Purpose: The combination of transarterial chemoembolization (TACE) plus lenvatinib and programmed death receptor-1 (PD-1) inhibitor has shown promising results for advanced hepatocellular carcinoma (HCC), but its benefits for unresectable huge HCC (maximum diameter ≥10 cm) are unknown. This study aimed to compare the efficacy between TACE combined with lenvatinib and PD-1 inhibitor (TACE + Len + PD-1) and TACE combined with lenvatinib (TACE + Len) for unresectable huge HCC. Methods: This study analyzed 147 and 241 patients in the TACE + Len and TACE + Len + PD-1 groups, respectively, from six hospitals. The PD-1 inhibitors used in this study (sintilimab, camrelizumab, pembrolizumab, toripalimab, tislelizumab, and nivolumab) were administered at standard doses. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and tumor response. Propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and coarsened exact matching (CEM) were used to balance bias between the two groups. Tumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors criteria based on a centralized and independent imaging review by blinded senior radiologists. A causal mediation analysis was employed to quantify the extent to which the survival benefit was mediated through early tumor response (objective response rate at 3- and 6-month) versus the direct effect of the treatment. Results: The median PFS was 6.03 months [95% confidence interval (CI) 5.63–7.37] in the TACE + Len group and 8.37 months (95% CI 7.50–9.70) in the TACE + Len + PD-1 group. Overall, compared with the TACE + Len group, the TACE + Len + PD-1 group had better PFS [hazard ratio (HR) 0.67, 95% CI 0.54–0.83; P < 0.001] and OS (HR, 0.66; 95% CI 0.57–0.83; P < 0.001), even after PSM, IPTW, and CEM. The objective response rate was higher in the TACE + Len + PD-1 group than in the TACE + Len group ( P < 0.001). Furthermore, mediation analysis demonstrated that the survival benefit of the triple therapy operated principally through the enhancement of the early tumor response rate. Conclusion: Compared with TACE plus lenvatinib, triple therapy with TACE, lenvatinib, and PD-1 inhibitor resulted in better PFS and OS. These findings support the consideration of this triple combination as a promising first-line treatment option for unresectable huge HCC and warrant further validation in prospective studies.

The prediction model of postoperative survival for single large and huge hepatocellular carcinoma (SLH-HCC, diameter > 5.0 cm) without portal vein tumour thrombus has not been well established. This study aimed to develop novel nomograms to predict postoperative recurrence and survival of these patients. Data from 2469 patients with SLH-HCC who underwent curative resection from January 2005 to December 2015 in China were retrospectively collected. Specifically, nomograms of recurrence-free survival (RFS) and overall survival (OS) using data from a training cohort were developed with the Cox regression model (n = 1012). The modes were verified in an internal validation cohort (n = 338) and an external cohort comprising four tertiary institutions (n = 1119). The nomograms of RFS and OS based on tumour clinicopathologic features (diameter, differentiation, microvascular invasion, α-fetoprotein), operative factors (preoperative transcatheter arterial chemoembolisation therapy, scope of liver resection and intraoperative blood transfusion), underlying liver function (albumin-bilirubin grade) and systemic inflammatory or immune status (neutrophil-to-lymphocyte ratio) achieved high C-indexes of 0.85 (95% confidence interval [CI], 0.79-0.91) and 0.86 (95% CI, 0.79-0.93) in the training cohort, respectively, which were significantly higher than those of the five conventional HCC staging systems (0.62-0.73 for RFS, 0.63-0.75 for OS). The nomograms were validated in the internal cohort (0.83 for RFS, 0.84 for OS) and external cohort (0.87 for RFS, 0.88 for OS) and had well-fitted calibration curves. Our nomograms accurately stratified patients with SLH-HCC into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. The two nomograms achieved optimal prediction for postsurgical recurrence and OS for patients with SLH-HCC after curative resection.

