Publications (11)30.61 Total impact
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Article: Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.
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ABSTRACT: Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome. Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence. Patients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version 3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours. First-line therapy after recurrence was surgery (n=6), radiation therapy (n=1), chemotherapy (n=1), and sorafenib (n=3). Finally, 11 patients were treated with sorafenib. Nine patients (82%) received an additionally targeted therapy with sirolimus as part of their immunosuppressive regimen. Most common grade 3 adverse events included diarrhoea (46%), hand-foot skin reaction (27%), nausea, fatigue, and leucopoenia (all 18%). Sorafenib had to be discontinued in two patients due to adverse events and six additional patients required a dose adjustment. No deterioration of liver graft function occurred. Median time to progression was 4.1 months; however, patients were treated with ongoing sorafenib in case of clinical benefit (median 8.9 months). Median overall survival after initiation of sorafenib treatment was 20.1 months. Sorafenib in combination with immunosuppression including sirolimus may be administered to patients with post-transplant hepatocellular carcinoma recurrence with acceptable toxicity and without deterioration of liver graft function.Digestive and Liver Disease 01/2012; 44(5):432-7. · 3.05 Impact Factor -
Article: New imaging techniques and opportunities in endoscopy.
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ABSTRACT: Gastrointestinal endoscopy is undergoing major improvements, which are driven by new available technologies and substantial refinements of optical features. In this Review, we summarize available and evolving imaging technologies that could influence the clinical algorithm of endoscopic diagnosis. Detection, characterization and confirmation are essential steps required for proper endoscopic diagnosis. Optical and nonoptical methods can help to improve each step; these improvements are likely to increase the detection rate of neoplasias and reduce unnecessary endoscopic treatments. Furthermore, functional and molecular imaging are emerging as new diagnostic tools that could provide an opportunity for personalized medicine, in which endoscopy will define disease outcome or predict the response to targeted therapy.Nature Reviews Gastroenterology & Hepatology 09/2011; 8(10):547-53. · 8.10 Impact Factor -
Article: Cell death and hepatocarcinogenesis: Dysregulation of apoptosis signaling pathways.
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ABSTRACT: Hepatocellular carcinoma (HCC) remains a disease with a poor prognosis despite recent advances in the pathophysiology and treatment. Although the disease is biologically heterogeneous, dysregulation of cellular proliferation and apoptosis both occur frequently and contribute to the malignant phenotype. Chronic liver disease is associated with intrahepatic inflammation which promotes dysregulation of cellular signaling pathways; this triggers proliferation and thus lays the ground for expansion of premalignant cells. Cancer emerges when immunological control fails and transformed cells develop resistance against cell death signaling pathways. The same mechanisms underlie the poor responsiveness of HCC towards chemotherapy. Only recently advances in understanding the signaling pathways involved has led to the development of an effective pharmacological therapy for advanced disease. The current review will discuss apoptosis signaling pathways and focus on apoptosis resistance of HCC involving derangements in cell death receptors (e.g. tumor necrosis factor-alpha [TNF], CD95/Apo-1, TNF-related apoptosis-inducing ligand [TRAIL]) and associated adapter molecules (e.g. FADD and FLIP) of apoptotic signaling pathways. In addition, the role of the transcription factor nuclear factor-kappaB (NFκB) and members of the B cell leukemia-2 (Bcl-2) family that contribute to the regulation of apoptosis in hepatocytes are discussed. Eventually, the delineation of cell death signaling pathways could contribute to the implementation of new therapeutic strategies to treat HCC.Journal of Gastroenterology and Hepatology 01/2011; 26 Suppl 1:213-9. · 2.87 Impact Factor -
Article: Mini-laparoscopy in the endoscopy unit: Safety and outcomes in over one thousand patients.
