Pancreatic Atrophy in Hepatocellular Carcinoma Patients Receiving Long-Term Treatment with Sorafenib

Objective: To date, sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). Pancreatic atrophy has recently been reported in 2 patients as a novel side effect after long-term sorafenib treatment. Methods: We retrospectively analyzed clinical and radiological data of patients with advanced HCC with long-term treatment of sorafenib (median 279 days, range 153–826 days). Pancreata were semi-manually segmented section by section to calculate the pancreas volumes before and under sorafenib treatment. Results: Sorafenib reduced pancreatic volume in 18/19 (95%) HCC patients with a mean pancreatic volume loss of 25% (p = 0.002). Pancreatic volume loss depended on the dose (r = 0.36) and exposure time of sorafenib (r = 0.35) and was detectable as early as after 3 months of sorafenib treatment and already after a cumulative sorafenib dose of <100 g. Median overall survival was 13.2 months (range 7.8–31.3 months) but did not correlate with sorafenibinduced pancreatic volume reduction (hazard ratio 1.002, 95% confidence interval 0.981–1.060, p = 0.24). Conclusion: We could confirm pancreatic atrophy as a novel adverse event of sorafenib therapy in HCC patients, correlating with sorafenib dose and exposure time

Orthotopic liver transplantation in human-immunodeficiency-virus-positive patients in Germany

Objectives: This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods: Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results: 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41-86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions: Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

Percutaneous treatment of biliary cast syndrome after orthotopic liver transplantation: comparison of mechanical versus hydraulic rheolytic cast extraction

Biliary cast syndrome (BCS) is the presence of casts within the intrahepatic or extrahepatic biliary system after orthotopic liver transplantation. Our work compares two percutaneous methods for BCS treatment: the mechanical cast-extraction technique (MCE) versus the hydraulic cast-extraction (HCE) technique using a rheolytic system

Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL

TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-κB) activity, specific suppression of NF-κB by mutIκBα failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)L and cFLIPS were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC. But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis. Copyright © 2005 by the American Association for the Study of Liver Diseases

Apoptosis and Cancer Therapy: From Cutting-edge Science to Novel Therapeutic Concepts

The death ligand TRAIL was discovered just over 10 years ago. In this chapter, we summarize the most important findings on the biochemistry, biology and potential therapeutic applicability of this promising novel cytokine. We address a number of eminent questions. How does TRAIL apoptosis signaling work and what is special about it? Why is this member of the tumor necrosis factor family of cytokines so interesting for cancer researchers and immunologists? What is the physiological role of the TRAIL\u2013TRAIL receptor system? We cannot provide full answers to all of these questions; however, we intend to point out to the reader the most important unsolved scientific questions regarding the biology of this fascinating cytokine and its receptors