Postoperative Recurrence Of Hepatocellular Carcinoma Research Articles

Spatial proteomic landscape of primary and relapsed hepatocellular carcinoma reveals immune escape characteristics in early relapse.

Surgical resection serves as the principal curative strategy for hepatocellular carcinoma (HCC), yet the incidence of postoperative recurrence remains alarmingly high. However, the spatial molecular structural alterations contributing to postoperative recurrence in HCC are still poorly understood. We employed imaging mass cytometry to profile the in-situ expression of 33 proteins within 358,729 single cells of 92 clinically annotated surgical specimens from 46 patients who were treated with surgical resections for primary and relapsed tumors. We revealed the recurrence progression of HCC was governed by the dynamic spatial distribution and functional interplay of diverse cell types across adjacent normal, tumor margin, and intratumor regions. Our exhaustive analyses revealed an aggressive, immunosuppression-related spatial ecosystem in relapsed HCC. Additionally, we illustrated the prominent implications of the TME of tumor margins in association with relapse HCC. Moreover, we identified a novel subpopulation of dendritic cells (PDL1+CD103+ DCs) enriched in the peritumoral area that correlated with early postoperative recurrence, which was further validated in an external cohort. Through the analysis of scRNA-seq data, we found the interaction of PDL1+CD103+ DCs with regulatory T cells and exhausted T cells enhanced immunosuppression and immune escape via multiple ligand-receptor pathways. We comprehensively depicted the spatial landscape of single-cell dynamics and multicellular architecture within primary and relapsed HCC. Our findings highlight spatial organization is a prominent determinant of HCC recurrence and provide a valuable insight into the immune evasion mechanisms driving recurrence.

In-situ-formed immunotherapeutic and hemostatic dual drug-loaded nanohydrogel for preventing postoperative recurrence of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by an exceedingly high recurrence rate post-surgery, significantly impairing the prognosis of HCC patients. However, a standard in-care strategy for postoperative therapy is still lacking. Although encouraging results have been obtained in a newly published clinical trial for postoperative therapy by targeting the vascular endothelial growth factor (VEGF) and programmed death ligand 1 (anti-PD-L1), its efficacy remains constrained. Combining a hemostatic hydrogel with a nanoparticle-based drug delivery system presents an opportunity to optimize the antitumor effect. Herein, we developed a nanoplatform, termed HMSN@Sor/aP@Gel, comprising a hemostatic fibrin hydrogel and functionalized hollow mesoporous silica nanoparticles (HMSNs) loaded with sorafenib and anti-PD-L1 for locally administered targeted-immunotherapy to prevent the postoperative recurrence and metastasis of HCC. The antitumor mechanism is grounded in dual inhibition of Ras/Raf/MEK/ERK (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, synergistically complemented by PD-L1 blockade. HMSN@Sor/aP@Gel facilitates dendritic cell maturation, enhances cytotoxic T-lymphocyte infiltration, promotes the polarization of tumor-associated macrophages to M1 phenotype, induces tumor immunogenic cell death, reverses immunosuppression, and establishes immune memory to counter postoperative recurrence. Animal studies corroborate that HMSN@Sor/aP@Gel-mediated targeted immunotherapy significantly impedes primary and metastatic tumor growth and establishes immune memory to prevent recurrence post-surgery. This investigation presents a promising strategy for postoperative therapy with considerable potential for clinical translation.

