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Hepatocellular carcinoma (HCC) is a prevalent malignant tumor characterized by extensive angiogenesis. However, the underlying mechanisms of HCC pathogenesis remain unclear. Previous studies have shown that RNA-binding proteins (RBPs) are implicated in HCC pathogenesis. In this study, we observed that increased RBM28 expression in HCC tissues was positively correlated with tumor microvascular density and negatively correlated with patient prognosis. Overexpression of RBM28 in HCC cells promoted tubule formation in human umbilical vein endothelial cells, whereas inhibition of RBM28 had the opposite effect, furthermore, the role of RBM28 in the progression of HCC was assessed using transgenic mouse models and chemically induced HCC models. We used various molecular assays and high-throughput detection methods to evaluate the role of RBM28 in promoting angiogenesis in HCC. Increased RBM28 expression in HCC directly binds to STAT3 mRNA, recruiting EIF4E to increase STAT3 expression and enhancing the secretion and expression of vascular endothelial growth factor A; consequently, promoting neovascularization in HCC. The potential of RBM28 as a viable diagnostic and therapeutic target for HCC was assessed using multi-cohort clinical samples and animal models. In summary, our results provide insights into the pathogenesis, clinical diagnosis, and treatment of HCC., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the common and fatal malignant tumors worldwide, and the burden of HCC is particularly severe in China. Physiologically, the blood supply to healthy liver is mainly from the portal vein, supplemented by the hepatic artery. While in the development of HCC, the main source of blood supply to HCC is changed from the portal vein to the hepatic artery. The characteristics of HCC vascularization are important for imaging, surgery, interventional therapy, targeted therapy, etc. Even in the future, with the development of radiation therapy technology, such as proton and heavy ion therapy and artificial intelligence technology, the dynamic changes in HCC blood perfusion can be used as a new biomarker of tumor activity to provide accurate information on the intensity modulation of radiotherapy, so that accurate measurements of HCC blood perfusion is of great significance in guiding the diagnosis and treatment of HCC. The technologies for measurement of HCC blood perfusion have developed from invasive techniques, such as inert gas scavenging, electromagnetic flowmeter, and radionuclide-labeled erythrocyte elution in the middle of the last century to the present non-invasive techniques of CT. With the development of CT imaging technology in the last 30 years, the CT-based imaging technology can assess the status of organ and tissue perfusion relatively easily and accurately. In this paper, the various CT measurement techniques of blood perfusion in HCC were categorized into three types: semi-quantitative technique, relative quantitative technique, and absolute quantitative technique. Their basic principle, scanning methods, and clinical applications were discussed to provide a reference for the diagnosis and treatment of HCC.

Purpose: To conduct a head-to-head comparison between deep learning (DL) and radiomics models across institutions for predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC) and to investigate the model robustness and generalizability through rigorous internal and external validation., Methods: This retrospective study included 2304 preoperative images of 576 HCC lesions from two centers, with MVI status determined by postoperative histopathology. We developed DL and radiomics models for predicting the presence of MVI using B-mode ultrasound, contrast-enhanced ultrasound (CEUS) at the arterial, portal, and delayed phases, and a combined modality (B + CEUS). For radiomics, we constructed models with enlarged vs. original regions of interest (ROIs). A cross-validation approach was performed by training models on one center's dataset and validating the other, and vice versa. This allowed assessment of the validity of different ultrasound modalities and the cross-center robustness of the models. The optimal model combined with alpha-fetoprotein (AFP) was also validated. The head-to-head comparison was based on the area under the receiver operating characteristic curve (AUC)., Results: Thirteen DL models and 25 radiomics models using different ultrasound modalities were constructed and compared. B + CEUS was the optimal modality for both DL and radiomics models. The DL model achieved AUCs of 0.802-0.818 internally and 0.667-0.688 externally across the two centers, whereas radiomics achieved AUCs of 0.749-0.869 internally and 0.646-0.697 externally. The radiomics models showed overall improvement with enlarged ROIs (P < 0.05 for both CEUS and B + CEUS modalities). The DL models showed good cross-institutional robustness (P > 0.05 for all modalities, 1.6-2.1% differences in AUC for the optimal modality), whereas the radiomics models had relatively limited robustness across the two centers (12% drop-off in AUC for the optimal modality). Adding AFP improved the DL models (P < 0.05 externally) and well maintained the robustness, but did not benefit the radiomics model (P > 0.05)., Conclusion: Cross-institutional validation indicated that DL demonstrated better robustness than radiomics for preoperative MVI prediction in patients with HCC, representing a promising solution to non-standardized ultrasound examination procedures., (© 2024. The Author(s).)

The apelin receptor (APJ) is a key player in tumour angiogenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to elucidate the function of the apelin/APJ pathway in HCC using a multi-omics approach and identify potential therapeutic biomarkers. Differentially expressed genes related to the apelin/APJ axis were identified from bulk transcriptomics to reveal HCC-associated disparities. Single-cell and spatial transcriptomics were used to localize and analyse the function of these genes. Machine learning models were constructed to predict outcomes based on apelin/APJ expression, and experimental validation was conducted to explore the pathway's impact on HCC angiogenesis. Single cell analysis revealed an overexpression of APJ/Aplin in the endothelium. The stemness of endothelial cell (EC) with high apelin/APJ was enhanced, as well as the expression of TGFb, oxidative stresses and PI3K/AKT pathway genes. Spatial transcriptomics confirmed that EC populations with high APJ scores were enriched within the tumour. Machine learning models showed high prognostic accuracy. High APJ expression was linked to worse outcomes (p = 0.001), and AUC values were high (1 year, 3 year, 5 year) (0.95, 0.97, 0.98). Immune suppression and non-responsiveness of immune therapy were also seen in high-risk groups. The experimental validation showed that silencing apelin reduced angiogenesis (p  < 0.05), endothelial proliferation, decreased expression of ANG2, KLF2, VEGFA and lower ERK1/2 phosphorylation. Apelin may serve as a potential therapeutic target in HCC, given its role in promoting tumour angiogenesis and poor patient outcomes., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) progresses through multiple stages of hepatocarcinogenesis, with each stage characterized by specific changes in vascular supply, drainage, and microvascular structure. These vascular changes significantly influence the imaging findings of HCC, enabling non-invasive diagnosis. Vascular changes in HCC are closely related to aggressive histological characteristics and treatment responses. Venous drainage from the tumor toward the portal vein in the surrounding liver facilitates vascular invasion, and the unique microvascular pattern of vessels that encapsulate the tumor cluster (known as a VETC pattern) promotes vascular invasion and metastasis. Systemic treatments for HCC, which are increasingly being used, primarily target angiogenesis and immune checkpoint pathways, which are closely intertwined. By understanding the complex relationship between histopathological vascular changes in hepatocarcinogenesis and their implications for imaging findings, radiologists can enhance the accuracy of imaging diagnosis and improve the prediction of prognosis and treatment response. This, in turn, will ultimately lead to better patient care., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Background: Accurate detection of Hepatocellular carcinoma (HCC) feeding vessels during transcatheter arterial chemoembolization (TACE) is important for an effective treatment, while limiting non-target embolization. This study aimed to investigate the feasibility and accuracy of pre-TACE three dimensional (3D) CT angiography for tumor-feeding vessels detection compared to DSA., Methods: Sixty-nine consecutive patients referred for TACE from May 2022 to May 2023 were included. (3D) CT images were reconstructed from the pre-TACE diagnostic multiphasic contrast enhanced CT images and compared with non-selective digital subtraction angiography (DSA) images obtained during TACE for detection of HCC feeding vessels. A "Ground truth" made by consensus between observers after reviewing all available pre-TACE CT images, and DSA and CBCT images during TACE to detect the true feeding vessels was the gold standard. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), accuracy and ROC curve with AUC were calculated for each modality and compared., Results: A total of 136 active HCCs were detected in the 69 consecutive patients included in the study. 185 feeding arteries were detected by 3D CT and DSA and included in the analysis. 3D CT detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV and accuracy of 91%, 71%, 98%, 36%, and 90%, respectively, with mean AUC = 0.81. DSA detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV, and accuracy of 80%, 58%, 96.5%, 16.5% and 78%, respectively, with mean AUC = 0.69., Conclusions: Pre-TACE 3D CT angiography has shown promise in improving the detection of HCC feeding vessels compared to DSA. However, further studies are required to confirm these findings across different clinical settings and patient populations., Trial Registration: This study was prospectively registered at Clinicaltrials.gov with ID NCT05304572; Date of registration: 2-4-2022., (© 2024. The Author(s).)

