONCLUSION: The downregulation of OCT1 is associated with tumor progression and a worse patient survival.

Early changes in dynamic biomarkers of liver fibrosis in hepatitis C virus-infected patients treated with sofosbuvir.

BACKGROUND: Chronic hepatitis C is a major cause of liver-associated mortality caused by decompensated cirrhosis and hepatocellular carcinoma. With the approval of sofosbuvir, therapeutic efficacy has markedly increased. Early changes in non-invasive biomarkers of liver fibrosis under effective antiviral therapy are widely unknown. AIM: To evaluate early changes of fibrosis markers determined by enhanced liver fibrosis (ELF) scores and liver stiffness measurement (FibroScan(®)) in patients treated with sofosbuvir. METHODS: A total of 32 hepatitis C patients treated prospectively with sofosbuvir were included. The ELF-panel and FibroScan measurements were performed at baseline, week 4, end-of-treatment and 12 weeks thereafter. RESULTS: Antiviral therapy resulted in a biochemical and virological response within 4 weeks. Sustained virological response rate at 12-week follow-up (SVR12) was 93.8%; there was a significantly decrease from baseline to 12-week post-treatment follow-up in ELF (10.00 vs. 9.37; p=0.007) and FibroScan (8.0 vs. 6.8 kPa; p=0.016) measurements, indicating improvement of the dynamics of liver fibrosis. CONCLUSION: We observed a rapid decrease in non-invasive fibrosis markers measured by ELF-scores and FibroScan in hepatitis C-infected patients receiving sofosbuvir treatment. These initial results need to be histologically confirmed by liver biopsy in the future.

Combination therapy with silibinin, pegylated interferon and ribavirin in a patient with hepatitis C virus genotype 3 reinfection after liver transplantation: a case report.

INTRODUCTION: Hepatitis C virus reinfection occurs universally after liver transplantation with accelerated cirrhosis rates of up to 30% within 5 years after liver transplantation. Management of hepatitis C virus reinfection is complicated by drug interactions and pre-treatment. Dual antiviral therapy with pegylated interferon and ribavirin only reaches sustained virological response rates of approximately 30% after liver transplantation. With the approval of the viral NS3/4A protease and NS5B ribonucleic acid -dependent ribonucleic acid polymerase inhibitors, combination therapy offers new therapeutic options resulting in considerably higher sustained virological response rates in the non-transplant setting. However, silibinin has also shown potent antiviral activity in non-responders to dual therapy. CASE PRESENTATION: We report the first case of antiviral therapy with pegylated interferon and ribavirin in combination with silibinin post-liver transplantation in a 50-year-old Caucasian man with genotype 3 reinfection with prior non-response.Silibinin was administered at a dose of 20mg/kg/day intravenously for 2 weeks and continued orally for 47 weeks in combination with a 48-week pegylated interferon and ribavirin therapy (180µg/week and 800mg/day), which was started on day 8. Pegylated interferon and ribavirin doses were adapted to 135µg/week and 600mg/day. After 4 weeks of therapy, the viral load declined 6 log10 and became undetectable in week 6, resulting in a sustained virological response 24 weeks after the end of therapy.In general, antiviral therapy was well tolerated. Side effects included pruritus and anaemia leading to erythropoietin therapy. CONCLUSIONS: Combination therapy with pegylated interferon, ribavirin and silibinin resulted in sustained virological response 24 weeks after the end of therapy in a patient reinfected with hepatitis C virus genotype 3 who was a prior non-responder after liver transplantation. Silibinin therapy may offer a new therapeutic option for patients reinfected with non-genotype 1 hepatitis C virus who have had a liver transplanted and are non-responders.

Impact of pancreatic comorbidities in patients with end-stage liver disease on outcome after liver transplantation.

BACKGROUND: Diseases leading to end-stage liver disease (ESLD), especially alcoholic liver cirrhosis cause comorbidities of the pancreas, too. The aim of this retrospective study was to determine the impact of pancreatic alterations diagnosed pretransplant on the outcome after liver transplantation (LT). METHODS: In total, data from 372 LT patients were analyzed. Patients were followed up for a mean of 4.2 years. Incidence of chronic pancreatitis (CP), pancreatic cysts (PC) and intraductal papillary mucinous neoplasm (IPMN) was acquired retrospectively from patient's charts. RESULTS: CP, IPMN and PC were rarely diagnosed in LT-recipients [CP (3.8%), PC (1.6%) and IPMN (1.6%)]. There was no significant correlation of IPMN, CP, PC and other patient characteristics. The prevalence of CP (log rank: p=0.315), PC (log rank: p=0.242) and IPMN (log rank: p=0.491) did not influence patient survival. CONCLUSION: Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low-risk for malignancy according to international consensus guidelines).

Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma.

Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long­term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum­based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor­surrounding tissue (TST). OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human CCA by real-time PCR (n=27). Protein expression was determined by western blot analysis and immunohistochemistry. Data were correlated with the clinicopathological parameters of CCA. Real-time PCR demonstrated a downregulation of the expression of SLC22A1 and SLC22A3 in CCA, compared to that in TST (p<0.001). A low SLC22A1 expression was associated with a worse patient survival (p<0.05). The downregulation of SLC22A1 was significantly associated with advanced CCA stages, since tumors with a low SLC22A1 mRNA expression presented with larger tumor diameters (p=0.02). There were no significant differences in tumor characteristics or patient survival in relation to the level of SLC22A3 expression. Western blot analysis and immunohistochemistry confirmed the downregulation of OCT1 and OCT3 protein levels in cancerous tissue compared to those in TST. In conclusion, the downregulation of OCT1 is associated with tumor progression and worse overall patient survival rates.