Friedrich Foerster

The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy

Treatment of hepatocellular carcinoma (HCC) is dependent on the stage of the disease. Intermediate stage HCC encompasses the largest subgroup of patients with the disease, and is characterized by substantial heterogeneity. The standard therapeutic approach, transarterial chemoembolization (TACE), is probably over-used and may not be appropriate for all patients with intermediate stage HCC. In patients with extensive tumour bulk, multi-nodular spread or impaired liver function, TACE may not be optimal and other treatments can be considered as a first-line treatment. These include surgery, percutaneous ablation, radioembolization or systemic treatment. In addition, patients who do not achieve complete or partial necrosis (TACE failure) and patients with early recurrence after TACE, should be managed individually, considering systemic treatments usually reserved for advanced disease. In selected cases and in patients who achieve downstaging, radical approaches such as hepatic resection or even liver transplantation can be considered. In this review, we evaluate the current literature for the treatment strategies for patients with intermediate Barcelona Clinic Liver Cancer (BCLC) B stage HCC.

In vivo gene-silencing in fibrotic liver by siRNA-loaded cationic nanohydrogel particles

Cationic nanohydrogel particles loaded with anti-Col1α1 siRNA suppress collagen synthesis and deposition in fibrotic mice: Systemically administered 40 nm sized nanogel particles accumulate in collagen-expressing cells in the liver. Their siRNA payload induces a sequence specific in vivo gene knockdown affording an efficient antifibrotic effect in mice with liver fibrosis.

The immune contexture of hepatocellular carcinoma predicts clinical outcome

The general relevance of the immune system for cancer development and therapy is increasingly recognized. However and although the immune contexture of most human cancer types has been determined, a global characterisation of the immune tumour microenvironment in hepatocellular carcinoma (HCC) is lacking. Equally, differences in the immune contexture of HCC between different patient subgroups and its effect on survival remain to be established. Here we report an in silico analysis of the immune contexture of human HCC. Using large deep sequencing HCC tumour, adjacent non-tumour and healthy liver high-dimensional data sets, we were able to reveal previously unrecognized differences in the immune contexture of HCC. Strikingly, we found that different etiologies and HCC stages were not associated with major changes in the immune contexture. In contrast, the presence of T cells and cytotoxic cells as well as the absence of macrophages and Th2 cells positively correlated with patient survival. Based on these novel findings, we developed a prognostic score that accurately distinguishes between patients with good and poor survival. Our study provides the first global characterisation of the immune contexture of HCC and will have direct implications for future HCC therapies.

[Cost-effective medical therapy of hepatitis C employing novel compensation models - pay for cure].

Direct acting antivirals (DAAs) have increased cure rates for chronic hepatitis C infection up to nearly 100u200a%. At the same time treatment costs have risen significantly. Treating all HCV infected patients in Germany with DAAs would generate medication costs ranging between 19 and 37 billion EUR depending on the drug regimen used. Expenses in patients who fail to respond to treatment would amount to approximately 0.9 to 2.15 billion EUR. In difficult to treat patient populations that are characterized by prior failure to treatment or advanced liver disease, lost drug expenses are particularly high due to lower cure rates and longer treatment duration. Outcome-based reimbursement schemes are used to improve the quality of care and to reduce costs in the health care system. In Germany, disease management programs have been implemented for defined chronic diseases. However, drug reimbursement is still based on packages sold (pay for pill). In this context, it would be appealing to link reimbursement and treatment success (pay for cure) in order to reward successful treatment, limit lost drug spending and develop a shared risk environment that would involve all concerned parties. Under the assumption that 20,000 patients with HCV are treated each year in Germany and that cure rates are 95.4u200a%, the saved treatment costs would amount up to 45 and 107 million EUR per year. By this approach, economic incentives to withhold therapy from difficult to treat patients could be avoided.

Ultrasound for Hepatocellular Carcinoma Surveillance: Still Looking for the Fortune Teller

In Philip K. Dicks short story The Minority Report (later made into a movie by Steven Spielberg), 3 fortune tellers called precogs predict crime before it happens, which allows the police to arrest criminals before any harm is done. Needless to say, treating malignancy before it occurs is any oncologists ultimate dream. While such prognostic capabilities are not at our disposal today, hepatocellular carcinoma (HCC) is a kind of cancer, which typically occurs in a specified population which in turn can be kept under surveillance. Therefore, all international guidelines recommend screening measures for patients at risk who are suited for treatment.(1-3) The guidelines differ to some extent regarding patient selection, but cirrhotic patients with Child-Pugh stage A and B, noncirrhotic hepatitis B virus infected patients at increased risk of HCC, and noncirrhotic F3 patients with bridging fibrosis based on an individual risk assessment appear to be good candidates for surveillance. Here, the most widely accepted procedure is ultrasound-sometimes in combination with serum alpha-fetoprotein (AFP) measurements. This article is protected by copyright. All rights reserved.

