Clinical utility of postablation liver tumor biopsy and possibility of gene mutation analysis.

AIM: Radiofrequency ablation (RFA) is regarded as a first-line treatment for hepatocellular carcinoma (HCC) at an early stage. When treated with RFA, tumor biopsy may not be performed due to the risk of neoplastic seeding. We previously revealed that the risk of neoplastic seeding is significantly reduced by performing biopsies after RFA. In this study, we investigated the possibility of pathological evaluation and gene mutation analysis of post-RFA tumor specimens. METHODS: Radiofrequency ablation was undertaken on diethylnitrosamine-induced mouse liver tumor, and tumor samples with or without RFA were subjected to whole exome sequencing. Post-RFA human liver tumor specimens were used for detection of TERT promoter mutations and pathological assessment. RESULTS: The average somatic mutation rate, sites of mutation, and small indels and base transition patterns were comparable between the nontreated and post-RFA tumors. We identified 684 sites of nonsynonymous somatic substitutions in the nontreated tumor and 704 sites of nonsynonymous somatic substitutions in the post-RFA tumor, with approximately 85% in common. In the human post-RFA samples, the TERT promoter mutations were successfully detected in 40% of the cases. Pathological evaluation was possible with post-RFA specimens, and in one case, the diagnosis of adenocarcinoma was made. CONCLUSION: Our findings suggest that post-RFA liver tumor biopsy is a useful and safe method for obtaining tumor samples that can be used for gene mutation analysis and for pathological assessment.

Steroid administration for ischemic complications after radiofrequency ablation: A retrospective study.

AIM: The aim of this study was to evaluate the effects of steroids on ischemic complications after radiofrequency ablation. METHODS: A total of 58 patients with ischemic complications were divided into two groups according to corticosteroid use or non-use. RESULTS: A total of 13 patients who were administered steroids had a shorter duration of fever than those who were not administered steroids (median 6.0 vs. 2.0 days; p < 0.001). Linear regression analysis showed that steroid administration was associated with a reduction of 3.9 days in the duration of fever (p = 0.008). CONCLUSIONS: Steroid administration for ischemic complications after radiofrequency ablation may reduce the risk of fatal outcomes by blocking systemic inflammatory reactions.

Radiofrequency Ablation of Liver Tumors in Patients on Antithrombotic Therapy: A Case-Control Analysis of over 10,000 Treatments.

PURPOSE: To evaluate the safety of radiofrequency ablation (RFA) for liver tumors in patients on antithrombotic therapy. MATERIALS AND METHODS: A total of 10,653 consecutive RFA treatments in 3,485 patients with liver tumors were analyzed. The incidence of complications was analyzed on a treatment basis. The treatments for patients who had received antithrombotic medication up to 1 week prior to RFA comprised the antithrombotic therapy group (n = 806), and the others comprised the control group (n = 9,847). Antithrombotic agents were ceased prior to RFA (aspirin, ticlopidine, clopidogrel, and prasugrel ceased 7 days before RFA; cilostazol, 2 or 3 days before RFA; warfarin, 3 days before RFA; and direct oral anticoagulants, 1 day before RFA) and resumed as soon as possible after RFA. Logistic regression analysis was performed to assess whether the antithrombotic therapy increased the risk of hemorrhagic complications. RESULTS: Hemorrhagic complications were diagnosed after 6 treatments (0.7%) in the antithrombotic group and 48 (0.5%) in the control group, and there was no significant difference between the groups (P = .30). In 3 treatments, hemorrhage was diagnosed on or after 8 days of RFA, all of which were in the antithrombotic group. Thrombotic complications were diagnosed after 2 treatments (0.2%) in the antithrombotic group and after 5 (0.1%) in the control group. In a multivariate analysis, receiving antithrombotic therapy was not an independent risk factor for hemorrhagic complications (adjusted odds ratio, 1.52; 95% confidence interval, 0.60-3.87; P = .38). CONCLUSIONS: RFA of liver tumors in patients on antithrombotic therapy is generally safe with appropriate cessation and resumption. Late-onset hemorrhage should be noted in the patients on antithrombotic therapy.

Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy.