Background: Liver cancer is a highly lethal malignancy with frequent recurrence, widespread metastasis, and low survival rates. The aim of this study was to explore the role of Endoglin (ENG) in liver cancer progression, as well as its impacts on angiogenesis, immune cell infiltration, and the therapeutic efficacy of sorafenib., Methods: A comprehensive evaluation was conducted using online databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), 76 pairs of clinical specimens of tumor and adjacent non-tumor liver tissue, and tissue samples from 32 hepatocellular carcinoma (HCC) patients treated with sorafenib. ENG expression levels were evaluated using quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blot, and immunohistochemical analysis. Cox regression analysis, Spearman rank correlation analysis, and survival analysis were used to assess the results. Functional experiments included Transwell migration assays and tube formation assays with Human Umbilical Vein Endothelial Cells (HUVECs)., Results: Tumor cells exhibited retro-differentiation into endothelial-like cells, with a significant increase in ENG expression in these tumor-derived endothelial cells (TDECs). High expression of ENG was associated with more aggressive cancer characteristics and worse patient prognosis. Pathway enrichment and functional analyses identified ENG as a key regulator of immune responses and angiogenesis in liver cancer. Further studies confirmed that ENG increases the expression of Collagen type Iα1 (COL1A1), thereby promoting angiogenesis in liver cancer. Additionally, HCC patients with elevated ENG levels responded well to sorafenib treatment., Conclusions: This study found that ENG is an important biomarker of prognosis in liver cancer. Moreover, ENG is associated with endothelial cell differentiation in liver cancer and plays a crucial role in formation of the tumor vasculature. The assessment of ENG expression could be a promising strategy to identify liver cancer patients who might benefit from targeted immunotherapies., (© 2024 The Author(s). Published by IMR Press.)

Extracellular vesicles are essential for intercellular communication and are involved in tumor progression. Inhibiting the direct release of extracellular vesicles seems to be an effective strategy in inhibiting tumor progression, but lacks of investigation. Here, we report a natural flavonoid compound, apigenin, could significantly inhibit the growth of hepatocellular carcinoma by preventing microvesicle secretion. Mechanistically, apigenin primarily targets the guanine nucleotide exchange factor ARHGEF1, inhibiting the activity of small G protein Cdc42, which is essential in regulating the release of microvesicles from tumor cells. In turn, this inhibits tumor angiogenesis related to VEGF 90K transported on microvesicles, ultimately impeding tumor progression. Collectively, these findings highlight the therapeutic potential of apigenin and shed light on its anticancer mechanisms through inhibiting microvesicle biogenesis, providing a solid foundation for the refinement and practical application of apigenin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Microvascular invasion (MVI) is a recognized biomarker associated with poorer prognosis in patients with hepatocellular carcinoma. Dual-energy computed tomography (DECT) is a highly sensitive technique that can determine the iodine concentration (IC) in tumour and provide an indirect evaluation of internal microcirculatory perfusion. This study aimed to assess whether the combination of DECT with laboratory data can improve preoperative MVI prediction., Methods: This retrospective study enrolled 119 patients who underwent DECT liver angiography at 2 medical centres preoperatively. To compare DECT parameters and laboratory findings between MVI-negative and MVI-positive groups, Mann-Whitney U test was used. Additionally, principal component analysis (PCA) was conducted to determine fundamental components. Mann-Whitney U test was applied to determine whether the principal component (PC) scores varied across MVI groups. Finally, a general linear classifier was used to assess the classification ability of each PC score., Results: Significant differences were noted (P < .05) in alpha-fetoprotein (AFP) level, normalized arterial phase IC, and normalized portal phase IC between the MVI groups in the primary and validation datasets. The PC1-PC4 accounted for 67.9% of the variance in the primary dataset, with loadings of 24.1%, 16%, 15.4%, and 12.4%, respectively. In both primary and validation datasets, PC3 and PC4 were significantly different across MVI groups, with area under the curve values of 0.8410 and 0.8373, respectively., Conclusions: The recombination of DECT IC and laboratory features based on varying factor loadings can well predict MVI preoperatively., Advances in Knowledge: Utilizing PCA, the amalgamation of DECT IC and laboratory features, considering diverse factor loadings, showed substantial promise in accurately classifying MVI. There have been limited endeavours to establish such a combination, offering a novel paradigm for comprehending data in related research endeavours., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Background: Preoperative microvascular invasion (MVI) of liver cancer is an effective method to reduce the recurrence rate of liver cancer. Hepatectomy with extended resection and additional adjuvant or targeted therapy can significantly improve the survival rate of MVI+ patients by eradicating micrometastasis. Preoperative prediction of MVI status is of great clinical significance for surgical decision-making and the selection of other adjuvant therapy strategies to improve the prognosis of patients., Purpose: Established a radiomics machine learning model based on multimodal MRI and clinical data, and analyzed the preoperative prediction value of this model for microvascular invasion (MVI) of hepatocellular carcinoma (HCC)., Method: The preoperative liver MRI data and clinical information of 130 HCC patients who were pathologically confirmed to be pathologically confirmed were retrospectively studied. These patients were divided into MVI-positive group (MVI+) and MVI-negative group (MVI-) based on postoperative pathology. After a series of dimensionality reduction analysis, six radiomic features were finally selected. Then, linear support vector machine (linear SVM), support vector machine with rbf kernel function (rbf-SVM), logistic regression (LR), Random forest (RF) and XGBoost (XGB) algorithms were used to establish the MVI prediction model for preoperative HCC patients. Then, rbf-SVM with the best predictive performance was selected to construct the radiomics score (R-score). Finally, we combined R-score and clinical-pathology-image independent predictors to establish a combined nomogram model and corresponding individual models. The predictive performance of individual models and combined nomogram was evaluated and compared by receiver operating characteristic curve (ROC)., Result: Alpha-fetoprotein concentration, peritumor enhancement, maximum tumor diameter, smooth tumor margins, tumor growth pattern, presence of intratumor hemorrhage, and RVI were independent predictors of MVI. Compared with individual models, the final combined nomogram model (AUC: 0.968, 95% CI: 0.920-1.000) constructed by radiometry score (R-score) combined with clinicopathological parameters and apparent imaging features showed the optimal predictive performance., Conclusion: This multi-parameter combined nomogram model had a good performance in predicting MVI of HCC, and had certain auxiliary value for the formulation of surgical plan and evaluation of prognosis., (© 2024 American Association of Physicists in Medicine.)

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor, and glutamine is vital for tumor cells. The role of glutamine transporter SLC1A5 in tumor progression and transarterial chemoembolization (TACE) efficacy is under study. This research seeks to determine the impact of SLC1A5 expression on the prognosis and TACE efficacy of HCC and elucidate its mechanisms., Methods: SLC1A5 expression in HCC, correlation with patient outcomes, and response to TACE were studied in an open access liver cancer dataset and confirmed in our cohort. Additionally, the correlation between SLC1A5 expression and hypoxia, angiogenesis and immune infiltration was analyzed and verified by immunohistochemistry, immunofluorescence and transcriptome sequencing. Liver cancer cell lines with SLC1A5 expression knockdown or overexpression were constructed, and cell proliferation, colony formation, apoptosis, migration and drug sensitivity as well as in vivo xenograft tumor were measured. A gene set enrichment analysis was conducted to determine the signaling pathway influenced by SLC1A5, and a western blot analysis was performed to detect protein expression alterations., Results: SLC1A5 expression was higher in HCC tissue and associated with poor survival and TACE resistance. Hypoxia could stimulate the upregulation of glutamine transport, angiogenesis and SLC1A5 expression. The SLC1A5 expression was positively correlated with hypoxia and angiogenesis-related genes, immune checkpoint pathways, macrophage, Tregs, and other immunosuppressive cells infiltration. Knockdown of SLC1A5 decreased proliferation, colony formation, and migration, but increased apoptosis and increased sensitivity to chemotherapy drugs. Downregulation of SLC1A5 resulted in a decrease in Vimentin and N-cadherin expression, yet an increase in E-cadherin expression. Upregulation of SLC1A5 increased Vimentin and N-cadherin expression, while decreasing E-cadherin. Overexpression of β-catenin in SLC1A5-knockdown HCC cell lines could augment Vimentin and N-cadherin expression, suppress E-cadherin expression, and increase the migration and drug resistance., Conclusions: Elevated SLC1A5 was linked to TACE resistance and survival shortening in HCC patients. SLC1A5 was positively correlated with hypoxia, angiogenesis, and immunosuppression. SLC1A5 may mediate HCC cell migration and drug resistance via Epithelial-mesenchymal transition (EMT) pathway., (© 2024. The Author(s).)

