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Purpose:We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).Patients and Methods:This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results:Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.Conclusions:Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.See related commentary by Pinato et al., p. 908

Supplementary Methods, Supplementary Figure S1-4, Supplementary Table S1-8

Objectives Effective and non-invasive biomarkers to predict and avoid posthepatectomy liver failure (PHLF) are urgently needed. This systematic review aims to evaluate the efficacy of gadoxetic acid–enhanced MRI-derived parameters as an imaging biomarker in preoperative prediction of PHLF. Methods A systematic literature search was performed in the databases of PubMed/Medline, Web of Science, Embase, and Cochrane Library up to 11 December 2020. Studies evaluating the incidence of PHLF on patients who underwent hepatectomy with preoperative liver function assessment using gadoxetic acid–enhanced MRI were included. Data was extracted using pre-designed tables. The Quality In Prognostic Studies (QUIPS) tool was adopted to evaluate the risk of bias. Results A total of 15 studies were identified for qualitative synthesis and most studies were marked as low to moderate risk of bias in each domain of QUIPS. The most commonly used parameter was relative liver enhancement or its related parameters. The reported incidence of PHLF ranged from 3.9 to 40%. The predictive sensitivity and specificity of gadoxetic acid–enhanced MRI parameters varied from 75 to 100% and from 54 to 93% in ten reported studies. A majority of the studies revealed that the gadoxetic acid–enhanced MRI parameter was a predictor for PHLF. Conclusions Gadoxetic acid–enhanced MRI showed a high predictive capacity for PHLF and represents a promising imaging biomarker in prediction of PHLF. Multicenter, prospective trials with large sample size and reliable, unified liver function parameters are required to validate the efficacy of individual liver function parameters. Key Points • There is an obvious heterogeneity of the published studies, not only in variance of MRI liver function parameters but also in indication and extent of the liver resection. • Signal intensity (SI)–based parameters derived from gadoxetic acid–enhanced MRI are the commonly used method for PHLF prediction. • Gadoxetic acid–enhanced MRI-derived parameters showed high predictive efficacy for PHLF and can potentially serve as a predictor for the incidence of PHLF.

To compare the short- and long-term treatment outcomes of open radiofrequency ablation combined with splenectomy and pericardial devascularization versus liver transplantation for hepatocellular carcinoma patients with portal hypertension and hypersplenism.During the study period, the treatment outcomes of consecutive HCC patients with portal hypertension and hypersplenism who underwent open radiofrequency ablation, splenectomy and pericardial devascularization (the study group) were compared with the treatment outcomes of a case-matched control group of HCC patients who underwent liver transplantation.The study group consisted of 32 patients, and the control group comprised 32 patients selected from 155 patients who were case-matched by tumor size, age, gender, MELD sore, tumor location, TNM classification, degree of splenomegaly and Child-Pugh staging. Baseline data on preoperative laboratory tests and tumor characteristics were comparable between the two groups. The mean follow-up was 43.2 ± 5.3 months and 44.9 ± 5.8 months for the study and control groups, respectively. Although the disease-free survival rates of the control group were better than those of the study group (Open radiofrequency ablation, splenectomy and pericardial devascularization for small HCCs with portal hypertension and hypersplenism can be an alternative therapy for a subset of carefully selected patients under the shortage of liver donors.

Microvascular invasion (MVI) affects recurrence after treatment of small hepatocellular carcinoma (sHCC) of ≤3 cm in size. The present study aimed to investigate whether abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and intermuscular adipose tissue (IMAT) are associated with MVI in patients with sHCC.A total of 124 patients with pathologically-confirmed sHCC diagnosed on surgical resection at the First Hospital Affiliated to Army Military University were recruited and divided into two groups according to MVI classification criteria (i.e., MVI-positive or MVI-negative). The SAT, VAT, and IMAT areas at the lumbar 3 vertebral level were imaged with abdominal computed tomography and measured using ImageJ software. Their association with MVI in sHCC was analyzed.Of the 124 patients with sHCC, 67 were MVI-positive and 57 were MVI-negative. Univariate analysis revealed a significant difference in the abdominal VAT and SAT between the MVI-positive and MVI-negative groups (The results of this study suggest that the areas of abdominal SAT and VAT are of significant clinical value because they can effectively predict the MVI status in patients with sHCC.