BACKGROUND & AIMS: It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C. METHODS: We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C). RESULTS: The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70). CONCLUSIONS: HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy. LAY SUMMARY: We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy.

Ischemic complications after percutaneous radiofrequency ablation of liver tumors: Liver volume loss and recovery.

AIM: The liver regrows after acute liver injury and liver resection. However, it is not clear whether the liver regenerates in advanced cirrhosis. This study aimed to evaluate the clinical course of, and liver volume change after, ischemic liver complications caused by radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: We enrolled 35 patients with ischemic complications after RFA. Ischemic complications were defined as rapid elevation of aspartate aminotransferase (AST) to over 500 U/L, with typical radiological findings. Patient characteristics and the ischemic liver volume were investigated. Long-term liver volume changes at 3-8 months after ischemic complications were also assessed in 32 patients. We also assessed the overall survival rate after ischemic complications. RESULTS: The median value of peak AST was 798 U/L (range, 531-4096 U/L). The median ischemic liver volume relative to the functional liver volume before RFA was 13% (range, 3.1-46.5%). There was a strong correlation between the peak AST value and the ischemic liver volume (r = 0.84, P < 0.001). The liver volume recovered to some extent in 18 of 32 (56%) patients after ischemic complications. The survival rate after ischemic complications was 45.7% at 5 years and correlated with the functional liver volume after ischemic complications (P = 0.02). CONCLUSIONS: Ischemic complications after RFA can lead to massive liver parenchymal loss. Although the liver volume recovered to some extent in the majority of our patients, ischemic liver complications after RFA should be avoided to improve the overall survival rate.

Early detection of bone metastases of hepatocellular carcinoma reduces bone fracture and paralysis.

BACKGROUND: With the improvement in survival of hepatocellular carcinoma patients, extrahepatic metastases have become a more frequent complication. Although pathological fractures or paralysis due to bone metastases deteriorate the quality of life of patients, no treatment guideline for bone metastases has been established. This study aimed to clarify the risk factors for these events and the clinical course of patients with bone metastases. METHODS: Out of 783 hepatocellular carcinoma patients treated in our institution between 2009 and 2016, 76 patients with bone metastases were enrolled. They were divided into two groups by the trigger of bone metastases detection. One was those diagnosed by surveillance (surveillance group), and the other was those based on symptom presentation (non-surveillance group). We investigated the clinical features, risk factors for fractures or paralysis and prognostic factors for survival after bone metastases. RESULTS: Baseline characteristics and survival were not significantly different between two groups. Fractures or paralysis occurred in 10 patients (13.2%), and the frequency was significantly higher in the non-surveillance group (20.9%) than the surveillance group (3.0%) in univariate analysis (p = 0.036). The median survival after diagnosis of bone metastases was 11.7 months. Age over 75 years (p = 0.002), hepatitis C-virus etiology (p = 0.007) and Child-Pugh class B/C (p < 0.001) were significantly associated with a shorter survival in multivariate analysis, but fractures or paralysis did not affect the survival. CONCLUSIONS: Early diagnosis through surveillance for hepatocellular carcinoma bone metastases may prevent fractures or paralysis and lead to a better quality of life for these patients.

Development of a transformer model for predicting the prognosis of patients with hepatocellular carcinoma after radiofrequency ablation.

INTRODUCTION: Radiofrequency ablation (RFA) is a widely accepted, minimally invasive treatment modality for patients with hepatocellular carcinoma (HCC). Accurate prognosis prediction is important to identify patients at high risk for cancer progression/recurrence after RFA. Recently, state-of-the-art transformer models showing improved performance over existing deep learning-based models have been developed in several fields. This study was aimed at developing and validating a transformer model to predict the overall survival in HCC patients with treated by RFA. METHODS: We enrolled a total of 1778 treatment-naïve HCC patients treated by RFA as the first-line treatment. We developed a transformer-based machine learning model to predict the overall survival in the HCC patients treated by RFA and compared its predictive performance with that of a deep learning-based model. Model performance was evaluated by determining the Harrel's c-index and validated externally by the split-sample method. RESULTS: The Harrel's c-index of the transformer-based model was 0.69, indicating its better discrimination performance than that of the deep learning model (Harrel's c-index, 0.60) in the external validation cohort. The transformer model showed a high discriminative ability for stratifying the external validation cohort into two or three different risk groups (p < 0.001 for both risk groupings). The model also enabled output of a personalized cumulative recurrence prediction curve for each patient. CONCLUSIONS: We developed a novel transformer model for personalized prediction of the overall survival in HCC patients after RFA treatment. The current model may offer a personalized survival prediction schema for patients with HCC undergoing RFA treatment.