Diffusion-derived vessel density (DVDD) is a physiological surrogate of the area of microvessels per unit tissue area. DDVD is calculated according to DDVD(b0b2) = Sb0/ROIarea0 - Sb2/ROIarea2, where Sb0 and Sb2 refer to the liver signal when b is 0 or 2 s/mm 2 . Pathohistological studies and contrast-enhanced CT/MRI data showed higher blood volume in hepatocellular carcinoma (HCC) relative to native liver tissue. With intravoxel incoherent motion (IVIM) imaging, most authors paradoxically reported a decreased perfusion fraction of HCC relative to the adjacent liver. This study applied DDVD to assess the perfusion of HCC. MRI was performed with a 3.0-T magnet. Diffusion-weighted images with b-values of 0 and 2 s/mm 2 were acquired in 72 HCC patients. Thirty-two patients had microvascular invasion (MVI(+)) and 40 patients did not have microvascular invasion (MVI(-)). Fifty-eight patients had Edmondson-Steiner grade I or II HCC, and 14 patients had Edmondson-Steiner grade III or IV HCC. DDVD measurement was conducted on the axial slice that showed the largest HCC size. DDVD(b0b2) T/L = HCC DDVD(b0b2)/liver DDVD(b0b2). DDVD(b0b2) T/L median (95% confidence interval) of all HCCs was 2.942 (2.419-3.522), of MVI(-) HCCs was 2.699 (2.030-3.522), of MVI(+) HCCs was 2.988 (2.423-3.990), of Edmondson-Steiner grade I/II HCCs was 2.873 (2.277-3.465), and of Edmondson-Steiner grade III/IV HCCs was 3.403 (2.008-4.485). DDVD(b0b2) T/L approximately agrees with contrast agent dynamically enhanced CT/MRI literature data, whereas it differs from earlier IVIM study results, where HCC perfusion fraction was paradoxically lower relative to native liver tissue. A weak trend was noted with MIV(+) HCCs had a higher DDVD(b0b2) T/L than that of MVI(-) HCCs, and a weak trend was noted with the poorly differentiated group of HCCs (Edmondson-Steiner grade III and IV) had a higher DDVD(b0b2) T/L than that of the better differentiated group of HCCs (Edmondson-Steiner grade I and II)., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Objectives: To demonstrate in vivo redistribution of the blood flow towards HCC's lesions by utilizing two-dimensional perfusion angiography in b-TACE procedures., Material and Methods: In total, 30 patients with 35 HCC nodules treated in the period between January 2019 and November 2021. For each patient, a post-processing software leading to a two-dimensional perfusion angiography was applied on each angiography performed via balloon microcatheter, before and after inflation. On the colour map obtained, reflecting the evolution of contrast intensity change over time, five regions of interests (ROIs) were assessed: one on the tumour (ROI-t), two in the immediate peritumoural healthy liver parenchyma (ROI-ihl) and two in the peripheral healthy liver parenchyma (ROI-phl). The results have been interpreted with a novel in silico model that simulates the hemodynamics of the hepatic arterial system., Results: Among the ROIs drawn inside the same segment of target lesion, the time-to-peak of the ROI-t and of the ROI-ihl have a significantly higher mean value when the balloon was inflated compared with the ROIs obtained with deflated balloon (10.33 ± 3.66 s vs 8.87 ± 2.60 s (p = 0.015) for ROI-t; 10.50 ± 3.65 s vs 9.23 ± 2.70 s (p = 0.047) for ROI-ihl). The in silico model prediction time-to-peak delays when balloon was inflated, match with those observed in vivo. The numerical flow analysis shows how time-to-peak delays are caused by the obstruction of the balloon-occluded artery and the opening of intra-hepatic collateral., Conclusion: The measurements identify predictively the flow redistribution in the hepatic arteries during b-TACE, supporting a proper positioning of the balloon microcatheter., (© 2024. The Author(s).)

20(S)-Ginsenoside Rh2 has significant anti-tumor effects in various types of cancers, including human hepatocellular carcinoma (HCC). However, its molecular targets and mechanisms of action remain largely unknown. Here, we aim to elucidate the potential mechanisms by which Rh2 suppresses HCC growth. We first demonstrate the role of Rh2 in inhibiting angiogenesis. We observe that Rh2 effectively suppresses cell proliferation and induces apoptosis in HUVECs. Furthermore, Rh2 significantly inhibits HepG2-stimulated HUVEC proliferation, migration and tube formation, accompanied by the downregulation of VEGF and MMP-2 expressions. We also reveal that Rh2 inhibits HCC growth through the downregulation of glypican-3-mediated activation of the Wnt/β-catenin pathway. We observe a dose-dependent inhibition of proliferation and induction of apoptosis in HepG2 cells upon Rh2 treatment, which is mediated by the inhibition of glypican-3/Wnt/β-catenin signaling. Moreover, downregulation of glypican-3 expression enhances the effects of Rh2 on the glypican-3/Wnt/β-catenin signaling pathway, resulting in greater suppression of tumor growth in HepG2 cells. Collectively, our findings shed light on the molecular mechanisms through which Rh2 modulates HCC growth, which involve the regulation of angiogenesis and the glypican-3/Wnt/β-catenin pathway. These insights may pave the way for the development of novel therapeutic strategies targeting these pathways for the treatment of HCC.

Objectives: To investigate the effect of the expression of low-density lipoprotein receptor associated protein (LDLR) on the vascular abnormalities in hepatocellular carcinoma (HCC) and its mechanisms. Methods: Based on the information of Oncomine Cancer GeneChip database, we analyzed the correlation between the expression level of LDLR and the expression level of carcinoembryonic antigen (CEA) and CD31 in hepatocellular carcinoma tissues. Lentiviral transfection of short hairpin RNA target genes was used to construct LDLR-knockdown MHCC-97H and HLE hepatocellular carcinoma cells. The differential genes and their expression level changes in LDLR-knockdown hepatocellular carcinoma cells were detected by transcriptome sequencing, real-time fluorescence quantitative polymerase chain reaction, and protein immunoblotting. The gene-related signaling pathways that involve LDLR were clarified by enrichment analysis. The effect of LDLR on CEA was assessed by the detection of CEA content in conditioned medium of hepatocellular carcinoma cells. Angiogenesis assay was used to detect the effect of LDLR on the angiogenic capacity of human umbilical vein endothelial cells, as well as the role of CEA in the regulation of angiogenesis by LDLR. Immunohistochemical staining was used to detect the expression levels of LDLR in 176 hepatocellular carcinoma tissues, and CEA and CD31 in 146 hepatocellular carcinoma tissues, and analyze the correlations between the expression levels of LDLR, CEA, and CD31 in the tissues, serum CEA, and alanine transaminase (ALT). Results: Oncomine database analysis showed that the expressions of LDLR and CEA in the tissues of hepatocellular carcinoma patients with portal vein metastasis were negatively correlated ( r =-0.64, P =0.001), whereas the expressions of CEA and CD31 in these tissues were positively correlated ( r =0.46, P =0.010). The transcriptome sequencing results showed that there were a total of 1 032 differentially expressed genes in the LDLR-knockdown group and the control group of MHCC-97H cells, of which 517 genes were up-regulated and 515 genes were down-regulated. The transcript expression level of CEACAM5 was significantly up-regulated in the cells of the LDLR-knockdown group. The Gene Ontology (GO) function enrichment analysis showed that the differential genes were most obviously enriched in the angiogenesis function. The Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis showed that the relevant pathways involved mainly included the cellular adhesion patch, the extracellular matrix receptor interactions, and the interactions with the extracellular matrix receptors. The CEA content in the conditioned medium of the LDLR-knockdown group was 43.75±8.43, which was higher than that of the control group (1.15±0.14, P ＜0.001). The results of angiogenesis experiments showed that at 5 h, the number of main junctions, the number of main segments, and the total area of the lattice formed by HUVEC cells cultured with the conditioned medium of MHCC-97H cells in the LDLR-knockdown group were 295.3±26.4, 552.5±63.8, and 2 239 781.0±13 8211.9 square pixels, which were higher than those of the control group (113.3±23.5, 194.8±36.5, and 660 621.0±280 328.3 square pixels, respectively, all P ＜0.01).The number of vascular major junctions, the number of major segments, and the total area of the lattice formed by HUVEC cells cultured in conditioned medium with HLE cells in the LDLR-knockdown group were 245.3±42.4, 257.5±20.4, and 2 535 754.5±249 094.2 square pixels, respectively, which were all higher than those of the control group (113.3±23.5, 114.3±12.2, and 1 565 456.5±219 259.7 square pixels, respectively, all P ＜0.01). In the conditioned medium for the control group of MHCC-97H cells,the number of main junctions, the number of main segments, and the total area of the lattice formed by the addition of CEA to cultured HUVEC cells were 178.9±12.0, 286.9±12.3, and 1 966 990.0±126 249.5 spixels, which were higher than those in the control group (119.7±22.1, 202.7±33.7, and 1 421 191.0±189 837.8 square pixels, respectively). The expression of LDLR in hepatocellular carcinoma tissues was not correlated with the expression of CEA, but was negatively correlated with the expression of CD31 ( r =-0.167, P =0.044), the level of serum CEA ( r =-0.061, P =0.032), and the level of serum ALT (r =-0.147, P =0.05). The expression of CEA in hepatocellular carcinoma tissues was positively correlated with the expression of CD31 ( r =0.192, P =0.020). The level of serum CEA was positively correlated with the level of serum ALT ( r =0.164, P =0.029). Conclusion: Knocking down LDLR can promote vascular abnormalities in HCC by releasing CEA.

