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Background Chemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), although their origins and latent molecular mechanisms remain elusive. The aim of this study was to investigate how activated hepatic stellate cells (a-HSCs) promote angiogenesis in HCC. Methods A total of 22 HCC patients were enrolled randomly. We used immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) to analyse the production of interleukin-8 (IL-8) in a-HSCs derived from HCC tissues. The angiogenic effects of IL-8 in vitro and in vivo were assessed by ELISA, real-time quantitative polymerase chain reaction, capillary tube formation assay, and chick embryo chorioallantoic membrane assay. Results The present study showed that IL-8 was enriched predominantly in the tumour stroma of HCC tissues and was mainly derived from a-HSCs, rather than from hepatoma cells, in vivo and in vitro. Angiogenesis was most active at the invading edge, which was close to the a-HSCs. The angiogenic effect was dramatically attenuated by an IL-8 neutralizing antibody both in vitro and in vivo. Moreover, the IL-8 neutralizing antibody down-regulated Ser727-phosphorylated STAT3 levels in hepatoma cells treated with a-HSCs conditioned medium. Conclusions These findings reveal that a-HSCs within the stroma of HCC contribute to tumour angiogenesis via IL-8.

Background Stimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE. Methods 30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab. Results Among the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm ( p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm ( p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post-TACE. Conclusions IV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14. Trial registration ClinicalTrials.gov NCT00049322 .

We assessed the safety and efficacy of sorafenib with cryotherapy (cryoRx) in advanced hepatocellular carcinoma (HCC). One hundred four HCC patients were enrolled, who met the following criteria: (i) Barcelona Clinic Liver Cancer stage C; (ii) HCC without distant metastasis; (iii) the presence of portal vein thrombosis (PVT); (iv) Child-Pugh class A or B; and (v) life expectancy of at least 12 weeks. The patients were randomly divided into sorafenib-cryoRx and sorafenib (control) groups. Primary endpoint was time to progression (TTP); secondary endpoints included overall survival (OS) and tolerability. Microvessel density (MVD) was assessed by CD34-immunostaining. After a median 10.5 (4–26) months follow-up, the data showed that median TTP was 9.5 (8.4–13.5) months in combinatorial therapy group vs. 5.3 (3.8–6.9) months in sorafenib group ( P  = 0.02). The median OS was 12.5 (95 % CI 10.6–16.4) months in combination therapy group vs. 8.6 (7.3–10.4) months in sorafenib group ( P  = 0.01). Low MVD patients in combination therapy exhibited significantly longer median TTP and OS than controls. High MVD was predictive of poor responses to sorafenib. CryoRx did not increase frequency/degree of sorafenib-related adverse events. Therefore, it was concluded that the addition of cryoRx significantly improved clinical outcomes of Sorafenib therapy in advanced HCC with acceptable tolerance and similar safety profiles as previously reported.

Background Hepatocellular carcinoma is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10 to 15% of hepatocellular carcinoma patients are suitable candidates for treatment with curative intent, such as hepatic resection and liver transplantation. A majority of patients have locally advanced, liver restricted disease (Barcelona Clinic Liver Cancer (BCLC) staging system intermediate stage). Transarterial loco regional treatment modalities offer palliative treatment options for these patients; transarterial chemoembolization (TACE) is the current standard treatment. During TACE, a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. Yttrium-90 radioembolization ( 90 Y-RE) involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a β-emitting isotope, delivering selective internal radiation to the tumor. 90 Y-RE is increasingly used in clinical practice for treatment of intermediate stage hepatocellular carcinoma, but its efficacy has never been prospectively compared to that of the standard treatment (TACE). In this study, we describe the protocol of a multicenter randomized controlled trial aimed at comparing the effectiveness of TACE and 90 Y-RE for treatment of patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma. Methods/design In this pragmatic randomized controlled trial, 140 patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma, with Eastern Cooperative Oncology Group performance status 0 to 1 and Child-Pugh A to B will be randomly assigned to either 90 Y-RE or TACE with drug eluting beads. Patients assigned to 90 Y-RE will first receive a diagnostic angiography, followed by the actual transarterial treatment, which can be divided into two sessions in case of bilobar disease. Patients assigned to TACE will receive a maximum of three consecutive transarterial treatment sessions. Patients will undergo structural follow-up for a timeframe of two years post treatment. Post procedural magnetic resonance imaging (MRI) will be performed at one and three months post trial entry and at three-monthly intervals thereafter for two years to assess tumor response. Primary outcome will be time to progression. Secondary outcomes will be overall survival, tumor response according to the modified RECIST criteria, toxicities/adverse events, treatment related effect on total liver function, quality of life, treatment-related costs and cost-effectiveness. Trial registration NCT01381211

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

Local tumor progression (LTP) in early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains high. Tumor feeding artery ablation (FAA) before target tumor ablation was reported to reduce LTP in patients with HCC >3 cm. The aim of our study is to investigate whether FAA before target tumor ablation may reduce LTP in HCC <3 cm. We retrospectively analysis the outcome of patients with HCC <3 cm undergoing FAA before target tumor ablation (N = 17) compared to direct RFA to target tumor alone (N = 35). FAA significantly reduces LTP (FAA vs. non-FAA: local tumor progression 17.6% vs. 48.6%, p = 0.038), but not in intrahepatic recurrence: 29.4% vs. 25.7%, p = 0.778; or in overall recurrence rate: 41.2% vs. 62.9%, p = 0.14). The cumulative 1-year and 2-year LTP rates in FAA group were 17.6% and 17.6%, while 11.4% and 42.9% in non-FAA group (p = 0.073), respectively. The cumulative overall recurrence rates at 1-year and 2-year were 29.4% and 35.3% in FAA group, while 14.3% and 57.1% in non-FAA group (p = 0.130), respectively. FAA before target tumor ablation may decrease LTP in HCC <3 cm. Further randomized control study will be helpful for validation.

