Transcatheter arterial chemoembolization using CalliSpheres beads loaded with arsenic trioxide for unresectable large or huge hepatocellular carcinoma: a prospective study.

OBJECTIVES: To determine the safety and efficacy of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) in the first-line treatment of patients with large (5 cm ≤ maximum diameter < 10 cm) or huge (maximum diameter ≥ 10 cm) hepatocellular carcinoma (HCC). METHODS: Patients were randomly allocated to the CBATO-TACE group and the conventional transcatheter arterial chemoembolization (cTACE) group. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS), treatment response, and treatment-related adverse events (TRAEs). The extrahepatic collateral arteries, liver function, and liver fibrosis after the first TACE were also evaluated. RESULTS: From September 2018 to September 2020, a total of 207 patients who underwent TACE were consecutively enrolled in this study. The median PFS was 9.5 months (range: 8.0 - 11.0) in the CBATO group, which was significantly longer than that in the cTACE group (6.0 months, range: 4.0-6.0) (p < 0.0001). Patients in the CBATO group had a median OS of 22 months (range: 20.0 - 27.0) compared with 16 months (range: 15.0 - 20.0) in the cTACE group (p = 0.0084). The most common TRAEs were fever (p = 0.043), and nausea and vomiting (p = 0.002), which were more observed in the cTACE group. In addition, the progressive disease time, pulmonary metastasis rate (p = 0.01), the mean number of extrahepatic collateral arteries (p = 0.01), and average number of TACE sessions (p = 0.025) were significantly decreased in the CBATO group. CONCLUSIONS: CBATO-TACE achieved better therapeutic outcomes and similar safety profile compared to cTACE in large or huge HCC patients. Furthermore, CBATO-TACE was able to reduce extrahepatic collateral arteries production and extrahepatic lung metastasis. CLINICAL RELEVANCE STATEMENT: Our study showed that CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) were effective and safe for the treatment of large and giant HCC. In addition, CBATO-TACE can reduce lateral hepatic branch artery formation and extrahepatic pulmonary metastasis, which provides a new treatment approach for unresectable HCC. KEY POINTS: • We compare long-term efficacy and safety of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) and conventional transcatheter arterial chemoembolization (cTACE) in patients with large (5 cm ≤ maximum diameter < 10 cm) or huge HCC (maximum diameter ≥ 10 cm). • Compared with cTACE, CBATO-TACE significantly improved therapeutic outcomes, overall survival, and progression-free survival in patients with large or huge HCC. The safety assessment suggested that CBATO-TACE is a safe treatment that improves the quality of life and has good treatment adherence.

Transarterial chemoembolization combined donafenib with/without PD-1 for unresectable HCC in a multicenter retrospective study.

Background & aims: This multicenter retrospective study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with donafenib and a programmed death-1 (PD-1) inhibitor (TACE+DP) and TACE combined with donafenib (TACE+D) for unresectable hepatocellular carcinoma (uHCC). Methods: The clinical data of 388 patients with uHCC who received TACE+DP or TACE+D as first-line treatment at six Chinese academic centers from July 2021 to July 2022 were collected and analyzed retrospectively. Patients in the TACE+DP group received an intravenous administration of a PD-1 inhibitor every three weeks and oral donafenib (0.2 g) twice daily until intolerable toxicity or disease progression. Patients in the TACE+D group received the same dose of donafenib for 3-5 days after TACE. Overall survival (OS) and progression-free survival (PFS)were analyzed by Kaplan-Meier method and log-rank test. The tumor response was compared between the two groups according to modified RECIST criteria. Adverse events were also analyzed between the two groups. Results: The TACE+D group included 157 patients and the TACE+DP group included 166 patients. Patients in the TACE+DP group had a longer median OS (18.1 vs. 13.2 months, P<0.001) and longer median PFS (10.6 vs. 7.9 months, P<0.001) than those in the TACE+D group. Patients in the TACE+DP group achieved a greater objective response rate (ORR; 50.6% vs. 41.4%, P=0.019) and greater disease control rate (DCR) (89.2% vs. 82.8%, P=0.010) than those in the TACE+D group. No significant differences were found in the incidence or severity of adverse events between the TACE+DP and TACE+D groups (any grade: 92.9% vs. 94.6%, P=0.270; grade 3 or 4: 33.8% vs. 37.3%, P=0.253). Conclusion: With favorable safety and tolerability, TACE combined with donafenib and PD-1 inhibitors significantly improved PFS, OS, and ORR compared to TACE combined with donafenib.

Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC. METHODS: This study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected. RESULTS: A total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9-21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups. CONCLUSIONS: Both TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit.

Correlation between magnetic resonance images of peritumor margin enhancement and prognosis in hepatocellular carcinoma after drug-eluting bead transcatheter arterial chemoembolization.

Purpose: The aim of this study is to investigate the morphological characteristics and clinical significance of magnetic resonance (MR) images of peritumor margin enhancement in hepatocellular carcinoma (HCC) after drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE). Methods: From January 2017 to December 2020, a total of 162 patients who received a diagnosis of HCC were included in our study. We began the follow-up with magnetic resonance imaging (MRI) for complete response assessment, and peritumor margin enhancements were classified as sharp and rough types according to morphology. During the follow-up, data such as progression or remission of the two enhancement modalities, morphological changes in terms of margin enhancements observed in MR images, and alpha-fetoprotein (AFP) levels were recorded. Results: In the follow-up period of 36 months, 70 and 92 patients with sharp- and rough-type peritumor margins, respectively, were observed. At the end of the follow-up, patients with sharp-type margins had lower AFP levels and longer progression-free survival than those with rough-type margins (P < 0.05). Furthermore, the sharp-type margin was thinner than the rough-type margin (all P < 0.05). Moreover, the sharp-type group had a high incidence of tumors with a diameter of < 5 cm, whereas the rough-type group had a high incidence of tumors with a diameter of ≥ 5 cm. Continuous enhancements of peritumor margins in MRI were greater in the sharp-type group than in the rough-type group. Most of the patients with a sharp-type margin achieved disease remission (94.3%, P < 0.05), whereas most of those with a rough-type margin experienced disease progression (84.8%, P < 0.05). Conclusions: Patients with HCC with a sharp-type margin enhancement on MRI after DEB-TACE mostly demonstrated benign lesions with a good prognosis, whereas those with a rough-type margin mostly demonstrated malignant growth.

The impact of drug-eluting bead (vs. conventional) transarterial chemoembolization on hepatic fibrosis in treating intermediate or advanced hepatocellular carcinoma.

OBJECTIVE: Limited studies have reported the impact of drug-eluting bead transarterial chemoembolization (DEB-TACE) on hepatic fibrosis in hepatocellular carcinoma (HCC). This study evaluated multiple hepatic fibrosis indicators, aiming to comprehensively compare the influence of DEB-TACE and conventional transarterial chemoembolization (cTACE) on hepatic fibrosis in treating HCC patients. METHODS: Intermediate/advanced HCC patients (N = 121) were divided into the DEB-TACE group (n = 62) and the cTACE group (n = 59) based on their chosen treatment. Serum hyaluronic acid (HA), pro-collagen type-III (PC-III), collagen type-IV (IV-C), and laminin (LN) were detected; aminotransferase to platelet ratio index (APRI) and fibrosis index based on the four factors (FIB-4) were calculated; liver stiffness measurement (LSM) was assessed by real-time shear wave elastography. RESULTS: HA, PC-III, IV-C, and LN at 1 month after the second TACE and at 12 months after the first TACE were all decreased in DEB-TACE group compared with cTACE group (all P < .050). Then, APRI, FIB-4, and LSM were further assessed, which also showed a decreasing trend at aforementioned timepoints in DEB-TACE group compared with cTACE group (all P < .050). Additionally, the multivariate logistic regression analysis revealed that DEB-TACE (vs. cTACE) was independently associated with reduced occurrence of severe hepatic fibrosis at 12 months (OR = 0.215, 95%CI: 0.058-0.802, P = .022). Concerning the liver function indexes, alanine aminotransferase, aspartate aminotransferase, and total bilirubin after treatment were not different between the two groups (all P > .050). CONCLUSION: DEB-TACE displays attenuated hepatic fibrosis progression and noninferior tolerance compared to cTACE in treating intermediate- or advanced-stage HCC patients.