Efficacy and safety of donafenib as adjuvant therapy for patients with hepatocellular carcinoma undergoing curative resection: A retrospective, multicenter cohort study.

e16234 Background: A growing incidence of hepatocellular carcinoma and its high risk of recurrence after curative-intent treatment underscore the need for effective adjuvant treatment options. This study aimed to assess the efficacy of adjuvant donafenib in patients with hepatocellular carcinoma (HCC) following radical resection. Methods: This multicenter, real-world study retrospectively gathered clinical data of 82 patients who had undergone radical resection of HCC and received adjuvant therapy with donafenib. The primary endpoint was recurrence-free survival (RFS). The secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analysis was performed to evaluate RFS and OS, while the Cox proportional-hazards model was used to estimate risk factors for tumor recurrence and death. Results: A total of 82 patients with HCC who received donafenib following surgical resection were included in the study, of which were classified as high risk for tumor recurrence (with multiple or large tumor, microvascular invasion, poor tumor differentiation). The median duration of donafenib adjuvant therapy was 10.6 months (range: 0.2–26.1 months). All patients completed follow-up as required, with a median follow-up time of 19.4 months (range: 2.8–57.6 months). During the follow-up period, a totally postoperative recurrence rate was 15.9% (13/82). 1-year recurrence rate and 2-year recurrence rate were 7.3% (6/82) and 12.2% (10/82), and 1-year survival rate and 2-year survival rate were 95.1% (78/82) and 93.9% (77/82). Kaplan-Meier analysis demonstrated that patients with higher preoperative AFP level (AFP > 400ng/mL), higher preoperative PIVKA-II level (PIVKA-II > 40mAU/mL), or poor tumor differentiation (Edmondson stage III-IV) exhibited higher rate of tumor recurrence after operation (all p value < 0.05). Multivariate analysis indicated that preoperative AFP level was an independent risk factor for tumor recurrence in patients with donafenib treatment. Treatment-related adverse events (TRAEs) occurred in 67.1% (55/82) of patients, of which the most frequent were hand-foot syndrome (25.6%, 21/82), diarrhea (20.7%, 17/82), and fatigue (17.1%, 14/82). Only 8.5% (7/82) of patients had a grade ≥3 TRAEs, with the most common being hand-foot syndrome (2.4%, 2/82) and hypertension (2.4%, 2/82). No treatment-related deaths were reported. Conclusions: This study represents the largest multicenter investigation of adjuvant therapy with donafenib to date, and the findings indicate that donafenib has the potential to be an effective treatment option for preventing postoperative recurrence in HCC. Furthermore, the preoperative AFP ≤400ng/mL can serve as an effective biomarker for postoperative administration of donafenib in HCC patients.

Combined image-guided radiofrequency and iodine-125 seeds implantation in the treatment of recurrent hepatocellular carcinoma after hepatectomy

BackgroundCurrently, there is no consensus on the treatment of recurrent hepatocellular carcinoma (HCC) after hepatectomy. It is necessary to assess the efficacy and safety of radiofrequency ablation (RFA) combined with iodine-125 seeds implantation (RFA-125I) in the treatment of recurrent HCC.MethodsThis study retrospectively analyzed the clinical data of patients with postoperative recurrence of HCC receiving RFA-125I or RFA treatment from January 2013 to January 2023. Both RFA and 125I seeds implantation were performed under dual guidance of ultrasound and CT. Overall survival (OS), progression-free survival (PFS), recurrence, and complications were compared between the two groups.ResultsA total of 210 patients with recurrent HCC were enrolled in this study, including 125 patients in the RFA-125I group and 85 patients in the RFA group. The RFA-125I group showed a significantly better survival benefit than RFA group (median OS: 37 months vs. 16 months, P < 0.001; median PFS: 15 months vs. 10 months, P = 0.001). The uni- and multivariate analysis showed that RFA-125I was a protective factor for OS and PFS. There were no procedure-related deaths and no grade 3 or higher adverse events in both groups.ConclusionsRFA combined with 125I seeds implantation under dual guidance of ultrasound and CT is effective and safe for the treatment of HCC patients with recurrence after hepatectomy.

New predictors of microvascular invasion for small hepatocellular carcinoma ≤ 3cm.

