Development and validation of nomograms for predicting prognosis in patients with solitary HCC: A TRIPOD-Compliant study.

Objective: To develop and validate nomograms for predicting the OS and CSS of patients with Solitary Hepatocellular Carcinoma (HCC). Methods: Using the TRIPOD guidelines, this study identified 5206 patients in the Surveillance, Epidemiology, and End Results (SEER) 17 registry database. All patients were randomly divided in a ratio of 7:3 into a training cohort (n = 3646) and a validation cohort (n = 1560), and the Chinese independent cohort (n = 307) constituted the external validation group. The prognosis-related risk factors were selected using univariate Cox regression analysis, and the independent prognostic factors of OS and CSS were identified using the Lasso-Cox regression model. The nomograms for predicting the OS and CSS of the patients were constructed based on the identified prognostic factors. Their prediction ability was evaluated using the concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve in both the training and validation cohorts. Results: We identified factors that predict OS and CSS and constructed two nomograms based on the data. The ROC analysis, C-index analysis, and calibration analysis indicated that the two nomograms performed well over the 1, 3, and 5-year OS and CSS periods in both the training and validation cohorts. Additionally, these results were confirmed in the external validation group. Decision curve analysis (DCA) demonstrated that the two nomograms were clinically valuable and superior to the TNM stage system. Conclusion: We established and validated nomograms to predict 1,3, and 5-year OS and CSS in solitary HCC patients, and our results may also be helpful for clinical decision-making.

Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma.

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

Selective internal radiation therapy with yttrium-90 resin microspheres followed by anatomical hepatectomy: A potential curative strategy in advanced hepatocellular carcinoma.

About 80% of hepatocellular carcinoma (HCC) patients are in advanced stages and ineligible for curative surgery. Palliative treatments just maintained limited survival, thus an effective downstaging therapy is badly needed. Here we report an initially unresectable patient who underwent radical hepatectomy after successful downstaging with selective internal radiation therapy (SIRT). A 34-year-old man was diagnosed with China Liver Cancer Staging (CNLC) IIIa HCC. Due to insufficient future liver remnant and vascular involvement, the patient was suggested to be unresectable. SIRT with yttrium-90 resin microspheres was given. At three months post-SIRT, a complete response was achieved. The tumor was downstaged to CNLC Ia stage. The patient underwent anatomical hepatectomy 5 months after SIRT. Histopathological examination of the resected specimen showed 4% viable tumor cells inside a necrotic mass. To our knowledge, this is the first case who underwent SIRT with yttrium-90 resin microspheres in China mainland. The success of the downstaging in this case renders a possible cure to be achieved in an initially unresectable patient. In addition, the nearly complete tumor necrosis in the resected specimen indicates a good prognosis post-surgery. This is the first case who underwent SIRT with yttrium-90 resin microspheres in China mainland. SIRT followed by anatomical hepatectomy is a potentially curative strategy for unresectable HCC, which deserves a confirmative trial in the future.

Manipulating HGF signaling reshapes the cirrhotic liver niche and fills a therapeutic gap in regeneration mediated by transplanted stem cells.

Long-term stem cell survival in the cirrhotic liver niche to maintain therapeutic efficacy has not been achieved. In a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis animal model, we previously showed that liver-resident stem/progenitor cells (MLpvNG2+ cells) or immune cells have improved survival in the fibrotic liver environment but died via apoptosis in the cirrhotic liver environment, and increased levels of hepatocyte growth factor (HGF) mediated this cell death. We tested the hypothesis that inhibiting HGF signaling during the cirrhotic phase could keep the cells alive. We used adeno-associated virus (AAV) vectors designed to silence the c-Met (HGF-only receptor) gene or a neutralizing antibody (anti-cMet-Ab) to block the c-Met protein in the DEN-induced liver cirrhosis mouse model transplanted with MLpvNG2+ cells between weeks 6 and 7 after DEN administration, which is the junction of liver fibrosis and cirrhosis at the site where most intrahepatic stem cells move toward apoptosis. After 4 weeks of treatment, the transplanted MLpvNG2+ cells survived better in c-Met-deficient mice than in wild-type mice, and cell activity was similar to that of the mice that received MLpvNG2+ cells at 5 weeks after DEN administration (liver fibrosis phase when most of these cells proliferated). Mechanistically, a lack of c-Met signaling remodeled the cirrhotic environment, which favored transplanted MLpvNG2+ cell expansion to differentiation into mature hepatocytes and initiate endogenous regeneration by promoting mature host hepatocyte generation and mediating functional improvements. Therapeutically, c-Met-mediated regeneration can be mimicked by anti-cMet-Ab to interfere functions, which is a potential drug for cell-based treatment of liver fibrosis/cirrhosis.