Covalent organic polymer induces apoptosis of liver cancer cells via photodynamic and photothermal effects.

The purpose of this study was to explore the photodynamic and photothermal effects of the supramolecular material Purp@COP and to test the anti-cancer effect on HepG2 cells in vitro. Materials and methods: Purp@COP is a covalent organic polymer (COP) with robust tailoring heteroatom incorporation, plentiful pore structure, and multiple functions similar to the metal-organic framework (MOF). Hepatocellular carcinoma cell line HepG2 was cultured with Purp@COP for 24 h and treated with near-infrared 808-nm laser 1 W/cm2 for 10 min. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, live-dead cell fluorescence staining, and Annexin V/propidium iodide (PI) staining flow cytometry were performed to detect the viability, proliferation, and apoptosis of the HepG2 cells. Results: The supramolecular material Purp@COP exhibited significant photothermal performance under near-infrared 808-nm laser irradiation in vitro. With the treatment of Purp@COP and near-infrared 808-nm laser irradiation on HepG2 cells, cell viability and colony formation capacity were decreased, and the number and proportion of apoptotic cells were increased. Conclusions: The supramolecular material Purp@COP has both photothermal and photodynamic effects and can significantly induce cancer cell death and inhibit the proliferation of cancer cells in vitro.

Occurrence, Related Factors and Prognostic Value of Vascular Lake in Hepatocellular Carcinoma Patients Treated with Drug-Eluting Bead Transarterial Chemoembolization.

PURPOSE: The present study aimed to assess the prevalence of vascular lake (VL), its associated factors and correlation with prognosis in hepatocellular carcinoma (HCC) patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE). PATIENTS AND METHODS:  A total of 286 primary HCC patients (with 384 treated nodules) receiving DEB-TACE treatment were recruited, and their clinical characteristics were documented. The occurrence of VL was recorded, and treatment responses were assessed according to the modified response evaluation criteria in solid tumor (mRECIST).In terms of treatment response, the total response status (including CR, PR, SD and PD), objective response rate (ORR) and disease control rate (DCR) were elevated in VL patients compared to non-VL patients as well as in VL nodules compared to non-VL nodules. Liver function indexes and adverse events were assessed. Progression-free survival (PFS) and overall survival (OS) were evaluated with the last follow-up date of March 2020. RESULTS: The patient-based and nodule-based VL occurrence rates were 17.1% and 16.4%, respectively. Larger tumor size, pseudocapsules and smaller bead size were independently associated with VL occurrence. PFS and OS were more prolonged in VL patients than in non-VL patients, and VL independently correlated with better PFS and OS. For liver function, the liver function indexes before and after DEB-TACE were of no difference between VL patients and non-VL patients. Additionally, the incidences of adverse events were similar between VL patients and non-VL patients. CONCLUSION:  VL occurs in 17.1% of HCC patients treated with DEB-TACE, and it is correlated with larger tumor size, pseudocapsule, smaller bead size, more favorable treatment response and better survival.

Upregulation of IL-6 is involved in moderate hyperthermia induced proliferation and invasion of hepatocellular carcinoma cells.

Increasing evidences suggested that insufficient radiofrequency ablation (RFA) can paradoxically promote tumor invasion and metastatic processes, while the effects of moderate hyperthermia on cancer progression are not well illustrated. Our present study confirmed moderate hyperthermia treatment can promote the proliferation, migration and invasion of hepatocellular carcinoma (HCC) cells, which was evidenced by the results that moderate hyperthermia induced up regulation of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2). Cellular studies indicated that moderate hyperthermia treatment can increase the mRNA and protein expression of IL-6 and IL-10, while not IL-2, IL-4, IL-8, IL-22, VEGF, TGF-ß, or TNF-α, in HCC cells. Silencing of IL-6, while not IL-10, attenuated moderate hyperthermia treatment induced proliferation and cell invasion. Furthermore, our data revealed the inhibition of NF-κB, while not ERK1/2 or PI3K/Akt, abolished moderate hyperthermia treatment induced production of IL-6. Collectively, our data showed that activation of NF-κB/IL-6 is involved in moderate hyperthermia treatment induced progression of HCC cells.