Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for liver cancer. To investigated whether TPZ-loaded microspheres enhance the synergy between TPZ and TAE in liver cancer, we prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and characterized their properties as a chemoembolization agent in vitro. Tumor hypoxia after TAE was detected in the rabbit VX2 model of liver cancer using a modified Clark-type microelectrode research system. CSMTPZ therapy was performed in the animal model. The plasma and tumor concentrations of TPZ and its metabolites were measured, and the efficacy and safety of CSMTPZ therapy were evaluated and compared with those of the conventional combination of intraarterial TPZ injection and embolization. The results showed that CSMTPZs displayed favorable in vitro properties including drug loading and release and microsphere size, shape, and surface profiles. TAE induced acute tumor hypoxia, but residual tumor cells responded to hypoxia through hypoxia-inducible factor 1α. CSMTPZ therapy improved TPZ delivery into tumor tissue with minimal systemic exposure. Accordingly, CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE. We revealed the improved synergistic anti-tumor effects of CSMTPZ therapy in the rabbit VX2 liver cancer model. Our data support the clinical evaluation of CSMTPZs in the treatment of hepatocellular carcinoma, and CSMTPZ administration might serve as a successful therapeutic strategy for this malignancy.

Objective: To evaluate whether the pretreatment Lung Immune Prognostic Index (LIPI) is associated with outcomes in advanced hepatocellular carcinoma (HCC) patients under ICI. Methods: A two-center retrospective study of patients with HCC treated with immune checkpoint inhibitors (ICIs) between January 2018 and January 2021 was performed. Based on pretreatment derived neutrophils/ (leukocytes minus neutrophils) ratio (dNLR) greater than 3 and a lactate dehydrogenase (LDH) level greater than the normal value, patients were stratified into three groups (good LIPI:0 risk factor, intermediate LIPI: 1 risk factor, and poor LIPI: 2 risk factors). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The second endpoints were disease control rate (DCR) and objective response rate (ORR). Results: In the pooled cohort (n = 224), 80 (35.7%) had a good LIPI (zero factor), 91 (40.6%) had intermediate LIPI (one factor), and 53 (23.7%) had poor LIPI (two factors). The median follow-up was 25.1 months. Median OS was 16.8 months, 12.5 months, and 9.5 months for the good, intermediate, and poor LIPI groups, respectively (P < 0.0001). Median PFS was 11.8 months, 7.8 months, and 4.0 months for the good, intermediate, and poor LIPI groups, respectively (P < 0.0001). Multivariate analysis indicated that the intermediate LIPI and poor LIPI both were independently associated with OS, PFS, and ORR, DCR (P < 0.05), as risk factors. Conclusion: Pretreatment LIPI was correlated with worse outcomes for ICIs suggesting that LIPI could be promising biomarker for advanced HCC patients under ICIs.

To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with sorafenib and camrelizumab or with sorafenib alone in patients with intermediate or advanced hepatocellular carcinoma (HCC). We retrospectively analysed 78 patients with intermediate or advanced HCC who were treated at our centres between January 2018 and December 2021. Twenty-six of them received sorafenib and camrelizumab plus TACE (the TACE + Sor + C group), while 52 received TACE and sorafenib (the TACE + Sor group). Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were evaluated. Univariate and multivariate analyses were used to determine the factors affecting survival. The median OS (22 vs 10 months, P < .001) and median PFS (11 vs 6 months, P = .008) of the TACE + Sor + C group were significantly higher than those of the TACE + Sor group. Multivariate analysis showed that compared with TACE + Sor + C, TACE + Sor increased the risk of all-cause mortality and tumour progression. For grade I and II AEs, the incidence of skin capillary hyperplasia and hypothyroidism in the TACE + Sor + C group was significantly higher than that in the TACE + Sor group. For serious AEs (grade III or IV), there was no significant difference in any adverse reaction between the 2 groups (P > .05). Patients with intermediate or advanced HCC appeared to benefit more in terms of survival from TACE + Sor + C than from TACE + Sor, and the AEs were tolerable. (1) Subgroup analysis demonstrated that TACE + sorafenib + camrelizumab could benefit HCC patients regardless of whether they had portal vein tumour thrombosis, Barcelona Clinic Liver Cancer B or C, or CHILD A or B; (2) We reported the immunotherapy-related AEs occurred with a significantly higher incidence in triple treatment, but all the AEs are tolerable.