Prognoses of Patients Treated With Surgical Therapy Versus Continuation of Local-Plus-Systemic Therapy Following Successful Down-Staging of Intermediate-Advanced Hepatocellular Carcinoma: A Multicenter Real-World Study.

BACKGROUND: The difference in the prognoses between treatment with surgical therapy and continuation of local-plus-systemic therapy following successful down-staging of intermediate-advanced hepatocellular carcinoma (HCC) remains unclear. METHODS: Data of 405 patients with intermediate-advanced HCC treated at 30 hospitals across China from January 2017 to July 2022 were retrospectively reviewed. All patients received local-plus-systemic therapy and were divided into the surgical (n = 100) and nonsurgical groups (n = 305) according to whether they received surgical therapy. The differences between long-term prognoses of the 2 groups were compared. Subgroup analysis was performed in 173 HCC patients who met the criteria for surgical resection following down-staging. RESULTS: Multivariable analysis of all patients showed that surgical therapy, hazard ratio (HR): 0.289, 95% confidence interval, CI, 0.136-0.613) was a protective factor for overall survival (OS), but not for event-free survival (EFS). Multivariable analysis of 173 intermediate-advanced HCC patients who met the criteria for surgical resection after conversion therapy showed that surgical therapy (HR: 0.282, 95% CI, 0.121-0.655) was a protective factor for OS, but not for EFS. Similar results were obtained after propensity score matching. For patients with Barcelona Clinic Liver Cancer stage B (HR: 0.171, 95% CI, 0.039-0.751) and C (HR: 0.269, 95% CI, 0.085-0.854), surgical therapy was also a protective factor for OS. CONCLUSIONS: Overall, for patients with intermediate-advanced HCC who underwent local-plus-systemic therapies, surgical therapy is a protective factor for long-term prognosis and can prolong OS, and for those who met the surgical resection criteria after conversion therapy, surgical therapy is recommended.

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance.

Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.

A radiomics model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging for predicting post-hepatectomy liver failure in patients with hepatocellular carcinoma.

Background: Post-hepatectomy liver failure (PHLF) is a fatal complication after liver resection in patients with hepatocellular carcinoma (HCC). It is of clinical importance to estimate the risk of PHLF preoperatively. Aims: This study aimed to develop and validate a prediction model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging to estimate the risk of PHLF in patients with HCC. Methods: A total of 276 patients were retrospectively included and randomly divided into training and test cohorts (194:82). Clinicopathological variables were assessed to identify significant indicators for PHLF prediction. Radiomics features were extracted from the normal liver parenchyma at the hepatobiliary phase and the reproducible, robust and non-redundant ones were filtered for modeling. Prediction models were developed using clinicopathological variables (Clin-model), radiomics features (Rad-model), and their combination. Results: The PHLF incidence rate was 24% in the whole cohort. The combined model, consisting of albumin-bilirubin (ALBI) score, indocyanine green retention test at 15 min (ICG-R15), and Rad-score (derived from 16 radiomics features) outperformed the Clin-model and the Rad-model. It yielded an area under the receiver operating characteristic curve (AUC) of 0.84 (95% confidence interval (CI): 0.77-0.90) in the training cohort and 0.82 (95% CI: 0.72-0.91) in the test cohort. The model demonstrated a good consistency by the Hosmer-Lemeshow test and the calibration curve. The combined model was visualized as a nomogram for estimating individual risk of PHLF. Conclusion: A model combining clinicopathological risk factors and radiomics signature can be applied to identify patients with high risk of PHLF and serve as a decision aid when planning surgery treatment in patients with HCC.

