RFA for early-stage HCC is not superior to hepatic resection, in terms of tumour recurrence, overall survival and disease-free survival. Registration number: HKUCTR-10 (http://www.hkuctr.com).

Laparoscopic liver resection for HCC is associated with less blood loss, shorter hospital stay, and fewer postoperative complications in selected patients with no compromise in survival.

No abstract

Liver metastasis is the commonest form of distant metastasis in colorectal cancer. Selection criteria for surgery and liver-directed therapies have recently been extended. However, resectability remains poorly defined. Tumour biology is increasingly recognized as an important prognostic factor; hence molecular profiling has a growing role in risk stratification and management planning. Surgical resection is the only treatment modality for curative intent. The most appropriate surgical approach is yet to be established. The primary cancer and the hepatic metastasis can be removed simultaneously or in a two-step approach; these two strategies have comparable long-term outcomes. For patients with a limited future liver remnant, portal vein embolization, combined ablation and resection, and associating liver partition and portal vein ligation for staged hepatectomy have been advocated, and each has their pros and cons. The role of neoadjuvant and adjuvant chemotherapy is still debated. Targeted biological agents and loco-regional therapies (thermal ablation, intra-arterial chemo- or radio-embolization, and stereotactic radiotherapy) further improve the already favourable results. The recent debate about offering liver transplantation to highly selected patients needs validation from large clinical trials. Evidence-based protocols are missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team.

BACKGROUND: The current study was a phase 2 open–label study to evaluate the efficacy and tolerability of single‐agent sorafenib in the treatment of advanced HCC patients in a hepatitis B–endemic Asian population. METHODS: Patients with advanced hepatocellular carcinoma (HCC) received sorafenib at a dose of 400 mg twice daily in 4‐week cycles. Tumor response was assessed every 3 cycles using Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Fifty‐one patients were enrolled in the study and were treated with sorafenib for at least 12 weeks. The median age was 56 years (range, 28‐79 years). Approximately 90% had hepatitis B virus–related HCC. Thirty‐six (71%) patients had underlying Child‐Pugh A cirrhosis, 13 (26%) Child‐Pugh B, and 2 (3%) Child‐Pugh C. Four (8%) patients achieved partial responses, and 9 (18%) patients had stable disease for at least 12 weeks. The median overall survival was 5 months (range, 4‐17 months). Patients without extrahepatic spread, particularly without lung metastasis (P<.01), are more likely to benefit from sorafenib treatment. The most common toxicities were diarrhea (67%), malaise (55%), and hand‐foot‐skin reaction (54%). The majority of patients had transient liver function derangement. Patients with and without underlying portal vein thrombosis had similar therapeutic benefits and likewise shared a similar treatment‐related toxicity profile with sorafenib treatment. CONCLUSIONS: Single‐agent sorafenib demonstrates good efficacy and acceptable tolerability in treating an advanced HCC patient population in a hepatitis B–endemic area. The presence of lung metastasis predicts poor response to sorafenib in advanced HCC patients. Cancer 2009. © 2009 American Cancer Society.

Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential.Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies.Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation.Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.

Portal vein tumor thrombosis (PVTT) is a common phenomenon in hepatocellular carcinoma (HCC). Compared to HCC without PVTT, HCC with PVTT is characterized by an aggressive disease course, worse hepatic function, a higher chance of complications related to portal hypertension and poorer tolerance to treatment. Conventionally, HCC with PVTT is grouped together with metastatic HCC during the planning of its management, and most patients are offered palliative treatment with sorafenib or other systemic agents. As a result, most data on the management of HCC with PVTT comes from subgroup analyses or retrospective series. In the past few years, there have been several updates on management of HCC with PVTT. First, it is evident that HCC with PVTT consists of heterogeneous subgroups with different prognoses. Different classifications have been proposed to stage the degree of portal vein invasion/thrombosis, suggesting that different treatment modalities may be individualized to patients with different risks. Second, more studies indicate that more aggressive treatment, including surgical resection or locoregional treatment, may benefit select HCC patients with PVTT. In this review, we aim to discuss the recent conceptual changes and summarize the data on the management of HCC with PVTT.

ObjectiveWe investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.DesignHCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.ResultsWe showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.ConclusionsTaken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.