The complex tumor microenvironment (TME) presents significant challenges to the development of effective therapies against solid tumors, highlighting the need for advanced in vitro models that better recapitulate TME biology. To address this, we developed a vascularized human liver tumor model using a microfluidic platform, designed to test both drug and cell-based therapies. This model mimics critical tumorigenic features such as hypoxia, extracellular matrix (ECM), and perfusable vascular networks. Intravascular administration of Sorafenib demonstrated its ability to disrupt vascular structures significantly, while eliciting heterogeneous responses in two distinct liver tumor cell lines, HepG2 and Hep3b. Furthermore, treatment with engineered T-cells revealed that the tumor vasculature impeded T-cell infiltration into the tumor core but preserved their cytotoxic capacity, albeit with reduced exhaustion levels. Cytokine analysis and spatial profiling of vascularized tumor samples identified proinflammatory factors that may enhance T-cell-mediated antitumor responses. By capturing key TME characteristics, this microfluidic platform provides a powerful tool enabling detailed investigation of tumor-immune and tumor-vascular interactions. Its versatility could serve as a promising bridge between preclinical studies and clinical testing, offering opportunities for developing and optimizing personalized therapeutic strategies for solid tumors.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.

Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

The introduction of several new systemic therapies in recent years has significantly altered the treatment landscape for advanced hepatocellular carcinoma. However, while the approval of the combination of atezolizumab and bevacizumab as the preferred first-line therapy over sorafenib represents progress, it has also raised uncertainties regarding optimal treatment sequencing for advanced disease.

This study evaluates the sequential treatment of hepatocellular carcinoma following therapy with atezolizumab and bevacizumab, providing evidence from a prospective real-world cohort.

Data were derived from the ongoing IMMUreal cohort, which investigates immunotherapy in hepatocellular carcinoma across two tertiary centres in Bavaria. A total of 124 patients treated with atezolizumab and bevacizumab as first-line therapy between June 2020 and December 2023 were analysed. Feasibility, treatment patterns, and outcomes of sequential therapy were assessed, with a focus on defined prognostic subgroups.

The median overall survival under real-world conditions was 19.8 months. Less than half of the patients (41.2%) proceeded to second-line therapy, and only 19.2% were eligible for third-line treatment. This decline in treatment eligibility corresponded to a marked reduction in therapy duration and progressive deterioration in liver function, as indicated by Albumin-Bilirubin and Child-Pugh scores. While patients with worse baseline liver function, such as patients with Child-Pugh B or ALBI > 1, had a significantly lower probability of transitioning to 2nd line therapy, no significant association was found between the number of treatment lines and factors such as liver cirrhosis, poor physical condition, extrahepatic disease, or macrovascular invasion.

Sequential therapy following atezolizumab and bevacizumab is feasible only for selected patients. However, preserving liver function seems crucial to optimising multi-line therapy and improving outcomes in advanced hepatocellular carcinoma.

Therapeutic drug monitoring (TDM) is used to optimize drug therapy by ensuring efficacy or preventing toxicity. For a limited number of cytotoxic antineoplastic drugs, for aminoglycoside antibiotics, and for vancomycin the use of TDM is common practice. In this article, we summarize recent advances and indications for the TDM of antineoplastic agents in children, focusing on protein kinase inhibitors and the cytotoxic drug fludarabine. We also summarize recent recommendations for antimicrobial TDM of beta-lactam antibiotics and vancomycin.

The aim of this study was to reveal the hepatotoxicity profile of different immune checkpoint inhibitor (ICI) used strategies in patients with Hepatocellular carcinoma (HCC) by meta-analysis.

Literature was searched through PubMed, Cochrane, Embase, and Web of Science up to October 14, 2023, and the subject terms were "Carcinoma, Hepatocellular" and "Immune Checkpoint Inhibitors". The main observations were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT and AST were graded according to CTCAE.

A total of 32 studies with 7662 patients were included in the analysis. The results of meta-analysis showed that among different ICI treatment regimens, ICI monotherapy had the lowest incidence of any grade of ALT and AST elevation, and the highest for ICI+multikinase inhibitor (MKI); ICI+anti-VEGFR/VEGFA and ICI monotherapy had a lower incidence of grade ≥3 ALT and AST elevations, while ICI + MKI, dual immunotherapy, and dual immunotherapy+MKI had a higher incidence of grade ≥3 ALT and AST elevations; ICI monotherapy was more prone to any grade ALT elevation than placebo, and ICI monotherapy was more prone to ≥ 3 grade AST elevation than MKI; combination immunotherapy was more prone than MKI to any grade ALT and AST elevations; in grade ≥3 ALT and AST elevations, combination immunotherapy was similar to ICI monotherapy and MKI; ICI + MKI was more likely to have grade ≥3 ALT.