FBXW10-S6K1 promotes ANXA2 polyubiquitination and KRAS activation to drive hepatocellular carcinoma development in males.

The incidence rate of human hepatocellular carcinoma (HCC) is approximately three times higher in males than in females. A better understanding of the mechanisms underlying HCC development in males could lead to more effective therapies for HCC. Our previous study found that FBXW10 played a critical role in promoting HCC development in male mice and patients, but the mechanism remains unknown. Here, we found that FBXW10 promoted K63-linked ANXA2 polyubiquitination and activation in HCC tissues from males, and this process was required for S6K1-mediated phosphorylation. Activated ANXA2 further translocated from the cytoplasm to the cell membrane to bind KRAS and then activated the MEK/ERK pathway, leading to HCC proliferation and lung metastasis. Interfering with ANXA2 significantly blocked FBXW10-driven HCC growth and lung metastasis in vitro and in vivo. Notably, membrane ANXA2 was upregulated and positively correlated with FBXW10 expression in male HCC patients. These findings offer new insights into the regulation and function of FBXW10 signaling in HCC tumorigenesis and metastasis and suggest that the FBXW10-S6K1-ANXA2-KRAS-ERK axis may serve as a potential biomarker and therapeutic target in male HCC patients with high FBXW10 expression.

Unsupervised Machine Learning of MRI Radiomics Features Identifies Two Distinct Subgroups with Different Liver Function Reserve and Risks of Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

OBJECTIVE: To identify subgroups of patients with hepatocellular carcinoma (HCC) with different liver function reserves using an unsupervised machine-learning approach on the radiomics features from preoperative gadoxetic-acid-enhanced MRIs and to evaluate their association with the risk of post-hepatectomy liver failure (PHLF). METHODS: Clinical data from 276 consecutive HCC patients who underwent liver resections between January 2017 and March 2019 were retrospectively collected. Radiomics features were extracted from the non-tumorous liver tissue at the gadoxetic-acid-enhanced hepatobiliary phase MRI. The reproducible and non-redundant features were selected for consensus clustering analysis to detect distinct subgroups. After that, clinical variables were compared between the identified subgroups to evaluate the clustering efficacy. The liver function reserve of the subgroups was compared and the correlations between the subgroups and PHLF, postoperative complications, and length of hospital stay were evaluated. RESULTS: A total of 107 radiomics features were extracted and 37 were selected for unsupervised clustering analysis, which identified two distinct subgroups (138 patients in each subgroup). Compared with subgroup 1, subgroup 2 had significantly more patients with older age, albumin-bilirubin grades 2 and 3, a higher indocyanine green retention rate, and a lower indocyanine green plasma disappearance rate (all p < 0.05). Subgroup 2 was also associated with a higher risk of PHLF, postoperative complications, and longer hospital stays (>18 days) than that of subgroup 1, with an odds ratio of 2.83 (95% CI: 1.58-5.23), 2.41(95% CI: 1.15-5.35), and 2.14 (95% CI: 1.32-3.47), respectively. The odds ratio of our method was similar to the albumin-bilirubin grade for postoperative complications and length of hospital stay (2.41 vs. 2.29 and 2.14 vs. 2.16, respectively), but was inferior for PHLF (2.83 vs. 4.55). CONCLUSIONS: Based on the radiomics features of gadoxetic-acid-enhanced MRI, unsupervised clustering analysis identified two distinct subgroups with different liver function reserves and risks of PHLF in HCC patients. Future studies are required to validate our findings.