Background The future liver remnant (FLR) faces a risk of poor growth in patients with cirrhosis-related hepatocellular carcinoma (HCC) after stage-1 radiofrequency-assisted ALPPS (RALPPS). The present study presents a strategy to trigger further FLR growth using supplementary radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI). Methods At RALPPS stage-1 the portal vein branch was ligated, followed by intraoperative RFA creating a coagulated avascular area between the FLR and the deportalized lobes. During the interstage period, patients not achieving sufficient liver size (≥ 40%) within 2–3 weeks underwent additional percutaneous RFA/PEI of the deportalized lobes (rescue RFA/PEI) in an attempt to further stimulate FLR growth. Results Seven patients underwent rescue RFA/PEI after RALPPS stage-1. In total five RFAs and eight PEIs were applied in these patients. The kinetic growth rate (KGR) was highest the first week after RALPPS stage-1 (10%, range − 1% to 15%), and then dropped to 1.5% (0–9%) in the second week (p Conclusions Rescue RFA/PEI may provide an alternative to trigger further growth of the FLR in patients with cirrhosis-related HCC showing insufficient FLR after RALPPS stage-1. Trial registration Retrospectively registered.

Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908

BACKGROUND This study aimed to evaluate whether combined therapy with PD-1 blockade (anti-PD-1) and radiofrequency ablation (RFA) is superior to RFA monotherapy for recurrent hepatocellular carcinoma (HCC). METHODS A total of 127 patients who underwent anti-PD-1 plus RFA treatment (n = 41) or RFA alone (n = 86) for recurrent HCC were included in this retrospective study. A matched cohort comprising 40 patients from each group was selected after propensity score matching analysis. Clinical data including post-RFA HCC recurrence (primary endpoint), overall survival (OS) (secondary endpoint), adverse events, and toxic effects were retrospectively analyzed. RESULTS The 1-year recurrence-free survival rates for the anti-PD-1 plus RFA and RFA groups were 32.5% and 10.0% after propensity score matching. There were statistically significant differences between the two groups in terms of the recurrence-free survival rate (p = 0.001) and OS rate (p = 0.016). Tumor number, tumor-node metastasis (TNM) stage, antiviral therapy, and anti-PD-1 treatment were demonstrated to be important factors associated with 1-year recurrence-free survival probability by univariate and multivariate analyses. Univariate and multivariate analyses demonstrated that tumor number, TNM stage and anti-PD-1 treatment were significant prognostic factors for OS. RFA treatment-related adverse events included pleural effusions that require drainage and a mild or moderate increase in body temperature. Grade 3 or higher events related to anti-PD-1 treatment occurred in 12.8% (6) of patients and were infrequent. CONCLUSIONS Combination therapy with anti-PD-1 plus RFA was superior to RFA alone in improving survival in patients with recurrent HCC.