ICI monotherapy was more likely to cause severe hepatotoxicity than MKI. Combination immunotherapy treatment increased the incidence of hepatotoxicity compared to monotherapy, and ICI + MKI was prone to develop severe hepatotoxicity.

This study aims to develop and validate a novel radiomics model utilizing magnetic resonance imaging (MRI) to predict progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (uHCC) who are receiving a combination of immune checkpoint inhibitors (ICIs) and antiangiogenic agents. This is an area that has not been previously explored using MRI-based radiomics.

111 patients with uHCC were enrolled in this study. After performing univariate cox regression and the least absolute shrinkage and selection operator (LASSO) algorithms to extract radiological features, the Rad-score was calculated through a Cox proportional hazards regression model and a random survival forest (RSF) model. The optimal calculation method was selected by comparing the Harrell's concordance index (C-index) values. The Rad-score was then combined with independent clinical risk factors to create a nomogram. C-index, time-dependent receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis were employed to assess the forecast ability of the risk models.

The combined nomogram incorporated independent clinical factors and Rad-score calculated by RSF demonstrated better prognosis prediction for PFS, with C-index of 0.846, 0.845, separately in the training and the validation cohorts. This indicates that our model performs well and has the potential to enable more precise patient stratification and personalized treatment strategies. Based on the risk level, the participants were classified into two distinct groups: the high-risk signature (HRS) group and the low-risk signature (LRS) group, with a significant difference between the groups (P < 0.01).

The effective clinical-radiomics nomogram based on MRI imaging is a promising tool in predicting the prognosis in uHCC patients receiving ICIs combined with anti-angiogenic agents, potentially leading to more effective clinical outcomes.

Hepatocellular Carcinoma (HCC) is related to dysregulated lipid metabolism and immunosuppressive microenvironment. This study developed a genetic risk model using lipid metabolism-related genes to predict survival and immune patterns in HCC patients.

Differentially expressed genes (DEGs) related to lipid metabolism were identified in HCC via the TCGA-LIHC dataset. A risk model for survival prediction was constructed via DEGs related to survival. The immune signature associated with the risk model was also evaluated by the CIBERSORT algorithm, tumor immune dysfunction and exclusion algorithm, and single sample gene set enrichment analysis.

This study identified six lipid metabolism-related genes, ADH4, LCAT, CYP2C9, CYP17A1, LPCAT1, and ACACA, to construct a lipid metabolism-related gene risk model that can divide HCC patients into low- and high-risk groups. Internal and external validation verified that the risk model could be a signature that could effectively predict HCC patient prognosis. High-risk patients showed disrupted immune cell profiles, reduced tumor-killing capacity, and increased expression of immune checkpoint genes. However, they responded more favorably to immune checkpoint inhibitor (ICB) therapy. The top ten hub genes related to the risk model were associated with tumor progression and deteriorating prognosis. In vitro experiments verified that the downregulation of the top 1 hub gene CDK1 was correlated to the HCC cell proliferation.

The risk model constructed using lipid metabolism-related genes could effectively predict prognosis and was related to the immunosuppressive microenvironment and ICB immunotherapy. The hub genes related to the risk model were potential therapeutic targets.

The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

Background: The transcription factor SOX9 plays a critical role in various diseases, including hepatocellular carcinoma (HCC), and has been implicated in resistance to sorafenib treatment. Accurate assessment of SOX9 expression is important for guiding personalized therapy in HCC patients; however, a reliable non-invasive method for evaluating SOX9 status remains lacking. This study aims to develop a deep learning (DL) model capable of preoperatively and non-invasively predicting SOX9 expression from CT images in HCC patients. Methods: We retrospectively analyzed a dataset comprising 4011 CT images from 101 HCC patients who underwent surgical resection followed by sorafenib therapy at West China Hospital, Sichuan University. A deep reinforcement learning (DRL) approach was proposed to enhance prediction accuracy by identifying and focusing on image regions highly correlated with SOX9 expression, thereby reducing the impact of background noise. Results: Our DRL-based model achieved an area under the curve (AUC) of 91.00% (95% confidence interval: 88.64-93.15%), outperforming conventional DL methods by over 10%. Furthermore, survival analysis revealed that patients with SOX9-positive tumors had significantly shorter recurrence-free survival (RFS) and overall survival (OS) compared to SOX9-negative patients, highlighting the prognostic value of SOX9 status. Conclusions: This study demonstrates that a DRL-enhanced DL model can accurately and non-invasively predict SOX9 expression in HCC patients using preoperative CT images. These findings support the clinical utility of imaging-based SOX9 assessment in informing treatment strategies and prognostic evaluation for patients with advanced HCC.