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ABSTRACT: To investigate the safety of consecutive mini-laparoscopy guided liver biopsies for the diagnosis and staging of liver diseases. In this study we retrospectively analyzed the safety of mini-laparoscopic liver biopsy performed in an endoscopy unit in 1071 patients. We measured the incidence of bleeding and evaluated the management and outcome of bleeding interventions. The most common etiologies of liver injury were viral hepatitis and autoimmune liver disease. 250 patients had macroscopically and histologically proven cirrhosis. 13 patients had no pathological findings. 33% of all patients had bleeding that required argon plasma coagulation of the puncture site during laparoscopy. Significant bleeding occurred more often in patients with liver cirrhosis compared to non-cirrhotic liver diseases but was effectively treated with laparoscopic coagulation. In conclusion, mini-laparoscopy liver biopsy can be performed safely and effectively in high risk patients with advanced liver disease; mini-laparoscopy with liver biopsy can be done safely in an endoscopy unit.World journal of gastrointestinal endoscopy. 01/2011; 3(1):6-10. -
Article: Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells.
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ABSTRACT: The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomal-dominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins. In order to investigate the role of CYLD in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first studied the expression levels of CYLD in HCC tissues. CYLD expression was lower in HCC both at protein and mRNA levels compared to the surrounding non-malignant tissue. In order to further study the role of CYLD in the apoptotic sensitivity of HCC cells, CYLD was specifically down-regulated in HCC cell lines via RNA interference. The specific down-regulation of CYLD resulted in increased resistance towards treatment with doxorubicin, 5-fluorouracil and cisplatin. In addition, the down-regulation of CYLD in HCC cells decreased the sensitivity towards tumor necrosis factor-α-induced apoptosis. The CYLD knockdown also led to the degradation of the NF-κB inhibitor, IκB-α, resulting in enhanced NF-κB activity in HCC cells. Finally, we found that CYLD expression was triggered by the multikinase inhibitor, sorafenib, by the inhibition of Raf-1, as well as by the blockage of the pro-survival kinases, MEK (U0126) and the epidermal growth factor receptor (AG1478). In summary, we show that CYLD is down-regulated in human HCC and is involved in the apoptotic resistance of HCC cells. Our data identify the reconstitution of CYLD expression as an attractive approach for overcoming resistance to treatment in HCC.International Journal of Oncology 01/2011; 38(1):121-31. · 2.40 Impact Factor -
Article: Sunitinib in patients with advanced hepatocellular carcinoma after progression under sorafenib treatment.
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ABSTRACT: To evaluate the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) after progression under sorafenib treatment. Sunitinib was administered at 37.5 mg daily (4-weeks-on/2-weeks-off schedule) after progression under sorafenib treatment. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST. Data were analyzed retrospectively. Eleven patients with metastatic disease were treated. Seven patients (64%) presented with no liver cirrhosis, including 3 patients with a history of liver transplantation. The first radiological follow-up showed stable disease in 40% of patients after marked radiological progression under sorafenib. The median time to progression was 3.2 months. Treatment was discontinued due to radiological progression (n = 9) or AEs (n = 2; hemorrhages) in all patients after 3.5 months. The median overall survival was 8.4 months. All patients with Child-Pugh class B liver cirrhosis suffered a clinical deterioration of liver function and died within 4 months due to tumor progression. Sunitinib provided modest antitumor activity in patients with advanced HCC after progression under sorafenib treatment. Patients with Child-Pugh class B liver cirrhosis might not receive a clinical benefit from this second-line approach. Hemorrhagic complications may represent a clinically relevant problem of sunitinib in patients with advanced HCC.Oncology 11/2010; 79(1-2):85-92. · 2.27 Impact Factor -
Article: Novel inhibitors in development for hepatocellular carcinoma.
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ABSTRACT: The multikinase inhibitor sorafenib was the first agent to demonstrate a survival benefit for patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Although sorafenib represents a landmark in the treatment of HCC and proved molecularly targeted therapy to be effective in this disease, it represents just the first step towards an improvement in systemic therapy. Since then, novel inhibitors have been evaluated in early clinical trials, showing potential activity. This article aims to review novel inhibitors emerging in the field of advanced HCC. An Internet-based search was performed to identify abstracts, clinical trials ( www.clinicaltrials.gov , last accessed 30 November 2009), and original research and review articles. Readers will gain a comprehensive survey of current molecularly targeted therapy approaches in advanced HCC. In addition, challenges such as the design of clinical trials, the assessment of radiological response, the role of combination therapy, and future developments in molecularly targeted therapy are discussed. Sorafenib is the standard of care in patients with advanced HCC. However, promising novel inhibitors are under investigation. Combined molecularly targeted therapies according to an individual genomic and proteomic profiling will probably lead to more personalised medicine in advanced HCC.Expert Opinion on Investigational Drugs 04/2010; 19(5):615-29. · 5.27 Impact Factor -
Article: Systemic therapies in hepatocellular carcinoma.