Microvascular invasion (MVI) is a risk factor for postoperative recurrence of hepatocellular carcinoma (HCC), even in early-stage HCC. In small HCC ≤ 3cm, treatment options include anatomical resection or non-anatomical resection, and MVI has a major effect on treatment decisions. We aimed to identify the predictors of MVI in small HCC ≤ 3cm. We retrospectively studied 129 patients with very early or early-stage HCC ≤ 3cm who had undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography and subsequent hepatic resection from January 2016 to August 2023. These patients were divided into the derivation cohort (n = 86) and validation cohort (n = 43). We examined the risk factors for MVI using logistic regression analysis, and established a predictive scoring system in the derivation cohort. We evaluated the accuracy of our scoring system in the validation cohort. In the derivation cohort, a Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), prothrombin induced by vitamin K deficiency or antagonist-II (PIVKA-II), and metabolic tumor volume (MTV) were independent predictors of MVI. We established the scoring system using these three factors. In the validation test, there were no MVI-positive cases with a score of 0 and 1, and all cases were MVI-positive with a score of 4. Moreover, with a score ≥ 2, the sensitivity, specificity, and accuracy of our scoring system were 100%, 71.4%, and 81.4%, respectively. Our scoring system can accurately predict MVI in small HCC ≤ 3cm, and could contribute to establishing an appropriate treatment strategy.

Pre-operative enhanced magnetic resonance imaging combined with clinical features predict early recurrence of hepatocellular carcinoma after radical resection.

Indentifying predictive factors for postoperative recurrence of hepatocellular carcinoma (HCC) has great significance for patient prognosis. To explore the value of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) combined with clinical features in predicting early recurrence of HCC after resection. A total of 161 patients with pathologically confirmed HCC were enrolled. The patients were divided into early recurrence and non-early recurrence group based on the follow-up results. The clinical, laboratory, pathological results and Gd-EOB-DTPA enhanced MRI imaging features were analyzed. Of 161 patients, 73 had early recurrence and 88 were had non-early recurrence. Univariate analysis showed that patient age, gender, serum alpha-fetoprotein level, the Barcelona Clinic Liver Cancer stage, China liver cancer (CNLC) stage, microvascular invasion (MVI), pathological satellite focus, tumor size, tumor number, tumor boundary, tumor capsule, intratumoral necrosis, portal vein tumor thrombus, large vessel invasion, nonperipheral washout, peritumoral enhancement, hepatobiliary phase (HBP)/tumor signal intensity (SI)/peritumoral SI, HBP peritumoral low signal and peritumoral delay enhancement were significantly associated with early recurrence of HCC after operation. Multivariate logistic regression analysis showed that patient age, MVI, CNLC stage, tumor boundary and large vessel invasion were independent predictive factors. External data validation indicated that the area under the curve of the combined predictors was 0.861, suggesting that multivariate logistic regression was a reasonable predictive model for early recurrence of HCC. Gd-EOB-DTPA enhanced MRI combined with clinical features would help predicting the early recurrence of HCC after operation.

Assessing recent recurrence after hepatectomy for hepatitis B-related hepatocellular carcinoma by a predictive model based on sarcopenia.

