Hepatocellular carcinoma with hepatic vein invasion should not be considered as a contraindication for liver resection

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Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: more details, more significance

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Sofosbuvir, Peg Interferon & Ribavirin for retreatment of HCV genotype 1b following Sofosbuvir and Ledipasvir failure

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Mesenchymal stromal cells in treatment of acute-on-chronic liver failure

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Glecaprevir/Pibrentasvir in Patients with HCV Genotype 1 or 4 and Prior Direct-acting Antiviral Treatment Failure

ABSTRACT

Methods: MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and prior virologic failure on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12).

Results: Among 91 patients treated, 87 had GT1 and four had GT4 infection. SVR12 was achieved by 89% (39/44) and 91% (43/47) of patients who received 12 and 16 weeks of G/P, respectively. Virologic relapse occurred in 9% (4/44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Prior treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, while prior treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event was headache (≥10% of patients) and there were no serious adverse events (AEs) assessed as related to study drugs or AEs leading to discontinuation.

Conclusions: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and prior failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors.

Background: Patients with hepatitis C virus (HCV) who have virologic failure after treatment containing an NS5A inhibitor have limited retreatment options. This article is protected by copyright. All rights reserved.

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New insights into diagnosis and therapeutic options for proliferative hepatoblastoma

ABSTRACT

Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70-80% of patients. However, some important challenges remain in diagnosing high risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of hepatoblastoma tumors have been described, namely C1 and C2; C2 being the subgroup with the poorest prognosis, a more advanced tumor stage and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed but it has not been transferred into clinical routine. To address these issues we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A and C2B, identifiable by a concise four-gene signature: HSD17B6, ITGA6, TOP2A and VIM, with TOP2A being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by RT-qPCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in Fanconi Anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, an FDA-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway associated double-strand DNA repair and significantly impedes HB growth in vivo.

In conclusion, the highly proliferating C2A subtype is characterized by TOP2A gene up-regulation and FA pathway activation and HB therapeutic arsenal could include Bortezomib for the treatment of patients with the most aggressive tumors. This article is protected by copyright. All rights reserved.

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Cytoplasmic localization of the cell polarity factor Scribble supports liver tumor formation and tumor cell invasiveness

Abstract

The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the baso-lateral cell polarity complex protein Scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison to HCC cells stably expressing wildtype Scrib (Scrib^WT), mutated Scrib with enforced cytoplasmic enrichment (Scrib^P305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic Scrib^P305L stimulated a gene signature and a phenotype, which were characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. Scrib^P305L-dependent invasion was mediated by the AP-1 constituents ATF2 and JunB via induction of paracrine-acting secreted protein acidic and cysteine rich (SPARC). Co-expression of Scrib^P305L and the oncogene c-MYC via hydrodynamic gene delivery in mouse livers promoted tumor formation and increased pAKT, pATF2, and SPARC abundance in comparison to controls. Lastly, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues and the Scrib^P305L-dependent gene signature was enriched in cancer patients with poor prognosis.

Conclusion: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination via specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patient groups with higher risk for the development of metastasis. This article is protected by copyright. All rights reserved.

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