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Metabolic reprogramming plays a critical role in hepatocarcinogenesis. However, the mechanisms regulating metabolic reprogramming in primary liver cancer (PLC) are unknown. Differentially expressed miRNAs between PLC and normal tissues were identified using bioinformatic analysis. RT-qPCR was used to determine miR-10b-5p and SCL38A2 expression levels. IHC, WB, and TUNEL assays were used to assess the proliferation and apoptosis of the tissues. The proliferation, migration, invasion, and apoptosis of PLC cells were determined using the CCK-8 assay, Transwell assay, and flow cytometry. The interaction between miR-10b-5p and SLC38A2 was determined using dual-luciferase reporter assay. A PLC xenograft model in BALB/c nude mice was established, and tumorigenicity and SLC38A2 expression were estimated. Finally, liquid chromatography - mass spectrometry (LC-MS) untargeted metabolomics was used to analyze the metabolic profiles of xenograft PLC tissues in nude mice. miR-10b-5p was a key molecule in the regulation of PLC. Compared with para-carcinoma tissues, miR-10b-5p expression was increased in tumor tissues. miR-10b-5p facilitated proliferation, migration, and invasion of PLC cells. Mechanistically, miR-10b-5p targeted SLC38A2 to promote PLC tumor growth. Additionally, miR-10b-5p altered the metabolic features of PLC in vivo . Overexpression of miR-10b-5p resulted in remarkably higher amounts of lumichrome, folic acid, octanoylcarnitine, and Beta-Nicotinamide adenine dinucleotide, but lower levels of 2-methylpropanal, glycyl-leucine, and 2-hydroxycaproic acid. miR-10b-5p facilitates the metabolic reprogramming of PLC by targeting SLC38A2, which ultimately boosts the proliferation, migration, and invasion of PLC cells. Therefore, miR-10b-5p and SLC38A2 are potential targets for PLC diagnosis and treatment.

Background The clinicopathologic-radiologic and prognostic characteristics of intratumoral fat in hepatocellular carcinoma (HCC) are critical for personalized treatment but remain understudied. Purpose To investigate the clinicopathologic-radiologic associations and prognostic implications of MRI-assessed intratumoral fat in HCCs. Materials and Methods This retrospective cohort study included consecutive adult patients who underwent resection for solitary HCCs and preoperative contrast-enhanced MRI from two tertiary-care hospitals in East Asia (March 2011 to December 2021) and Western Europe (September 2012 to December 2019). MRI scans were independently evaluated by three radiologists at each hospital. Based on Liver Imaging Reporting and Data System (LI-RADS) version 2018, intratumoral fat was defined as "fat in mass more than adjacent liver," and the homogeneous subtype was defined as intratumoral fat "in absence of mosaic and nodule-in-nodule architecture." Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox regression analyses were conducted to identify factors associated with RFS and OS. Results A total of 933 patients were included in the Asian ( n = 736; median age, 53 years [IQR, 45-62 years]; 626 male) and European ( n = 207; median age, 64 years [IQR, 55-70 years]; 161 male) cohorts. MRI-assessed intratumoral fat was detected in 30% (215 of 726) and 31% (64 of 207) of patients in the Asian and European cohorts, respectively ( P = .72). In both cohorts, the steatohepatitic subtype, nonperipheral washout, enhancing capsule, and mosaic architecture were more frequent in tumors with intratumoral fat ( P value range, <.001 to .04). Intratumoral fat in general was not associated with RFS or OS in either cohort ( P value range, .48-.97). However, in the Asian cohort, homogeneous intratumoral fat was associated with longer RFS (hazard ratio [HR], 0.60; P = .009) and OS (HR, 0.33; P = .008) in multivariable Cox regression analyses. Conclusion MRI-assessed intratumoral fat was more frequent in steatohepatitic HCCs and associated with nonperipheral washout, enhancing capsule, and mosaic architecture. Although intratumoral fat was generally nonprognostic, homogeneous intratumoral fat was associated with longer RFS and OS in the Asian cohort. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Harmath in this issue.

Objectives: To investigate associations between tissue diffusion, stiffness, and different tumor microenvironment features in resected hepatocellular carcinoma (HCC)., Methods: Seventy-two patients were prospectively included for preoperative magnetic resonance (MR) diffusion-weighted imaging and MR elastography examination. The mean apparent diffusion coefficient (ADC) and stiffness value were measured on the central three slices of the tumor and peri-tumor area. Cell density, tumor-stroma ratio (TSR), lymphocyte-rich HCC (LR-HCC), and CD8 + T cell infiltration were estimated in resected tumors. The interobserver agreement of MRI measurements and subjective pathological evaluation was assessed. Variables influencing ADC and stiffness were screened with univariate analyses, and then identified with multivariable linear regression. The potential relationship between explored imaging biomarkers and histopathological features was assessed with linear regression after adjustment for other influencing factors., Results: Seventy-two patients (male/female: 59/13, mean age: 56 ± 10.2 years) were included for analysis. Inter-reader agreement was good or excellent regarding MRI measurements and histopathological evaluation. No correlation between tumor ADC and tumor stiffness was found. Multivariable linear regression confirmed that cell density was the only factor associated with tumor ADC (Estimate = -0.03, p = 0.006), and tumor-stroma ratio was the only factor associated with tumor stiffness (Estimate = -0.18, p = 0.03). After adjustment for fibrosis stage (Estimate = 0.43, p < 0.001) and age (Estimate = 0.04, p < 0.001) in the multivariate linear regression, intra-tumoral CD8 + T cell infiltration remained a significant factor associated with peri-tumor stiffness (Estimate = 0.63, p = 0.02)., Conclusions: Tumor ADC surpasses tumor stiffness as a biomarker of cellularity. Tumor stiffness is associated with tumor-stroma ratio and peri-tumor stiffness might be an imaging biomarker of intra-tumoral immune microenvironment., Clinical Relevance Statement: Tissue stiffness could potentially serve as an imaging biomarker of the intra-tumoral immune microenvironment of hepatocellular carcinoma and aid in patient selection for immunotherapy., Key Points: Apparent diffusion coefficient reflects cellularity of hepatocellular carcinoma. Tumor stiffness reflects tumor-stroma ratio of hepatocellular carcinoma and is associated with tumor-infiltrating lymphocytes. Tumor and peri-tumor stiffness might serve as imaging biomarkers of intra-tumoral immune microenvironment., (© 2024. The Author(s).)

Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1 high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the current study, bioinformatics analysis of the hepatocellular carcinoma (HCC) dataset was conducted with the hepatoprotective effect of the Fuzheng Huayu (FZHY) capsule against the diethylnitrosamine-induced HCC progression analyzed. Eight cell clusters were defined and tanshinone IIA , arachidonic acid , and quercetin , compounds of the FZHY capsule, inhibit HCC progression-related fibrosis by regulating the expression of PLAU and IGFBP3 . Combined with the ameliorative effect of the FZHY capsule against liver dysfunctions and expression of PLAU and IGFBP3, our study confirmed the effect of the FZHY capsule on inhibiting the fibrosis-associated HCC progression via regulating the expression of PLAU and IGFBP3.

The use of multi-modality non-contrast images (i.e., T1FS, T2FS and DWI) for segmenting liver tumors provides a solution by eliminating the use of contrast agents and is crucial for clinical diagnosis. However, this remains a challenging task to discover the most useful information to fuse multi-modality images for accurate segmentation due to inter-modal interference. In this paper, we propose a dual-stream multi-level fusion framework (DM-FF) to, for the first time, accurately segment liver tumors from non-contrast multi-modality images directly. Our DM-FF first designs an attention-based encoder-decoder to effectively extract multi-level feature maps corresponding to a specified representation of each modality. Then, DM-FF creates two types of fusion modules, in which a module fuses learned features to obtain a shared representation across multi-modality images to exploit commonalities and improve the performance, and a module fuses the decision evidence of segment to discover differences between modalities to prevent interference caused by modality's conflict. By integrating these three components, DM-FF enables multi-modality non-contrast images to cooperate with each other and enables an accurate segmentation. Evaluation on 250 patients including different types of tumors from two MRI scanners, DM-FF achieves a Dice of 81.20%, and improves performance (Dice by at least 11%) when comparing the eight state-of-the-art segmentation architectures. The results indicate that our DM-FF significantly promotes the development and deployment of non-contrast liver tumor technology., 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 Elsevier Ltd. All rights reserved.)