Improved prognosis of hepatitis C-related hepatocellular carcinoma in the era of direct-acting antivirals.

The prognostic impact of direct-acting antivirals (DAAs) on patients with hepatitis C-related hepatocellular carcinoma (C-HCC) is still unclear. This study aimed to evaluate the prognosis of C-HCC in the DAA era. We enrolled 1237 consecutive patients with treatment-naive C-HCC who underwent radical radiofrequency ablation between 1999 and 2019. We also enrolled 350 patients with nonviral HCC as controls. We divided these patients into three groups according to the year of initial treatment: 1999-2005 (cohort 1), 2006-2013 (cohort 2), and 2014-2019 (cohort 3). The use of antiviral agents and their effect in patients with C-HCC was investigated. Overall survival was evaluated for each cohort using the Kaplan-Meier method and a multivariable Cox proportional hazards regression model. Sustained virologic response (SVR) was achieved in 52 (10%), 157 (26%), and 102 (74%) patients with C-HCC in cohorts 1-3, respectively. The 3- and 5-year survival rates of patients with C-HCC were 82% and 59% in cohort 1; 80% and 64% in cohort 2; and 86% and 78% in cohort 3, respectively (p = 0.003). Multivariable analysis adjusted for age, liver function, and tumor extension showed that the prognosis of C-HCC improved in cohort 3 compared to cohort 1 (adjusted hazard ratio [aHR], 0.49; 95% confidence interval [CI], 0.32-0.73; p < 0.001), whereas the prognosis of nonviral HCC did not improve significantly (aHR, 0.96; 95% CI, 0.59-1.57; p = 0.88). The prognosis of C-HCC drastically improved with the advent of DAAs.

Infectious complications related to radiofrequency ablation of liver tumors: The role of antibiotics.

BACKGROUND AND AIM: Prophylactic administration of antibiotics within 24 hours of surgery is recommended to reduce the risk of infection. We conducted a prospective study to compare the efficacy of single administration of antibiotics with a historical control of continuous administration of antibiotics for radiofrequency ablation (RFA) of malignant liver tumors. METHODS: Between February 1, 1999 and November 30, 2010, a total of 6,763 RFA treatments were performed in 2,355 patients, using a protocol with continuous administration of prophylactic antibiotics. On December 1, 2010, we began using a revised protocol with a single administration of prophylactic antibiotics, while continuing to use the old continuous administration protocol for patients who declined the new protocol. Interim analysis was performed to assess the safety of the single administration protocol. Thereafter, from April 1, 2012, all patients were treated using the new protocol. Risk factors for infectious complications of RFA were assessed using logistic regression. RESULTS: From December 2010 to March 2012, 766 RFA treatments were performed in 663 patients using the new antibiotic protocol. Infectious complications were observed following 4 of these treatments (0.52%). As the upper limit of the confidence interval (CI) resulting from a one-sided binomial test was exactly the prespecified limit of 1.0%, from April 2012 onwards, we treated all patients using the new protocol with single administration of prophylactic antibiotics. A total of 3,547 RFA treatments were performed using the single administration protocol. Univariable logistic regression indicated that prior transcatheter arterial chemoembolization (TACE) and maximal tumor diameter were significant risk factors for infectious complications (P = 0.04 and P < 0.001, respectively). Multivariable analysis indicated that the adjusted hazard ratio of single vs. continuous administration of antibiotics was 1.20 (95% CI: 0.53-2.75; P = 0.66). CONCLUSIONS: The rate of infectious complications related to RFA was acceptably low. Single administration of prophylactic antibiotics did not significantly increase the rate of infectious complications related to RFA, compared with a more intensive antibiotic protocol.

Post-treatment cell-free DNA as a predictive biomarker in molecular-targeted therapy of hepatocellular carcinoma.