The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality, with limited therapeutic options available for advanced stages of the disease. Treatment strategies for HCC are multimodal and largely depend on the disease stage, liver function, and individual patient factors. Based on the WHO's VigiAccess database, this study employed a retrospective descriptive analysis of adverse drug reaction (ADR) reports associated with four widely used tyrosine kinase inhibitors (TKIs) for HCC, including Sorafenib, Cabozantinib, Lenvatinib, and Regorafenib. The analysis included demographic data such as patient age, gender, and geographical distribution, alongside clinical information on the systems and symptoms associated with ADR reports. A total of 112,975 ADR reports related to the four TKI-targeted drugs were identified. Sorafenib exhibited the highest ADR reporting rate (30.7%), followed by Cabozantinib (29.4%), Lenvatinib (24.5%), and Regorafenib (15.4%). The odds ratio method was employed to assess the statistical correlation between the use of these targeted drugs and the occurrence of ADRs. Notably, Sorafenib (3,746) and Regorafenib (2,496) served to have the highest number of reported palmar-plantar erythrodysaesthesia syndrome. Chi-square analyses suggested that ADRs related to Lenvatinib were reported significantly more frequently in female patients compared to their male counterparts. The findings of this study can enhance public awareness of drug-related adverse events and provide an evidence-based foundation for prioritizing the management of ADRs associated with TKIs in second-line HCC therapy.

Hepatic arterial infusion chemotherapy (HAIC) with a combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown excellent local control for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). In China, both camrelizumab (a programmed cell death-1 [PD-1] inhibitor) and sorafenib have been approved for the first-line treatment of advanced HCC. This study aimed to investigate the efficacy and safety of hepatic artery infusion of FOLFOX chemotherapy plus camrelizumab combined with sorafenib in BCLC stage C advanced HCC.

This was a single-arm phase II trial (ChiCTR2100041874) with a Simon's two-stage design. Eligible patients were given a maximum of 6 cycles of hepatic artery infusion with FOLFOX chemotherapy plus camrelizumab (200 mg once every 3 weeks). Sorafenib (400 mg orally twice daily) was given since day 3 after the completion of the first cycle of hepatic artery infusion until disease progression, intolerable toxicity, or conversion to surgical resection. The primary endpoint was objective response rate (ORR) based on the modified Response Evaluation Criteria In Solid Tumors (mRECIST).

Between January 4, 2021, and December 11, 2023, 25 patients were enrolled. Eleven patients had partial response, with an ORR of 44.0% (95% CI, 24.6-63.5%). The primary endpoint was not met, and the study failed to enter the second stage. Median progression-free survival was 4.87 months (95% CI, 2.07-7.66), with a 12-month rate of 23.2%. Median overall survival was 8.87 months (95% CI, 8.17-9.57), with 12- and 24-month rates of 40.3% and 26.9%, respectively. Two (8.0%) patients received curative resection after the study treatment. Grade ≥ 3 treatment-related adverse events occurred in 19 (76.0%) patients, with the most common being decreased lymphocyte count (13 [52.0%]), increased aspartate aminotransferase (11 [44.0%]), and increased alanine aminotransferase (seven [28.0%]).

Hepatic artery infusion of FOLFOX chemotherapy plus camrelizumab combined with oral sorafenib shows manageable safety profile but modest antitumor activity in patients with BCLC stage C advanced HCC.

Significant advances have occurred in the locoregional and systemic therapy landscape for hepatocellular carcinoma (HCC), with the most notable being the introduction of immune checkpoint inhibitor (ICI) combinations. ICI combinations have significantly improved the overall survival of patients with unresectable HCC, affording median survival over 2 years and long-term survival exceeding 5 years in a subset of patients. Accordingly, there has been increased interest in the earlier application of systemic therapies, including (neo)adjuvant therapy in the perioperative setting or in combination with intra-arterial therapies. However, recent data failed to demonstrate improved recurrence-free survival with use of adjuvant ICI therapy. Conversely, 2 trials showed improved progression-free survival when ICI therapies were combined with transarterial chemoembolization, although data regarding the impact on overall survival are still immature. These improved outcomes raise several new questions, including which patients with liver-localized HCC should receive systemic therapy, how should this be sequenced or combined with other available therapies, and how to manage those patients with marked responses, including consideration of liver transplantation. These questions are often determined on a case-by-case basis and best made in a multidisciplinary manner considering several factors, including tumor burden, degree of liver dysfunction, performance status, and patient's long-term goals of care.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.