Development and External Validation of a Radiomics Model Derived from Preoperative Gadoxetic Acid-Enhanced MRI for Predicting Histopathologic Grade of Hepatocellular Carcinoma.

Histopathologic grade of hepatocellular carcinoma (HCC) is an important predictor of early recurrence and poor prognosis after curative treatments. This study aims to develop a radiomics model based on preoperative gadoxetic acid-enhanced MRI for predicting HCC histopathologic grade and to validate its predictive performance in an independent external cohort. Clinical and imaging data of 403 consecutive HCC patients were retrospectively collected from two hospitals (265 and 138, respectively). Patients were categorized into poorly differentiated HCC and non-poorly differentiated HCC groups. A total of 851 radiomics features were extracted from the segmented tumor at the hepatobiliary phase images. Three classifiers, logistic regression (LR), support vector machine, and Adaboost were adopted for modeling. The areas under the curve of the three models were 0.70, 0.67, and 0.61, respectively, in the external test cohort. Alpha-fetoprotein (AFP) was the only significant clinicopathological variable associated with HCC grading (odds ratio: 2.75). When combining AFP, the LR+AFP model showed the best performance, with an AUC of 0.71 (95%CI: 0.59-0.82) in the external test cohort. A radiomics model based on gadoxetic acid-enhanced MRI was constructed in this study to discriminate HCC with different histopathologic grades. Its good performance indicates a promise in the preoperative prediction of HCC differentiation levels.

Exosomes derived from human adipose-derived stem cells alleviate hepatic ischemia-reperfusion (I/R) injury through the miR-183/ALOX5 axis.

Ischemia-reperfusion (I/R) injury is a crucial factor causing liver injury in the clinic. Recent research has confirmed that human adipose-derived stem cells (ADSCs) can differentiate into functional hepatocytes. However, the mechanism of the effects of ADSCs in the treatment of liver injury remains unclear. The characteristics of ADSCs were first identified, and exosome-derived ADSCs were isolated and characterized. The function and mechanism of action of miR-183 and arachidonate 5-lipoxygenase (ALOX5) were investigated by functional experiments in HL-7702 cells with I/R injury and in I/R rats. Our data disclosed that exosome release from ADSCs induced proliferation and inhibited apoptosis in HL-7702 cells with I/R injury. The effect of miR-183 was similar to that of exosomes derived from ADSCs. In addition, ALOX5, as a target gene of miR-183, was involved in the related functions of miR-183. Moreover, in vivo experiments confirmed that miR-183 and exosomes from ADSCs could improve liver injury in rats and inhibit the MAPK and NF-κB pathways. All of these findings demonstrate that exosomes derived from ADSCs have a significant protective effect on hepatic I/R injury by regulating the miR-183/ALOX5 axis, which might provide a therapeutic strategy for liver injury.

Degradation of helicase-like transcription factor (HLTF) by ß-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis.

Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumour suppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, we observed that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with the survival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated ß-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR) activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked ß-TrCP overexpression- or HLTF knockdown-mediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlated with elevated expression of ß-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCC cell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by ß-TrCP, indicating that the ß-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potential therapeutic strategy for HCC patients by targeting the ß-TrCP/HLTF/p62/mTOR axis.

Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8+ T cells in normal and cirrhotic livers.

Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis, which potentially facilitates progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptosis through its only receptor, c-Met. In addition to binding with HGF, c-Met also binds to Fas to form a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunostaining, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we found that HGF secretion was significantly higher at 10 weeks post-DEN, the liver cirrhotic phase (LCP), than at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, differences in CD8+ T cell proliferation and apoptosis were noted between the two phases. Interestingly, staining and TUNEL assays revealed lower smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cells (HSCs), in the LFP group than in the LCP group, which suggested a beneficial correlation among HGF, CD8+ T cells and HSCs in improving the fibrotic load during damaged liver repair. In cultures, when met different concentrations of recombinant HGF (rHGF), phytohemagglutinin (PHA)-stimulated naive mouse splenic CD8+ T cells (pn-msCD8+ T cells) responded differently; as increases in rHGF increased were associated with decreases in the clonal numbers of pn-msCD8+ T cells, and when the rHGF dose was greater than 200 ng/mL, the clonal numbers significantly decreased. In the presence of 400 ng/mL rHGF, the death-inducing signaling complex (DISC) can be directly activated in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), as indicated by recruitment of FADD and caspase-8 because DISC forms via the recruitment of FADD and caspase-8, among others. These findings suggest that Fas-mediated apoptosis, may also indicate a regulatory role of HGF signaling in hepatic homeostasis.