Objective This study aimed to retrospectively evaluate the safety and short-term therapeutic efficacy of radiofrequency ablation (RFA) with a multiple-electrode switching system (MESS) to treat medium-sized (3.1–5.0 cm) hepatocellular carcinomas (HCCs). Summary of Background Data Conventional monopolar RFA is limited in achieving local control for tumors larger than 3 cm. Therefore, MESS-RFA was developed, and it can create a sufficiently large ablation volume, including the target tumor and a 5- to 10-mm safety margin in medium-sized tumors. Methods We performed a total of 168 RFAs with a MESS for 166 patients. The patients were treated under ultrasonographic guidance by a percutaneous switching system RFA with a multichannel RF generator and 2 or 3 internally cooled electrodes. Technical effectiveness, local progression, and remote recurrence of HCC were determined. Results For the 166 isolated HCC tumors, the complete ablation rate of MESS-RFA was 98.79% (164 of 166). Mean ablation time per procedure was 12.33 ± 3.01 minutes; mean ablation diameter was 5.79 ± 0.61 cm. The complication rate was 2.41%. During follow-up (averaging 16.54 months), local tumor progression occurred in 15 of 166 patients (9.03%) with technical effectiveness, whereas new HCCs were detected in 40 of 166 patients (24.09%). Multivariate analyses revealed that local tumor progression was only associated with serum α-fetoprotein levels above 100 ng/mL as a risk factor. Conclusion MESS-RFA for achieving sufficient ablation volume is safe and efficient. This method also showed relatively successful therapeutic effectiveness on short-term follow-up in the treatment of medium-sized HCCs.

The therapeutic efficacy of radiofrequency ablation (RFA) against liver cancer is often limited by proliferation and metastasis of residual tumor cells. These phenomena are closely associated with the Warburg effect, wherein ErbB2 is activated. While RFA inhibits the Warburg effect of residual tumor cells at the early stage, the specific mechanisms remain unclear. We explored the regulatory relationship between the long noncoding RNA ENST00000570843.1 (lncENST) and ErbB2 using lentiviral transfection of lncENST and ErbB2 overexpression/interference vectors in in vitro and in vivo models of hepatocellular carcinoma in the presence of sublethal heat at 50°C. ErbB2-mediated Warburg effect was suppressed by lncENST, as manifested by reduced glucose uptake and lactic acid production in SMMC-7721 cells. lncENST also increased tumor apoptosis and inhibited tumor progression in nude Balb/c mice for up to 28 days after RFA. Additionally, we predicted through bioinformatic analysis that the promoter of ErbB2 binds to the transcription factor Nkx2-5, resulting in a negative regulatory effect. This speculation was confirmed by chromatin immunoprecipitation of the Nkx2-5 protein and ErbB2, indicating that ErbB2 transcription was curbed by Nkx2-5. We propose that lncENST downplays the Warburg effect in residual tumor cells by downregulating ErbB2 via Nkx2-5 activation. This study is aimed at providing molecular targets that can prevent residual tumor cell proliferation after RFA, with clinical significance in hepatocellular carcinoma treatment.

Background: To evaluate the feasibility and efficacy of sequential portal vein embolization (PVE) and radiofrequency ablation (RFA) (PVE+RFA) as a minimally invasive variant for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) stage-1 in treatment of cirrhosis-related hepatocellular carcinoma (HCC).Methods: For HCC patients with insufficient FLR, right-sided PVE was first performed, followed by percutaneous RFA to the tumor as a means to trigger FLR growth. When the FLR reached a safe level (at least 40%) and the blood biochemistry tests were in good condition, the hepatectomy was performed. FLR dynamic changes and serum biochemical tests were evaluated. Postoperative complications, mortality, intraoperative data and long-term oncological outcome were also recorded.Results: Seven patients underwent PVE+RFA for FLR growth between March 2016 and December 2019. The median baseline of FLR was 353 ml (28%), which increased to 539 (44%) ml after 8 (7–18) days of this strategy (p < 0.05). The increase of FLR ranged from 40% to 140% (median 47%). Five patients completed hepatectomy. The median interval between PVE+RFA and hepatectomy was 19 (15–27) days. No major morbidity ≥ III of Clavien-Dindo classification or in-hospital mortality occurred. One patient who did not proceed to surgery died within 90 days after discharge. After a median follow-up of 18 (range 3–50) months, five patients were alive.Conclusion: Sequential PVE+RFA is a feasible and effective strategy for FLR growth prior to extended hepatectomy and may provide a minimally invasive alternative for ALPPS stage-1 for treatment of patients with cirrhosis-related HCC.