BACKGROUND: Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA), are rapidly emerging as a non-invasive alternative to tumor biopsies. However, clinical applications of ctDNA analysis in hepatocellular carcinoma (HCC) have not been fully elucidated. METHODS: We measured the amount of plasma-derived cell-free DNA (cfDNA) in HCC patients before (n = 100) and a few days after treatment (n = 87), including radiofrequency ablation, transarterial chemoembolization, and molecular-targeted agents (MTAs), and prospectively analyzed their associations with clinical parameters and prognosis. TERT promoter mutations in cfDNA were analyzed using droplet digital PCR. Furthermore, we performed a comprehensive mutational analysis of post-treatment cfDNA via targeted ultra-deep sequencing (22,000× coverage) in a panel of 275 cancer-related genes in selected patients. RESULTS: Plasma cfDNA levels increased significantly according to HCC clinical stage, and a high cfDNA level was independently associated with a poor prognosis. TERT promoter mutations were detected in 45% of all cases but were not associated with any clinical characteristics. cfDNA levels increased significantly a few days after treatment, and a greater increase in post-treatment cfDNA levels was associated with a greater therapeutic response to MTAs. The detection rate of TERT mutations increased to 57% using post-treatment cfDNA, suggesting that the ctDNA was enriched. Targeted ultra-deep sequencing using post-treatment cfDNA after administering lenvatinib successfully detected various gene mutations and obtained promising results in lenvatinib-responsive cases. CONCLUSIONS: Post-treatment cfDNA analysis may facilitate the construction of biomarkers for predicting MTA treatment effects.

Improved liver function in patients with cirrhosis due to chronic hepatitis C virus who achieve sustained virologic response is not accompanied by increased liver volume.

BACKGROUND: Serum albumin level improves in patients with chronic hepatitis C virus (HCV) infection who achieve sustained virologic response (SVR) with antiviral therapy. However, it remains controversial whether liver volume increases along with SVR. METHODS: Patients with chronic HCV infection with a history of hepatocellular carcinoma (HCC) who achieved SVR with anti-HCV treatment from March 2003 to November 2017 were enrolled. Patients were followed up with periodic computed tomography (CT) scans to detect HCC recurrence. Patients who underwent treatment for HCC recurrence within 1 year after initiation of anti-HCV treatment were excluded. Laboratory data, including alanine aminotransferase (ALT) level, serum albumin level, and platelet count, were collected at baseline and timepoints after treatment initiation. Liver volume was evaluated at baseline and 24 and 48 weeks after treatment initiation using a CT volume analyzer. A linear mixed-effects model was applied to analyze the chronologic change in liver volume. The correlations between changes in ALT level, albumin level, and liver volume were also evaluated. RESULTS: Of 108 enrolled patients, 78 had cirrhosis. Serum albumin level continued to increase through 48 weeks after treatment initiation. A significant increase in liver volume was observed only in patients without cirrhosis (P = 0.005). There was a significant correlation between ALT level decrease and albumin level increase (P = 0.018). CONCLUSIONS: Improved liver albumin production with SVR was contributed by improved liver cell function rather than increased liver volume in patients with cirrhosis.

A Novel Non-invasive Method for Predicting Liver Fibrosis by Quantifying the Hepatic Vein Waveform.

The hepatic vein (HV) waveform by Doppler ultrasound reflects the severity of liver fibrosis. We conducted a proof-of-concept study of a new method for quantifying the HV waveform. We calculated the coefficient of variation (CV) of the HV flow velocity and created a new index "q-HV" (quantified HV) and analyzed its performance for predicting histologic liver fibrosis in 114 patients with chronic liver disease. The CV of the HV flow velocity was well associated with flattening of the waveform and the q-HV significantly increased with the progression of liver fibrosis. The areas under the curve for the prediction of fibrosis stage were 0.732 for F2, 0.772 for F3 and 0.805 for F4. Combined q-HV and FIB-4 index (widely used liver fibrosis score) increased the diagnostic accuracy for liver fibrosis. The q-HV showed good accuracy for predicting liver fibrosis; thus, q-HV is feasible and acceptable as a non-invasive tool for predicting liver fibrosis.