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Abstract Background We aimed to identify the main determinants of long-term overall survival (OS), including virologic control, and recurrence after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) on cirrhosis. Methods Cirrhotic patients treated by RFA for HCC within Milan criteria were included. Associations between patient features and events were estimated by the Kaplan–Meier method with the log rank test and using uni/multivariate Cox models. Results 389 cirrhotic patients (Child–Pugh A 86.6%, 473 tumors) were included. OS was 79.8%, 42.4% and 16%, and overall tumor recurrence 45%, 78% and 88% at 2, 5 and 10 years, respectively. In multivariate analysis, age, Child–Pugh, GGT, HCC near major vessels, esophageal varices, alkaline phosphatase and HBV predicted OS. Gender, ALT, AFP and alcohol intake were associated with tumor recurrence. Multinodular HCC (19.5%) was associated with risk of tumor recurrence outside Milan criteria. HBV patients had longer OS than other patients (P = 0.0059); negative HBV PCR at RFA was associated with decreased tumor recurrence (P = 0.0157). Using time-dependent analysis in HCV patients, a sustained virologic response was associated with increased OS (124.5 months) compared to other patients (49.2 months, P < 0.001). Conclusion Virologic response and severity of underlying liver disease were the main determinants of long-term OS after RFA for HCC developing on cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence. Methods We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs). Results A pathological study identified hepatocellular adenomas and well-differentiated carcinomas in both patients. Tumors exhibited Wnt/β-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations ( p = 0.03). miRNA profiling identified a specific expression profile in DICER1 -mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations. Conclusions Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with β-catenin activation. Lay summary DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs. [ABSTRACT FROM AUTHOR]

Background Prognostic biomarkers are needed in a heterogeneous population of patients with intermediate hepatocellular carcinoma (HCC) treated by transarterial (chemo)embolization. We aimed to validate the prognostic value of serum CRP levels and the STATE score, combining CRP, albumin and tumor burden. Methods All cirrhotic patients with HCC treated by a first transarterial (chemo)embolization (2007–2013) in our institution were included. Overall survival was assessed using the Kaplan–Meier method, log rank, univariate and multivariate Cox analyses. Results Among 157 patients included, 87% were men, 86% had Child Pugh A. Etiologies of liver disease included alcohol (57%), hepatitis C (32%), hepatitis B (11%) and/or metabolic syndrome (32%); 89% of patients were classified BCLC B. 33% of the patients had a CRP >1 mg/dl and 33% a STATE score conferring poor prognosis (<18). Patients with CRP <1 mg/dl had better overall survival than patients with CRP >1 mg/dl (20 vs. 8 months, P = 0.00186). Median overall survival was 6.73 months for patients with a STATE score <18 vs. 22.23 months for patients with STATE-score ≥18 ( P = 0.0002). In multivariate analysis, a STATE score <18 was independently associated with increased mortality (HR: 2.06 (CI95%: 1.28–3.34), P = 0.0031). Conclusion In cirrhotic patients with HCC who underwent transarterial treatment, serum CRP level and STATE score at baseline can predict overall survival. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To compare histopathologically the completeness of radiofrequency (RF) ablation to treat hepatocellular carcinoma (HCC) with monopolar or multipolar technique. Materials and Methods: Thirty-five consecutive patients (mean age, 59 y) with cirrhosis and HCC (n = 59) within Milan criteria received RF ablation and subsequently underwent liver transplantation (LT) for tumor progression or liver failure. Data were extracted retrospectively from a prospective database. Thirty nodules were treated with a monopolar device with internally cooled (n = 17) or perfused (n = 13) electrodes, and 29 were treated with a multipolar technique with internally cooled electrodes based on the “no-touch” concept. This consisted of inserting two or three straight electrodes around the nodule to avoid intratumor puncture to the greatest extent possible. Effectiveness of the three devices was compared by histopathologic examination of explants. Fisher exact and χ2 tests and multivariate logistic regression analysis were performed. Results: Mean sizes of nodules ablated (25, 22, and 21.6 mm) and median times from ablation to LT (11, 7.5, and 8.4 months) for patients treated with the monopolar internally cooled electrode device (MoICD), monopolar perfused electrode device (MoPED), and multipolar internally cooled electrode device (MuICD), respectively, were similar (P = .8 and P = .9, respectively). Pathologic examination showed complete necrosis for eight of 17 and six of 13 nodules treated with the MoICD and MoPED, respectively, versus 26 of 29 treated with the MuICD (P = .0019). In multivariate analysis, RF technique remained the predictive factor for complete necrosis (P = .005). Conclusions: Ablation of small HCCs with multipolar RF ablation based on the no-touch concept improves the rate of complete necrosis during pathologic examination compared with monopolar techniques. [Copyright &y& Elsevier]

Purpose: To compare the results of radiofrequency (RF) ablation with internally cooled electrodes (ICEs) versus perfused electrodes (PEs) in patients with cirrhosis with small (≤3 cm) hepatocellular carcinoma ineligible for resection. Materials and Methods: Patients treated with RF ablation over two consecutive periods were analyzed retrospectively. From 2000 to 2002, 45 patients were treated with 17-gauge ICEs, and from 2002 to 2004, 44 patients were treated with 15-gauge PEs. The two groups were similar in age, sex, Child-Pugh stage, serum α-fetoprotein (AFP) level, and size and number of tumors (54 tumors in each group). Results were assessed by contrast medium–enhanced CT. Results: In both groups, 52 of 54 tumors (96.3%) were completely ablated. Eight of 54 tumors (14.8%) treated with ICEs and 39 of 54 tumors (72.2%) treated with PEs required multiple RF applications (P < .00005). In the respective groups, one of 54 tumors (1.8%) and seven of 54 tumors (12.9%) required multiple RF sessions (P = .03). Complication rates were similar. The 2-year probabilities of local and distant (ie, separated from the ablation zone) tumor progression in the ICE and PE groups were 11% and 15%, respectively (P = .65), and 31% and 64% (P = .01), respectively. On multivariate analysis, serum AFP level greater than 100 ng/mL (P = .006) and the use of a PE (P = .003) were risk factors for distant tumor progression. Conclusions: RF ablation with the use of a PE requires more applications and sessions and is associated with a higher risk of distant tumor progression compared with the use of an ICE. [Copyright &y& Elsevier]