Purpose: To assess whether diffusion-weighted imaging (DWI) with Compressed SENSE (CS) and deep learning (DL-CS-DWI) can improve image quality and lesion detection in patients at risk for hepatocellular carcinoma (HCC)., Methods: This single-center prospective study enrolled consecutive at-risk participants who underwent 3.0 T gadoxetate disodium-enhanced MRI. Conventional DWI was acquired using parallel imaging (PI) with SENSE (PI-DWI). In CS-DWI and DL-CS-DWI, CS but not PI with SENSE was used to accelerate the scan with 2.5 as the acceleration factor. Qualitative and quantitative image quality were independently assessed by two masked reviewers, and were compared using the Wilcoxon signed-rank test. The detection rates of clinically-relevant (LR-4/5/M based on the Liver Imaging Reporting and Data System v2018) liver lesions for each DWI sequence were independently evaluated by another two masked reviewers against their consensus assessments based on all available non-DWI sequences, and were compared by the McNemar test., Results: 67 participants (median age, 58.0 years; 56 males) with 197 clinically-relevant liver lesions were enrolled. Among the three DWI sequences, DL-CS-DWI showed the best qualitative and quantitative image qualities (p range, <0.001-0.039). For clinically-relevant liver lesions, the detection rates (91.4%-93.4%) of DL-CS-DWI showed no difference with CS-DWI (87.3%-89.8%, p = 0.230-0.231) but were superior to PI-DWI (82.7%-85.8%, p = 0.015-0.025). For lesions located in the hepatic dome, DL-CS-DWI demonstrated the highest detection rates (94.8%-97.4% vs 76.9%-79.5% vs 64.1%-69.2%, p = 0.002-0.045) among the three DWI sequences., Conclusion: In patients at high-risk for HCC, DL-CS-DWI improved image quality and detection for clinically-relevant liver lesions, especially for the hepatic dome., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale and Objectives: We aimed to evaluate clinical characteristics and quantitative CT imaging features for the prediction of liver metastases (LMs) in patients with pancreatic neuroendocrine tumors (PNETs)., Methods: Patients diagnosed with pathologically confirmed PNETs were included, 133 patients were in the training group, 22 patients in the prospective internal validation group, and 28 patients in the external validation group. Clinical information and quantitative features were collected. The independent variables for predicting LMs were confirmed through the implementation of univariate and multivariate logistic analyses. The diagnostic performance was evaluated by conducting receiver operating characteristic curves for predicting LMs in the training and validation groups., Results: PNETs with LMs demonstrated significantly larger diameter and lower arterial/portal tumor-parenchymal enhancement ratio, arterial/portal absolute enhancement value (AAE/PAE value) (p < 0.05). After multivariate analyses, A high level of tumor marker (odds ratio (OR): 5.32; 95% CI, 1.54-18.35), maximum diameter larger than 24.6 mm (OR: 7.46; 95% CI, 1.70-32.72), and AAE value ≤ 51 HU (OR: 4.99; 95% CI, 0.93-26.95) were independent positive predictors of LMs in patients with PNETs, with area under curve (AUC) of 0.852 (95%CI, 0.781-0.907). The AUCs for prospective internal and external validation groups were 0.883 (95% CI, 0.686-0.977) and 0.789 (95% CI, 0.602-0.916), respectively., Conclusion: Tumor marker, maximum diameter and absolute enhancement value in arterial phase were independent predictors with good predictive performance for the prediction of LMs in patients with PNETs. Combining clinical and quantitative features may facilitate the attainment of good predictive precision in predicting LMs., 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. Disclosure statement None., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To evaluate the effectiveness of the PRECEDE-PROCEED model (PPM) in helping patients with liver cancer be aware of their knowledge, skills, and abilities in self-oral health behaviors and improve their oral health status., Methods: This is a quasi-experimental study of 90 patients with liver cancer assigned to an oral health education or a control group. The intervention group was educated with the PRECEDE-PROCEED model. A brief oral scale and the knowledge, attitude, and practice oral health questionnaire were employed to measure the oral health status and cognitive behavioral ability to seek oral health in patients., Results: Among 102 eligible patients, 90 (88.23%) agreed to participate in the present study and were divided to intervention (n = 45) or control (n = 45) groups. After the intervention and one month after discharge, the oral health scores of patients in the Intervention group were lower than those of the control group (P < 0.05). In addition, after the intervention and one month after discharge, the patients in the test group had higher scores on knowledge, beliefs, and behaviors of oral health than the control group (P < 0.05). One month after discharge, the mean knowledge and skills scores were significantly higher in the intervention group than in the control group., Conclusions: Our findings suggest that oral health education may be a useful health intervention for patients with liver cancer. It may also improve the knowledge and beliefs of liver cancer patients seeking oral health. Larger long-term investigations are necessary to provide more support for these preliminary conclusions., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth., Methods: We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (ICD), and be used in conjunction with immune checkpoint blockade (ICB) for the treatment of hepatocellular carcinoma (HCC)., Results: The synthesized IR780@FOM-cRGD nanoparticles had an average diameter of 28.23±1.750 nm and a Zeta potential of -23.95±1.926. Confocal microscopy demonstrated that IR780@FOM-cRGD could target HCC cells while minimizing toxicity to healthy cells. Upon sonodynamic activation, these nanoparticles consumed significant amounts of oxygen and generated substantial reactive oxygen species (ROS), effectively killing tumor cells and inhibiting the proliferation, invasion, and migration of H22 cells. Hemolysis assays confirmed the in vivo safety of the nanoparticles, and in vivo fluorescence imaging revealed significant accumulation in tumor tissues. Mouse model experiments showed that combining ICB(which induced by Anti-PD-L1) with ICD (which induced by IR780@FOM-cRGD), could effectively activated anti-tumor immunity and suppressed tumor growth., Discussion: This study highlights the potential of IR780@FOM-cRGD nanoparticles to facilitate tumor eradication and immune activation when used in conjunction with Anti-PD-L1 therapy. This combination represents a non-invasive, efficient, and targeted approach for the treatment of hepatocellular carcinoma (HCC). By integrating sonodynamic therapy with immunotherapy, this strategy promises to substantially improve the effectiveness of traditional treatments in combating HCC, offering new avenues for clinical application and therapeutic innovation., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2024 Wei et al.)

Circulating tumor cells (CTCs) serve as important biomarkers in the liquid biopsy of hepatocellular carcinoma (HCC). Herein, a homogeneous dual fluorescence indicators aptasensing strategy is described for CTCs in HCC, with the core assistance of a steric hindrance-mediated enzymatic reaction. CTCs in the sample could specifically bind to a 5'-biotin-modified glypican-3 (GPC3) aptamer and remove the steric hindrance formed by the biotin-streptavidin system. This influences the efficiency of the terminal deoxynucleotidyl transferase enzymatic reaction. Then, methylene blue (MB) was introduced to react with the main product poly cytosine (polyC) chain, and trivalent cerium ion (Ce 3+ ) was added to react with the byproduct pyrophosphate to form fluorescent pyrophosphate cerium coordination polymeric nanoparticles. Finally, the CTCs were quantified by dual fluorescence indicators analysis. Under optimized conditions, the linear range was 5 to 10 4 cells/mL, and the limits of detection reached 2 cells/mL. Then, 40 clinical samples (15 healthy and 25 HCC patients) were analyzed. The receiver operating characteristic curve analysis revealed an area under the curve of 0.96, a sensitivity of 92%, and a specificity of 100%. Therefore, this study established a sensitive and accurate CTCs sensing system for clinical HCC patients, promoting early tumor diagnosis.