Long-term efficacy of no-touch radiofrequency ablation in the treatment of single small hepatocellular carcinoma: A single center long-term follow-up study.

OBJECTIVE: To evaluate the long-term efficacy of no-touch radiofrequency ablation (NT-RFA) for treating single hepatocellular carcinoma (HCC) less than 3 cm. METHODS: A total of 331 patients with HCC less than 3 cm undergoing RFA in Southwest Hospital from 2015 to 2020 were analyzed retrospectively. All patients were divided into NT-RFA group (n = 113) and conventional RFA (C-RFA) group (n = 218). The survival rate, local tumor progression (LTP) and intrahepatic distant recurrence (IDR) of the two groups were calculated and compared. RESULTS: A significant difference was observed in ablation range (p = 0.000) and safety margin (p = 0.000) between the two groups. The 1-, 2-, 3-, 4-and 5-year overall survival (OS) rates in NT-RFA and C-RFA group were 99.12%, 93.73%, 76.18%, 57.00%, 45.17% and 99.08%, 89.91%, 71.26%, 54.28%, 41.77%, respectively. There was no significant difference between the two groups (p = 0.281). The 1-, 2-, 3-, 4-and 5-year recurrence-free survival (RFS) rates in NT-RFA and C-RFA group were 78.51%, 52.59%, 41.02%, 34.36%, 30.92% and 68.81%, 44.95%, 30.88%, 23.73%, 22.88%, respectively. The two groups differed significantly (p = 0.044). The 1-, 3-and 5-year LTP-free survival rates in NT-RFA and C-RFA group were 87.12%, 74.99%, 72.32% and 75.75%, 65.52%, 65.52%, respectively. The two groups also differed significantly (p = 0.024). Furthermore, the RFS rates of D ≤ 2 cm subgroups in NT-RFA and C-RFA groups differed significantly (p = 0.037), while the RFS rates of 2 cm < D ≤ 3 cm subgroups in two groups showed no significant difference (p = 0.578). CONCLUSIONS: The RFS rates of single HCC less than 3 cm treated by NT-RFA was significantly higher than that of C-RFA. Due to a larger ablation range and safety margin, NT-RFA could significantly reduce LTP and improve RFS. Dual-electrode NT-RFA can significantly improve the RFS rate of patients with HCC less than 2 cm, but there is no obvious advantage compared with C-RFA in the treatment of HCC over 2 cm.

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.

Background & Aims: Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC). Mutant Kras could induce aggressive HCCs. Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs. Methods: We generated transgenic mice in which hepatocytic mTOR was hyperactivated through Tsc1 insufficiency with or without oncogenic KrasG12D. Bioinformatics and gain- or loss-of-function studies were used to illustrate the mechanisms underlying oncogenic pathway alterations. Transcriptional profiling was used to identify biomarker for the subtype of HCC. The therapeutic efficacy of targeting mTOR was tested in a liver orthotropic homogeneous murine model. Results: Oncogenic KrasG12D facilitated mTOR activation via the Mek/Erk/ROS axis, leading to HCC tumorigenesis and metastasis. Inhibition of Mek/Erk enhanced the anticancer effect of mTOR inhibitor via reduction of mTOR activity. Paternally expressed 3 (PEG3) was responsible for Kras/Erk- and mTOR-driven HCC. Elevated PEG3 protein interacted with STAT3 and promoted its transcriptional activity, resulting in the upregulation of proliferation- and metastasis-related proteins. Targeting mTOR significantly inhibited these actions in vitro and in vivo. Moreover, in clinical samples, PEG3 was identified as a new poor prognostic marker for HCC patients with Kras/Erk and mTOR hyperactivation. Conclusion: These findings reveal the underlying mechanism of hepatocytic Kras/Erk-driven mTOR activation and its downstream targets (PEG3 and STAT3) in HCC, identify PEG3 as a new prognostic biomarker for HCC with Kras/Erk and mTOR hyperactivation, and provide a potential therapeutic strategy for this subset of HCC patients.