Background: Patients with different primary tumor oligometastases can obtain survival benefits from external radiotherapy. The study was conducted to explore the efficacy and safety of transarterial chemoembolization (TACE) plus iodine 125 seed (TACE-I) implantation for hepatocellular carcinoma (HCC) oligometastases. Methods: 187 patients who received TACE-I in our institution were retrospectively reviewed from January 2014 to December 2018. Thirty-two patients were included in the analysis. The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). The secondary endpoints of the study were tumor response and PFS of the metastatic sites. Results: The median OS (mOS) of patients was 18 months, and the median PFS (mPFS) was 7 months. The objective response rate (ORR) and disease control rate (DCR) of patients three months after receiving TACE-I were 34.4% and 71.9%, respectively. The ORR and DCR of patients for metastatic sites were 50% and 81.3%, respectively. The mPFS of patients for metastatic sites was 14 months. The univariable and multivariable regression analyses indicated that the ECOG score was an independent predictor for mOS and mPFS. The number of iodine seeds and ECOG scores were independent predictors for mPFS for metastatic sites. After patients received TACE-I, the most common adverse events were abdominal pain, fever, and appetite. The adverse events of patients were relieved after receiving symptomatic treatments. Conclusion: Iodine 125 seed implantation may be an effective and safe treatment for patients with hepatocellular carcinoma with oligometastasis, thereby providing a new selective option for these patients.

Introduction: Transarterial chemoembolization (TACE) remains a cornerstone therapy for hepatocellular carcinoma (HCC), but its efficacy is frequently limited by inadequate drug penetration and tumor dissemination. Methods: We developed a thermosensitive PND nanogel co-encapsulating tirapazamine (TPZ) and folic acid (FA), TPZ/FA@PND. The system was evaluated for sustained drug release, physiological temperature-triggered sol-gel transition, in vitro antitumor effects under normoxia and hypoxia, calcification induction, biocompatibility, and in vivo therapeutic efficacy in a VX2 tumor-bearing rabbit TACE model. Results: TPZ/FA@PND showed sustained release and physiological temperature-triggered gelation. In vitro, TPZ/FA@PND inhibited tumor cell proliferation, migration, and invasion under hypoxia while inducing extracellular calcification, with negligible hemolysis and minimal hepatotoxicity. In vivo, TPZ/FA@PND delivered via TACE achieved complete embolization, induced marginal calcification, reduced metastasis, inhibited VEGF and MMP-9 expression, enhanced CD8+ T-cell infiltration, and promoted systemic antitumor immunity. Discussion: This dual-starvation nanogel strategy integrates embolization, calcification-mediated containment, and immune activation, offering a clinically translatable approach to improve the therapeutic efficacy and long-term outcomes of TACE for HCC.

Background: The combination of hepatic arterial infusion chemotherapy (HAIC) with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents a potential therapeutic strategy for advanced hepatocellular carcinoma (HCC). This study aimed to compare the efficacy and safety of triple therapies combining HAIC with ICIs and either bevacizumab or tyrosine kinase inhibitors (TKIs) in these patients. Methods: This retrospective single-center study enrolled 65 consecutive patients with advanced HCC who received HAIC combined with ICIs plus either bevacizumab (bevacizumab group, n = 31) or TKIs (TKIs group, n = 34) between June 2021 and June 2023. Primary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety profiles. Results: The bevacizumab group demonstrated significantly prolonged median PFS (10.9 vs. 7.4 months, p = 0.001) and higher ORR (83.9% vs. 61.8%, p = 0.047) compared with the TKIs group. DOR was longer in the bevacizumab group (7.9 vs. 5.3 months, p = 0.008). Median overall survival (OS) was not reached in the bevacizumab group versus 22.6 months in the TKIs group. Grade 3–4 adverse events occurred in 67.7% of the bevacizumab group and 73.5% of the TKIs group, with distinct toxicity profiles. Gastrointestinal hemorrhage (45.2%) and gastric ulcer (22.6%) predominated in the bevacizumab group, whereas the TKIs group exhibited more hepatic enzyme elevations (aspartate aminotransferase, 67.6%; alanine aminotransferase, 61.8%), proteinuria (29.4%), diarrhea (26.5%), hand-foot syndrome (20.6%), and reactive cutaneous capillary endothelial proliferation (11.8%). Conclusions: Bevacizumab-containing triplet therapy was associated with improved tumor control and delayed progression compared to TKIs-based regimens in advanced HCC. The higher bleeding risk in the bevacizumab group highlights the necessity of standardized baseline evaluation and adequate preventive measures.