Background & Aims: Hepatocellular carcinoma (HCC) is characterized by an immune-suppressive microenvironment, which contributes to tumor progression, metastasis, and immunotherapy resistance. Identification of HCC-intrinsic factors regulating the immunosuppressive microenvironment is urgently needed. Here, we aimed to elucidate the role of SYR-Related High-Mobility Group Box 18 (SOX18) in inducing immunosuppression and to validate novel combination strategies for SOX18-mediated HCC progression and metastasis., Methods: The role of SOX18 in HCC was investigated in orthotopic allografts and diethylinitrosamine/carbon tetrachloride-induced spontaneous models by using murine cell lines, adeno-associated virus 8, and hepatocyte-specific knockin and knockout mice. The immune cellular composition in the HCC microenvironment was evaluated by flow cytometry and immunofluorescence., Results: SOX18 overexpression promoted the infiltration of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) while diminishing cytotoxic T cells to facilitate HCC progression and metastasis in cell-derived allografts and chemically induced HCC models. Mechanistically, transforming growth factor-beta 1 (TGF-β1) upregulated SOX18 expression by activating the Smad2/3 complex. SOX18 transactivated chemokine (C-X-C motif) ligand 12 (CXCL12) and programmed death ligand 1 (PD-L1) to induce the immunosuppressive microenvironment. CXCL12 knockdown significantly attenuated SOX18-induced TAMs and Tregs accumulation and HCC dissemination. Antagonism of chemokine receptor 4 (CXCR4), the cognate receptor of CXCL12, or selective knockout of CXCR4 in TAMs or Tregs likewise abolished SOX18-mediated effects. TGFβR1 inhibitor Vactosertib or CXCR4 inhibitor AMD3100 in combination with anti-PD-L1 dramatically inhibited SOX18-mediated HCC progression and metastasis., Conclusions: SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in the microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFβR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim of this study was to establish a new surgical scheme defining risk classification of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among HCC patients with CSPH., Backgrounds: Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC., Methods: Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram., Results: This study included 924 patients, of whom 137 patients (14.8%) suffered from mild-CSPH and 66 patients suffered from (7.1%) with severe-CSPH confirmed preoperatively. Our data showed that preoperative prolonged prothrombin time, total bilirubin, indocyanine green retention rate at 15 min, CSPH grade, and standard future liver remnant volume were independent predictors of severe PHLF. By incorporating these factors, the nomogram achieved good prediction performance in assessing severe PHLF risk, and its concordance statistic was 0.891, 0.850 and 0.872 in the training cohort, internal validation cohort and external validation cohort, respectively, and good calibration curves were obtained. Moreover, the calculations of total points of diagnostic errors with 95% CI were concentrated in 110.5 (range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR., Conclusion: This new surgical scheme established in our study is practical to stratify risk classification in assessing severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy., (© 2024. The Author(s).)

Backgrounds: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone ., Methods: A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups., Results: After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P < 0.001), disease control rate (DCR) (94.3%% vs. 72.9%, P < 0.001), and conversion rates before and after propensity matching were 44.1% and 41.4%, respectively, compared with the TACE group. The median progression free survival (PFS) was longer in the TLC group than in the TACE group (12.7 vs. 6.1 months, P = 0.005). The median overall survival (OS) was longer in the TLC group than in the TACE group (19.4 vs. 13.0 months, P = 0.023). Cox multivariate analysis with different modes of adjustment showed that treatment was an independent influencing factor of PFS and OS. The interaction analysis showed that cirrhosis and Child-Pugh stage an interactive role in the PFS of different treatment. Decreased AFP after treatment portends higher ORR and DCR., Conclusion: TACE combined Lenvatinib plus Camrelizumab regimen was safe and superior to TACE alone in improving PFS, OS, and tumor response rates for unresectable recurrent HCC patients., (© 2024. The Author(s).)

Background: Conversion therapy for initially unresectable hepatocellular carcinoma (iuHCC) using lenvatinib combined with transcatheter arterial chemoembolization (TACE) plus a PD-1 inhibitor (LTP) has achieved promising results. However, further comparative research is necessary to evaluate the effectiveness and safety of conversion surgery (CS) for iuHCC., Methods: Data for 32 consecutive patients with iuHCC receiving CS and 419 consecutive patients with resectable HCC receiving initial surgery (IS) between November 2019 and September 2022 were collected retrospectively. After propensity score matching (PSM), 65 patients were selected., Results: Before matching, the CS group had longer EFS (not reached vs. 12.9 months, P < 0.001) and similar OS (not reached vs. not reached, P = 0.510) compared with the IS group. Similar results for EFS (P = 0.001) and OS (P = 0.190) were obtained after matching. The multivariable Cox model (HR = 0.231, 95% CI: 0.105-0.504; P < 0.001) and subgroup analyses confirmed that CS could improve EFS. The CS group had significantly lower incidence of microvascular invasion (MVI) than the IS group (3.1% vs. 50.4%, P < 0.001). Moreover, the two groups had similar safety profiles., Conclusions: CS is effective and safe for patients with iuHCC receiving LTP. LTP has the potential to reduce risk factors for postoperative recurrence, especially MVI, which may influence surgical decision-making., Competing Interests: Conflict of interest None., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: In clinical practice, hepatocellular carcinoma (HCC) is widely diagnosed by using MRI, however, whether the imaging features are affected by hepatic steatosis (HS) is still unknown., Purpose: To investigate and compare the differences in HCC related imaging features between with- and without-HS groups, and to further determine whether HS affects the diagnosis accuracy of Liver Imaging Reporting and Data System (LI-RADS) v2018 of HCC in MRI., Study Type: Prospective., Subjects: One hundred and seventy-one patients (mean age, 52 ± 11 years; range, 26-83 years) including 137 men and 34 women., Field Strength/sequence: 3.0 T, gradient echo (GRE)., Assessment: Subjects were classified as HS and non-HS groups according to MRI-proton density fat-fraction (PDFF). HS was defined as MRI-PDFF >5.6%. Three radiologists accessed HCC features and assigned LI-RADS categories in MRI independently based on LI-RADS v2018. Frequencies of HCC major features and LR categorization assignment between the two groups as well as interobserver agreement between the two radiologists were assessed., Statistical Tests: Unpaired t-test, Chi-square test, Fisher's exact test, kappa statistic, intraclass correlation coefficient (ICC). A two-sided P value <0.05 was considered as statistically significant., Results: Major features including arterial hyperenhancement (APHE), enhancing "capsule" and nonperipheral "washout" observed between HS and non-HS groups were not significantly different (78.95% vs.78.62%, P = 0.866; 57.89% vs.52.98%, P = 0.483; and 75% vs.81.46%, P = 0.257, respectively), and the assessment of observation size showed a borderline difference (P = 0.059). No significant difference in LR-5 assignment between the two groups (69.74% vs. 72.85% for reader 1, P = 0.641; 71.05% vs. 72.19% for reader 2, P = 0.877). Interobserver agreement between the two radiologists showed almost perfect in LR-5 assignment (κ = 0.869) and size observation (ICC = 0.997)., Data Conclusion: The diagnosis of HCC based on LI-RADS v2018 in MRI is of comparable performance regardless of HS, in which there is no significant difference in either the major imaging features or LR categorization., Level of Evidence: 2 Technical Efficacy Stage: 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: Microvascular invasion (MVI) is a critical factor in predicting the recurrence and prognosis of hepatocellular carcinoma (HCC) after liver transplantation (LT). However, there is a lack of reliable preoperative predictors for MVI. The purpose of this study is to evaluate the potential of an 18 F-FDG PET/CT-based nomogram in predicting MVI before LT for HCC., Methods: 83 HCC patients who obtained 18 F-FDG PET/CT before LT were included in this retrospective research. To determine the parameters connected to MVI and to create a nomogram for MVI prediction, respectively, Logistic and Cox regression models were applied. Analyses of the calibration curve and receiver operating characteristic (ROC) curves were used to assess the model's capability to differentiate between clinical factors and metabolic data from PET/CT images., Results: Among the 83 patients analyzed, 41% were diagnosed with histologic MVI. Multivariate logistic regression analysis revealed that Child-Pugh stage, alpha-fetoprotein, number of tumors, CT Dmax, and Tumor-to-normal liver uptake ratio (TLR) were significant predictors of MVI. A nomogram was constructed using these predictors, which demonstrated strong calibration with a close agreement between predicted and actual MVI probabilities. The nomogram also showed excellent differentiation with an AUC of 0.965 (95% CI 0.925-1.000)., Conclusion: The nomogram based on 18 F-FDG PET/CT metabolic characteristics is a reliable preoperative imaging biomarker for predicting MVI in HCC patients before undergoing LT. It has demonstrated excellent efficacy and high clinical applicability., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP + and α-SMA high , were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-β expression in nearby tumor cells. Then, TGF-β promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis., 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.)