Background Radiofrequency ablation (RFA) is one of the definitive treatment modalities for liver cancer and has been increasingly used in the scenario of small-sized liver cancer. It is generally believed that RFA is minimally invasive and associated with a favorable safety profile in liver cancer patients. However, this interventional technique is subject to some morbidity in high-risk patients, such as those with complicating cirrhosis or a liver cancer located at a refractory segment. Methods Herein, we report the case of a middle-aged woman who developed acute liver failure with a complicating respiratory failure after RFA of recurrent intrahepatic cholangiocarcinoma. Results A diagnosis of hepatopulmonary syndrome was established. The patient was hospitalized in the intensive care unit for mechanical ventilation. Finally, the patient recovered from an eventful clinical course and survived free of recurrence until the last follow-up visit at 1 year after the discharge. Conclusion Our case report warns that hepatopulmonary syndrome, a less common morbidity secondary to liver cancer RFA, should require timely identification and appropriate management due to its life-threatening outcome.

Aim: To compare the short- and long-term treatment outcomes of bisegmentectomy 7–8 vs. right hepatectomy for patients with hepatocellular carcinoma and cirrhosis.Methods: Thirty six cirrhotic HCC patients with infiltration of right hepatic vein in segments 7–8 underwent bisegmentectomy 7–8 for small-for-size remanant liver under right hemi-hepatectomy. Its outcome was compared with a case-matched control group of cirrhotic HCC patients who underwent right hemi-hepatectomy during the study period.Results: The study group consisted of 36 patients and the control group 36 patients selected from 1,526 patients matched with age, tumor size, tumor location, and Pugh-Child staging. There were no significant differences between the two groups in operative parameters and in perioperative main complications which included hemorrhage, bile leakage, ascites, pleural effusion, and liver failure. The overall morbidity rate and morbidity rate classified according to Clavien's classification were similar. There was no in-hospital mortality or 90 day post-operative mortality. The mean follow-up was 30 and 32 months for the study group and control group, respectively. The disease free survival rate (DFS) for the study group was just significantly better than the control group. The median DFS was 24 months for the study group and 8 months for the control group (P = 0.049). Meanwhile, the median cumulative overall survival was 35 months for the study group and 27 months for the control group (P = 0.494).Conclusion: Bisegmentectomy 7–8 was safe and feasible for selected cirrhosis patients, and did not increase the perioperative risk and inferior long-term overall survival outcomes. It extended the indications for liver resection in patients with borderline volumes of future liver remnant for HCC cirrhotic liver.

Effective and non-invasive biomarkers to predict and avoid posthepatectomy liver failure (PHLF) are urgently needed. This systematic review aims to evaluate the efficacy of gadoxetic acid-enhanced MRI-derived parameters as an imaging biomarker in preoperative prediction of PHLF.A systematic literature search was performed in the databases of PubMed/Medline, Web of Science, Embase, and Cochrane Library up to 11 December 2020. Studies evaluating the incidence of PHLF on patients who underwent hepatectomy with preoperative liver function assessment using gadoxetic acid-enhanced MRI were included. Data was extracted using pre-designed tables. The Quality In Prognostic Studies (QUIPS) tool was adopted to evaluate the risk of bias.A total of 15 studies were identified for qualitative synthesis and most studies were marked as low to moderate risk of bias in each domain of QUIPS. The most commonly used parameter was relative liver enhancement or its related parameters. The reported incidence of PHLF ranged from 3.9 to 40%. The predictive sensitivity and specificity of gadoxetic acid-enhanced MRI parameters varied from 75 to 100% and from 54 to 93% in ten reported studies. A majority of the studies revealed that the gadoxetic acid-enhanced MRI parameter was a predictor for PHLF.Gadoxetic acid-enhanced MRI showed a high predictive capacity for PHLF and represents a promising imaging biomarker in prediction of PHLF. Multicenter, prospective trials with large sample size and reliable, unified liver function parameters are required to validate the efficacy of individual liver function parameters.• There is an obvious heterogeneity of the published studies, not only in variance of MRI liver function parameters but also in indication and extent of the liver resection. • Signal intensity (SI)-based parameters derived from gadoxetic acid-enhanced MRI are the commonly used method for PHLF prediction. • Gadoxetic acid-enhanced MRI-derived parameters showed high predictive efficacy for PHLF and can potentially serve as a predictor for the incidence of PHLF.