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide in the human population. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with advanced disease. However, a better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Positive data from the pivotal phase III SHARP trial assessing the efficacy and safety of the multikinase inhibitor sorafenib broadened the horizon for patients with advanced disease. After years of therapeutic nihilism, sorafenib was the first agent to demonstrate a statistically significant improvement in overall survival for patients with advanced HCC. This article reviews the historical perspective of systemic therapy in HCC and provides a brief overview of molecular hepatocarcinogenesis and potential targets in HCC. Most promising molecular targeted agents tested within clinical trials in advanced HCC are summarized, with a special attention to sorafenib, sunitinib, bevacizumab, and erlotinib.Digestive Diseases 02/2009; 27(2):175-88. · 2.37 Impact Factor -
Article: Susceptibility to collagen-induced arthritis is modulated by TGFbeta responsiveness of T cells.
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ABSTRACT: The objective of our study was to determine the regulatory effects that endogenous transforming growth factor beta (TGFbeta) exerts on T cells in the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in transgenic mice expressing a dominant negative TGFbeta type II receptor in T cells under the control of the human CD2 promoter. Clinical and histological arthritis scores were determined and experiments on disease induction and the healing phase of disease were performed. The proliferation and cytokine production of draining lymph node cells in vitro were analyzed. Transgenic mice were more susceptible to induction of CIA. The overall incidence was higher in transgenic mice than in wild-type mice (57% vs 35%, P < 0.05). Affected transgenic animals displayed a significantly higher clinical (4.5 +/- 0.6 vs 1.67 +/- 0.19, P = 0.001) and histological arthritis score (8.01 +/- 0.9 vs 4.06 +/- 1.1, P < 0.05). Draining lymph node cells of transgenic mice secreted more tumor necrosis factor alpha and IFNgamma and proliferated more vigorously in response to collagen type II and upon CD3/CD28 costimulation in vitro. Therefore, the regulation of T cells by endogenous TGFbeta is important for the maintenance of joint integrity after arthritis induction. Defects in TGFbeta-signalling as a susceptibility factor for rheumatoid arthritis may warrant further investigation.Arthritis research & therapy 01/2004; 6(2):R114-9. · 4.27 Impact Factor -
Article: Proteinase-3 as the major autoantigen of c-ANCA is strongly expressed in lung tissue of patients with Wegener's granulomatosis.
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ABSTRACT: Proteinase-3 (PR-3) is a neutral serine proteinase present in azurophil granules of human polymorphonuclear leukocytes and serves as the major target antigen of antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA) in Wegener's granulomatosis (WG). The WG disease appears as severe vasculitis in different organs (e.g. kidney, nose and lung). Little is known about the expression and distribution of PR-3 in the lung. We found that PR-3 is expressed in normal lung tissue and is upregulated in lung tissue of patients with WG. Interestingly, the parenchymal cells (pneumocytes type I and II) and macrophages, and not the neutrophils, express PR-3 most strongly and may contribute to lung damage in patients with WG via direct interaction with antineutrophil cytoplasmic antobodies (ANCA). These findings suggest that the PR-3 expression in parenchymal cells of lung tissue could be at least one missing link in the etiopathogenesis of pulmonary pathology in ANCA-associated disease.Arthritis Research 02/2002; 4(3):220-5. -
Article: Proteinase-3 mRNA expressed by glomerular epithelial cells correlates with crescent formation in Wegener's granulomatosis
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2009–2011
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Johannes Gutenberg-Universität Mainz
- I. Department of Medicine
Mainz, Rhineland-Palatinate, Germany
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