Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to !40 C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (d max ) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA AE LTLD. The 701 enrolled patients had to have 4 unresectable HCC lesions, at least one of which had a d max of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-totreat analysis, the PFS HR of RFA þ LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P ¼ 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P ¼ 0.67). Among 285 patients with a solitary HCC lesion who received !45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA þ LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA þ LTLD efficacy is improved when RFA dwell time for a solitary lesion !45 minutes. Clin Cancer Res; 24(1); 73-83.Ó2017 AACR.

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To assess the efficacy of combining radioimmunoconjugate [(131)I] metuximab with radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) treatment compared with RFA alone, a single-center randomized controlled trial was conducted on 127 patients with Barcelona Clinic Liver Cancer staging system (BCLC) classifications of 0-B stage. Patients received either RFA followed by [(131)I] metuximab (n = 62) or RFA alone (n = 65). The primary outcome was overall tumor recurrence. Statistical tests were two-sided. The one- and two-year recurrence rates in the combination group were 31.8% and 58.5%, whereas those in the RFA group were 56.3% and 70.9%, respectively. The median time to overall tumor recurrence was 17 months in the combination group and 10 months in the RFA group (P = .03). The RFA-[(131)I] metuximab treatment showed a greater antirecurrence benefit than RFA in the metuximab target (ie, CD147)-positive subpopulation (P = .007). [(131)I] metuximab may yield prevention of tumor recurrence after RFA.

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BackgroundHepatocellular carcinoma (HCC) is prevalent worldwide and early diagnosis of HCC is critical for effective treatment and optimal prognosis.MethodsSerum was screened first by immunoproteomic analysis for HCC-related tumor associated antigens (TAAs). Selected TAAs were clinically evaluated retrospectively in patients with HCC, liver cirrhosis, chronic hepatitis and healthy controls. Levels of autoantibody to the selected TAAs were measured by protein microarrays containing protein antigens of the candidate TAAs. Analyses were done by using receiver operating characteristics (ROC) to calculate diagnostic accuracy.FindingsTwenty-two candidate TAAs were assessed by protein microarray analysis in 914 participants with serum α-fetoprotein (AFP) available. Twelve candidate TAAs were statistically different in signal intensity between HCC and controls. Among them, CENPF, HSP60 and IMP-2 showed AUC (area under the curve) values of 0.826, 0.764 and 0.796 respectively for early HCC. The highest prevalence of autoantibody positivity was observed in HCC cases with BCLC tumor stage A, well-differentiated histology and Child-Pugh grade C. Specifically, 73.6% or 79.3% cases of early HCC with negative AFP were positive for autoantibody to CENPF or HSP60.InterpretationTumor-associated autoimmune reactions may be triggered by early stage HCCs. Measurement of serum autoantibody to TAAs may be complementary to AFP measurements and improve diagnosis of early HCC.

This study was carried out to evaluate the effects of a Huaier polysaccharide (TP-1) on the tumor growth and immune function in hepatocellular carcinoma (HCC) H22-based mouse in vivo. Results showed that TP-1 was capable of repressing transplanted H22 solid hepatic tumor cell growth in vivo, prolonging the live time of mice bearing ascetic H22 tumors, and repressing the pulmonary metastasis of H22-bearing mice. Moreover, the relative weight of immune organ (spleen and thymus) and lymphocyte proliferation were improved after TP-1 treatment. Furthermore, the treatment with TP-1 could promote immune-stimulating serum cytokines, such as IL-2 and IFN-γ, but inhibit immune-suppressing serum cytokines IL-10 secretion in H22-bearing mice. Besides, the percentage of CD4+ T cells and NK cells was increased, whereas the number of CD8+ T cells decreased in tumor-bearing mice following TP-1 administration. In addition, this compound displayed little toxic effects to major organ of tumor-bearing mice at the therapeutic dose, such as the liver and kidney. This experimental finding suggested that TP-1 exhibited prominent antitumor activities in vivo via enhancement of host immune system function in H22 tumor-bearing mice. This product could be developed individually as a safe and potent biological response modifier for HCC therapy.

BackgroundIn the advanced stages of hepatocellular carcinoma (HCC), a tumor thrombus (TT) can form in the portal or hepatic vein. The management of patients with advanced HCC and a TT extending into the right atrium (RA) and inferior vena cava (IVC) is extremely difficult and risky.Case presentationWe report the case of a patient with HCC and a large TT (85 × 45 mm) extending into the RA through the hepatic vein and IVC, which is very rare. We performed percutaneous microwave ablation of the TT and the two intrahepatic tumors (maximum diameter, 57 mm). The treatment shrank the tumors, and the patient is in good condition and has survived for 16 months thus far. A literature review was also performed. This is the first such case to be treated with percutaneous microwave ablation.ConclusionThe outcomes in this case suggest that percutaneous ablation is useful for the treatment of TT extending into the RA and IVC in patients with HCC.

The role of cancer stem cells (CSCs) in inducing the recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains unclear. Here, we found that a dramatic increase in plasma vascular endothelial growth factor (VEGF) and an induction of local CD133+ CSCs are associated with early HCC recurrence, suggesting that VEGF expression and tumour stemness contribute to the relapse. In vitro studies demonstrated that VEGF, via activation of VEGFR2, increased the number of CD133+ CSCs and enhanced their capacity for self-renewal by inducing the expression of Nanog. In vivo studies further demonstrated that VEGF-treated CD133+ CSCs formed tumours larger than those developing from unstimulated cells and VEGF pre-treatment increased the tumorigenic cell frequency of primary HCC cells dependently on the presence of Nanog and VEGFR2. In HCC tissue derived from patients with early recurrence, almost all CD133+ cells were Nanog and p-VEGFR2 positive, suggesting that activation of VEGFR2 is critical for RFA-induced tumour stemness in HCC. In summary, RFA-induced VEGF promotes tumour stemness and accelerates tumourigenesis in HCC in a manner dependent on Nanog and VEGFR2, which is valuable for the prediction of HCC recurrence after RFA and the development of novel therapeutics.