Sarcopenia may be associated with hepatocellular carcinoma (HCC) following hepatectomy. But traditional single clinical variables are still insufficient to predict recurrence. We still lack effective prediction models for recent recurrence (time to recurrence < 2 years) after hepatectomy for HCC. To establish an interventable prediction model to estimate recurrence-free survival (RFS) after hepatectomy for HCC based on sarcopenia. We retrospectively analyzed 283 hepatitis B-related HCC patients who underwent curative hepatectomy for the first time, and the skeletal muscle index at the third lumbar spine was measured by preoperative computed tomography. 94 of these patients were enrolled for external validation. Cox multivariate analysis was per-formed to identify the risk factors of postoperative recurrence in training cohort. A nomogram model was developed to predict the RFS of HCC patients, and its predictive performance was validated. The predictive efficacy of this model was evaluated using the receiver operating characteristic curve. Multivariate analysis showed that sarcopenia [Hazard ratio(HR) = 1.767, 95%CI: 1.166-2.678, P < 0.05], alpha-fetoprotein ≥ 40 ng/mL (HR = 1.984, 95%CI: 1.307-3.011, P < 0.05), the maximum diameter of tumor > 5 cm (HR = 2.222, 95%CI: 1.285-3.842, P < 0.05), and hepatitis B virus DNA level ≥ 2000 IU/mL (HR = 2.1, 95%CI: 1.407-3.135, P < 0.05) were independent risk factors associated with postoperative recurrence of HCC. Based on the sarcopenia to assess the RFS model of hepatectomy with hepatitis B-related liver cancer disease (SAMD) was established combined with other the above risk factors. The area under the curve of the SAMD model was 0.782 (95%CI: 0.705-0.858) in the training cohort (sensitivity 81%, specificity 63%) and 0.773 (95%CI: 0.707-0.838) in the validation cohort. Besides, a SAMD score ≥ 110 was better to distinguish the high-risk group of postoperative recurrence of HCC. Sarcopenia is associated with recent recurrence after hepatectomy for hepatitis B-related HCC. A nutritional status-based prediction model is first established for postoperative recurrence of hepatitis B-related HCC, which is superior to other models and contributes to prognosis prediction.

Predicting One-year Recurrence of HCC based on Gadoxetic Acid-enhanced MRI by Machine Learning Models.

Accurate prediction of recurrence risk after resction in patients with Hepatocellular Carcinoma (HCC) may help to individualize therapy strategies. This study aimed to develop machine learning models based on preoperative clinical factors and multiparameter Magnetic Resonance Imaging (MRI) characteristics to predict the 1-year recurrence after HCC resection. Eighty-two patients with single HCC who underwent surgery were retrospectively analyzed. All patients underwent preoperative gadoxetic acidenhanced MRI examination. Preoperative clinical factors and MRI characteristics were collected for feature selection. Least Absolute Shrinkage and Selection Operator (LASSO) was applied to select the optimal features for predicting postoperative 1-year recurrence of HCC. Four machine learning algorithms, Multilayer Perception (MLP), random forest, support vector machine, and k-nearest neighbor, were used to construct the predictive models based on the selected features. A Receiver Operating Characteristic (ROC) curve was used to assess the performance of each model. Among the enrolled patients, 32 patients experienced recurrences within one year, while 50 did not. Tumor size, peritumoral hypointensity, decreasing ratio of liver parenchyma T1 value (ΔT1), and α-fetoprotein (AFP) levels were selected by using LASSO to develop the machine learning models. The area under the curve (AUC) of each model exceeded 0.72. Among the models, the MLP model showed the best performance with an AUC, accuracy, sensitivity, and specificity of 0.813, 0.742, 0.570, and 0.853, respectively. Machine learning models can accurately predict postoperative 1-year recurrence in patients with HCC, which may help to provide individualized treatment.

Transcriptomic sequencing analysis of key long noncoding RNAs and mRNAs expression profiles in postoperative recurrence of hepatocellular carcinoma.

Recurrence is the main cause of death in hepatocellular carcinoma (HCC) patients after liver resection. The long non-coding RNAs (lncRNAs) have been reported participated in progression and prognosis of HCC, however, the vital role of lncRNA in postoperative recurrence of HCC has rarely been systematically identified. RNA-sequencing (RNA-seq) was performed between orthotopic model of HCC and hepatoma postoperative recurrent model to comprehensively analyze the integrated transcriptome expression profiles of lncRNA and mRNA. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was then conducted to quantify the expression levels of DElncRNAs and their target mRNAs. In our study, 211 lncRNAs (P-value < 0.05) and 1125 mRNAs (P-adjust < 0.05) were significantly differentially expressed (DE) between two groups. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DElncRNAs and DEmRNAs were mainly enriched in lipid metabolism, including Arachidonic acid metabolism, PPAR signaling pathway, Steroid hormone biosynthesis, Linoleic acid metabolism, Inflammatory mediator regulation of TRP channels, and Fatty acid degradation. Furthermore, we constructed lncRNA-mRNA interaction networks and protein-protein interaction (PPI) network, and verified by qRT-PCR, suggesting that increased DEIncRNAs (XLOC_063499 and XLOC_042016) may prevent HCC recurrence after surgery by upregulating on targeted cytochrome P450 (CYP) family genes in the lipid metabolism pathway, such as cyp3a16, cyp3a44, cyp2c39, cyp2c40 and cyp2c68. Overall, Our findings provided new insights for further investigation of biological function in lncRNA related HCC recurrence.

