Radiofrequency ablation (RFA) is considered a curative treatment option for hepatocellular carcinoma (HCC). Growing data have demonstrated that cryoablation represents a safe and effective alternative therapy for HCC, but no randomized controlled trial (RCT) has been reported to compare cryoablation with RFA in HCC treatment. The present study was a multicenter RCT aimed to compare the outcomes of percutaneous cryoablation with RFA for the treatment of HCC. In all, 360 patients with Child-Pugh class A or B cirrhosis and one or two HCC lesions £ 4 cm, treatment-na€ ıve, without metastasis were randomly assigned to cryoablation (n 5 180) or RFA (n 5 180). The primary endpoints were local tumor progression at 3 years after treatment and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (P 5 0.043). For lesions >3 cm in diameter, the local tumor progression rate was significantly lower in the cryoablation group versus the RFA group (7.7% versus 18.2%, P 5 0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 40% for cryoablation and 97%, 66%, and 38% for RFA, respectively (P 5 0.747). The 1-, 3-, and 5-year tumor-free survival rates were 89%, 54%, and 35% in the cryoablation group and 84%, 50%, and 34% in the RFA group, respectively (P 5 0.628). Multivariate analyses demonstrated that Child-Pugh class B and distant intrahepatic recurrence were significant negative predictors for overall survival. Major complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P 5 0.776). Conclusion: Cryoablation resulted in a significantly lower local tumor progression than RFA, although both cryoablation and RFA were equally safe and effective, with similar 5-year survival rates. (HEPATOLOGY 2015;61:1579-1590 See Editorial on Page 1465 H epatocellular carcinoma (HCC) is the sixth ranking cancer and the third leading cause of cancer-related mortality globally.1 The incidence of HCC in China accounts for 55% of all HCC cases worldwide.2 Although hepatic resection remains a first-line treatment for HCC and orthotopic liver transplantation (OLT) offers high rates of disease-free remission, only 10-15% of HCC patients are suitable for hepatic resection or OLT. Therefore, percutaneous local ablative techniques including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave (MV), and cryoablation (CRYO) have been the alternative options to unresectable HCC in cirrhosis patients.

Background The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced with one isoform containing an extended proline rich region (PRRL) compared to the other (PRRS). PRRL was recently reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remain unexplored. Main Results We report here that Numb PRRL expression is increased in HCC and is associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRRL generally promotes and PRRS suppresses proliferation, migration, invasion and colony formation. PRRS knockdown leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRRS knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor Rbfox2 and the kinase SRPK2. Rbfox2 knockdown causes accumulation of PRRL while SRPK2 knockdown causes accumulation of PRRS. SRPK2 subcellular location is regulated by the molecular chaperone Hsp90, and Hsp90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRRS. Finally, HCC cell lines that predominately express PRRL are differentially sensitive to Hsp90 inhibition. Conclusion Our data suggest that alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable.

PurposeTo evaluate the efficacy and safety of ultrasound (US)-guided percutaneous argon-helium cryoablation for hepatocellular carcinoma (HCC) and determine appropriate indications.MethodsWe reviewed outcomes of 300 HCC patients who underwent US-guided percutaneous cryoablation.ResultsOverall, 223 tumors (mean diameter 7.2 ± 2.8 cm) in 165 patients were incompletely ablated, while 185 tumors (mean diameter 5.6 ± 0.8 cm, P = 0.0001 vs. incomplete ablation) in 135 patients were completely ablated. Nineteen patients (6.3%) developed serious complications while in hospital, including cryoshock syndrome in six patients, hepatic bleeding in five, stress-induced gastric bleeding in four, liver abscess in one and intestinal fistulas in one. Two patients died because of liver failure. The median follow-up was 36.7 months (range 6–63 months). The local tumor recurrence rate was 31%, and was related to tumor size (P = 0.029) and tumor location (P = 0.037). The mean survival duration of patients with early, intermediate and advanced HCC (Barcelona Clinic Liver Cancer staging system) was 45.7 ± 3.8, 28.4 ± 1.2 and 17.7 ± 0.6 months, respectively.ConclusionsUS-guided percutaneous cryoablation is a relatively safe and effective therapy for selected HCC patients.

BackgroundAccumulating evidences have suggested that percutaneous cryoablation could be a valuable alternative ablation therapy for HCC but there has been no large cohort-based analysis on its long-term outcomes.MethodsA series of 866 patients with Child-Pugh class A-B cirrhosis and HCC within Milan criteria who underwent percutaneous cryoablation was long-term followed. The safety, efficacy, 5-year survival, and prognostic factors of percutaneous cryoablation in the treatment of HCC were analyzed.ResultsA total of 1197 HCC lesions were ablated with 1401 cryoablation sessions. Complete response (CR) was achieved in 1163 (97.2%) lesions and 832 (96.1%) patients with 34 (2.8%) major complications, but no treatment-related mortality. After a median of 30.9 months follow-up, 502 (60.3%) patients who achieved CR developed different types of recurrence. The cumulative local tumor recurrence rate was 24.2% at 5-years. Multiple tumor lesions, tumor size > 3 cm, and repeated ablation of same lesion were independent risk factors associated with local recurrence. The 5-year overall survival (OS) rates were 59.5%. Age < 36 years, HCC family history, baseline hepatitis B virus DNA >106 copies/ml, and three HCC lesions were independently and significantly negative predictors to the post-cryoablation OS.ConclusionsPercutaneous cryoablation is an effective therapy for patients with HCC within Milan criteria, with comparable efficacy, safety and long-term survival to the reported outcomes of radiofrequency ablation.

BackgroundEpigenetic alterations are well documented in hepatocarcinogenesis. However, hypomethylation of long interspersed nuclear element 1(LINE-1) promoter and its relationship with clinicopathological features in hepatocellular carcinoma (HCC) remain unknown.MethodsThe bisulfite-specific PCR and DNA sequencing analysis was performed to assess the methylation status of LINE-1 promoter in a pilot cohort of 71 patients with HCC. Additionally, methylation levels of two hot CpG sites of LINE-1 promoter, site 7 and 18 were measured by real-time PCR and compared with clinicopathological parameters in a cohort of 172 HCC. All the patients included were in BCLC stage A or B.ResultsMost patients with HCC (87.3%) showed hypomethylation of LINE-1 promoter compared with HBV-related cirrhosis and normal controls (P < 0.001). The HCC patients with LINE-1 promoter hypomethylation had a median tumour-free survival (TFS) and overall survival (OS) post-resection of 22.0 (95% CI: 13.3–30.7) months and 35.0 (95% CI: 24.0–46.1) months, respectively, compared with 40 months and ∼60 months for those with LINE-1 promoter hypermethylation (P < 0.05). Multivariate analyses showed that the hypomethylation level at CpG site 7 and 18 of LINE-1 promoter, along with tumour size and tumour differentiation, was independently associated with both TFS and OS for patients with HCC after resection.ConclusionPromoter hypomethylation of LINE-1, especially at the CpG site 7 and 18, was associated with a poor prognosis in HCC.