Overexpression of EphB3 has been documented across various cancers and essential for cell proliferation, survive and metastasis, making it a valuable therapeutic target. In this study, a series of novel penta-1,4-dien-3-one and quinoxaline conjugates were designed and synthesized using pharmacophore fusion strategies to explore potential EphB3 inhibitors. CCK-8 experiments revealed significant anti-cancer activity of most newly synthesized compounds against hepatocellular carcinoma (HCC). Among them, compound W8 displaying the highest inhibitory activity against MHCC97H (IC50 = 1.87 μM), which arrests MHCC97H cells in the G0/G1 phase and induces apoptosis. Furthermore, compound W8 suppresses tumor growth in an MHCC97H xenograft model in vivo by suppressing phosphorylation level of EphB3 and down-regulating the SRC-AKT signaling pathway, leading to a dose-dependent reduction in tumor volumes and weights, with a 40 mg/kg dose achieving decreases of 68.4 % and 65.3 %, respectively. Given its ability to modulate EphB3 signaling, W8 represents a promising lead compound for further drug development, particularly for cancers characterized by EphB3 overexpression, and may offer new opportunities for targeted therapy in precision oncology.

This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the efficacy and safety of triple therapy with tyrosine kinase inhibitors (TKIs) combined with transcatheter arterial chemoembolization (TACE) plus programmed death 1 (PD-1) inhibitors (T-T-P) and dual therapy with TKIs combined with TACE (T-T) for the treatment of advanced unresectable hepatocellular carcinoma (uHCC).

Literature related to the efficacy of TKIs combined with TACE plus PD-1 inhibitors in uHCC was searched using the Embase, PubMed, and Cocrane libraries. TSA was used to reduce false positive results due to random error.

Seventeen articles were included in this meta-analysis, including 2,561 patients. In the T-T-P group, OS [HR 0.45, 95% confidence interval (CI) 0.39-0.52; p = 0.000], PFS [HR 0.43, 95% CI 0.38 - 0.48; p = 0.000], were significantly prolonged compared to those in the T-T group; ORR (RR 1.59 [95% CI 1.39-1.81]; p = 0.000) and DCR (RR 1.26 [95% CI 1.15-1.37]; p = 0.000) were significantly higher. TSA analysis showed early results without further testing. Prognostic factor analysis demonstrated that portal vein tumor thrombus (PVTT) and extrahepatic metastasis were common independent risk factors for OS and PFS. Regarding grade 3/4 adverse events results showed no statistically significant differences in any of them.

Compared with T-T treatment group, the T-T-P treatment group exhibited a notable improvement in OS and PFS, particularly in cases of PVTT and extrahepatic metastasis. Furthermore, it can markedly enhance the ORR and DCR in patients with uHCC.

SCARA5 (Scavenger Receptor Class A Member 5), a member of scavenger receptor class A, is a type II transmembrane protein. Previous studies, including our own, have suggested that SCARA5 acts as a tumor suppressor in various cancers. Additionally, SCARA5 has been identified as a ferritin receptor that facilitates iron delivery independent of transferrin. However, it remains unclear whether ferroptosis is involved in the tumor-suppressive function of SCARA5 in hepatocellular carcinoma (HCC). In this study, we found that SCARA5-deficient cells, including mouse embryonic fibroblasts (MEFs) and HCC cells, exhibited reduced sensitivity to ferroptosis induced by erastin and RSL3. We measured the cell viability, cellular reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA) and ferrous iron concentration to assess the role of SCARA5 in ferroptosis. Mechanistically, we confirmed that SCARA5 might enhance the intracellular availability of bioactive ferrous iron by promoting autophagic degradation of the major iron storage protein ferritin. Furthermore, we found that SCARA5 deficiency contributed to the resistance of HCC cells to sorafenib, a therapeutic agent for HCC, possibly by inhibiting ferroptosis. Collectively, our study revealed the role of SCARA5 in regulating ferroptosis, providing a profound understanding of sorafenib resistance in HCC systemic therapy.