Objectives: Based on enhanced MRI, a prediction model of microvascular invasion (MVI) for hepatocellular carcinoma (HCC) was developed using graph convolutional network (GCN) combined nomogram., Methods: We retrospectively collected 182 HCC patients confirmed histopathologically, all of them performed enhanced MRI before surgery. The patients were randomly divided into training and validation groups. Radiomics features were extracted from the arterial phase (AP), portal venous phase (PVP), and delayed phase (DP), respectively. After removing redundant features, the graph structure by constructing the distance matrix with the feature matrix was built. Screening the superior phases and acquired GCN Score (GS). Finally, combining clinical, radiological and GS established the predicting nomogram., Results: 27.5% (50/182) patients were with MVI positive. In radiological analysis, intratumoural artery (P = 0.007) was an independent predictor of MVI. GCN model with grey-level cooccurrence matrix-grey-level run length matrix features exhibited area under the curves of the training group was 0.532, 0.690, and 0.885 and the validation group was 0.583, 0.580, and 0.854 for AP, PVP, and DP, respectively. DP was selected to develop final model and got GS. Combining GS with diameter, corona enhancement, mosaic architecture, and intratumoural artery constructed a nomogram which showed a C-index of 0.884 (95% CI: 0.829-0.927)., Conclusions: The GCN model based on DP has a high predictive ability. A nomogram combining GS, clinical and radiological characteristics can be a simple and effective guiding tool for selecting HCC treatment options., Advances in Knowledge: GCN based on MRI could predict MVI on HCC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Both contrast-enhanced ultrasound (CEUS) and contrast-enhanced magnetic resonance (CEMR) are important imaging methods for hepatocellular carcinoma (HCC). This study aimed to establish a model using preoperative CEUS parameters to predict microvascular invasion (MVI) in HCC, and compare its predictive efficiency with that of CEMR model., Methods: A total of 93 patients with HCC (39 cases in MVI positive group and 54 cases in MVI negative group) who underwent surgery in our hospital from January 2020 to June 2021 were retrospectively analyzed. Their clinical and imaging data were collected to establish CEUS and CEMR models for predicting MVI. The predictive efficiencies of both models were compared., Results: By the univariate and multivariate regression analyses of patients' clinical information, preoperative CEUS static and dynamic images, we found that serrated edge and time to peak were independent predictors of MVI. The CEUS prediction model achieved a sensitivity of 92.3%, a specificity of 83.3%, and an accuracy of 84.6% (Az: 0.934). By analyzing the clinical and CEMR information, we found that tumor morphology, fast-in and fast-out, peritumoral enhancement, and capsule were independent predictors of MVI. The CEMR prediction model achieved a sensitivity of 97.4%, a specificity of 77.8%, and an accuracy of 83.2% (Az: 0.900). The combination of the two models achieved a sensitivity of 84.6%, a specificity of 87.0%, and an accuracy of 86.2% (Az: 0.884). There was no significant statistical difference in the areas under the ROC curve of the three models., Conclusion: The CEUS model and the CEMR model have similar predictive efficiencies for MVI of HCC. CEUS is also an effective method to predict MVI before operation., (© 2023 American Institute of Ultrasound in Medicine.)

Purpose: To elucidate incidence rates of vascular lake phenomenon (VLP) in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatic metastasis (HMT) on transarterial angiography before chemoembolization, and to identity CT features predictive for it., Materials and Methods: A comprehensive evaluation involved 665 subjects for incidence analysis, comprising 527 of HCC, 33 of ICC and 105 of HMT. VLP was characterized as intratumoral contrast material pool persisting late into venous phase. Incidences were cataloged on both super-selective and common hepatic artery angiography. For CT features analysis, a subset of 182 cases were analyzed. Enhancement ratio served as an index for comparative analysis of nodule enhancement degrees., Results: In HCC, incidence of VLP ascertained via super-selective angiography was 13.5%, whereas it as 7.8% on common hepatic artery angiography. Remarkably, no incidences of VLP were recorded in either ICC or HMT cases. On pre-interventional CT, the prevalence of pseudocapsule was statistically greater in VLP group than Non-VLP group (66.6% vs. 37.6%, P = 0.015). The Houndsfield units (HU) of tumors in plain scan (P = 0.007), arterial phase (P = 0.001), venous phase (P = 0.041), arterial phase enhancement ratio (P < 0.001) were statistically higher in VLP group compared to Non-VLP group. Arterial phase enhancement ratio (P = 0.025), presence of pseudocapsule (P = 0.001), HU of tumor in plain scan (P = 0.035) serve as independent risk factors for VLP manifestation., Conclusion: VLP is a distinct angiography phenomenon uniquely associated with HCC. High arterial phase enhancement ratio, presence of pseudocapsule, high HU of tumor in plain scan are independent risk factors for VLP., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Purpose: To develop a nomogram for preoperative assessment of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) based on the radiological features of enhanced CT and to verify two imaging techniques (CT and MRI) in an external centre., Method: A total of 346 patients were retrospectively included (training, n = 185, CT images; external testing 1, n = 90, CT images; external testing 2, n = 71, MRI images), including 229 MVI-negative patients and 117 MVI-positive patients. The radiological features and clinical information of enhanced CT images were analysed, and the independent variables associated with MVI in HCC were determined by logistic regression analysis. Then, a nomogram prediction model was constructed. External validation was performed on CT (n = 90) and MRI (n = 71) images from another centre., Results: Among the 23 radiological and clinical features, size, arterial peritumoral enhancement (APE), tumour margin and alpha-fetoprotein (AFP) were independent influencing factors for MVI in HCC. The nomogram integrating these risk factors had a good predictive effect, with AUC, specificity and sensitivity values of 0.834 (95% CI: 0.774-0.895), 75.0% and 83.5%, respectively. The AUC values of external verification based on CT and MRI image data were 0.794 (95% CI: 0.700-0.888) and 0.883 (95% CI: 0.807-0.959), respectively. No statistical difference in AUC values among training set and testing sets was found., Conclusion: The proposed nomogram prediction model for MVI in HCC has high accuracy, can be used with different imaging techniques, and has good clinical applicability., (© 2024. The Author(s).)

Objective: This study aimed to investigate the feasibility of using dual-layer spectral CT multi-parameter feature to predict microvascular invasion of hepatocellular carcinoma., Methods: This retrospective study enrolled 50 HCC patients who underwent multiphase contrast-enhanced spectral CT studies preoperatively. Combined clinical data, radiological features with spectral CT quantitative parameter were constructed to predict MVI. ROC was applied to identify potential predictors of MVI. The CT values obtained by simulating the conventional CT scans with 70 keV images were compared with those obtained with 40 keV images., Results: 50 hepatocellular carcinomas were detected with 30 lesions (Group A) with microvascular invasion and 20 (Group B) without. There were significant differences in AFP,tumer size, IC, NIC,slope and effective atomic number in AP and ICrr in VP between Group A ((1000(10.875,1000),4.360±0.3105, 1.7750 (1.5350,1.8825) mg/ml, 0.1785 (0.1621,0.2124), 2.0362±0.2108,8.0960±0.1043,0.2830±0.0777) and Group B (4.750(3.325,20.425),3.190±0.2979,1.4700 (1.4500,1.5775) mg/ml, 0.1441 (0.1373,0.1490),1.8601±0.1595, 7.8105±0.7830 and 0.2228±0.0612) (all p < 0.05). Using 0.1586 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.875 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.625 with CT value at 70 keV and improved to 0.843 at 40 keV., Conclusion: Dual-layer spectral CT provides additional quantitative parameters than conventional CT to enhance the differentiation between hepatocellular carcinoma with and without microvascular invasion. Especially, the normalized iodine concentration (NIC) in arterial phase has the greatest potential application value in determining whether microvascular invasion exists, and can offer an important reference for clinical treatment plan and prognosis assessment.

Aim: To evaluate inter-reader agreement between novice and expert radiologists in assessing contrast-enhanced ultrasonography (CEUS) and magnetic resonance imaging (MRI) images for detecting viable tumours with different sizes after conventional transarterial chemoembolisation (cTACE)., Materials and Methods: This prospective study included patients who had less than five hepatomas and who underwent cTACE. Hepatomas with one or two feeding arteries were selected as target lesions. CEUS and MRI were performed within 1 week after cTACE to evaluate viable tumours., Results: The expert group had higher kappa values in evaluating all tumour sizes via CEUS compared with MRI. The novice group had similar kappa values. In patients with tumours measuring ≤3 cm, the expert group had higher kappa values in reading CEUS compared with MRI images; however, in the novice group, the kappa value was lower in evaluating CEUS compared with MRI images. In patients with tumours measuring >3 cm, the expert and novice groups had good to excellent kappa values. The confidence level of the two groups in reading MRI images was high; however, the novice group had a lower confidence level., Conclusion: CEUS is a convenient, cost-effective, and easy to apply imaging tool that can help interventionists perform early detection of viable hepatocellular carcinoma post-TACE. It has a higher inter-rater agreement in interpreting CEUS images compared with MRI images among expert radiologists even when they are extremely familiar with post-cTACE MRI images. In novice radiologists, there may be a learning curve to achieve good consistency in CEUS interpretation., (Copyright © 2023. Published by Elsevier Ltd.)