Background: This study was recruited to compare the efficacy and safety of radiotherapy (RT) and transarterial chemoembolization (TACE) as postoperative adjuvant therapy after narrow-margin hepatectomy in hepatocellular carcinoma (HCC) patients., Methods: This single-center prospective randomized study was conducted in the Cancer Hospital, Guang Xi Medical University, Nanning. A total of 72 patients who received treatment in this hospital between August 2017 and July 2019 were included and randomly allocated to TACE group (n = 48) and RT group (n = 24). Next, overall survival (OS) and progression-free survival (PFS) rates, recurrence patterns, financial burden, and safety were evaluated., Results: The difference between the RT and TACE groups was not significant in one-, three-, and five-year OS (87.5%, 79.0%, and 62.5% vs. 93.8%, 75.9%, and 63.4%, respectively, P = 0.071) and PFS rates (79.0%, 54.2%, and 22.6% vs. 75.0%, 47.9%, and 32.6%, respectively, P = 0.071). Compared to the TACE group, the RT group had significantly lower intrahepatic recurrence rate (20.8% vs. 52.1%, P = 0.011), higher extrahepatic recurrence rate (37.5% vs. 14.6%, P = 0.034), and no marginal and diffuse recurrences (0% vs. 16.7%, P < 0.05). The mean overall treatment cost was higher (¥62,550.59 ± 4397.27 vs. ¥40,732.56 ± 9210.54, P < 0.01), the hospital stay (15.1 ± 3.7 vs. 11.8 ± 4.1 days, P < 0.01) was longer, and the overall treatment stay (13.3 ± 5.3 vs. 41.29 ± 12.4 days, P < 0.01) was shorter in the TACE group than in the RT group. Besides, both groups did not exhibit significant differences in the frequency and severity of adverse events., Conclusion: Both adjuvant TACE and RT can better the OS and PFS of patients with HCC. However, RT has a significantly better performance than TACE in terms of improving intrahepatic recurrence rate, treatment cost and hospital stay., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC)., Methods: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4., Results: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC., Conclusions: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To compare the diagnostic ability between magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in distinguishing intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC)., Methods: Original studies reporting the diagnostic accuracy of MRI and CEUS in differentiating ICC from HCC were identified in PubMed and EMBASE databases. Histopathological examination was used as the reference standard for tumor diagnosis. Study quality was assessed using QUADAS-2 scale. Data were extracted to calculate the pooled diagnostic sensitivity, specificity, and diagnostic odds ratio (DOR) using a bivariate random-effects model, as well as the area under the curve (AUC). Sensitivity analysis, subgroup analysis, meta-regression, and investigation of publication bias were also performed., Results: A total of 26 studies with 28 data subsets (18 on MRI, 10 on CEUS) were included, consisting of 4169 patients with 1422 ICC lesions and 2747 HCC lesions. Most MRI studies were performed at 3T with hepatobiliary agents, and most CEUS studies used SonoVue as the contrast agent. In MRI, the pooled sensitivity, specificity, DOR, and AUC in distinguishing ICC from HCC were 0.81 (0.79, 0.84), 0.90 (0.88, 0.91), 41.47 (24.07, 71.44), and 0.93 (0.90, 0.96), respectively. The pooled sensitivity, specificity, DOR, and AUC of CEUS were 0.88 (0.84, 0.90), 0.80 (0.78, 0.83), 42.06 (12.38, 133.23), and 0.93 (0.87, 0.99), respectively. Subgroup analysis and meta-regression analysis demonstrated significant heterogeneity among the studies associated with the type of contrast agent in MRI studies. No publication bias was found., Conclusion: Both MRI and CEUS showed excellent diagnostic performance in differentiating ICC from HCC. CEUS showed higher pooled sensitivity and MRI showed higher pooled specificity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The tumor immune response plays a vital role in cancer recurrence in patients with malignancies. We aim to clarify the risk factors for early recurrence and investigate the efficacy of blood-based biomarkers to predict the risk of early recurrence in early-stage hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy., Materials and Methods: A total of 101 cases of HCC with MVI who underwent liver resection were enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of early recurrence. We calculated the area under the receiver operating characteristic curve to evaluate the performance of the four biomarkers identified as risk factors for early recurrence., Results: Multiple logistic regression analysis indicated that complement (C)4, cluster of differentiation (CD)4+, immunoglobulin A (IgA), and hepatitis B virus (HBV) DNA of greater than 500 IU/mL were correlated with early recurrence of HCC. The area under the curve was greater for the combination model than for the HBV DNA, CD4+, IgA, or C4 models alone., Conclusion: Preoperative serum CD4+, C4, IgA, and HBV DNA levels were linked with early recurrence of early-stage HCC with MVI and the combination model was of considerable predictive value for the prognosis of HCC with MVI.

Background: The current study probed into how tumor cell-derived exosomes (Exos) mediated hsa&#95;circ&#95;0001739/lncRNA AC159540.1 to manipulate microRNA (miR)-218-5p/FTO-N6-methyladenosine (m6A)/MYC signal axis in liver metastasis in colorectal cancer (CRC)., Methods: hsa&#95;circ&#95;0001739 and lncRNA AC159540.1 were identified as the upstream regulator of miR-218-5p using ENCORI and LncBase databases. Expression patterns of miR-218-5p, hsa&#95;circ&#95;0001739, lncRNA AC159540.1, FTO, and MYC were detected, accompanied by loss-and-gain-of function assays to examine their effects on CRC cell biological functions. SW480 cells-derived Exos were purified, followed by in vitro studies to uncover the effect of hsa&#95;circ&#95;0001739/lncRNA AC159540., Results: miR-218-5p was downregulated while hsa&#95;circ&#95;0001739/lncRNA AC159540.1 was upregulated in CRC tissues and cells. Silencing of hsa&#95;circ&#95;0001739/lncRNA AC159540.1 restrained the malignant phenotypes of CRC cells. Exos-mediated hsa&#95;circ&#95;0001739/lncRNA AC159540.1 competitively inhibited miR-218-5p to elevate FTO and MYC. The inducing role of Exos-mediated hsa&#95;circ&#95;0001739/lncRNA AC159540.1 in CRC was also validated in vivo., Conclusion: Conclusively, Exos-mediated circ&#95;0001739/lncRNA AC159540.1 regulatory network is critical for CRC, offering a theoretical basis for CRC treatment., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Laparoscopic anatomical liver resection of segment 8 (LALR-S8) remains a challenge for anatomical laparoscopic segmentectomy. Most current reports on LALR-S8 are case series using one surgical approach, and there is a lack of multicenter data on identifying intersegmental planes using different approaches. In this study, the authors aimed to elucidate the short-term results of three different approaches for LALR-S8 for hepatocellular carcinoma (HCC), focusing on intersegmental plane determination, and to reflect on current practice regarding different approaches at multiple centers in China., Materials and Methods: The clinical cohort data of 122 patients who underwent LALR-S8 for HCC at seven leading centers in China were retrospectively analyzed. The surgical procedures of all approaches were summarized and standardized according to the method of the Glissonean pedicle of segment 8 identification. The postoperative short-term outcomes and oncological results of the three approaches were evaluated and compared., Results: Three approaches were used: laparoscopic ultrasonography-guided indocyanine green fluorescent positive staining approach (11/122, 9.02%), hepatic vein-guided approach (99/122, 81.15%), and Glissonean indocyanine green fluorescent negative staining approach (12/122, 9.83%). Seven (5.73%) patients experienced complications according to the Clavien-Dindo classification, and the rate of grade ≥IIIa complications was 2.46%. The R0 resection rates among the groups (margin >1 mm) and the margin width showed no statistical difference., Conclusion: LALR-S8 is safe and feasible for treating HCC under standardized surgical techniques and appropriate surgical approaches. The three reported approaches had comparable short-term oncological outcomes, while the hepatic vein-guided approach was most commonly used., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A high incidence of hepatocellular carcinoma (HCC), the most frequently diagnosed form of liver cancer, is observed in Africa and Asia. SYVN1 is upregulated in HCC; however, the biological roles of SYVN1 in immune evasion remain unclear., Methods: RT-qPCR and western blot were employed to detect the expression levels of SYVN1 and the key molecules in HCC cells and tissues. Flow cytometry was used to determine the proportion of T cells, and an ELISA assay was used to determine the amount of IFN-γ secreted. Cell viability was monitored by CCK-8 and colony formation assays. The metastatic properties of HCC cells were detected by Transwell assays. Bioinformatics analysis, ChIP, and luciferase assays were used to study the transcriptional regulation of PD-L1. Co-IP was used to detect direct interaction between SYVN1 and FoxO1, as well as the ubiquitination of FoxO1. The in vitro findings were validated in xenograft and lung metastasis models., Results: In HCC cells and tissues, SYVN1 was upregulated while FoxO1 was downregulated. SYVN1 knockdown or FoxO1 overexpression reduced PD-L1 expression, and inhibited immune evasion, cell growth, and metastasis in HCC cells. Mechanistically, FoxO1 regulated PD-L1 transcription in a β-catenin-independent or -dependent manner. Functional studies further showed that SYVN1 promoted immune evasion, cell proliferation, migration and invasion via facilitating ubiquitin-proteasome-dependent degradation of FoxO1. In vivo investigations showed that silencing of SYVN1 inhibited immune evasion and metastasis of HCC cells, possible via the FoxO1/PD-L1 axis., Conclusion: SYVN1 regulates FoxO1 ubiquitination to stimulate β-catenin nuclear translocation and promotes PD-L1-mediated metastasis and immune evasion in HCC., (© 2023. The Author(s).)