PURPOSE: To evaluate the effectiveness of radiofrequency (RF) ablation for liver tumors located in the caudate lobe. MATERIALS AND METHODS: Ten patients (46–79 years of age; median, 70 y), eight with hepatocellular carcinoma (HCC) and cirrhosis and two with colorectal metastases in the caudate lobe, were treated with 5.8% NaCl tissue-perfused monopolar (n = 7) or bipolar (n = 3) RF ablation. The median tumor diameter was 41 mm (range, 25–70 mm). Procedures were performed under ultrasound and computed tomography (CT) guidance in eight and two patients, respectively. One month later, the treatment response was assessed by CT. RESULTS: Transhepatic right intercostal and transomental anterior epigastric routes were used for tumor puncture in eight and two patients, respectively. The entire RF ablation treatment required one or two procedures (median, 1.5), including two to 15 electrode repositionings (median, 6). After RF ablation procedure, one patient experienced jaundice that resolved spontaneously. In one patient, CT follow-up showed asymptomatic segmental biliary duct dilations. Median total hospital stay was 3 days (range, 2–9 d). Complete ablation was achieved in nine of 10 tumors. In one patient, ethanol ablation was necessary to complete RF ablation treatment. After a median follow up of 9.5 months (range, 5–25 mo), three patients remained tumor-free and seven had tumor relapse: two local, four distant, and one mixed. Repeat RF ablation was successfully performed in four cases. CONCLUSION: RF ablation of liver tumors located in the caudate lobe is effective despite the deep location of tumors and the vicinity of major vessels. [Copyright &y& Elsevier]

Background & Aims The primary aim of this study was to compare the rate of global radiofrequency ablation (RFA) failure between monopolar RFA (MonoRFA) vs. no-touch multi-bipolar RFA (NTmbpRFA) for small hepatocellular carcinoma (HCC) ⩽5 cm in cirrhotic patients. Methods A total of 362 cirrhotic patients were included retrospectively across four French centres (181 per treatment group). Global RFA failure (primary RFA failure or local tumour progression) was analysed using the Kaplan-Meier method after coarsened exact matching. Cox regression models were used to identify factors associated with global RFA failure and overall survival (OS). Results Patients were well matched according to tumour size (⩽30/>30 mm); tumour number (one/several); tumour location (subcapsular and near large vessel); serum AFP (<10; 10–100; >100 ng/ml); Child-Pugh score (A/B) and platelet count (30 mm and HCC near large vessel were independent factors associated with global RFA failure. Five-year OS was 37.2% following MonoRFA vs. 46.4% following NTmbpRFA p = 0.378. Conclusions This large multicentre case-matched study showed that NTmbpRFA provided better primary RFA success and sustained local tumour response without increasing severe complications rates, for HCC ⩽5 cm. Lay summary Using no-touch multi-bipolar radiofrequency ablation for hepatocellular carcinoma ⩽5 cm provide a better sustained local tumour control compared to monopolar radiofrequency ablation. [ABSTRACT FROM AUTHOR]

Background & Aims: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA. Methods: All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson’s grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models. Results: 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-ß-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p =0.045) and ESM-1 expression (HR 1.56 [1.004; 2.43], p =0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 [1.02; 3.21], p =0.042). Conclusions: ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA. [ABSTRACT FROM AUTHOR]

Background & Aims: In patients with hepatocellular carcinoma (HCC) within the Milan criteria, liver transplantation (LT) may be the best therapeutic option. However, the shortage of grafts, leads to attempt liver resection (LR) or radiofrequency ablation (RFA) as a first-line treatment for patients with Child-Pugh A cirrhosis. Methods: We report results, obtained between 2000 and 2007 from a single center, involving 67 patients (mean age: 57years) eligible for LT, who were treated with RFA, followed by LT if there was recurrence or liver failure. Results: Eighty three tumors were treated (mean size: 29±9mm; 16 binodular forms). RFA achieved complete ablation in 96% of nodules. No mortality occurred. During a post-RFA median follow-up of 48months, 38 patients experienced recurrence, corresponding to a 5-year recurrence rate of 58%. Of these, 14 patients did not receive a transplant because they fell outside the Milan criteria, 21 were transplanted, and 3 were treated by RFA after refusing LT. Binodularity (95% CI HR=2, 1.0–4.0; p =0.049) was the unique risk factor for recurrence. By the study’s end-point, 24 patients had undergone LT (21 for HCC recurrence and three for liver failure). No HCC recurrence occurred after LT. Among the 43 non-transplant patients, 12 died due to HCC progression, and 27 were alive without detectable viable tumor. The probability rates for 5-year overall and tumor-free survival were 74% and 69%, respectively. Conclusions: First line RFA followed by salvage LT allows survival figures that are at least as good as a first-line LT, while limiting the number of grafts. [ABSTRACT FROM AUTHOR]