Background: The aim of this study was to evaluate whether combined therapy with PD-1 blockade (anti-PD-1) and radiofrequency ablation (RFA) was superior to RFA monotherapy for recurrent hepatocellular carcinoma (HCC).METHODS: A total of 127 patients who underwent anti-PD-1 plus RFA treatment (n = 41) or RFA alone treatment (n = 86) for recurrent HCC were enrolled in this retrospective study. Clinical data including post-RFA HCC recurrence (the primary end point), overall survival (OS) (the secondary end point), adverse events and toxic effects were retrospectively analyzed.RESULTS: The 1-year recurrence-free survival rates for the anti-PD-1 plus RFA and RFA groups were 36.6% and 16.3%, respectively. The corresponding overall survival rates for the two groups were 95.1% and 74.4%, respectively. There were statistically significant differences between the two groups in recurrence-free survival rate (P = 0.002) or overall survival rate (P = 0.008). Tumor number, TNM stage and anti-PD-1 treatment were demonstrated to be important factors associated with 1-year recurrence-free survival probability by univariate and multivariate analyses. Univariate and multivariate analyses demonstrated that tumor number, TNM stage and anti-PD-1 treatment were significant prognostic factors for OS. RFA treatment-related adverse events were pleural effusion requiring drainage and mild or moderate increase in body temperature. Grade 3 or higher events related to anti-PD-1 treatment occurred in 12.8% (6) patients and were infrequent.CONCLUSIONS: Combination therapy of anti-PD-1 plus RFA was superior to RFA alone in improving survival for recurrent HCC.

e16148 Background: No response and resistance occurred for the most uHCC patients with the treatment of molecular targeted agents and\or anti-PD-1 inhibitors. And the second-line therapies are still unmet the ideal clinical outcome. A pilot study that assessed the effectiveness of the combination therapy of REGO + PD-1 inhibitor in second-line setting for pts with advance uHCC showed promising result. Methods: This single-center, retrospective, real-world study was conducted between Jan 2019 to Jul 2021. All patients with uHCC, who were treated with second-line REGO + PD-1 inhibitor or REGO monotherapy were evaluated. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS) were observed. Results: Forty-six patients with uHCC were included in the study, and most had received previous systemic treatment including targeted therapy and immunotherapy. In all pts, median treatment duration of regorafenib was 152.5 days. Median follow-up was 9.0 months. Tumor response was evaluated in 25 and 21 pts in REGO + PD-1 inhibitor and REGO monotherapy group respectively, ORR was 40% and 19.0% respectively; DCR was 88% and 71.4% respectively. Median OS was not reached in either group; the median PFS of the REGO + PD-1 inhibitor group was 11.5 months, which was significantly higher than that of the REGO monotherapy group (5.1 months) (C2=3.867; P=0.049). The most common AE grade ≥3 was diarrhea (4.3%), and was solely observed in REGO monotherapy group. Conclusions: Our preliminary findings suggested that the striking improvement in PFS and ORR were compelling in the REGO + PD-1 inhibitor group, and regardless of previous treatment, regorafenib was clinically effective for uHCC pts in second-line treatment whether in combination with PD-1 inhibitor or not in Chinese patients. And there was a trend to increased efficacy with no increased toxicity in combination therapy. Further analysis in a real-world study with a large sample size is crucial to substantiate our results.