Infiltrative Vessel Co-optive Growth Pattern Induced by IQGAP3 Overexpression Promotes Microvascular Invasion in Hepatocellular Carcinoma.

Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms. IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.

Novel nomograms based on microvascular invasion grade for early-stage hepatocellular carcinoma after curative hepatectomy

Microvascular invasion (MVI) is a critical risk factor for postoperative recurrence of hepatocellular carcinoma (HCC). This study aimed to firstly develop and validate nomograms based on MVI grade for predicting recurrence, especially early recurrence, and overall survival in patients with early-stage HCC after curative resection. We retrospectively reviewed the data of patients with early-stage HCC who underwent curative hepatectomy in the First Affiliated Hospital of Fujian Medical University (FHFU) and Mengchao Hepatobiliary Hospital of Fujian Medical University (MHH). Kaplan–Meier curves and Cox proportional hazards regression models were used to analyse disease-free survival (DFS) and overall survival (OS). Nomogram models were constructed on the datasets from the 70% samples of and FHFU, which were validated using bootstrap resampling with 30% samples as internal validation and data of patients from MHH as external validation. A total of 703 patients with early-stage HCC were included to create a nomogram for predicting recurrence or metastasis (DFS nomogram) and a nomogram for predicting survival (OS nomogram). The concordance indexes and calibration curves in the training and validation cohorts showed optimal agreement between the predicted and observed DFS and OS rates. The predictive accuracy was significantly better than that of the classic HCC staging systems.

Huaier granule improves liver inflammation and fibrosis and prevents recurrence in hepatitis B virus related hepatocellular carcinoma.

There is basic research suggesting that Huaier granule can inhibit liver cirrhosis and hepatocellular carcinoma (HCC), but this conclusion has not been clinically verified. We analyzed the distant cancer tissue of two groups of hepatitis B virus (HBV) related HCC with/without Huaier granule, to clarify the effect of Huaier granule on liver inflammation, liver fibrosis, and postoperative recurrence. We collected clinicopathological data of HCC patients who received two surgery procedures at Mengchao Hepatobiliary Hospital of Fujian Medical University in China from January 2014 to December 2020. Patients according to taking/not taking Huaier granule after the first hepatectomy were divided into two groups, 51 patients with Huaier granule for more than 6 months after operation (Group A); 56 patients without Huaier granule (Group B). The effects on liver inflammation, fibrosis grade, and postoperative recurrence were compared between two groups. The results showed that liver inflammation improved significantly in the Group A [19 (37.3%) cases improved, 31 (60.8%) cases remained unchanged, and 1 (2.0%) case deteriorated] was significantly more than that in the Group B [7 (12.5%) cases improved, 32 (57.1%) cases remained unchanged, and 17 (30.4%) cases deteriorated] (P<0.001). The liver fibrosis in the Group A [17 (33.3%) cases improved, 32 (62.7%) cases remained unchanged, and 2 (3.9%) cases deteriorated] was significantly improved in the Group B [5 (8.9%) cases improved, 45 (80.4%) cases remained unchanged, and 6 (10.7%) cases deteriorated] (P=0.005). The recurrence interval (27.0±21.2 months) in the Group A was significantly longer than that in the Group B (19.0±14.2 months) (P=0.026). Huaier granule can improve liver inflammation, fibrosis, and liver function and prolong the time to recurrence in HBV-related HCC. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Prognostic value and potential mechanism of cellular senescence and tumor microenvironment in hepatocellular carcinoma: Insights from bulk transcriptomics and single-cell sequencing analysis.