This study aimed to investigate the toxic effects of ellipticine on liver cancer cells and predict its anti-liver cancer mechanism through network pharmacology, especially by targeting FGFR3 to regulate the RAS/MAPK-P38 signaling pathway, thereby inducing apoptosis of liver cancer cells. The inhibitory effect of ellipticine on the proliferation of HepG2, Huh-7, SMMC7721, BEL-7402, SK-HEP-1, LX-2, and MHCC97H cells was detected by CCK-8 assay, and the IC50 value was calculated. The potential targets of ellipticine were predicted by the database, and the intersection analysis with liver cancer-related targets was performed to construct a protein interaction network (PPI), (KEGG) pathway enrichment analysis, and molecular docking verification. FGFR3 in HepG2 cells was knocked down by siRNA, and the effects on cell proliferation, apoptosis, and ROS levels were observed. The expression changes of FGFR3, RAS, P38, and their phosphorylated forms after ellipticine treatment, as well as the effects of RAS agonist ML-908 and P38 inhibitor PD169316 on cell proliferation, apoptosis, and migration, were detected by Western blotting. Ellipticine has an inhibitory effect on all tested liver cancer cell lines, among which HepG2 has the strongest inhibitory effect, with an IC50 of 5.15 ± 0.25 μM. Ellipticine is predicted to have 32 potential targets, and 5 common targets among the 225 targets related to liver cancer, including PDGFRA, KIT, FGFR3, ERBB2, and STAT3. KEGG analysis showed that these targets are mainly involved in cancer pathways. Molecular docking showed that Ellipticine can bind strongly to FGFR3. FGFR3 expression is highest in HepG2 cells. After knocking down FGFR3, the proliferation ability of HepG2 cells is further weakened, and the addition of apoptosis inhibitor ZVAD can partially restore the proliferation ability. ROS levels increase after Ellipticine treatment, and ROS levels further increase after knocking down FGFR3, and ZVAD treatment can reduce ROS levels. After Ellipticine treatment, the expression levels of FGFR3, RAS, and p-P38 decrease. Ellipticine-induced cell proliferation inhibition and apoptosis were reversed by RAS agonist ML-908, whereas P38 inhibitor PD169316 exacerbated cell apoptosis and migration inhibition. Ellipticine induces apoptosis of liver cancer cells by targeting FGFR3 and inhibiting the RAS/MAPK-P38 signaling pathway. This discovery provides new mechanistic insights into Ellipticine as a liver cancer treatment and may lay the foundation for the development of targeted therapeutic strategies.

Hepatocellular carcinoma (HCC) accounts for 85%-90% of all primary liver cancers (PLCs). Owing to the occult nature of HCC, most patients present at an advanced stage at the time of initial diagnosis and have a poor prognosis. With regard to systemic therapy, targeted therapy and immunotherapy are currently the centers of clinical research. With regard to local treatment, surgical resection, radiofrequency ablation, hepatic artery chemoembolization, and radiotherapy are commonly used. Interstitial brachytherapy is commonly used for the treatment of cervical and genitourinary cancers. In this case, interstitial brachytherapy was used to treat gluteus medius muscle metastasis from PLC, with good local control and symptom relief.

Chronic hepatitis B virus (HBV) infection is an etiology of HCC, but clinical trials using immune checkpoint inhibitors (ICIs) usually exclude patients with chronic active hepatitis B (serum HBV viral load > 2000 IU/mL). This study examined the safety and efficacy of concurrently administering the ICI and anti-HBV medications in this patient population.

In this single-arm phase 2 clinical trial, we enrolled patients with advanced HCC and untreated chronic active hepatitis B. Patients received 1500 mg of durvalumab every 4 weeks alone or in combination with 300 mg of tremelimumab on day 1 (the STRIDE regimen). Anti-HBV treatment with entecavir was simultaneously initiated. The primary endpoint was the rate of HBV reactivation.

We enrolled 30 patients, whose mean baseline HBV viral load was 770,986 IU/mL. No patients experienced HBV reactivation or HBV-associated hepatitis. Hepatitis flare was noted in 8 (26.7%) patients, but none of them were associated with HBV reactivation. The objective tumor response rate was 10% and 25% for the durvalumab treatment alone and the STRIDE regimen, respectively.

For patients with chronic active hepatitis B, ICI therapy could be promptly initiated as long as anti-HBV medications were administered simultaneously.

NCT04294498.

The prevalence of hepatocellular carcinoma (HCC) among older patients is rising due to the aging population. This study aimed to compare the efficacy and safety of targeted therapy alone versus its combination with immunotherapy in older patients (≥ 65 years old) with unresectable HCC (uHCC).

We retrospectively analyzed 158 patients aged ≥ 65 diagnosed with uHCC who received targeted therapy alone or in combination with immunotherapy from the CLEAP database between March 2019 and July 2023. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety assessments for adverse events (AEs).

The ORR was 3.6% in the targeted monotherapy group compared to 29.4% in the combination therapy group, while the DCRs were 53.6% and 54.9%, respectively. Survival analysis indicated a median PFS of 7.3 months for monotherapy versus 13.2 months for combination therapy (P = 0.137) and a median OS of 16.0 months versus 20.0 months, respectively (P = 0.140). AEs occurred in 44.6% of the monotherapy group and 58.8% in the combination therapy group, with 20.5% in the combination group withdrawing due to adverse reactions, significantly higher than in monotherapy group.