Hepatocellular carcinoma: one world, one cancer—different guidelines?

Hepatocellular carcinoma (HCC) is a healthcare challenge in virtually all parts of the world. Therefore, it is no wonder that different guidelines have been developed reflecting expert consensus on the management of HCC in different regions, namely guidelines from the American Association for the Study of Liver Diseases (AASLD) for the USA (1,2), the Asian Pacific Association for the Study of the Liver (APASL) for the Asia-Pacific region (3), the European Association for the Study of the Liver (EASL) for Europe (4), and the Japan Society of Hepatology (JSH) for Japan (5,6). In 2018 an update of the EASL clinical practice guidelines (CPG) will appear.

Recipient liver function before liver transplantation influences post-transplantation survival in patients with HCC

BACKGROUNDnLiver transplantation (LT) is a complex yet curative treatment for a subset of patients with hepatocellular carcinoma (HCC). Due to donor organ shortage, patients with HCC need to be carefully selected for LT. In European countries, selection of patients is based on the Milan criteria, and donor organs are allocated by Eurotransplant. In order to optimize the utilization of available liver grafts, the outcome of HCC patients after LT needs to be closely monitored and evaluated.nnnMETHODSnWe assessed the outcome of 304 HCC patients who underwent LT at a tertiary medical center over a period of nearly 20u202fyears (February 1998 until June 2017).nnnRESULTSnThe 5-, 10- and 15-year survival rates were 62, 47 and 30%, respectively. The strongest survival-determining factor was tumour recurrence. Apart from a high tumour grading, the pre-LT MELD score was significantly and negatively associated with survival after LT.nnnCONCLUSIONnOur results confirm the importance of recurrence for the outcome of HCC patients after LT and highlight the relevance of HCC patients liver function before LT. Our findings encourage efforts to identify prognostically relevant factors for LT in HCC with the overall goal of refining the organ allocation system and maximizing the survival benefit after LT.

Enhanced protection of C57 BL/6 vs Balb/c mice to melanoma liver metastasis is mediated by NK cells

ABSTRACT The B16F10 murine melanoma cell line displays a low expression of MHC class I molecules favoring immune evasion and metastases in immunocompetent C57 BL/6 wild-type mice. Here, we generated metastases to the liver, an organ that is skewed towards immune tolerance, by intrasplenic injection of B16F10 cells in syngeneic C57 BL/6 compared to allogeneic Balb/c mice. Surprisingly, Balb/c mice, which usually display a pronounced M2 macrophage and Th2 T cell polarization, were ∼3 times more susceptible to metastasis than C57 BL/6 mice, despite a much higher M1 and Th1 T cell immune response. The anti-metastatic advantage of C57 BL/6 mice could be attributed to a more potent NK-cell mediated cytotoxicity against B16F10 cells. Our findings highlight the role of NK cells in innate anti-tumor immunity in the context of the liver – particularly against highly aggressive MHC I-deficient cancer cells. Moreover, the B16F10 model of melanoma liver metastasis is suited for developing novel therapies targeting innate NK cell related immunity in liver metastases and liver cancer.

P0312 : Preclinical evaluation of dextran-based therapeutic nanoparticles for hepatic drug delivery

AIMnEvaluation of dextran-based nanoparticles (DNP) as a drug delivery system to target myeloid cells of the liver.nnnMATERIALS & METHODSnDNP were synthesized and optionally PEGylated. Their toxicity and cellular uptake were studied in vitro. Empty and siRNA-carrying DNP were tested in vivo with regard to biodistribution and cellular uptake.nnnRESULTSnIn vitro, DNP were taken up by cells of the myeloid lineage without compromising their viability. In vivo, empty and siRNA-carrying DNP distributed to the liver where a single treatment addressed approximately 70% of macrophages and dendritic cells. Serum parameters indicated no in vivo toxicity.nnnCONCLUSIONnDNP are multifunctional liver-specific drug carriers which lack toxic side effects and may be utilized in clinical applications targeting liver macrophages.