The high mortality rate and postoperative recurrence of hepatocellular carcinoma (HCC) contribute to the burden on society and healthcare. The prognostic value and underlying mechanisms of cellular senescence and tumor microenvironment (TME) in HCC remain unclear. Bulk transcriptomic data were obtained from 368 HCC samples in The Cancer Genome Atlas-liver hepatocellular carcinoma cohort and 64 samples from the GSE116174 dataset. Single-cell RNA sequencing (scRNA-seq) data of HCC were obtained from the GSE149614 dataset, including 18 tumor samples from 10 patients. Prognosis-related cellular senescence genes and immune cells were identified through univariate analysis. Least absolute shrinkage and selection operator regression analysis was performed to construct the CellAge score and TME score, both of which were identified as independent prognostic factors for HCC based on multivariate Cox analysis. The combined CellAge and TME scores showed improved prognostic stratification for HCC patients, as confirmed by multivariate Cox analysis (p < .001). The gene set enrichment analysis (GSEA) revealed enrichment of the extracellular matrix receptor interaction signaling pathway in the group with high CellAge scores and low TME scores, which exhibited a worse prognosis. Single-cell sequencing results revealed higher expression activity of the cAMP response element modulator (CREM) extended transcription factor in HCC cells and most immune cells, indicating its involvement in TME remodeling. Finally, the tumor immune dysfunction and exclusion (TIDE) analysis demonstrated that the combined scores could predict the outcomes of immune therapy in patients with HCC. In conclusion, cellular senescence contributes to TME remodeling in HCC, and the developed CellAge and TME scores serve as independent prognostic factors and predictors of immune therapy in HCC.

Clinical significance of CDT1 mRNA expression in chronic hepatitis C or liver cirrhosis.

We have previously reported that chromatin licensing and DNA replication factor 1 (CDT1) is associated with the postoperative recurrence of hepatocellular carcinoma (HCC). Based on this fact, we verified whether CDT1 mRNA expression is also associated with HCC development from chronic hepatitis C (CHC) and liver cirrhosis (LC). There were 142 cases with CHC or LC who underwent liver biopsy. Detection of CDT1 mRNA in liver was performed by RT-qPCR using frozen liver biopsy tissues. We examined the association between the CDT1 mRNA expression and clinical conditions and long-term outcome. We then examined the association between serum cytokine/chemokine levels and CDT1 mRNA expression in 58 cases. The cumulative incidence rates of HCC development in cases with CDT1 mRNA in the low expression group showed significantly lower than those in the high expression group (p = 0.0391). A significant correlation was found between CDT1 mRNA expression and the extent of proliferation of atypical hepatocytes in hematoxylin and eosin-stained sections (p<0.0001). CDT1 mRNA expression has been associated with cytokines involved in tumorigenesis in experimental and human cancers. We found that cases with high CDT1 mRNA expression were at risk for developing HCC, even if they were CHC or LC.

ACTB may serve as a predictive marker for the efficacy of lenvatinib in patients with HBV-related early-stage hepatocellular carcinoma following partial hepatectomy: a retrospective cohort study.