Ten previously undescribed sesquiterpenes, carpespenes A-J (1-10), and eight known compounds (11-18), were isolated from the whole plants of Carpesium faberi. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Carpespene A (1) is eudesmanolide-type sesquiterpene lactone with an open five membered ring involving C-2 and C-3. Furthermore, compound 1 showed significant cytotoxic effects against four cancer cell lines with IC 50 values from 8.20 to 18.45 μM, compared with the positive controls cisplatin and doxorubicin. Mechanistically, compound 1 induced apoptosis in the HepG2 cells by triggering excessive ROS accumulation. The latter however induced cytoprotective autophagy, which impaired the cytotoxicity of compound 1. Simultaneous antophagy inhibition with compound 1 treatment augmented the cytotoxic effects of the latter on HepG2 cells. Our findings further establish the structural diversity and bioactivity of sesquiterpenes, and provide an experimental basis for targeting cytoprotective autophagy as a potential chemotherapeutic strategy., 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 Ltd. All rights reserved.)

Purpose: To develop a predictive model integrating clinical and MRI features for postoperative survival in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT)., Method: Between January 2008 and May 2021, consecutive HCC patients with PVTT who underwent preoperative contrast-enhanced MRI and surgical resection at a tertiary hospital were retrospectively enrolled. The MR images were independently reviewed by two blinded radiologists. Univariate and multivariate Cox regression analyses were performed to construct a prognostic score for overall survival (OS)., Results: Ninety-four patients were included (mean age, 50.1 years; 84 men). During a median follow-up period of 15.3 months, 72 (76.6%) patients died (median OS, 15.4 months; median disease-free survival [DFS], 4.6 months). The sum size of the two largest tumors (hazard ratio [HR], 3.050; p < 0.001) and tumor growth subtype (HR, 1.928; p = 0.006) on MRI, serum albumin (HR, 0.948; p = 0.02), and age (HR, 0.978; p = 0.04) were associated with OS and incorporated in the prognostic score. Accordingly, patients were stratified into a high-risk or low-risk group, and the OS in the high-risk group was shorter than that in the low-risk group for the entire cohort (11.7 vs. 25.0 months, p < 0.001) and for patients with Cheng's type I (12.1 vs. 25.9 months, p = 0.002) and type II PVTT (11.7 vs. 25.0 months, p = 0.004). The DFS in the high-risk group was shorter than that in the low-risk group for the entire cohort (4.5 vs. 6.1 months, p = 0.001)., Conclusions: Based on the sum size of the two largest tumors, tumor growth subtype, albumin, and age, the prognostic score allowed accurate preoperative risk stratification in HCC patients with PVTT, independent of Cheng's PVTT classification., 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 : Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71 + erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. Methods: The role of CD71 + EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45 + EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45 + EPCs was explored in vivo in a murine model. Results: The CD45 + EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45 + EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45 + EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45 + EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45 + EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45 + EPCs within the TME compared with those in the spleen. The CD45 + EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45 + EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45 + EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45 + EPCs in the TME. WTAP, a major RNA m 6 A writer, stabilized FX and FVII mRNA and enhanced their nuclear export in CD45 + EPCs from the TME. CD45 + EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45 + EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45 + EPCs to splenectomized HCC-bearing mice. Conclusions: The CD45 + EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl 4 -induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aerobic glycolysis has pleiotropic roles in the pathogenesis of hepatocellular carcinoma (HCC). Emerging studies revealed key promoters of aerobic glycolysis, however, little is known about its negative regulators in HCC. In this study, an integrative analysis identifies a repertoire of differentially expressed genes ( DNASE1L3 , SLC22A1 , ACE2 , CES3 , CCL14 , GYS2 , ADH4 , and CFHR3 ) that are inversely associated with the glycolytic phenotype in HCC. ACE2, a member of the rennin-angiotensin system, is revealed to be downregulated in HCC and predicts a poor prognosis. ACE2 overexpression significantly inhibits the glycolytic flux as evidenced by reduced glucose uptake, lactate release, extracellular acidification rate, and the expression of glycolytic genes. Opposite results are noticed in loss-of-function studies. Mechanistically, ACE2 metabolizes Ang II to Ang-(1-7), which activates Mas receptor and leads to the phosphorylation of Src homology 2-containing inositol phosphatase 2 (SHP-2). SHP2 activation further blocks reactive oxygen species (ROS)-HIF1α signaling. Addition of Ang-(1-7) or the antioxidant N-acetylcysteine compromises in vivo additive tumor growth and aerobic glycolysis induced by ACE2 knockdown. Moreover, growth advantages afforded by ACE2 knockdown are largely glycolysis-dependent. In clinical settings, a close link between ACE2 expression and HIF1α or the phosphorated level of SHP2 is found. Overexpression of ACE2 significantly retards tumor growth in patient-derived xenograft model. Collectively, our findings suggest that ACE2 is a negative glycolytic regulator, and targeting the ACE2/Ang-(1-7)/Mas receptor/ROS/HIF1α axis may be a promising therapeutic strategy for HCC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Angiogenesis is vital for tumor growth and metastasis. Emerging evidence suggests that metabolic reprogramming in endothelial cells (EC) may affect angiogenesis. Here, we showed that multiple regulators in the fructose metabolism pathway, especially fructose transporter SLC2A5 and fructose-metabolizing enzyme ketohexokinase (KHK), were upregulated in tumor endothelial cells from hepatocellular carcinoma (HCC). In mouse models with hepatoma xenografts or with Myc/sgp53-induced liver cancer, dietary fructose enhanced tumor angiogenesis, tumor growth, and metastasis, which could be attenuated by treatment with an inhibitor of SLC2A5. Furthermore, vessel growth was substantially increased in fructose-containing Matrigel compared with PBS-Matrigel. Inhibiting fructose metabolism in EC cells in vivo using EC-targeted nanoparticles loaded with siRNA against KHK significantly abolished fructose-induced tumor angiogenesis. Fructose treatment promoted the proliferation, migration, and tube formation of ECs and stimulated mitochondrial respiration and ATP production. Elevated fructose metabolism activated AMPK to fuel mitochondrial respiration, resulting in enhanced EC migration. Fructose metabolism was increased under hypoxic conditions as a result of HIF1α-mediated upregulation of multiple genes in the fructose metabolism pathway. These findings highlight the significance of fructose metabolism in ECs for promoting tumor angiogenesis. Restricting fructose intake or targeting fructose metabolism is a potential strategy to reduce angiogenesis and suppress tumor growth., Significance: Fructose metabolism in endothelial cells fuels mitochondrial respiration to stimulate tumor angiogenesis, revealing fructose metabolism as a therapeutic target and fructose restriction as a dietary intervention for treating cancer., (©2023 American Association for Cancer Research.)