Among older patients with uHCC, the combination therapy demonstrated higher ORR and longer PFS and OS, although it had higher incidences of AEs and drug withdrawal.

The FACT-Hep questionnaire has been used to evaluate the health-related quality of life (HRQOL) in various types of hepatobiliary cancer. Nevertheless, the application in intrahepatic cholangiocarcinoma (iCCA) has been limited. The study aimed to validate the applicability of FACT-Hep as a reliable tool for evaluating HRQOL in patients with advanced-stage iCCA.

Atractylodes lancea capsules were tested for efficacy and safety in a randomized, controlled phase IIA. Internal consistency, intraclass correlation, test-retest reliability, discriminant and convergent validity, and FACT-Hep score-clinical response connection were assessed.

Thirty-nine patients qualified for the research. Cronbach's alpha coefficients > 0.7 showed internal consistency for all subscale items from baseline (day 1) to 90 days. For ICC, convergent, and discriminant validity, all items except the HepCS subscale were reliable. Patients with ECOG scores of 0-1 or 2 had significantly different HepCS subscale values-calculated effect size for subscale score change over time. FACT-G and FWB differed significantly in low-dose group 1. At 3-month, 1-month, and 2-month follow-ups, Group 2 (high dose) patients had significant differences in FACT-Hep, TOI, and HepCS. The effect size was the same in Group 3 (untreated). Group 1 and 2 non-progressive patients exhibited lower FWB and EWB scores than progressive patients. The treated survivors had lower FACT-Hep, TOI, HepCS, FWB, and EWB scores than the non-treated survivors, which was linked to AL treatment side effects.

The FACT-Hep detects changes and is a reliable and valid tool for assessing HRQOL in patients with advanced-stage iCCA.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Multiple treatment modalities are available for the management of HCC, depending on its stage as determined by the Barcelona Clinic Liver Cancer staging system. Because liver transplantation (LT) theoretically removes the cancer and replaces the organ at risk for future malignancy, LT is often considered the most definitive and one of the most efficacious treatment options for HCC. Nevertheless, the success and efficacy of liver transplantation depend on various tumor characteristics. As a result, multiple criteria have been developed to assess the appropriateness of a case of HCC for LT, with the pioneering Milan Criteria established in 1996. Over the past 20 to 30 years, these criteria have been critically evaluated, expanded, and often liberalized to make LT for patients with HCC a more universally applicable option. Furthermore, the development of other treatment modalities has enabled downstaging and bridging strategies for HCC prior to LT. In this narrative and comprehensive review, we provided an update on recent trends in the epidemiology of HCC, selection criteria for LT, implementation of LT across different regions, treatment modalities available as bridges, downstaging strategies, alternatives to LT, and, finally, post-LT surveillance.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence suggests that epigenetic dysregulation contributes to the initiation and progression of HCC. We aimed to investigate key epigenetic regulators that contribute to tumorigenesis and progression, providing a theoretical basis for targeted therapy for HCC. We performed a comprehensive epigenetic analysis of differentially expressed genes in LIHC from the TCGA database. We identified fibrillarin (FBL), an rRNA 2'-O-methyltransferase, as an essential contributor to HCC. A series of in vitro and in vivo biological experiments were performed to investigate the potential mechanisms of FBL. FBL knockdown suppressed the proliferation of HCC cells. In vivo studies using cell-derived xenograft (CDX), patient-derived xenograft (PDX), and diethylnitrosamine (DEN)-induced HCC models in Fbl liver-specific knockout mice demonstrated the critical role of FBL in HCC carcinogenesis and progression. Mechanistically, FBL regulates the expression of CAD in HCC cells by recruiting YY1 to the CAD promoter region. We also revealed that fludarabine phosphate is a novel inhibitor of FBL and can inhibit HCC growth in vitro and in vivo. The antitumor activity of lenvatinib has been shown to be synergistically enhanced by fludarabine phosphate. Our study highlights the cancer-promoting role of the FBL-YY1-CAD axis in HCC and identifies fludarabine phosphate as a novel inhibitor of FBL. A schematic diagram depicting the FBL-YY1-CAD signaling pathway and its regulatory role in HCC progression.