Background: To predict the microvascular invasion (MVI) in patients with cHCC-ICC., Methods: A retrospective analysis was conducted on 119 patients who underwent CT enhancement scanning (from September 2006 to August 2022). They were divided into MVI-positive and MVI-negative groups., Results: The proportion of patients with CEA elevation was higher in the MVI-positive group than in the MVI-negative group, with a statistically significant difference (P = 0.02). The MVI-positive group had a higher rate of peritumoral enhancement in the arterial phase (P = 0.01) whereas the MVI-negative group had more oval and lobulated masses (P = 0.04). According to the multivariate analysis, the increase in CEA (OR = 10.15, 95% CI: 1.11, 92.48, p = 0.04), hepatic capsular withdrawal (OR = 4.55, 95% CI: 1.44, 14.34, p = 0.01) and peritumoral enhancement (OR = 6.34, 95% CI: 2.18, 18.40, p < 0.01) are independent risk factors for predicting MVI. When these three imaging signs are combined, the specificity of MVI prediction was 70.59% (series connection), and the sensitivity was 100% (parallel connection)., Conclusions: Our multivariate analysis found that CEA elevation, liver capsule depression, and arterial phase peritumoral enhancement were independent risk factors for predicting MVI in cHCC-ICC., (© 2023. The Author(s).)

Objectives: The purpose of this study was to establish a model for predicting the prognosis of patients with microvascular invasion (MVI)-negative hepatocellular carcinoma (HCC) based on qualitative and quantitative analyses of Gd-EOB-DTPA magnetic resonance imaging (MRI)., Materials and Methods: Consecutive patients with MVI-negative HCC who underwent preoperative Gd-EOB-DTPA MRI between January 2015 and December 2019 were retrospectively enrolled.In total, 122 patients were randomly assigned to the training and validation groups at a ratio of 7:3. Univariate and multivariate logistic regression analyses were performed to identify significant clinical parameters and MRI features, including quantitative and qualitative parameters associated with prognosis, which were incorporated into a predictive nomogram. The end-point of this study was recurrence-free survival. Outcomes were compared between groups using the Kaplan-Meier method with the log-rank test., Results: During a median follow-up period of 58.86 months, 38 patients (31.15 %) experienced recurrence. Multivariate analysis revealed that lower relative enhancement ratio (RER), hepatobiliary phase hypointensity without arterial phase hyperenhancement, Liver Imaging Reporting and Data System category, mild-moderate T2 hyperintensity, and higher aspartate aminotransferase levels were risk factors associated with prognosis and then incorporated into the prognostic model. C-indices for training and validation groups were 0.732 and 0.692, respectively. The most appropriate cut-off value for RER was 1.197. Patients with RER ≤ 1.197 had significantly higher postoperative recurrence rates than those with RER > 1.197 (p = 0.004)., Conclusion: The model integrating qualitative and quantitative imaging parameters and clinical parameters satisfactorily predicted the prognosis of patients with MVI-negative HCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To analyze changes in angiogenesis factors after transarterial radioembolization (TARE) with Yttrium- 90-loaded resin microspheres in hepatocellular carcinoma (HCC) patients., Methods: Interleukin-6, interleukin-8, hepatocyte growth factor, platelet-derived growth factor, fibroblast growth factor, vascular endothelial growth factor-A (VEGF-A), and angiopoietin-2 levels in 26 patients were measured before TARE and on day 1, 7, 14, and 30 after TARE and evaluated regarding radiological response., Results: In the sixth month of follow-up, 11 (42.30%) patients had a complete or partial response to treatment, while progressive disease was found in 15 (57.69%) patients. The percentage changes in VEGF-A in the non-responders on day 30 ( P = 0.034) after TARE were significantly more obvious. Peak formation rates of VEGF-A were higher in non-responders ( P = 0.036)., Conclusion: Short-term changes in angiogenesis factors in HCC patients after TARE with Yttrium-90-loaded resin microspheres fluctuate with different amplitudes at different times. The upregulation of growth factors has a prognostic capacity. Changes in VEGF-A after TARE may be helpful for the early recognition of non-responders., Competing Interests: The authors declared no conflicts of interest.

Objective: To evaluate the diagnostic ability and clinical imaging features in maxillofacial soft tissue hypervascular tumours by 64-slice multidetector spiral computed tomography (64-MDCT) contrast-enhanced scanning., Methods: In a retrospective study of 21 cases of hypervascular tumours, the degree of blood supply and indexes were assessed, and the pathological results were used as the diagnostic gold standard to evaluate the sensitivity and specificity of 64-MDCT plain scan and enhanced CT in the diagnosis of oral and maxillofacial soft tissue hypervascular tumours, using the receiver operating characteristic curve to analyse and evaluate the efficacy., Results: Among 21 patients, the diagnostic accuracy of 64-MDCT contrast-enhanced scan was 90.48%, the area under the curve of venous phase CT value was 0.80, the sensitivity was 83.30% and the specificity was 72.73%., Conclusion: 64-MDCT contrast-enhanced scan can be used to evaluate the blood supply of maxillofacial soft tissue hypervascular tumours before an operation. The CT value in the venous phase of tumours has the highest diagnostic effectiveness, which can reduce the risk of blood loss during surgery for maxillofacial hypervascular tumours. In addition, it has certain guiding significance for the formulation of clinical treatment plans.

Objective: Microvascular invasion (MVI) is significantly associated with prognosis in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients. The study aimed to explore the value of preoperative contrast-enhanced CT (CECT) features and clinical data in predicting MVI of cHCC-CCA., Methods: A total of 33 patients with MVI-positive and 27 with MVI-negative were enrolled, and underwent preoperative CECT imaging from January 2016 to December 2021. Preoperative clinical data and CECT imaging features were retrospectively analyzed. Univariable and multivariable logistic regression analysis were performed to identify potential predictors of MVI in cHCC-CCA. The diagnostic performance was evaluated by the receiver operating characteristic (ROC) curve and its area under the curve (AUC) value., Results: The mean age of the patients was 54.0 ± 10.3 years, and 53 of the 60 patients (88.3%) were male. Preoperative imaging features on CECT (non-smooth contour and arterial phase peritumoral enhancement) and clinical data (hepatitis B virus (HBV) infection and protein induced by vitamin K absence or antagonist-II (PIVKA-II)) were highly distinct between those in MVI-positive group and MVI-negative group. On multivariable logistic analysis, arterial phase peritumoral enhancement (odds ratio (OR), 6.514; 95% confidence interval (CI), 1.588-26.728, p = 0.012) and high serum PIVKA-II level (OR, 6.810; 95% CI, 1.796-25.820, p = 0.005) were independent predictors associated with MVI of cHCC-CCA. The combination of these two predictors had high sensitivity (31/33, 93.9%; 95% CI, 80.4% - 98.3%) in the prediction of MVI with an area under the receiver operating characteristic (ROC) curve of 0.763 (95% CI, 0.635-0.863)., Conclusions: The findings indicated that arterial phase peritumoral enhancement on preoperative CECT and high serum PIVKA-II level were identified as potential predictors for MVI in cHCC-CCA patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to evaluate perfusion parameters of triphasic computed tomography (CT) scans in predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). All patients were pathologically diagnosed as HCC and underwent triple-phase enhanced CT imaging, which was used to calculate the blood perfusion parameters of hepatic arterial supply perfusion (HAP), portal vein blood supply perfusion (PVP), hepatic artery perfusion Index (HPI), and arterial enhancement fraction (AEF). Receiver operating characteristic (ROC) curve was used to evaluate the performance. The mean values of PVP(Min), AEF(Min), the difference in PVP, HPI and AEF related parameters, the relative PVP(Min) and AEF(Min) in MVI negative group were significantly higher than those in MVI positive group, while for the difference in HPI(Max), the relative HPI(Max) and AEF(Max), the value of MVI positive group significantly higher than that of negative group. The combination of PVP, HPI and AEF had the highest diagnostic efficacy. The two parameters related to HPI had the highest sensitivity, while the combination of PVP related parameters had higher specificity. A combination of perfusion parameters in patients with HCC derived from traditional triphasic CT scans can be used as a preoperative biomarker for predicting MVI., (© 2023. The Author(s).)

