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Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents

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World Journal of Hepatology 2015年第3期7卷 532-538页

作者： kerstin herzer Guido Gerken Department of Gastroenterology and Hepatology University Hospital Essen Department of General Visceral and Transp-lantation Surgery University Hospital Essen

The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus(HCV). In the liver transplant(LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better responserates achieved with boceprevir-based and telaprevirbased triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.

关键词： Hepatitis C virus Liver transplant Interferon Sofosbuvir Simeprevir Daclatasvir

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Hepatitis C-associated liver carcinogenesis:Role of PML nuclear bodies

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World Journal of Gastroenterology 2014年第35期20卷 12367-12371页

作者： kerstin herzer Guido Gerken Thomas G Hofmann Department for Gastroenterology and Hepatology University Hospital Essen Department of General- Visceral- und Transplantation SurgeryUniversity Hospital Essen Cellular Senescence Group DKFZ-ZMBH AllianceDeutsches Krebsforschungszentrum (dkfz.)

Successful escape from immune response characterises chronic hepatitis C virus (HCV) infection, which results in persistence of infection in about 80% of the patients. The deleterious consequences are cirrhosis and hepatocellular carcinoma. HCV accounts the most frequent cause for hepatocellular carcinoma (HCC) and liver transplantation (LT) in the western world. The underlying molecular mechanisms how HCV promotes tumor development are largely unknown. There is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of HCC. The tumor suppressor protein “promyelocytic leukemia” (PML) has been implicated in the regulation of important cellular processes like differentiation and apoptosis. In cancer biology, PML and its associated nuclear bodies (NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia (APL). More recently, loss of PML has been implicated in human cancers of various histologic origins. Moreover, number and intensity of PML-NBs increase in response to interferons (IFNs) and there is evidence that PML-NBs may represent preferential targets in viral infections. Thus, PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on hepatocytes. This review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.

关键词： Hepatitis C virus Promyelocytic leukemia Nuclear bodies Hepatocellular carcinoma Apoptosis

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Killing of p53-deficient hepatoma cells by parvovirus H-1 and chemotherapeutics requires promyelocytic leukemia protein

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World Journal of Gastroenterology 2008年第24期14卷 3819-3828页

作者： Maike Sieben kerstin herzer Maja Zeidler Vera Heinrichs Barbara Leuchs Martin Schuler Jan J Cornelis Peter R Galle Jean Rommelaere Markus Moehler First Department of Internal Medicine Johannes Gutenberg University of Mainz German Cancer Research Center Infection and Cancer ProgramDept.F010 and Institut National de la Santé et de la Recherche Médicale Unité 701 Department of Medicine (Cancer Research) West German Cancer CenterUniversity Hospital Essen

AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML). METHODS: The role of p53 and PML in regulating cy-totoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Further-more,H-1 PV infection was combined with cytostatic drug treatment. RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis,the cytotoxicity of H-1 PV was morepronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses,H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition,H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death. CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents,and it enhances the apoptotic process which is dependent on functional PML. Thus,H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC,particularly for p53-negative tumors.

关键词： Autonomous parvovirus Apoptosis p53 Promyelooltic leukemia protein Human hepatocellularcarcinoma Hepatooltes

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Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant

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World Journal of Hepatology 2015年第9期7卷 1287-1296页

作者： kerstin herzer Angela Papadopoulos-Khn Anne Achterfeld Ali Canbay Katja Piras-Straub Andreas Paul Andreas Walker Jrg Timm Guido Gerken Department of Gastroenterology and Hepatology University Hospital Essen Department of General-Visceral and Transplantation Surgery University Hospital Essen Institute for Virology Heinrich Heine University

AIM: To characterize management of telaprevir(TVR)-based triple therapy of hepatitis C virus(HCV) reinfection after liver transplantation(LT).METHODS: We retrospectively analyzed safety and efficacy of telaprevir- based triple therapy in a single center cohort of 19 patients with HCV genotype(GT) 1 recurrence after LT, with respect to factors possibly predicting sustained viral response(SVR) or non-SVR. All patients were treated with TVR, pegylated(PEG) and ribavirine(RBV) for 12 wk followed by a dual phase with PEG/RBV for 12 wk in 7 patients and for 36 wk in 5 patients. RESULTS: In total 11/19(58%) of patients achieved a sustained response. All(11/11) SVR patients showed a rapid viral response at treatment weeks 4 and 11/14 rapid virological response(RVR) patients achieved SVR. Notably, all(7/7) patients who completed 48 wk of therapy and 80%(4/5) patients who completed 24 wk of therapy achieved SVR24. Treatment failure was significantly(P > 0.049) more frequent in GT1 a infection(5/7) compared to GT1b(3/12) infection and was associated with emergence of resistance-associated mutations in the NS3 protease domain. Bilirubin level at baseline is also related to SVR(P > 0.030). None of the patients had to discontinue treatment due to side effects. CONCLUSION: RVR, GT and bilirubin are clearly related to achievement of SVR. Providing a thorough patient selection and monitoring, a full course of TVR-based triple therapy in LT patients is feasible and achieves high SVR rates.

关键词： Liver transplantation Telaprevir HepatitisC virus recurrence Predictors Hepatitis C virus therapy

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Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma-a rationale for a molecular targeting strategy?

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World Journal of Gastroenterology 2007年第26期13卷 3605-3609页

作者： Daniel Drescher Markus Moehler Ines Gockel Kirsten Frerichs Annett Müller Friedrich Dünschede Thomas Borschitz Stefan Biesterfeld Martin Holtmann Thomas Wehler Andreas Teufel kerstin herzer Thomas Fischer Martin R Berger Theodor Junginger Peter R Galle Carl C Schimanski Department of General and Abdominal Surgery Johannes Gutenberg University of Mainz MainzGermany First Department of Internal Medicine Johannes Gutenberg University of Mainz MainzGermany Institute of Pathology Johannes Gutenberg University of MainzMainzGermany Third Department of Internal Medicine Johannes Gutenberg University of Mainz MainzGermany Unit of toxicology and chemotherapy German Cancer Research CenterGermany

AIM： To define the （co-）expression pattern of target receptor-tyrosine-kinases （RTK） in human gastric adenocarcinoma. METHODS： The （co-）expression pattern of VEGFR1-3, PDGFR（α/β and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS： The majority of samples revealed a VEGFR1 （98%）, VEGFR2 （80%）, VEGFR3 （67%）, PDGFRα （82%） and PDGFRβ （82%） expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRα revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFRβ was restricted to stromal pericytes, which also depicted a PDGFRα expression. CONCLUSION： Our results reveal a high rate ofreceptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy.

关键词： VEGFR EGFR PDGFR Cancer Adeno-carcinoma Gastric Stomach

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