Introduction
The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop ...consensus recommendations.
Methods
The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements.
Results
Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.
Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate‐stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular ...endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double‐blind, placebo‐controlled, phase III study, 870 patients with TACE‐eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once‐daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow‐up was approximately 16 months. Intention‐to‐treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 95% confidence interval {CI}: 19.1 to not reached vs. 26.1 months 19.0‐30.9; hazard ratio HR: 0.90 95% CI: 0.66‐1.23; log‐rank P = 0.5280). Brivanib improved TTES/VI (HR, 0.64 95% CI: 0.45‐0.90), TTP (0.61 0.48‐0.77), and rate of TACE (0.72 0.61‐0.86), but not TTDP (0.94 0.72‐1.22) versus placebo. Most frequent grade 3‐4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS. (Hepatology 2014;60:1697–1707)
Hepatocellular carcinoma (HCC) is a malignant form of liver cancer that ranks the second leading cause of cancer-related deaths in China and many Asia regions. The dismal outcome reflects the need ...for a better understanding of the transcriptional control of oncogenic signaling pathway. Our recent findings have identified yes-associated protein (YAP) is a potent oncogenic driver and independent prognostic risk factor of HCC. The present study aims to elucidate the transcriptional regulation of YAP targeted by microRNA (miRNA). miR-375 is a putative target and was found significantly down-regulated in the tumor versus adjacent non-tumor tissues of HCC patients (
n
=
48). As determined by luciferase reporter assay, we found ectopic expression of miR-375 could diminish the transcriptional activity of YAP. Furthermore, immunoblotting revealed miR-375 suppressed endogenous YAP protein level. Functional assays showed that miR-375 was able to inhibit proliferation and invasion of HCC cells.
Conclusion: miR-375 is an important regulator of YAP oncogene, implicating a potential therapeutic role in HCC treatment.
Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide. No more than 30% of HCC patients receive curative treatment. Factors limiting curative therapy ...include tumor size and degree of liver impairment. Objective: To develop a cure for medium (3.1 - 5.0 cm) and large ( > 5 cm) tumors in seriously impaired livers. Method: Combine radiofrequency ablation (RFA) with lyso-thermosensitive liposomal doxorubicin (LTLD). Results/conclusions: RFA is used safely in patients with medium/large tumors and severe liver impairment; unclear tumor margins limit its curative efficacy. LTLD concentrates in the liver, where the anti-HCC chemotherapeutic, doxorubicin, is released into tumor margins by hyperthermia. RFA/LTLD can treat Child-Pugh class A-B patients with tumors up to 7 cm, a substantial increase in curable patients.
Increasing evidence has revealed the importance of cancer stem cells (CSCs) in carcinogenesis. Although liver CSCs have been identified in hepatocellular carcinoma (HCC) cell lines, no data have ...shown the presence of these cells in human settings. The present study was designed to delineate CSCs serially from HCC cell lines, human liver cancer specimens to blood samples, using CD90 as a potential marker. The number of CD90+ cells increased with the tumorigenicity of HCC cell lines. CD45−CD90+ cells were detected in all the tumor specimens, but not in the normal, cirrhotic, and parallel nontumorous livers. In addition, CD45−CD90+ cells were detectable in 90% of blood samples from liver cancer patients, but none in normal subjects or patients with cirrhosis. A significant positive correlation between the number of CD45−CD90+ cells in the tumor tissues and the number of CD45−CD90+ cells in the blood samples was identified. CD90+ cells sorted from cell lines and CD45−CD90+ cells from the tumor tissues and blood samples of liver cancer patients generated tumor nodules in immunodeficient mice. Serial transplantation of CD90+ cells from tumor xenografts generated tumor nodules in a second and subsequently third batch of immunodeficient mice. Treatment of CD90+ CSCs with anti‐human CD44 antibody induced cell apoptosis in a dose‐dependent manner. Conclusion: Identification of CD45−CD90+ CSCs in both tumor tissues and circulation suggests that CD45−CD90+ could be used as a marker for human liver cancer and as a target for the diagnosis and therapy of this malignancy. (HEPATOLOGY 2008.)