Purpose Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) and deep learning based on CT images to predict MVI preoperatively. Methods In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models. Results Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923–0.973) and 0.980 (95% CI 0.959–0.993), respectively ( p  = 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797–0.947) and 0.906 (95% CI 0.821–0.960), respectively ( p  = 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months, p  < 0.001; 3D-CNN Model: 64.06 vs. 31.05 months, p  = 0.027). Conclusion The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.

Vessels encapsulating tumor clusters (VETC) are significantly associated with poor prognosis in hepatocellular carcinoma (HCC). However, identifying VETC early remains challenging. Recently, machine learning has shown promise for VETC detection, but their diagnostic accuracy lacks systematic validation. This meta-analysis aimed to systematically evaluate the diagnostic accuracy of machine learning models for detecting VETC in patients with HCC. The Cochrane Library, Embase, Web of Science, and PubMed were searched up to June 21, 2025. Eligible studies focused on machine learning models for HCC VETC diagnosis. Studies that merely analyzed risk factors or lacked outcome measures were excluded. The Prediction Model Risk of Bias Assessment Tool was used to evaluate the risk of bias. A bivariate mixed-effects model was used for a meta-analysis based on 2×2 diagnostic tables. Subgroup analyses were performed according to modeling variables (nonradiomic vs radiomic features) and model types (traditional machine learning vs deep learning). This meta-analysis included 31 studies comprising 6755 patients with HCC (2699 VETC-positive). Nineteen studies used machine learning models based on nonradiomic features, and 12 used radiomic features (including deep learning). In the validation set, the nonradiomic model demonstrated a pooled sensitivity of 0.72 (95% CI 0.66-0.78), specificity of 0.74 (95% CI 0.68-0.80), and an area under the summary receiver operating characteristic curve (SROC AUC) of 0.80 (95% CI 0.76-0.83). The radiomic model showed sensitivity of 0.81 (95% CI 0.73-0.87), specificity of 0.73 (95% CI 0.67-0.79), and SROC AUC of 0.84 (95% CI 0.80-0.87). Traditional machine learning achieved sensitivity of 0.84 (95% CI 0.71-0.92), specificity of 0.75 (95% CI 0.67-0.81), and SROC AUC of 0.83 (95% CI 0.80-0.86). Deep learning exhibited sensitivity of 0.77 (95% CI 0.69-0.84), specificity of 0.70 (95% CI 0.59-0.79), and SROC AUC of 0.81 (95% CI 0.77-0.85). This meta-analysis is the first to quantitatively assess the efficacy of machine learning models in HCC VETC diagnosis, addressing an evidence gap in this field. Unlike previous descriptive reviews, this analysis provides the first quantitative evidence revealing the potential value of machine learning in detecting HCC VETC. The findings provide a foundation for developing and refining subsequent intelligent detection tools. Despite their promising prospects, machine learning models have not yet reached the maturity required for clinical translation, owing to methodological heterogeneity, limited validation, and a high risk of bias. Future research should focus on conducting multicenter, large-sample, standardized, prospective studies to advance clinical translation. PROSPERO CRD420251084894; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251084894.

The development of hepatocellular carcinomas (HCC) depends on their local microenvironment and the induction of neovascularization is a decisive step in tumor progression, since the growth of solid tumors is limited by nutrient and oxygen supply. Hypoxia is the critical factor that induces transcription of the hypoxia inducible factor-1α (HIF-1α) encoding gene HIF1A and HIF-1α protein accumulation to promote angiogenesis. However, the basis for the transcriptional regulation of HIF1A expression in HCC is still unclear. Here, we show that Bclaf1 levels are highly correlated with HIF-1α levels in HCC tissues, and that knockdown of Bclaf1 in HCC cell lines significantly reduces hypoxia-induced HIF1A expression. Furthermore, we found that Bclaf1 promotes HIF1A transcription via its bZIP domain, leading subsequently to increased transcription of the HIF-1α downstream targets VEGFA, TGFB, and EPO that in turn promote HCC-associated angiogenesis and thus survival and thriving of HCC cells. Moreover, we demonstrate that HIF-1α levels and microvessel density decrease after the shRNA-mediated Bclaf1 knockdown in xenograft tumors. Finally, we found that Bclaf1 levels increase in hypoxia in a HIF-1α dependent manner. Therefore, our study identifies Bclaf1 as a novel positive regulator of HIF-1α in the hypoxic microenvironment, providing new incentives for promoting Bcalf1 as a potential therapeutic target for an anti-HCC strategy.

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.