Systemic therapy has now become mainstream for the treatment of hepatocellular carcinoma (HCC) and is also changing from molecular-targeted therapy, such as with sorafenib and lenvatinib, to immunotherapy, such as with the atezolizumab plus bevacizumab and durvalumab plus tremelimumab combination regimens. Molecular-targeted therapy is selected as the first-line treatment when immunotherapy is not indicated or as second- or later-line treatment when immunotherapy is ineffective. It is necessary to select the appropriate treatment taking into consideration the expected treatment efficacy and adverse events, as well as the hepatic reserve. Currently, newer agents and combination regimens as first-line/second-line treatment for advanced-stage HCC, combined therapy with transarterial chemoembolization for intermediate-stage HCC, and perioperative adjuvant therapy for curative treatment for early-stage HCC are being developed. Therefore, systemic therapy is now indicated for any stage of the disease. While local therapies were previously used as the main treatment strategy for HCC, systemic therapy in combination with local therapies is being actively attempted at present. Systemic therapy is currently the main focus of development of novel treatments for HCC.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Despite the rapid evolution of targeted and immunotherapies for hepatocellular carcinoma (HCC), a systematic comparison of their adverse event profiles remains limited. This review addresses this critical gap by synthesizing data from 13 randomized controlled trials (RCTs) to prioritize treatment regimens on the basis of safety, thereby guiding clinical decision-making in an era of expanding therapeutic options.

Clinical studies focusing on targeted and immunotherapies in HCC patients were chosen from databases such as PubMed, Embase, Web of Science and the Cochrane Library, which spans from 2008 to 2023. Data processing and evaluation followed PRISMA guidelines, with a random-effects model employed to merge the data. Network models were then developed, with adverse events serving as the primary endpoint for analysis.

A comprehensive review of the relevant literature was conducted, identifying 13 randomized controlled trials (RCTs) encompassing 13 treatment protocols for HCC. This study included a total of 10,760 patients. Adverse events within the same category were initially consolidated, followed by the sequential construction of a network model to assess the risk probabilities associated with different targeted immunotherapy regimens for various adverse events and establish priority rankings.

Cabozantinib, camrelizumab, and their combination therapy for HCC are associated with a higher incidence of common adverse reactions, whereas durvalumab, lenvatinib, and their combination therapy are less likely to cause common adverse effects.

Hepatocellular carcinoma (HCC) is a common and challenging malignancy of the digestive tract. Unfortunately, patients with advanced HCC frequently experience limited long-term benefits from current treatments, highlighting the critical need for innovative therapeutic agents. The discovery and development of new small-molecule compounds that target tumours have become crucial aspects of cancer research. In this study, we report on L-741626, a compound that has significant inhibitory effects on HCC. Both in vivo and in vitro experiments confirmed that L-741626 inhibited the growth of HCC by suppressing the MAPK/ERK signalling pathway. Molecular docking simulations and drug affinity responsive target stability assays further identified redox Factor 1 (Ref-1) as a target of L-741626. Ref-1 is overexpressed in HCC and is correlated with poor prognosis and high stage. Further studies demonstrated that Ref-1 interacts with CRAF, a crucial component of the MAPK/ERK signalling pathway. Knockdown of Ref-1 in HCC cells led to inhibition of the MAPK/ERK pathway. Sorafenib is a well-established targeted therapy for the treatment of HCC, with its primary antitumor mechanism being the inhibition of the MAPK/ERK signalling pathway. However, the presence of tumor stem cells is a key factor contributing to resistance to sorafenib. Our study demonstrates that L-741626 can suppress tumor stemness in HCC. The combination of L-741626 and sorafenib significantly enhances the sensitivity of HCC, resulting in increased tumoricidal effects. Our findings reveal a novel pharmacological effect of L-741626, which inhibits MAPK/ERK signalling activity in HCC by targeting Ref-1. Furthermore, L-741626 exhibits a synergistic effect when combined with sorafenib, suggesting a new potential approach for HCC treatment.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. While early-stage HCC can be effectively managed with surgical resection and other interventions, treatment options for advanced HCC are limited. Current systemic treatments for advanced HCC include VEGF-targeted tyrosine kinase inhibitors (Sorafenib, Lenvatinib), and the combination therapy of anti PD-1/PD-L1 and anti VEGF (Atezolizumab plus Bevacizumab, Camrelizumab plus Rivoceranib). However, the lack of response to these drugs and the emergence of acquired drug resistance significantly impairs their efficacy. Numerous studies have demonstrated that the tumor immune microenvironment (TIME) plays a crucial role in modulating the response to these therapies. Various immune cells and their secreted factors within the TIME play a pivotal role in the emergence of secondary drug resistance in HCC. This article reviews the mechanism of TIME promoting drug resistance, discusses the influence of current systemic HCC treatment drugs on TIME, and evaluates how these TIME changes affect the efficacy of treatment. A deeper understanding of the interaction between TIME and systemic treatment drugs may be beneficial to enhance the treatment effect, mitigate drug resistance of advanced HCC, and ultimately improve the prognosis of patients.

Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver cancers, with its incidence continually rising, posing a threat to socio-economic development. Currently, liver resection is the standard treatment for HCC. However, post-hepatectomy liver failure (PHLF) is a severe and formidable postoperative complication that increases patients' medical expenses and mortality risk. Additionally, liver failure can occur at any stage of HCC development, severely affecting patients' quality of life and prognosis.

Using the Web of Science Core Collection, this bibliometric study analyzed English articles and reviews on HCC and liver failure from 2003 to 2023. Bibliometric tools like CiteSpace, VOSviewer, and R-studio were employed for data visualization and analysis, focusing on publication trends, citation metrics, explosive intensity, and collaborative networks. Use the Comparative Toxicogenomics and Genecards databases to screen for genes related to liver failure, and perform enrichment analyses using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and PubMed on the identified differentially expressed genes.

The study identified a significant increase in publications on HCC and liver failure, with key contributions from journals such as the World Journal of Gastroenterology and the Journal of Hepatology. The United States, China, and Japan were the leading countries in research output. Prominent authors and institutions, including Kudo Masatoshi and Sun Yat-sen University, were identified. Enrichment analysis showed drug metabolism, oxidative stress, lipid metabolism, and other pathways are closely related to this field. Research hotspots included risk prediction models and novel therapies.

This bibliometric analysis highlights the growing research interest and advancements in HCC and liver failure. Future research should focus on improving risk prediction, developing new therapies, and enhancing international collaboration to address these critical health issues.

The gut microbiota is often altered in chronic liver diseases and hepatocellular carcinoma (HCC), and increasing evidence suggests that it may influence response to cancer immunotherapy. Strategies to modulate the gut microbiome (i.e., fecal microbiota transplant (FMT)) may help to improve efficacy of immune checkpoint inhibitors (ICIs) or even overcome resistance to ICIs. Here, we describe the design and rationale of FAB-HCC, a single-center, single-arm, phase II pilot study to assess safety, feasibility, and efficacy of FMT from patients with HCC who responded to PD-(L)1-based immunotherapy or from healthy donors to patients with HCC who failed to achieve or maintain a response to atezolizumab plus bevacizumab.

In this single-center, single-arm, phase II pilot study (ClinicalTrials.gov identifier: NCT05750030), we plan to include 12 patients with advanced HCC who failed to achieve or maintain a response to atezolizumab/bevacizumab. Patients will receive a single FMT via colonoscopy from donors with HCC who responded to PD-(L)1-based immunotherapy or from healthy individuals, followed by atezolizumab/bevacizumab every 3 weeks. The primary endpoint is safety, measured by incidence and severity of treatment-related adverse events. The main secondary endpoint is efficacy, as assessed by best radiological response according to RECISTv1.1 and mRECIST. Additional exploratory endpoints include data on the effect of FMT on recipient gut microbiota, as well as metagenomic analysis of stool samples, analyses of circulating immune cells and serum and stool proteomic, metabolomic and lipidomic signatures.

The results of this study will help to define the potential of FMT as add-on intervention in the systemic treatment of advanced HCC, with the potential to improve efficacy of immunotherapy or even overcome resistance.

EudraCT Number: 2022-000234-42 Clinical trial registry & ID: ClinicalTrials.gov identifier: NCT05750030 (Registration date: 16.01.2023).

Hepatocellular carcinoma (HCC) is the main phenotype of liver cancer with a poor prognosis. Copper is vital in liver function, and HCC cells rely on it for growth and metastasis, leading to cuproplasia. Excessive copper can induce cell death, termed cuproptosis. Tumor microenvironment (TME) is pivotal in HCC, especially in immunotherapy, and copper is closely related to the TME pathogenesis. However, how these two mechanisms contribute to the TME is intriguing.

We conducted the latest progress literature on cuproplasia and cuproptosis in HCC, and summarized their specific roles in TME and treatment strategies. The mechanisms of cuproplasia and cuproptosis and their relationship and role in TME have been deeply summarized. Cuproplasia fosters TME formation, angiogenesis, and metastasis, whereas cuproptosis may alleviate mitochondrial dysfunction and hypoxic conditions in the TME. Inhibiting cuproplasia and enhancing cuproptosis in HCC are essential for achieving therapeutic efficacy in HCC.

An in-depth analysis of cuproplasia and cuproptosis mechanisms within the TME of HCC unveils their opposing nature and their impact on copper regulation. Grasping the equilibrium between these two factors is crucial for a deeper understanding of HCC mechanisms to shed light on novel directions in treating HCC.