BackgroundNo-touch combined directed perfusion radiofrequency ablation (NTDP-RFA) is a new technique for the treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the short-term efficacy of this new technique for the treatment of small HCC with cirrhosis.MethodsFrom January 2017 to March 2018, 56 consecutive patients treated with NTDP-RFA at our center were enrolled in this retrospective study. All NTDP-RFA procedures involved the use of internally cooled wet electrodes with a directional injection function, which can perform both intraelectrode cooling and extraelectrode saline perfusion. Survival curves were analyzed using Kaplan-Meier methods, and Cox proportional hazards regression analyses were used to assess predictors of tumor progression and overall survival. Operative characteristics and complications were also assessed.ResultsNo technical failure occurred, and the complete ablation rate after single NTDP-RFA treatment was 98.2%. The median ablation time was only 8 (6-8) min. Only 5 patients (8.9%) experienced mild complications postoperation, and the median hospital stay was only 4 (3-5) days. In the 18 patients (32.1%) with poor liver function reserve (indocyanine green retention rate at 15 min > 15%), their liver function returned to normal on the third day after the postoperation. The 1-year and 2-year local and distant progression rates were 1.7%, 7.1%, 3.5% and 10.7%, respectively.ConclusionsNTDP-RFA in the treatment of small HCC with cirrhosis has a low incidence of complications and provides a high survival rate without local tumor progression. Further prospective randomized controlled studies are needed to investigate the long-term results.

The coronavirus disease 2019 (COVID-19) has become a global pandemic since its outbreak in December 2019, which posed a threat to the safety and well-being of people on a global scale. Cancer patients are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and their critical morbidity and case fatality rates are high. The ablation expert committee of the Chinese Society of Clinical Oncology compiled corresponding expert recommendations. These recommendations summarize the preventive measures and management of tumor ablation treatment in medical institutions, including outpatient clinics, oncology wards, ablation operation room, and postablation follow-ups in accordance with the guidelines and protocols imposed by the National Health Commission of the People's Republic of China and the experience in management and prevention according to various hospitals. This consensus aims to reduce and prevent the spread of SARS-CoV-2 and its cross-infection between cancer patients in hospitals and provide regulatory advice and guidelines for medical personnel.

Purpose: Radiofrequency ablation (RFA) is widely accepted as a curative treatment for small hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can lead to rapid local recurrence. The underlying mechanisms remain poorly understood. This study aimed to elucidate the role and regulatory mechanisms of autophagy in the recurrence of HCC after IRFA. Materials and methods: SMMC7721 and Huh7 cells were exposed to sublethal heat stress to stimulate the transition zone of IRFA treatment. The levels of autophagy were measured by western blot, immunofluorescence and transmission electron microscopy. Functional assays, such as CCK-8, EdU incorporation and flow cytometry, were performed to determine the role of heat-induced autophagy. The involved signaling pathways were explored by western blot. Finally, the antitumor effects of chloroquine (CQ) on heat-treated HCC cells were evaluated via an in vivo xenograft tumor model. Results: Sublethal heat stress induced autophagy in a temperature- and time-dependent manner in HCC cells. Furthermore, the inhibition of autophagy by CQ or siRNA targeting the autophagy-related genes Beclin-1 and Atg5 enhanced heat-induced apoptosis. The combination of CQ and heat treatment significantly suppressed tumor growth both in vitro and in vivo. Mechanistically, we reported for the first time that the ATP-AMPK-mTOR signaling pathway was involved in heat-induced autophagy. Conclusions: Heat stress induced protective autophagy against heat-induced apoptosis in HCC via the ATP-AMPK-mTOR axis, suggesting that targeting autophagy may be a promising strategy for improving the efficacy of RFA treatment for HCC.