Ethnopharmacological Relevance: Dahuang Zhechong pill (DHZCP), a traditional Chinese medicine, was derived from the famous book Unk "Synopsis of Prescriptions of the Golden Chamber" during the Han dynasty. Owing to its ability to invigorate the circulation of blood in Chinese medicine, DHZCP is usually used for treating liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Clinical application have shown that DHZCP exhibits satisfactory therapeutic effects in HCC adjuvant therapy; however, little is known about its underlying mechanisms., Aim of the Study: We aimed to clarify the mechanism of DHZCP against hepatic sinusoidal capillarization in rats with LC and HCC by inhibiting the MK/integrin signaling pathway of liver sinusoidal endothelial cells (LSECs)., Materials and Methods: The contents of 29 characteristic components in DHZCP were determined by ultraperformance liquid chromatography-tandem mass spectrometry. DEN (Diethylnitrosamine)-induced LC and HCC rat models were constructed, and DHZCP was administered when the disease entered the LC stage. After 4 or 12 weeks of administration, hematoxylin and eosin staining, Masson staining, Metavir score, and SSCP (Single strand conformation polymorphism) gene mutation detection were used to confirm tissue fibrosis and cancer. The levels of NO, ET-1 and TXA2, which can regulate vasomotor functions and activate the MK/Itgα6/Src signaling pathway were evaluated by using immunohistochemistry, chemiluminescence, immunofluorescence, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Similar methods were also used to evaluate the levels of VEGF, VEGFR, Ang-2 and Tie, which can promote pathological angiogenesis and activate the MK/Itgα4/NF-κB signaling pathway. In vitro cell experiments were performed using potential pharmacodynamic molecules targeting integrins in DHZCP were selected by molecular docking, and the effects of these molecules on the function of LSECs were studied by Itgα4 + and Itgα6 + cell models., Results: At the stage of LC, the animal experiments demonstrated that DHZCP mainly inhibited the MK/Itgα6 signaling pathway to increase the number and size of hepatic sinus fenestration, reversed the ET-1/NO and TXA2/NO ratios, regulated hepatic sinus relaxation and contraction balance, reduced the portal vein pressure, and inhibited cirrhotic carcinogenesis. At the HCC stage, DHZCP could also significantly inhibit the MK/Itgα4 signaling pathway, reduce pathological angiogenesis, and alleviate disease progression. The results of the cell experiments showed that Rhein, Naringenin, Liquiritin and Emodin-8-O-β-D-glucoside (PMEG) were involved in vascular regulation by affecting the MK/integrin signaling pathway. Liquiritin and PMEG mainly blocked the MK/α6 signal, which is important in regulating the vasomotor function of the liver sinus. Naringenin and Rhein mainly acted by blocked the signaling of MK/α4 action signal, which are potent molecules that inhibit pathological angiogenesis., Conclusions: DHZCP could improve the hepatic sinusoidal capillarization of LC and HCC by inhibiting the MK/Itgα signaling pathway and inhibited disease progression. Rhein, Naringenin, Liquiritin and PMEG were the main active molecules that affected the MK/Itgα signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rationale and Objectives: To investigate the predictive value of gadoxetic acid-enhanced magnetic resonance imaging (MRI) features on the pathologic grade, microvascular invasion (MVI), and cytokeratin-19 (CK19) expression in hepatocellular carcinomas (HCC), and to evaluate their association with postoperative recurrence of HCC., Materials and Methods: This retrospective study included 147 patients with surgically confirmed HCCs who underwent gadoxetic-enhanced MRI. The lesions were evaluated quantitatively in terms of the relative enhancement ratio (RER), and qualitatively based on imaging features and clinical parameters. Logistic regression analyses were performed to investigate the value of these parameters in predicting the pathologic grade, MVI, and CK19 in HCC. Predictive factors for postoperative recurrence were determined using a Cox proportional hazards model., Results: Peritumoral enhancement (odds ratio [OR], 3.396; p = 0.025) was an independent predictor of high pathologic grades. Serum protein induced by vitamin K absence or antagonist (PIVKA) level > 40 mAU/mL (OR, 3.763; p = 0.018) and peritumoral hypointensity (OR, 4.343; p = 0.003) were independent predictors of MVI. Predictors of CK19 included serum alpha-fetoprotein (AFP) level > 400 ng/mL (OR, 4.576; p = 0.005), rim enhancement (OR, 5.493; p = 0.024), and lower RER (OR, 0.013; p = 0.011). Peritumoral hypointensity (hazard ratio [HR], 1.957; p = 0.027) and poor pathologic grades (HR, 2.339; p = 0.043) were independent predictors of recurrence., Conclusion: We demonstrated the value of preoperative gadoxetic-enhanced MRI in predicting aggressive pathological features of HCC. Poor pathologic grades and peritumoral hypointensity may independently predict the recurrence of HCC., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Ultrasound has few reports on its application in prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). The purpose of this study was to explore the diagnostic efficacies of preoperative ultrasound and magnetic resonance imaging (MRI) for HCC MVI and compare these two imaging methods for the diagnosis of this condition. The clinical and preoperative ultrasound and MR imaging data of 26 patients with newly diagnosed HCC were collected between October 2020 and October 2021. According to the gold standard (postoperative pathology), the patients were divided into MVI-positive and MVI-negative groups, and the efficacies of ultrasound and MRI in diagnosing HCC MVI and the consistency between the two imaging modalities were analyzed. For the preoperative diagnosis of MVI using ultrasound, the sensitivity was 93.33%, the specificity was 81.82%, and the accuracy was 88.46%. For preoperative MRI, the sensitivity was 66.67%, the specificity was 100%, and the accuracy was 80.77%. In diagnosing MVI, the two methods had significantly different efficacy (P = 0.031). Ultrasound and MRI have high diagnostic efficiency for MVI, but the accuracy of preoperative MRI was lower than that of preoperative ultrasound. These results indicate that ultrasound has a certain guiding significance in the diagnosis of HCC MVI., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To investigate the added value of contrast enhancement boost (CE-boost) images in multiphasic contrast-enhanced CT (CE-CT) for diagnosing small (<20 mm) hypervascular hepatocellular carcinoma (HCC)., Materials and Methods: This retrospective study included 69 patients (age, 74 ± 8 years; 52 men) with 70 hypervascular HCCs (<20 mm) who underwent multiphasic CE-CT (pre-contrast, late arterial phase [LAP], portal venous phase [PVP], and equilibrium phase). Two types of CE-boost images were generated by subtracting PVP from LAP (LA-PV) images and LAP from PVP (PV-LA) images to enhance the contrast effect of hepatic arterial and portal venous perfusion more selectively. Tumor-to-liver contrast-to-noise ratios (CNRs) in CE-boost images were compared with those in CE-CT images using the Wilcoxon signed-rank test. Two independent readers reviewed the imaging datasets: CE-CT alone and CE-CT with CE-boost images. The diagnostic performance of each dataset was compared using jackknife alternative free-response receiver operating characteristics (JAFROC-1)., Results: The tumor-to-liver CNRs in the LA-PV (6.4 ± 3.0) and PV-LA (-3.3 ± 2.1) images were greater than those in the LAP (3.2 ± 1.7) and PVP images (-1.1 ± 1.4) (p <.001 for both). The reader-averaged figures of merit were 0.751 for CE-CT alone and 0.807 for CE-CT with CE-boost images (p <.001). Sensitivities increased by adding CE-boost images for both readers (p <.001 and = 0.03), while positive predictive values were equivalent (p >.99)., Conclusion: Adding CE-boost images to multiphasic CE-CT can improve the diagnostic accuracy and sensitivity for small hypervascular HCC by increasing the tumor-to-liver CNR., Competing Interests: Declaration of Competing Interest M.H. is supported by grants from Canon Medical Systems Corporation. M.N. is an employee of Canon Medical Systems Corporation., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Intra-arterial treatment has been identified as one of the mainstays in the management of unresectable hepatocellular carcinoma. A thorough knowledge of tumor arterial supply enables selective therapy, which improves both safety and efficacy. The inferior phrenic artery (IPA) is the most common extrahepatic collateral artery that feeds hepatocellular carcinoma. The bilateral IPAs are known to have a specific vascular anatomy. A systemic-to-pulmonary shunt and a gastric branch from the IPAs may be present and should not be confused with tumor blush. The supraceliac aorta and celiac trunk are the common origin sites of the IPAs, and their orifice may be compressed by the diaphragm. Various techniques and catheters are used for catheterization of the IPAs, depending on their origin sites. Because the IPA is normally connected with the intercostal, internal mammary, retroperitoneal, and hepatic arteries, its hemodynamics may be altered when its orifice is occluded. In general, superselective chemoembolization via the target branch of the IPA is safe and effective. When a systemic-to-pulmonary shunt from the IPA is adequately embolized with coils or particles, radioembolization through the IPA can be performed safely in most cases. The cystic artery branches into deep and superficial cystic arteries; deep cystic arteries often supply tumors near the gallbladder. Chemoembolization through the cystic artery is relatively safe, with transient embolic materials. Radioembolization through the cystic artery has been recently tried, with acceptable efficacy and toxicity results, but it requires further investigation. © RSNA, 2022.

Background: The preoperative diagnosis of microvascular invasion (MVI) for the solitary small hepatocellular carcinoma (sHCC) is crucial for the decision of surgical strategies., Purpose: To compare the kinetic parameters and diagnostic effects of two contrast agents for preoperatively predicting MVI of sHCC on multiphase enhanced magnetic resonance imaging (MRI)., Material and Methods: Two groups of patients with known solitary sHCC underwent an enhanced MRI examination before hepatic resection: Data A (n = 61) patients underwent Gd-EOB-DTPA-enhanced MRI, and Data B (n = 41) patients had a normal contrast agent. The two sets of data were processed in the same way. Arterial peritumoral enhancement measured from multiphase enhanced MRI was analyzed using quantitative kinetic parameters, including initial signal enhancement (SE 1 ), peak signal enhancement (SE peak ), and calculation of the signal enhancement ratio (SE R )., Results: The statistical analysis showed that the average SE 1 and SE R (Data A) for the MVI-positive group were significantly higher ( P  < 0.05) than those in the MVI-negative group. The SE R (Data B) and SE peak showed no significant difference for either group. In Data A, the receiver operating characteristic analysis between the two groups had an area under the curve of 0.74 and 0.71 for SE 1 and SE R , respectively, which was higher than that of Data B. The different contrast agents had the same enhancement curve trend., Conclusion: Gd-EOB-DTPA-enhanced MRI had a better quantitative kinetic parameter analysis effect for arterial peritumoral enhancement on predicting MVI of sHCC in clinical practice.