Distant metastasis is one of the leading causes of cancer-related mortality of colorectal cancer (CRC). Dysregulation of E3 ubiquitin ligases has been implicated in acting vital roles in multiple cancers. In this study, we found that the E3 ubiquitin ligase, PRPF19 was positively correlated with liver metastasis, and predicted a worse clinical outcome in CRC. However, the biological effects and the underlying molecular mechanisms of PRPF19 in CRC remain elusive thus far. We illustrated that PRPF19 promoted the migration and invasion capability of CRC cells in both gain- and loss- of function assays. Mechanistically, we uncovered that myosin light chain 9 (MYL9) was the downstream substrate of PRPF19. PRPF19 enhanced the stability of MYL9 via K63-linked ubiquitination, and promoted the migration and invasion capability of CRC cells in an MYL9-mediated manner. Furthermore, the Src-YAP1 cascade was identified as the downstream effector mechanism by which the PRPF19/MYL9 axis promoted metastasis in CRC. Taken together, our findings highlighted that the PRPF19/MYL9 axis served as a novel mechanism in CRC metastasis, which provided an attractive therapeutic strategy for CRC treatment., (© 2023. The Author(s).)

Objective: To assess and compare the diagnostic performance of gallium-68-labelled fibroblast activation protein inhibitor ([ 68 Ga]FAPI-04) and fluorine-18 fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) in gastrointestinal cancer., Methods: Fifty-one patients who underwent both [ 18 F]FDG and [ 68 Ga]FAPI-04 PET/CT for initial staging or restaging were enrolled. Histopathological findings, typical radiological appearances, and clinical imaging follow-up were used as the reference standard. The diagnostic performance of the two tracers was calculated and compared. The maximum standardised uptake value (SUVmax), mean SUV (SUVmean), tumour-to-mediastinal blood pool ratio (TBR), and tumour-to-liver ratio (TLR) of primary and metastatic lesions were measured and compared between two imaging modalities., Results: In patient-based analysis, [ 68 Ga]FAPI-04 showed much better diagnostic sensitivity than [ 18 F]FDG in detecting primary tumour (94.44% [17/18] vs. 61.11% [11/18]), postoperative recurrence and metastases (95.65% [22/23] vs. 69.57% [16/23]), and peritoneal carcinomatosis (100% [28/28] vs. 60.71% [17/28]) (all p < 0.05). In lesion-based analysis, [ 68 Ga]FAPI-04 showed higher sensitivity than [ 18 F]FDG for detecting lymph node metastases. In peritoneal carcinomatosis, the median SUVmax (12.12 vs. 7.18) and SUVmean (6.84 vs. 4.11) with [ 68 Ga]FAPI-04 were significantly higher than those with [ 18 F]FDG (all p < 0.005). The TBR and TLR of [ 68 Ga]FAPI-04 were significantly higher than those of [ 18 F]FDG for detecting primary tumour, lymph node, liver, and peritoneal metastases (all p < 0.005). Therapeutic management changed in 13 patients according to [ 68 Ga]FAPI-04 PET/CT compared with conventional imaging., Conclusions: [ 68 Ga]FAPI-04 is superior to [ 18 F]FDG PET/CT for detecting primary tumour, postoperative recurrence and metastasis, and peritoneal carcinomatosis in gastrointestinal cancer., Key Points: • [ 68 Ga]FAPI-04 PET/CT showed significantly higher sensitivity than [ 18 F]FDG PET/CT in the detection of primary tumour and postoperative recurrence and metastasis in patients with gastrointestinal carcinoma. • [ 68 Ga]FAPI-04 PET/CT had obvious advantages over [ 18 F]FDG PET/CT in the detection of peritoneal carcinomatosis from gastrointestinal carcinoma with a much higher FAPI uptake value, TBR, and TLR. • Although the median SUVmax and SUVmean of [ 68 Ga]FAPI-04 were similar to those of [ 18 F]FDG for the primary tumour, lymph node metastases, and liver metastases in gastrointestinal carcinoma, the TBR and TLR of the SUVmax and SUVmean were significantly higher on [ 68 Ga]FAPI-04 PET/CT, causing the lesions to be displayed more clearly., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Aims: Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance., Methods: By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma., Results: FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients., Conclusion: Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance., Competing Interests: Conflict of interest disclosure The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic hepatitis B (CHB) virus infection is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) immune escape is regulated by the exhaustion of virus-specific CD8 + T cells, which is associated with abnormal expression of negative regulatory molecule CD244. However, the underlying mechanisms are unclear. To investigate the important roles of non-coding RNAs play in CD244 regulating HBV immune escape, we performed microarray analysis to determine the differential expression profiles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in patients with CHB and patients with spontaneous clearance of HBV. Competing endogenous RNA (ceRNA) was analyzed by bioinformatics methods and confirmed by the dual-luciferase reporter assay. Furthermore, gene silencing and overexpression experiments were used to further identify the roles of lncRNA and miRNA in HBV immune escape through CD244 regulation. The results showed that the expression of CD244 on the surface of CD8 + T cells was significantly increased in CHB patients and in the co-culture system of T cells and HBV-infected HepAD38 cells, which was accompanied by the reduction of miR-330-3p and the elevation of lnc-AIFM2-1. The down-regulated miR-330-3p induced the apoptosis of T cells by lifting the inhibition of CD244, which was reversed by miR-330-3p mimic or CD244-siRNA. Lnc-AIFM2-1 promotes the accumulation of CD244, which is mediated by decreased miR-330-3p, and then reduced the clearance ability of CD8 + T cells to HBV through regulated CD244 expression. And the injury in the ability of CD8 + T cells to clear HBV can be reversed by lnc-AIFM2-1-siRNA, miR-330-3p mimic, or CD244-siRNA. Collectively, our findings indicate that lnc-AIFM2-1 on CD244 by acting as a ceRNA of miR-330-3p contributes to HBV immune escape, which may provide novel insights into the roles of interaction networks among lncRNA, miRNA, and mRNA in HBV immune escape, highlighting potential applications of lnc-AIFM2-1 and CD244 for diagnosis and treatment in CHB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xie, Wang, Zhang, Zhu, Jiang, Shi, Si and Chen.)

Small extracellular vesicles (sEVs) derived from tissue can reflect the functional status of the source cells and the characteristics of the tissue's interstitial space. The efficient enrichment of these sEVs is an important prerequisite to the study of their biological function and a key to the development of clinical detection techniques and therapeutic carrier technology. It is difficult to isolate sEVs from tissue because they are usually heavily contaminated. This study provides a method for the rapid enrichment of high-quality sEVs from liver cancer tissue. The method involves a four-step process: the incubation of digestive enzymes (collagenase D and DNase Ι) with tissue, filtration through a 70 µm cell strainer, differential ultracentrifugation, and filtration through a 0.22 µm membrane filter. Owing to the optimization of the differential ultracentrifugation step and the addition of a filtration step, the purity of the sEVs obtained by this method is higher than that achieved by classic differential ultracentrifugation. It provides an important methodology and supporting data for the study of tissue-derived sEVs.