Radiofrequency ablation in the treatment of hepatocellular carcinoma.

OBJECTIVE: The purpose of this article is to discuss the use, comparative efficacy, and research progress of radiofrequency ablation (RFA), alone or in combination with other therapies, for the treatment of hepatocellular carcinoma (HCC). METHOD: To search and summarize the basic and clinical studies of RFA in recent years. RESULTS: RFA is one of the radical treatment methods listed in the guidelines for the diagnosis and treatment of HCC. It has the characteristics of being minimally invasive and safe and can obtain good local tumor control, and it can improve the local immune ability, improve the tumor microenvironment and enhance the efficacy of chemotherapy drugs. It is commonly used for HCC treatment before liver transplantation and combined ALPPS and hepatectomy for HCC. In addition, the technology of RFA is constantly developing. The birth of noninvasive, no-touch RFA technology and equipment and the precise RFA concept have improved the therapeutic effect of RFA. CONCLUSION: RFA has good local tumor control ability, is minimally invasive, is safe and has other beneficial characteristics. It plays an increasingly important role in the comprehensive treatment strategy of HCC. Whether RFA alone or combined with other technologies expands the surgical indications of patients with HCC and provides more benefits for HCC patients needs to be determined.

Guidelines for Diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus in China (2021 Edition).

Portal vein tumor thrombus (PVTT) is very common and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the guideline in 2016 and revised in 2018. Over the past several years, many new evidences for the treatment of PVTT become available, especially for the advent of new targeted drugs and immune checkpoint inhibitors which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association revised the 2018 version of the guideline to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials.

A Radiomics Model Based on Gd-EOB-DTPA-Enhanced MRI for the Prediction of Microvascular Invasion in Solitary Hepatocellular Carcinoma ≤ 5 cm.

Aim: The aim of this study is to establish and validate a radiomics-based model using preoperative Gd-EOB-DTPA-enhanced MRI to predict microvascular invasion (MVI) in patients with hepatocellular carcinoma ≤ 5 cm. Methods: Clinicopathologic and MRI data of 178 patients with solitary hepatocellular carcinoma (HCC) (≤5 cm) were retrospectively collected from a single medical center between May 2017 and November 2020. Patients were randomly assigned into training and test subsets by a ratio of 7:3. Imaging features were extracted from the segmented tumor volume of interest with 1-cm expansion on arterial phase (AP) and hepatobiliary phase (HBP) images. Different models based on the significant clinical risk factors and/or selected imaging features were established and the predictive performance of the models was evaluated. Results: Three radiomics models, the AP_model, the HBP_model, and the AP+HBP_model, were constructed for MVI prediction. Among them, the AP+HBP_model outperformed the other two. When it was combined with a clinical model, consisting of tumor size and alpha-fetoprotein (AFP), the combined model (AP+HBP+Clin_model) showed an area under the curve of 0.90 and 0.70 in the training and test subsets, respectively. Its sensitivity and specificity were 0.91 and 0.76 in the training subset and 0.60 and 0.79 in the test subset, respectively. The calibration curve illustrated that the combined model possessed a good agreement between the predicted and the actual probabilities. Conclusions: The radiomics-based model combining imaging features from the arterial and hepatobiliary phases of Gd-EOB-DTPA-enhanced MRI and clinical risk factors provides an effective and reliable tool for the preoperative prediction of MVI in patients with HCC ≤ 5 cm.