Objective: This study aimed to evaluate the predictive value of gadoxetic acid disodium magnetic resonance imaging (MRI) in the microvascular invasion (MVI) of hepatocellular carcinoma (HCC)., Methods: 87 HCC patients (2019-01-2022-01) admitted to the hospital were selected for retrospective analysis, gadoxetic acid disodium MRI scan was performed before surgery, and the patients were divided into two groups according to whether the MVI occurred, including the invasion group ( n  = 47) and the non-invasion group ( n  = 40). The influencing factors of MVI in HCC patients were explored, independent risk factors were determined, and the correlation between independent risk factors and MVI in HCC patients was analyzed., Results: There were significant differences in tumor margin, peritumoral low signal (hepatobiliary phase), peritumoral enhancement (arterial phase), and peritumoral hyperintensity ring (arterial phase) between the two groups ( P < 0.05). Logistic regression analysis showed that unsmooth tumor margin, peritumoral low signal (hepatobiliary phase), peritumoral enhancement (arterial phase), and peritumoral hyperintensity ring (arterial phase) were independent risk factors for MVI in HCC patients ( P < 0.05). The results of Spearman correlation analysis showed that unsmooth tumor margin was negatively correlated with MVI in HCC patients ( r  = -0.66, P =0.037). Moreover, peritumoral low signal (hepatobiliary phase), peritumoral enhancement (arterial phase), and peritumoral hyperintensity ring (arterial phase) were positively correlated with MVI in HCC patients ( r 1  = 0.63, r 2  = 0.68, r 3  = 0.72, P 1 = 0.030, P 2  = 0.023, P 3  = 0.017)., Conclusion: Unsmooth tumor margin, peritumoral low signal (hepatobiliary phase), peritumoral enhancement (arterial phase), and peritumoral hyperintensity ring (arterial phase) are significantly correlated with MVI in patients with HCC, which can provide a reference for the formulation and implementation of clinical interventions., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Jiao Chen et al.)

To evaluate the role of dysmorphic intratumoral vessels as imaging marker for the prediction of high lung shunt fraction (LSF) in patients with hepatocellular carcinoma (HCC). This retrospective study included 403 patients with HCC who underwent a planning arteriography for transarterial radioembolization with administration of 99m Tc-macroaggregated albumin to calculate LSF. The LSF was measured by using planar body scans. Two radiologists evaluated the pre-treatment contrast-enhanced CT findings, including tumor number, size, margin, distribution, tumor burden, portal and hepatic vein invasion, early hepatic vein enhancement, and dysmorphic intratumoral vessels. The logistic regression analysis was performed to determine significant predictors for high LSF > 20%. Using the identified predictors, diagnostic criteria for high LSF were proposed. Among 403 patients, 52 (13%) patients had high LSF > 20%, and dysmorphic tumor vessels were present in 115 (28.5%) patients. Predictors for LSF > 20% were tumor size > 11 cm, hepatic vein invasion, early hepatic vein enhancement, and dysmorphic intratumoral vessel. If the patient had three or more of the four predictors for LSF > 20% on imaging, the accuracy and specificity for diagnosing LSF > 20% were 88.8% and 96.3% respectively. Dysmorphic intratumoral vessel in HCC is an imaging marker suggesting a high LSF, which may be applicable to treatment modification or patient exclusion for radioembolization with combined interpretation of tumor size and hepatic vein abnormality., (© 2022. The Author(s).)

Purpose: To evaluate the additional value of superb microvascular imaging (SMI) to characterize focal liver lesions (FLLs)., Method: Between July 2020 and December 2020, 70 patients (39 men and 31 women; mean age [± standard deviation], 61.1 ± 10.1 years) with FLLs were prospectively enrolled and underwent B-mode ultrasound (US), color Doppler imaging (CDI), power Doppler imaging (PDI), and SMI examinations on the same day. All the malignant FLLs were confirmed by histological diagnosis, while the benign FLLs were confirmed by typical imaging features at contrast-enhanced CT and/or MRI. Tumor vascularity scores in CDI, PDI, and SMI were graded using a 5-point scale. For tumors in which vascularity was detected on SMI, tumor vascular pattern on SMI was assessed in each lesion. The diagnostic performance of a combination of B-mode US and SMI, based on vascular pattern on SMI, was compared to B-mode US alone to diagnose malignant lesions; and hemangiomas., Results: Seventy FLLs (34 benign [31 hemangiomas, 3 focal nodular hyperplasias] and 36 malignant tumors [16 hepatocellular carcinomas, 10 cholangiocarcinomas, 10 metastases]) were enrolled. Tumor vascularity score in SMI was significantly higher than those in CDI and PDI (P < 0.001). Using a combination of B-mode US and SMI, the diagnostic performance was improved from 0.867 and 0.834 to 0.945 and 0.921 (P = 0.035 and 0.112) to diagnose malignant tumors and from 0.896 and 0.853 to 0.975 and 0.987 (P = 0.027 and 0.006) to diagnose hemangiomas by reviewers 1 and 2, respectively., Conclusions: SMI provides higher sensitivity than CDI and PDI to detect tumor vascularity, and a combination of B-mode US and SMI can improve the characterization of FLLs when vascular pattern of tumor is considered., (Copyright © 2022. Published by Elsevier B.V.)

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide with high lethality and prevalence. The deregulated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an indispensable role in mediating the progression of HCC. Among them, PI3K acts as the most pivotal initiator, contributing to multiple malignant biological processes, like proliferation, apoptosis and angiogenesis. Many PI3K inhibitors (PI3Kis) have been proved or proceeded into clinical as antineoplastic drugs. Nevertheless, the application of PI3Kis for the treatment of HCC remains a blank. Accordingly, our study identified a novel PI3Ki (DZW-310) with strong anti-HCC activity in vitro and in vivo. This study aimed to evaluate its anti-HCC effect and elucidate its potential mechanism. Our current results revealed that DZW-310 significantly attenuated HCC cell growth through promoting intrinsic apoptosis and G0/G1 phase cell arrest. Moreover, DZW-310 suppressed angiogenesis by regulating the HIF-1α/VEGFA axis. Further mechanistic investigation demonstrated that DZW-310, functioned as a PI3Ki, exerted strong anti-HCC activity by acting on PI3Kα (a major subtype of PI3K) and ulteriorly deactivating the PI3K/AKT/mTOR pathway. Collectively, our studies identified that DZW-310 is expected to become a promising HCC therapeutic agent and broaden clinical application of PI3Ki in HCC chemotherapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To investigate whether systemic inflammatory biomarkers compared with the imaging features interpreted by radiologists can offer complementary value for predicting the risk of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC)., Methods: A total of 156 patients with histologically confirmed HCC between Jan 2018 and Dec 2020 were retrospectively enrolled in the primary cohort. Preoperative clinical-inflammatory biomarkers and MR imaging of the patients were recorded and then evaluated as an inflammatory score (Inflam-score) and imaging feature score (Radio-score). Six Inflam-scores and 12 Radio-scores were determined from each patient by univariate analysis. Logistic regression was performed to select risk factors for MVI and establish a predictive nomogram. Decision curve analysis was applied to estimate the incremental value of the Inflam-score to the Radio-score for predicting MVI., Results: Four Radio-scores and 2 Inflam-scores, namely, larger tumor size, non-smooth tumor margin, presence of satellite nodules, presence of peritumoral enhance, higher neutrophil-lymphocyte ratio (NLR), and lower prognostic nutritional index (PNI), were significantly associated with MVI (p < 0.05). An MVI risk prediction nomogram was then constructed with an area under the curve (AUC) of 0.868 (95% CI 0.806-0.931). Adding Inflam-scores to Radio-scores improved the sensitivity of the model from 60.9 to 80.4% in receiver operating characteristic (ROC) curve analysis and led to a net benefit in decision curve analysis., Conclusion: Systemic inflammatory biomarkers are complementary tools that provide additional benefit to conventional imaging estimation for predicting MVI in HCC patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The antitumor effect of a drug is considered to be associated with a decrease in tumor blood flow., Aims: We investigated whether the efficacy of lenvatinib (LEN) could be accurately assessed by measuring blood flow in hepatocellular carcinoma (HCC) during early treatment stages., Methods and Results: Blood flow changes and treatment results of 19 patients who underwent contrast-enhanced ultrasound (CEUS), before and after LEN administration, in Kurume University Hospital from July 2018 to June 2020 were examined. Blood flow was evaluated after the intravenous administration of perflubutane (0.015 ml/kg). The vascular phase was photographed and used as RAW data, and time-intensity curve analysis was used to obtain the region of interest (ROI) on the entire tumor nodule and quantify tumor blood flow. The evaluation was performed before and 1 and 4 weeks after LEN administration. Mean ± standard deviation (SD) values of the brightness of blood flow in the background liver before and 1 and 4 weeks after LEN administration were 2.84 × 10 -4 ± 2.94 × 10 -4 , 3.07 × 10 -4 ± 3.79 × 10 -4 , and 10.0 × 10 -4 ± 20.8 × 10 -4 dB, respectively. Blood flow in the background liver did not significantly decrease at 1 and 4 weeks compared with that before treatment. Mean ± SD values of the brightness of blood flow in HCC before and 1 and 4 weeks after administration were 3.49 × 10 -3 ± 4.58 × 10 -3 , 1.16 × 10 -3 ± 1.57 × 10 -3 , and 6.39 × 10 -3 ± 22.8 × 10 -3 dB, respectively. Blood flow in HCC after 1 week was significantly lower than that before administration (p = .0192). The therapeutic effects were significantly higher in the group with ≥50% blood flow reduction in HCC at 1 week after administration (p = .0038) and the group with reduced blood flow in HCC at 4 weeks after administration (p = .0051) than those before administration., Conclusion: Early blood flow evaluation by CEUS may be useful in predicting the therapeutic effect of LEN for unresectable advanced HCC., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Due to the low accuracy of traditional three-dimensional fusion technology in radiofrequency ablation of hepatocellular carcinoma, this paper studies the advantages of three-dimensional CT fusion technology over traditional two-dimensional imaging technology in preoperative visualization and radiofrequency ablation path selection of hepatocellular carcinoma. To study the prognostic differences of hepatocellular carcinoma patients with different ablation margins (AM) in the three groups, so as to explore the best AM value, so as to minimize the liver injury caused by radiofrequency ablation. The selected patients underwent CT plain scan and three-phase enhancement at 1, 3, 6, and 12 months after operation and were rechecked every 6 months. For recurrent patients, CT was rechecked every three months. The images were obtained by GE 64-slice spiral CT. The thickness of the reconstruction layer is 1 mm, and the interval is 1 mm. The reconstructed image is imported into 3D fusion software. The three-dimensional images of tumor focus, hepatic artery, portal vein, and hepatic vein were reconstructed by two experienced doctors by superimposing the saved tumor images, merging the vascular images into the display, and measuring the ablation boundary (AM value). The results showed that the recurrence rate in group A was higher than that in group B ( P = 0.041), and there was no significant difference between group B and group C ( P = 1.000). Compared with traditional two-dimensional imaging, three-dimensional CT fusion technology can display the anatomical structure and three-dimensional spatial relationship of tumors and blood vessels and select the best radiofrequency ablation path, so as to achieve accurate radiofrequency ablation., Competing Interests: There is no potential conflict of interest in our paper, and all authors have seen the manuscript and approved to submit to your journal., (Copyright © 2022 Haihao Du et al.)