Background
Orthotopic liver transplantation (OLT) is the best available option for early hepatocellular carcinoma (HCC), although its application is limited by stringent selection criteria, costs, ...and deceased donor graft shortage, particularly in Asia, where living donor liver transplant (LDLT) has been developed.
Methods
This article reviews the present standards for patient selection represented by size-and-number criteria with particular references to Milan Criteria and novel prediction models based on results achieved in patients exceeding those limits, with consideration of the expanded indication represented by the UCSF Criteria.
Results
The expected outcomes after deceased donor liver transplant (DDLT) or LDLT are favorable if predetermined selection criteria are applied. However, selection bias, difference in waiting time, and ischemia-regeneration injuries of the graft among DDLT vs LDLT may influence long-term results. In the article, the differences between East and West in first-line treatments for HCC (resection vs transplantation), indications, and ethics for the donor, are summarized as well as possible novel predictors of tumor biology (especially DNA mutation and fractional allelic loss, FAI) to be considered for better outcome prediction.
Conclusions
Liver transplantation remains the most promising product of modern surgery and represents a cornerstone in the management of patients with HCC.
To identify the risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after resection.
Seventy-two patients who underwent liver resection for HBV-related HCC ...were recruited. Demographic, biochemical, tumor, and viral factors at the time of resection were evaluated by univariate and multivariate analyses to identify risk factors associated with recurrence after resection.
The median follow-up period was 18.9 months and the median age was 53 yr, with male-to-female ratio of 59:13. Age >60 yr, tumor size >5 cm, poorly differentiated tumor, lymphovascular permeation, the presence of microsatellite lesions, alpha-fetoprotein (AFP) level >1,000 ng/mL and HBV viral load >2,000 IU/mL (4 log(10) copies/mL) at the time of tumor resection, HBV genotype C, core promoter mutations, and patients with no antiviral treatment after tumor resection were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV viral load >2,000 IU/mL (4 log(10) copies/mL) (P= 0.001, odds ratio OR 22.3), AFP >1,000 ng/mL (P= 0.02, OR 7.4), tumor size >5 cm (P= 0.02, OR 5.1), and age >60 yr (P= 0.01, OR 4) at the time of tumor resection remained to be the independent risk factors.
Viral load of >2,000 IU/mL (4 log(10) copies/mL) is the most important correctable risk factor for HCC recurrence after resection. Whether antiviral therapy in these patients can decrease tumor recurrence requires further investigations.
Purpose: We aimed to investigate the effects of adiponectin on liver cancer growth and metastasis and explore the underlying mechanisms.
Experimental Design: An orthotopic liver tumor nude mice model ...with distant metastatic potential was applied. Either Ad-adiponectin (1 × 10 8 ; treatment group) or Ad-luciferase (control group) was injected via portal vein after tumor implantation. Tumor growth and
metastasis were monitored by Xenogen In vivo Imaging System. Hepatic stellate cell activation by α-smooth muscle actin staining, microvessel density by CD34 staining,
macrophage infiltration in tumor tissue, and cell signaling leading to invasion, migration Rho kinase (ROCK), IFN-inducible
protein 10 (IP10), and matrix metalloproteinase 9, and angiogenesis vascular endothelial growth factor (VEGF) and angiopoietin
1 were also compared. Tumor-nontumor margin was examined under electron microscopy. Direct effects of adiponectin on liver
cancer cells and endothelial cells were further investigated by a series of functional studies.
Results: Tumor growth was significantly inhibited by adiponectin treatment, accompanied by a lower incidence of lung metastasis. Hepatic
stellate cell activation and macrophage infiltration in the liver tumors were suppressed by adiponectin treatment, along with
decreased microvessel density. The treatment group had less Ki-67–positive tumor cells and downregulated protein expression
of ROCK1, proline-rich tyrosine kinase 2, and VEGF. Tumor vascular endothelial cell damage was found in the treatment group
under electron microscopy. In vitro functional study showed that adiponectin not only downregulated the ROCK/IP10/VEGF signaling pathway but also inhibited the
formation of lamellipodia, which contribute to cell migration.
Conclusion: Adiponectin treatment significantly inhibited liver tumor growth and metastasis by suppression of tumor angiogenesis and
downregulation of the ROCK/IP10/matrix metalloproteinase 9 pathway. Clin Cancer Res; 16(3); 967–77
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