Objectives: The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the causality of the associations of plasma phospholipid AA with NALFD, cirrhosis, and liver cancer using Mendelian randomization analysis., Methods: Nine independent single-nucleotide polymorphisms associated with plasma phospholipid AA at the genome-wide significance were used as instrumental variables. Summary-level data for three outcomes were obtained from 1) a genome-wide association study for NAFLD, 2) the UK Biobank study, and 3) the FinnGen study. The sensitivity analysis excluding the pleiotropic variant rs174547 in the FADS1 gene was performed. Estimates from different sources were combined using the fixed-effects meta-analysis method., Results: Per standard deviation increase in AA levels, the combined odds ratio was 1.06 (95% confidence interval, 1.02-1.11; P = 0.008) for NAFLD, 1.05 (95% confidence interval, 1.01-1.09; P = 0.009) for cirrhosis, and 0.99 (95% confidence interval, 0.94-1.05; P = 0.765) for liver cancer. The associations remained stable in the sensitivity analysis excluding rs174547., Conclusions: This study suggests potential causal associations of high levels of plasma phospholipid AA with the risk of NAFLD and cirrhosis., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To establish a risk score integrating preoperative gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and clinical parameters to predict recurrence after hepatectomy for patients with hepatocellular carcinoma (HCC) and to compare its performance with that of a postoperative score and four clinical staging systems., Methods: Consecutive patients with surgically confirmed HCC who underwent preoperative EOB-MRI between July 2015 and November 2020 were retrospectively included. Two recurrence risk scores, one incorporating only preoperative variables and the other incorporating all preoperative and postoperative variables, were constructed via Cox regression models., Results: A total of 214 patients (derivation set, n = 150; test set, n = 64) were included. Six preoperative variables, namely tumor number, infiltrative appearance, corona enhancement, alpha-fetoprotein (AFP) level, aspartate aminotransferase (AST) level, and sex, were independently associated with recurrence. After adding postoperative features, microvascular invasion and tumor differentiation were additional significant variables in lieu of corona enhancement and AFP level. Using the above variables, the preoperative score achieved a C-index of 0.741 on the test set, which was comparable with that of the postoperative score (0.729; p = 0.235). The preoperative score yielded a larger time-dependent area under the receiver operating characteristic curve at 1 year (0.844) than three existing systems (0.734-0.742; p < 0.05 for all). Furthermore, the preoperative score stratified patients into two prognostically distinct risk strata with low and high risks of recurrence (p < 0.001)., Conclusion: The preoperative score integrating EOB-MRI features, AFP and AST levels, and sex improves recurrence risk estimation in HCC., Key Points: • The preoperative risk score incorporating three EOB-MRI findings, AFP and AST levels, and sex achieved comparable performance with that of the postoperative score for predicting recurrence after hepatectomy in patients with HCC. • Two risk strata with low and high risks of recurrence were obtained based on the preoperative score. • The preoperative score may help tailor pretreatment decision-making and facilitate candidate selection for adjuvant clinical trials., (© 2022. The Author(s).)

Background: Presurgical assessment of hepatocellular carcinoma (HCC) aggressiveness can benefit patients' treatment options and prognosis., Purpose: To develop an artificial intelligence (AI) tool, namely, LiSNet, in the task of scoring and interpreting HCC aggressiveness with computed tomography (CT) imaging., Methods: A total of 358 patients with HCC undergoing curative liver resection were retrospectively included. Three subspecialists were recruited to pixel-wise annotate and grade tumor aggressiveness based on CT imaging. LiSNet was trained and validated in 193 and 61 patients with a deep neural network to emulate the diagnostic acumen of subspecialists for staging HCC. The test set comprised 104 independent patients. We subsequently compared LiSNet with an experience-based binary diagnosis scheme and human-AI partnership that combined binary diagnosis and LiSNet for assessing tumor aggressiveness. We also assessed the efficiency of LiSNet for predicting survival outcomes., Results: At the pixel-wise level, the agreement rate of LiSNet with subspecialists was 0.658 (95% confidence interval [CI]: 0.490-0.779), 0.595 (95% CI: 0.406-0.734), and 0.369 (95% CI: 0.134-0.566), for scoring HCC aggressiveness grades I, II, and III, respectively. Additionally, LiSNet was comparable to subspecialists for predicting histopathological microvascular invasion (area under the curve: LiSNet: 0.668 [95% CI: 0.559-0.776] versus subspecialists: 0.699 [95% CI: 0.591-0.806], p > 0.05). In a human-AI partnered diagnosis, combining LiSNet and experience-based binary diagnosis can achieve the best predictive ability for microvascular invasion (area under the curve: 0.705 [95% CI: 0.589-0.820]). Furthermore, LiSNet was able to indicate overall survival after surgery., Conclusion: The designed LiSNet tool warrants evaluation as an alternative tool for radiologists to conduct automatic staging of HCC aggressiveness at the pixel-wise level with CT imaging. Its prognostic value might benefit patients' treatment options and survival prediction., (© 2022 American Association of Physicists in Medicine.)

Background: Despite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis, other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma (HCC) remain obscure. Here, we explored the interplay between Piezo1 and integrin β1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness-induced angiogenesis., Methods: The role of Piezo1 in matrix stiffness-induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background, and its clinical significance was evaluated in human HCC tissues. Matrix stiffness-mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin (FN)-coated cell culture system with different stiffness, Western blotting and Ca 2+ probe. The effects of shPiezo1-conditioned medium (CM) on angiogenesis were examined by tube formation assay, wound healing assay and angiogenesis array. The underlying mechanism by which Piezo1 participated in matrix stiffness-induced angiogenesis was analyzed by microRNA quantitative real-time polymerase chain reaction (qRT-PCR), matrix stiffness measurement, dual-luciferase reporter assay, ubiquitination assay and co-immunoprecipitation., Results: Increased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels, and high expression of Piezo1 indicated an unfavorable prognosis. High matrix stiffness also noticeably enhanced the activation level of Piezo1, similar to its expression level. Piezo1 knockdown significantly suppressed tumor growth, angiogenesis, and lung metastasis of HCC rat models with high liver stiffness background. shPiezo1-CM from HCC cells attenuated tube formation and migration abilities of vascular endothelial cells remarkably, and analysis of differentially expressed pro-angiogenic factors revealed that Piezo1 promoted the expression and secretion of vascular endothelial growth factor (VEGF), CXC chemokine ligand 16 (CXCL16) and insulin-like growth factor binding protein 2 (IGFBP2). Matrix stiffness-caused Piezo1 upregulation/activation restrained hypoxia inducible factor-1α (HIF-1α) ubiquitination, subsequently enhanced the expression of downstream pro-angiogenic factors to accelerate HCC angiogenesis. Besides, collagen 1 (COL1)-reinforced tissue stiffening resulted in more expression of Piezo1 via miR-625-5p., Conclusions: This study unravels a new mechanism by which the integrin β1/Piezo1 activation/Ca 2+ influx/HIF-1α ubiquitination/VEGF, CXCL16 and IGFBP2 pathway participates in matrix stiffness-driven HCC angiogenesis. Simultaneously, a positive feedback regulation loop as stiff matrix/integrin β1/miR-625-5p/Piezo1 and COL1/stiffer matrix mediates matrix stiffness-caused Piezo1 upregulation., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Hepatocellular carcinoma (HCC) is the fourth most lethal malignancy with an increasing incidence worldwide. Management of HCC has followed several clinical staging systems that rely on tumour morphologic characteristics and clinical variables. However, these algorithms are unlikely to profile the full landscape of tumour aggressiveness and allow accurate prognosis stratification. Noninvasive imaging biomarkers on computed tomography (CT) or magnetic resonance imaging (MRI) exhibit a promising prospect to refine the prognostication of HCC. The Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive system for standardizing the terminology, techniques, interpretation, reporting and data collection of liver imaging. At present, it has been widely accepted as an effective diagnostic system for HCC in at-risk patients. Emerging data have provided new insights into the potential of CT/MRI LI-RADS in HCC prognostication, which may help refine the prognostic paradigm of HCC that promises to direct individualized management and improve patient outcomes. Therefore, this review aims to summarize several prognostic imaging features at CT/MRI for patients with HCC; the available evidence regarding the use of LI-RDAS for evaluation of tumour biology and clinical outcomes, pitfalls of current literature, and future directions for LI-RADS in the management of HCC., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