Jun Yan,1– 3,* Zhongsong Man,3,* Qian Lu,1 Kuansheng Ma2 1Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, People’s Republic of China; 2The Institute of Hepatobiliary Surgery, The First Hospital Affiliated of Army Medical University, Chongqing, People’s Republic of China; 3Center of Hepatobiliary Pancreatic Disease, Xuzhou Central Hospital, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuansheng MaThe Institute of Hepatobiliary Surgery, The First Hospital Affiliated of Army Medical University, Chongqing, People’s Republic of ChinaEmail makuansheng@vip.sina.comQian LuBeijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, People’s Republic of ChinaEmail luqian01971@tsinghua.edu.cnObjective: To evaluate the survival outcomes of combined liver resection (LR) and radiofrequency ablation (RFA) on multi-focal hepatocellular carcinoma (HCC) in patients with Barcelona clinic liver cancer (BCLC) stage B.Methods: A total of 210 cases of HCC were included in this study. In 42 cases, patients were treated with combination therapy using LR and RFA (LRCRFA). In 84 cases, patients underwent transarterial chemoembolization (TACE), and in another 84 cases, patients underwent LR; both the TACE and LR groups served as controls. It both categorized as BCLC stage B for LRCRFA and TACE groups but as BCLC stage A for LR group.Results: The overall survival (OS) rate of the LRCRFA group was significantly higher than that of the TACE group (P< 0.001) but was not significantly different when compared with the LR group (P=0.544). The disease-free survival (DFS) rate of the LRCRFA group was significantly lower than that of the LR group (P=0.029). Patients with ≤ 4 tumors or those with ≤ 5 tumors no larger than 6 cm in diameter experienced better long-term outcomes than other patients in the same LRCRFA group. The OS rates and DFS rates were not significantly different from those of patients in the LR group (P> 0.05). Having more than 2 existing tumors was an independent risk factor for OS rate.Conclusion: Combination therapy using LR and RFA can more effectively improve the prognosis of these patients than TACE. Patients with BCLC stage B HCC with ≤ 4 tumors or ≤ 5 tumors smaller than 6 cm in diameter are the ideal candidates for the application of LRCRFA.Keywords: hepatocellular carcinoma, surgical resection, radiofrequency ablation, transarterial chemoembolization, survival, Barcelona clinic liver cancer stage

This study aimed to analyze the influence of the cellular differentiation, the tumor size and the underlying hepatic condition on the enhancement pattern of hepatocellular carcinoma (HCC) on contrast-enhanced ultrasound (CEUS). 276 patients with single lesion ≤ 5 cm who underwent CEUS exam and were pathologically confirmed as HCC were retrospectively enrolled. Enhancement patterns, washout patterns, wash-in time and washout time were observed and recorded. During the arterial phase, more poorly differentiated HCCs (42.5%) and lesions > 3 cm (35.2%) performed inhomogeneous enhancement (p 3 cm (97.2 ± 51.3 s) washed out more rapidly than lesions ≤ 3 cm (113.9 ± 53.5 s) (p

Interleukin-22 (IL-22) is a recently identified regulator of inflammation, but little is known about its role in liver transplantation. Therefore, in this study, we explored the roles and the underlying mechanisms of IL-22 in acute allograft rejection by using a rat allogeneic liver transplantation model. Results showed that allograft liver transplantation led to damage of the parent liver and to significantly increased IL-22 expression in the allograft liver and plasma of the recipient rats compared with the rats who received isografts. Moreover, the significantly increased IL-22 expression was accompanied by markedly increased level of phospho-STAT3 in the allogeneic liver tissues after transplantation. Of note, neutralization of the IL-22 protein in recipient rats significantly worsened the function of the allograft liver at 1 day post-transplantation (ischemia-reperfusion injury, IRI) but improved the function at 7 days post-transplantation (acute rejection, AR). At IRI stage, IL-22 protected liver function through the increase of anti-apoptosis and pro-regeneration cytokines. However, IL-22 led to the increase of pro-inflammation factors at AR stage, accompanied by the marked increase of the Th17 and the marked decrease of Treg cells in allograft recipient rats through modulating the expression of chemokines for different cell types, which however were reversed by in vivo IL-22 neutralization. Results indicate the dual roles of IL-22 and suggest the differential potential clinical application of IL-22 at different stage of allograft liver transplantation.