The lack of effective biomarkers for the treatment of postoperative recurrence in hepatocellular carcinoma (HCC) persists despite lenvatinib therapy. This study aims to identify beta-actin (ACTB) as a predictive biomarker for lenvatinib that can facilitate individualized treatment for HCC. This retrospective study included a subset of patients with HCC who underwent partial hepatectomy, with some receiving postoperative lenvatinib treatment and others not receiving lenvatinib treatment. A propensity score matching (PSM) analysis of patients who underwent treatment with or without lenvatinib following HCC partial hepatectomy was performed. Immunohistochemistry was employed to determine the levels of ACTB expression in HCC samples obtained from matched patients (n=225) enrolled in this study. The X-Tile was employed to determine the optimal cut-off point of ACTB levels for predicting time to recurrence (TTR). To assess the correlation between ACTB levels and lenvatinib efficacy, a subgroup analysis of TTR was conducted. A Cox regression model with an interaction term was utilized to assess the predictive significance of the model. Subsequently, a nomogram was developed and its discriminative ability and predictive accuracy were assessed using the concordance index (C-index) and calibration curve. For the investigation of the ACTB expression, HCC and para-tumoral normal tissues were employed. The patient-derived xenograft (PDX) model was utilized to validate the correlation between ACTB levels and lenvatinib responsiveness. After PSM, a total of 76 patients who underwent postoperative lenvatinib treatment were included in the analysis, with a median TTR of 24.35 months. Early-stage HCC patients with lower levels of ACTB exhibited a more favorable response to lenvatinib therapy compared to those with higher levels. The reduced expression of ACTB was indicative of the benefits of lenvatinib, as opposed to higher levels {hazard ratio (HR) =0.243 [95% confidence interval (CI): 0.096-0.619], P<0.001, P value for interaction =0.014}. In approximately 81.8% of cases involving HCC patients, there was an observed increase in the expression of ACTB. Multivariate analysis of the lenvatinib cohort revealed Child-Pugh [HR =5.416 (95% CI: 1.390-21.104), P=0.015], Barcelona Clinic Liver Cancer (BCLC) stage [HR =2.508 (95% CI: 1.116-5.639), P=0.026], and ACTB [HR =5.879 (95% CI: 2.424-14.259), P<0.001] score as independent factors for TTR, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.76 (95% CI: 0.71-0.84). Moreover, the PDXs derived from tumors exhibiting low levels of ACTB expression demonstrated a heightened sensitivity to lenvatinib treatment. In patients with tumors treated with lenvatinib, low ACTB expression can predict a lower risk of recurrence. The validation of this potential biomarker in independent cohorts is necessary prior to its implementation for precision treatment stratification in patients undergoing partial hepatectomy for early-stage HCC.

Development of a machine learning-based model for predicting risk of early postoperative recurrence of hepatocellular carcinoma

BACKGROUND Surgical resection is the primary treatment for hepatocellular carcinoma (HCC). However, studies indicate that nearly 70% of patients experience HCC recurrence within five years following hepatectomy. The earlier the recurrence, the worse the prognosis. Current studies on postoperative recurrence primarily rely on postoperative pathology and patient clinical data, which are lagging. Hence, developing a new pre-operative prediction model for postoperative recurrence is crucial for guiding individualized treatment of HCC patients and enhancing their prognosis. AIM To identify key variables in pre-operative clinical and imaging data using machine learning algorithms to construct multiple risk prediction models for early postoperative recurrence of HCC. METHODS The demographic and clinical data of 371 HCC patients were collected for this retrospective study. These data were randomly divided into training and test sets at a ratio of 8:2. The training set was analyzed, and key feature variables with predictive value for early HCC recurrence were selected to construct six different machine learning prediction models. Each model was evaluated, and the best-performing model was selected for interpreting the importance of each variable. Finally, an online calculator based on the model was generated for daily clinical practice. RESULTS Following machine learning analysis, eight key feature variables (age, intratumoral arteries, alpha-fetoprotein, pre-operative blood glucose, number of tumors, glucose-to-lymphocyte ratio, liver cirrhosis, and pre-operative platelets) were selected to construct six different prediction models. The XGBoost model outperformed other models, with the area under the receiver operating characteristic curve in the training, validation, and test datasets being 0.993 (95% confidence interval: 0.982-1.000), 0.734 (0.601-0.867), and 0.706 (0.585-0.827), respectively. Calibration curve and decision curve analysis indicated that the XGBoost model also had good predictive performance and clinical application value. CONCLUSION The XGBoost model exhibits superior performance and is a reliable tool for predicting early postoperative HCC recurrence. This model may guide surgical strategies and postoperative individualized medicine.