CTNNB1 , encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

Purpose: Contrast-enhanced ultrasound (CEUS) and gadoxetate disodium-enhanced MRI (EOB-MRI) may synergize in profiling hepatocellular carcinoma (HCC) aggressiveness considering distinct imaging traits. This study aimed to intra-individually compare CEUS and EOB-MRI with Liver Imaging Reporting and Data System (LI-RADS) in assessing HCC aggressiveness., Method: From January 2015 to November 2020, consecutive at-risk patients with surgically-confirmed HCC who underwent both preoperative CEUS and EOB-MRI examinations were retrospectively enrolled. Image analyses were conducted independently by two masked radiologists for CEUS and EOB-MRI, respectively. The diagnostic performance of each modality for macrovascular invasion against pathology was evaluated and compared with the McNemar's test, while Edmondson-Steiner grade and the presence of microvascular invasion (MVI) were compared between patients with and without LR-M features on each modality., Results: A total of 140 patients (mean age, 51.9 years ± 11.0; 116 men) were included. Inter-modality agreement was poor (κ = -0.087 ∼ 0.139) for major LI-RADS features and moderate (κ = 0.449) for overall LI-RADS categorization, and LR-TIV and LR-M were the top sources of inter-modality variations. Although CEUS demonstrated significantly higher specificity for diagnosing macrovascular invasion (96% vs. 89%, P =.02), LR-M features on EOB-MRI were more effective in identifying higher Edmondson-Steiner grades (P =.01) and MVI (P =.02)., Conclusions: Marked discrepancies were found between CEUS and EOB-MRI in evaluating LI-RADS features and categories. Whereas CEUS showed superior diagnostic specificity for macrovascular invasion, LR-M features on EOB-MRI provided more information regarding tumor grade and MVI status in HCC patients., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Matrix stiffness promotes hepatocellular carcinoma (HCC) metastasis. This study examined the contribution of lipid metabolic reprogramming to matrix stiffness-induced HCC metastasis. HCC cells were cultured on mechanically tunable polyacrylamide gels and subjected to lipidomic analysis. The key enzyme that responded to matrix stiffness and regulated lipid metabolism was identified. The comparative lipidomic screening revealed that stearoyl-CoA desaturase 1 (SCD1) is a mechanoresponsive enzyme that reprogrammed HCC cell lipid metabolism. The genetic and pharmacological inhibition of SCD1 expression/activity altered the cellular lipid composition, which in turn impaired plasma membrane fluidity and inhibited in vitro invasive motility of HCC cells in response to high matrix stiffness. Knockdown of SCD1 suppressed HCC invasion and metastasis in vivo. Conversely, the overexpression of SCD1 or exogenous administration of its product oleic acid augmented plasma membrane fluidity and rescued in vitro invasive migration in HCC cells cultured on soft substrates, mimicking the effects imposed by high matrix stiffness. In human HCC tissues, collagen content, a marker of increasing matrix stiffness, and increased expression of SCD1 together predicted poor survival of HCC patients. An SCD1-dependent mechanoresponsive pathway that responds to increasing matrix stiffness in the tumor microenvironment promotes HCC invasion and metastasis through lipid metabolic reprogramming., Competing Interests: Conflicts of interest The authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background & aims: Finding a way to comprehensively integrate the presence and grade of clinically significant portal hypertension, amount of preserved liver function and extent of hepatectomy into the guidelines for choosing appropriate candidates to hepatectomy remained challenging. This study sheds light on these issues to facilitate precise surgical decisions for clinicians. Methods: Independent risk factors associated with grade B/C post-hepatectomy liver failure were identified by stochastic forest algorithm and logistic regression in hepatitis B virus-related hepatocellular carcinoma patients. Results: The artificial neural network model was generated by integrating preoperative pre-ALB, prothrombin time, total bilirubin, AST, indocyanine green retention rate at 15 min, standard future liver remnant volume and clinically significant portal hypertension grade. In addition, stratification of patients into three risk groups emphasized significant distinctions in the risk of grade B/C post-hepatectomy liver failure. Conclusion: The authors' artificial neural network model could provide a reasonable therapeutic option for clinicians to select optimal candidates with clinically significant portal hypertension for hepatectomy and supplement the hepatocellular carcinoma surgical treatment algorithm.

Background: This study aimed to analyze the expression of 8-oxoguanine DNA glycosylase (OGG1) in patients with hepatocellular carcinoma (HCC) and its effect on prognosis by bioinformatics techniques and to determine its possible carcinogenic mechanism through data mining., Methods: The difference in OGG1 expression between healthy people and HCC patients was searched and analyzed by TCGA and GEO databases, and the effect of OGG1 on prognosis was judged by survival analysis. Meanwhile, the possible molecular mechanism of OGG1 in the tumorigenesis and development of HCC was explored by GO analysis, KEGG analysis, immune infiltration analysis, protein-protein interaction network, promoter methylation analysis, and so forth. Quantitative polymerase chain reaction (qPCR) was used to examine the gene expression in 36 pairs of HCC tissues and adjacent tissues., Results: The expression of OGG1 in HCC patients was higher than that in healthy people, and the overexpression of OGG1 might stimulate cell proliferation by increasing the activity of cell cycle-related proteins., Conclusion: The alteration of OGG1 was significantly correlated with the tumorigenesis and development of HCC. OGG1 is expected to be a new biomarker for evaluating the prognosis of HCC and a new target for the treatment of HCC., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Objective: To evaluate the efficacy and outcome of transarterial embolization (TAE) plus octreotide long-acting repeatable (LAR) on patients with low-to-intermediate neuroendocrine tumor liver metastases (NETLM)., Methods: One hundred and sixteen patients with G1/G2 NETLM treated with TAE plus octreotide LAR at the First Affiliated Hospital, Sun Yat-sen University between January 12, 2016 and September 24, 2020 were reviewed. Radiological response was evaluated according to response evaluation criterion in solid tumor version 1.1. Overall progression-free survival (PFS) was assessed. Intrahepatic and extrahepatic PFS were evaluated in the whole cohort and in patients with the extrahepatic disease (EHD), respectively. Factors affecting treatment response and overall PFS were analyzed using the logistic regression model and Cox proportional hazard model. Adverse events were recorded and evaluated according to Common Terminology Criteria for Adverse Events 5.0., Results: The median overall PFS of the whole cohort was 13.6 months. For the patients with EHD, the median intrahepatic PFS and extrahepatic PFS were 13.6 and 26.1 months, respectively. The median overall PFS of patients with hepatic tumor burden (HTB) <10%, 10%-25%, 25%-50%, and >50% were 25.2, 13.6, 11.2, and 12.3 months, respectively. Ki67 >10%, HTB >50%, and bone metastasis were independently associated with overall PFS. The objective response rate was 78.4%. In patients with HTB 25%-50% and >50%, responders (complete response or partial response) had significant prolonged PFS compared with nonresponders (stable disease or progression disease). Ki67 >10%, bone metastasis, and clear tumor margin were independently associated with response to TAE. The most frequent adverse events that occurred after TAE were postembolization syndrome, and no treatment-associated death occurred during the perioperative period., Conclusion: Transarterial embolization plus octreotide LAR can significantly prolong the PFS of neuroendocrine tumor liver metastases, especially with high HTB over 50%. Selected patients with HTB >25% (ki67 ≤10%, absence of bone metastasis, clear tumor margin) could derive prognostic advantage from the combined treatment., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Simultaneous sensitive and cost-effective detection of multiple tumor markers has shown great potential for cancer diagnostics. Herein, we reported a simple enzyme-free parallel catalytic hairpin assembly (CHA) amplification strategy with N -methyl mesoporphyrin IX (NMM) and quantum dots (QDs) as signal reporters for the homogeneous fluorescent simultaneous detection of alpha-fetoprotein (AFP) and glypican-3 (GPC3). Upon selective binding, the released single-stranded DNA (ssDNA) from the two-aptamer double-stranded DNA (dsDNA) probes triggers CHA amplification, further releasing the G-quadruplex sequence and Ag + from the C-Ag + -C structures at the same time. Then, NMM and CdTe QDs selectively recognize G-quadruplex and Ag + , respectively. Under optimized conditions, limits of detections (LODs) as low as 3 fg/mL for AFP and 0.25 fg/mL for GPC3 were achieved using fluorescence readout. Using color- and distance-based visual readouts, an LOD of 1 fg/mL for GPC3 was reached. This method was applied to quantitatively analyze AFP and GPC3 in 41 clinical serum samples of hepatocellular carcinoma (HCC) patients. The quantitative test results for AFP and GPC3 were consistent with those obtained using the electrochemiluminescence immunoassay (ECL-IA) clinical kit and correlated with radiological and pathological findings. The results of clinical tests demonstrated the potential of GPC3 as a tumor biomarker, and we propose a cut-off value of 2 ng/mL GPC3 for HCC.