Since hepatocellular carcinoma (HCC) is a typical hypervascular malignant tumor with poor prognosis, targeting angiogenesis is an important therapeutic strategy for advanced HCC. Involvement of bone morphologic protein 9 (BMP9), a transforming growth factor-beta superfamily member, has recently been reported in the development of liver diseases and angiogenesis. Here, we aimed to elucidate the role of BMP9 signaling in promoting HCC angiogenesis and to assess the antiangiogenic effect of BMP receptor inhibitors in HCC. By analyzing HCC tissue gene expression profiles, we found that BMP9 expression was significantly correlated with angiogenesis-associated genes, including HIF-1α and VEGFR2. In vitro, BMP9 induced HCC cell HIF-1α/VEGFA expression and VEGFA secretion. Silencing of the inhibitor of DNA-binding protein 1 (ID1), a transcription factor targeted by BMP9 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression and VEGFA secretion, resulting in decreased human umbilical vein endothelial cell (HUVEC) lumen formation. BMP receptor inhibitors, which inhibit BMP9-ID1 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression, VEGFA secretion, and HUVEC lumen formation. In vivo, the BMP receptor inhibitor LDN-212854 successfully inhibited HCC tumor growth and angiogenesis by inhibiting BMP9-ID1 signaling. In summary, BMP9-ID1 signaling promotes HCC angiogenesis by activating HIF-1α/VEGFA expression. Thus, targeting BMP9-ID1 signaling could be a pivotal therapeutic option for advanced HCC.

Background: Microvascular invasion (MVI) adversely affects postoperative long-term survival outcomes in patients with hepatocellular carcinoma (HCC). There is no study addressing genetic changes in HCC patients with MVI. We first screened differentially expressed genes (DEGs) in patients with and without MVI based on TCGA data, established a prediction model and explored the prognostic value of DEGs for HCC patients with MVI., Methods: In this paper, gene expression and clinical data of liver cancer patients were downloaded from the TCGA database. The DEG analysis was conducted using DESeq2. Using the least absolute shrinkage and selection operator, MVI-status-related genes were identified. A Kaplan-Meier survival analysis was performed using these genes. Finally, we validated two genes, HOXD9 and HOXD10, using two sets of HCC tissue microarrays from 260 patients., Results: Twenty-three MVI-status-related key genes were identified. Based on the key genes, we built a classification model using random forest and time-dependent receiver operating characteristic (ROC), which reached 0.814. Then, we performed a survival analysis and found ten genes had a significant difference in survival time. Simultaneously, using two sets of 260 patients' HCC tissue microarrays, we validated two key genes, HOXD9 and HOXD10. Our study indicated that HOXD9 and HOXD10 were overexpressed in HCC patients with MVI compared with patients without MVI, and patients with MVI with HOXD9 and 10 overexpression had a poorer prognosis than patients with MVI with low expression of HOXD9 and 10., Conclusion: We established an accurate TCGA database-based genomics prediction model for preoperative MVI risk and studied the prognostic value of DEGs for HCC patients with MVI. These DEGs that are related to MVI warrant further study regarding the occurrence and development of MVI., (© 2021. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4., Competing Interests: The authors declare no conflict of interest.

to explore the value of transcatheter arterial chemoembolization (TACE) combined with targeted nanoparticle delivery system for sorafenib (SFB) to treat hepatocellular carcinoma (HCC) with microvascular invasion. 42 HCC patients with microvascular invasion after liver cancer surgery were selected from our hospital from December 2020 and February 2021. Patients were divided into experimental group and control group based on their willingness. Patients in experimental group (18 cases) were treated with combination therapy of TACE and Ab-SFB-NP system; while patients in control group (24 cases) took TACE and non-nano drug delivery system. There was no obvious difference in liver function and blood test results between two groups of patients before treatment and one month after treatment ( P > 0.05). Three months after treatment, differences of alanine aminotransferase (ALT) were statistically significant ( P < 0.05); while differences of other test results were not ( P > 0.05). The disease control rate (DCR) of patients in experimental group was higher slightly ( P > 0.05). The incidence of adverse reactions of patients in experimental group was lower than the control group and the differences were statistically significant ( P < 0.05). After three months of TACE, the DCR in the experimental group was significantly higher compared to control group. The toxic reactions of taking SFB with Ab-SFB-NP nano-drug delivery system mainly included hand-foot syndrome, diarrhea, and bleeding, the toxic reactions were mainly at level 1 ~ 2. After symptomatic treatment, the toxicity was effectively controlled, so the security was high.

Transdifferentiation (or activation) of hepatic stellate cells (HSCs) to myofibroblasts is a key event in liver fibrosis. Activated HSCs in the tumor microenvironment reportedly promote tumor progression. This study analyzed the effect of an inhibitor of HSC activation, retinol-binding protein-albumin domain III fusion protein (R-III), on protumorigenic functions of HSCs. Although conditioned medium collected from activated HSCs enhanced the migration, invasion, and proliferation of the hepatocellular carcinoma cell line Hepa-1c1c7, this effect was not observed in Hepa-1c1c7 cells treated with conditioned medium from R-III-exposed HSCs. In a subcutaneous tumor model, larger tumors with increased vascular density were formed in mice transplanted with Hepa-1c1c7+HSC than in mice transplanted with Hepa-1c1c7 cells alone. Intriguingly, when Hepa-1c1c7+HSC-transplanted mice were injected intravenously with R-III, a reduction in vascular density and extended tumor necrosis were observed. In an orthotopic tumor model, co-transplantation of HSCs enhanced tumor growth, angiogenesis, and regional metastasis accompanied by increased peritumoral lymphatic vessel density, which was abolished by R-III. In vitro study showed that R-III treatment affected the synthesis of pro-angiogenic and anti-angiogenic factors in activated HSCs, which might be the potential mechanism underlying the R-III effect. These findings suggest that the inhibition of HSC activation abrogates HSC-induced tumor angiogenesis and growth, which represents an attractive therapeutic strategy., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Linc-ROR have been well-demonstrated to play important roles in cancer progression and angiogenesis. However, the underlying oncogenic mechanism of Linc-ROR in hepatocellular carcinoma is poorly understood. In this study, we demonstrate that Linc-ROR plays an oncogenic role in part through its positive regulation of DEPDC1 expression. Mechanistically, Linc-ROR acts as competing endogenous RNA to stabilize DEPDC1 mRNA and regulates DEPDC1 mRNA stability by binding HNRNPK. Thus, these findings suggest that function of Linc-ROR-mediated DEPDC1 could predispose hepatocellular carcinoma patients to progression and angiogenesis, and may serve as a potential target for anticancer therapies., (© 2021. The Author(s).)