Recent studies have shown that radiofrequency (RF) ablation therapy is a safe, feasible, and effective procedure for hepatic hemangiomas, even huge hepatic hemangiomas. RF ablation has the following advantages in the treatment of hepatic hemangiomas: minimal invasiveness, definite efficacy, high safety, fast recovery, relatively simple operation, and wide applicability. It is necessary to formulate a widely accepted consensus among the experts in China who have extensive expertise and experience in the treatment of hepatic hemangiomas using RF ablation, which is important to standardize the application of RF ablation for the management of hepatic hemangiomas, regarding the selection of patients with suitable indications to receive RF ablation treatment, the technical details of the techniques, therapeutic effect evaluations, management of complications, etc. A final consensus by a Chinese panel of experts who have the expertise of using RF ablation to treat hepatic hemangiomas was reached by means of literature review, comprehensive discussion, and draft approval.

Background The aim of this study was to determine the effect of anatomic resection (AR) versus non-anatomic resection (NAR) on recurrence rates in patients with hepatocellular carcinoma (HCC). Methods Eligible patients were randomized to AR or NAR from January 2006 to July 2007 at a single center. The primary outcome was the 2-year recurrence-free survival (RFS). Secondary outcomes were postoperative complications, time to first recurrence, 1-, 3-, and 5-year RFS, and overall survival (OS). Results Fifty-three (51%) and 52 (50%) patients underwent NAR and AR, respectively. A larger proportion of patients achieved margins ≥20 mm in the AR group (52% vs. 30%; P = 0.023). Complications (blood loss, transfusion requirement, and hospital stay) were similar between the two groups. Median follow-up was 33 (range, 2–77) months. Incidence of local recurrence at 2 years was 30% and 59% in the AR and NAR groups, respectively. Median time to first local recurrence in the AR group was significantly longer than in the NAR group (53 vs. 10 months, P = 0.010). There was no difference in overall RFS between the two groups (P = 0.290). Discussion AR decreased the 2-year local recurrence rate and increased the time to first local recurrence compared to NAR in patients with HCC.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has high morbidity and mortality. In this study, the safety and efficacy of a modification of ALPPS (radiofrequency-assisted ALPPS, RALPPS) were assessed in patients with hepatocellular carcinoma (HCC).Patients who were diagnosed with HCC and were considered to have an insufficient future liver remnant (FLR) were enrolled. In stage I, a radiofrequency ablation (RFA) device was used to cauterise along the planned transection plane to form a coagulum avascular area. When the FLR reached above 40%, hepatectomy was performed in stage II along the coagulum area established previously. After two stages, operative morbidity, mortality, per cent increase in FLR, operative time and blood loss were evaluated.Between July 2014 and September 2015, 10 patients with HCC (9 with hepatitis-related cirrhosis) were treated with the RALPPS procedure. The incidence of severe complications (Clavien-Dindo ≥ IIIb) was 20% (2/10). One patient died. No biliary leakage, intraperitoneal infection or post-hepatectomy liver failure (PHLF) occurred after both stages. The median FLR before stage I was 31% (364 ml). This increased to 47% (632 ml) before stage II after a median interval of 28 days. The median percentage increase in FLR was 53% (210 ml). Additionally, the median operative time during the first and second stages was 214 and 281 min, respectively. The corresponding median blood loss was 200 and 550 ml, respectively.RALPPS has a potential advantage in eliminating serious complications of biliary leakage and PHLF associated with classic ALPPS. On the basis of rigorous patient selection criteria, RALPPS may achieve the same effect of promoting significant growth of the FLR in patients with cirrhosis-related HCC and insufficient FLR volume, albeit at the cost of a longer interval time.