Background: Radiofrequency ablation (RFA) is considered as a convenient treatment with mild damage in treating recurrent hepatocellular carcinoma (RHCC). However, for patients with high risk of progression after RFA still needs new strategies to decrease the repeat recurrence. Methods: A total of 460 patients with RHCC within Milan criteria in four institutions were enrolled. 174 pairs were enrolled after propensity score matching (PSM). Overall survival (OS) and tumor-free survival (TFS) were compared between the two groups. A quantitative score system was established to screen out the beneficial population from RFA–sorafenib treatment. Results: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% for RFA–sorafenib group, and 93.1%, 61.3%, 30.9% for RFA group after PSM, respectively. Compared with the RFA group, the RFA–sorafenib group had significantly better OS (P < 0.001). The 1-, 3-, and 5-year TFS rates were 90.8%, 49.0%, 20.4% for RFA–sorafenib group, and 67.8%, 28.0%, 14.5% for RFA group after PSM. The difference was observed significantly between RFA–sorafenib group and RFA group (P < 0.001). A quantitative risk score system was established to precisely screen out the beneficial population from RFA–sorafenib treatment. Conclusions: Adjuvant sorafenib after RFA was superior to RFA alone in improving survival outcomes in patients with recurrent HCC within Milan criteria after initial hepatectomy. Subgroup analyses concluded that patients with high risk score had significantly longer survival from sorafenib administration.

Background: Lenvatinib combined with a PD-1 inhibitor has obtained a satisfactory antitumor effect in several solid tumors. However, the efficacy and tumor response of lenvatinib with a PD-1 inhibitor in advanced intrahepatic cholangiocarcinoma still need further exploration.Methods: This is a single-arm study for the assessment of the efficacy and tolerability of lenvatinib with a PD-1 inhibitor in intrahepatic cholangiocarcinoma patients who had chemotherapy failure. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1).Results: A total of 40 patients with advanced intrahepatic cholangiocarcinoma were enrolled after the chemorefractory effect. The median progression-free survival was 5.83 ± 0.76 months. The 3-month and 6-month progression-free survival rates were 80.0% and 32.5%, respectively. The median overall survival was 14.30 ± 1.30 months. The 12-month and 18-month overall survival rates were 61.4% and 34.7%. The 3-month RECIST 1.1 evaluation was that seven patients (17.5%) showed partial response, 23 patients (57.5%) had stable disease, and 10 patients (25.0%) had progressive disease. The objective response rate was 17.5%, and the disease control rate was 75.0%. All the recorded any-grade adverse events inducing treatment termination were controllable, and there were no AE-related deaths.Conclusion: Our study showed that a combination of lenvatinib with the PD-1 inhibitor could be an effective treatment for advanced intrahepatic cholangiocarcinoma after the chemorefractory effect.

Microwave ablation (MWA) is a promising minimally invasive therapy that has been widely used to treat hepatocellular carcinoma (HCC). However, the efficiency of MWA in treating HCC is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Here, we report the value of using liposomes packed with sodium chloride (NaCl-LPs) as effective thermo-seeds for MWA of HCC. The prepared liposomes exhibited excellent heat conversion ability by showing a more rapid temperature increase than free NaCl medium, blank liposomes or water under microwave irradiation. The high efficiency of this new microwave sensitization strategy was fully demonstrated in vitro in subcutaneous and orthotopic tumors. The results showed that MWA combined with NaCl-LPs clearly enhanced the ablation efficiency, leading to apparent tumor inhibition and low recurrence. What's more, we verified the susceptibility of NaCl-LPs on orthotopic tumors. Based on the unique properties of NaCl-LPs, sublethal MWA was used to mimic the transitional zone, and large-scale necrosis was observed in tumors combined with NaCl-LPs. In addition, HE staining and blood hematology analysis revealed no noticeable toxicity of NaCl-LPs in vivo, which confirmed that NaCl-LPs possessed good biocompatibility. Conclusion: The effective nanoparticles could play a valuable role in enhancing the thermo-sensitizing effect of MWA for achieving better therapeutic efficacy.