Prognostic Factors for Patients with Proliferative Hepatocellular Carcinoma After Liver Resection.

There is a scarcity of predictive models currently accessible for prognosticating proliferative hepatocellular carcinoma (HCC), an integrated class of subtype, characterized by a dismal prognosis. Consequently, this study aimed to develop and validate a novel prognostic model capable of accurately predicting the prognosis of proliferative HCC after curative resection. This retrospective multicenter study included patients with solitary HCC who underwent curative liver resection from August 2014 to December 2020 (n = 816). Patients were stratified into either the proliferative HCC cohort (n = 259) or the nonproliferative HCC cohort (n = 557) based on histological criteria. Disease-free survival (DFS) was compared between the two groups before and after one-to-one propensity score matching (PSM). Of all the proliferative HCC patients, 203 patients were assigned to training cohort, and 56 patients were assigned to validation cohort. Univariate and multivariate analyses were performed in training cohort to identify risk factors associated with worse DFS. Thereafter, a predictive model was constructed, subsequently validated in the validation cohort. The DFS of proliferative HCC was significantly worse than nonproliferative HCC before and after PSM. Meanwhile, multivariate regression analysis revealed that liver cirrhosis (P = 0.032) and larger tumor size (P = 0.000) were independent risk factors of worse DFS. Lastly, the discriminative abilities of the predictive model for 1, 3, 5-year DFS rates, as determined by receiver operating characteristic (ROC) curves, were 0.702, 0.720, and 0.809 in the training cohort and 0.752, 0.776, and 0.851 in the validation cohort, respectively. This study developed a predictive model with satisfactory accuracy to predict the worse DFS in proliferative HCCs after liver resection. Moreover, this predictive model may serve as a valuable tool for clinicians to predict postoperative HCC recurrence, thereby enabling them to implement early preventative strategies.

Impact of Liver Fibrosis Severity on Oncological Prognosis in Hepatocellular Carcinoma

Introduction: Cirrhosis is deemed to be a contributing factor to the postoperative recurrence of hepatocellular carcinoma (HCC); however, the precise impact of liver fibrosis on both cancer-specific prognoses remains unclear. This investigation sought to elucidate the effect of liver fibrosis severity on the cancer-specific prognosis. Methods: A total of 524 consecutive patients were included. Recurrence-free survival (RFS) and disease-specific survival (DSS) were compared according to fibrosis stage. Moreover, postoperative outcomes were subjected to analysis in cohorts of patients with F0 and F1–3, as well as in those with F1–3 and F4, who were carefully matched for background factors. Results: The 5-year RFS exhibited a significantly worse outcome in the F4 group compared to other stages of fibrosis: 5-year RFS – F0 (46.6%), F1–3 (33.1%), and F4 (23.5%), p = 0.03 (F0 vs. F1–3) and p < 0.01 (F1–3 vs. F4). Additionally, the 5-year DSS also presented a significantly worse prognosis in the F4 group: 5-year DSS – F0 (82.9%), F1–3 (73.6%), and F4 (57.4%), p = 0.04 (F0 vs. F1–3) and p < 0.01 (F1–3 vs. F4). In multivariate analysis, fibrosis 1, 2, 3, and 4 stage (compared with F0) (HR: 1.70, 1.81, 1.89, and 3.99, 95% confidence interval: 1.10–1.99, 1.39–2.22, 1.41–2.55, and 2.25–5.01, p = 0.022, p = 0.008, p < 0.001, and p < 0.001, respectively) was independent risk factor for RFS. After matched analysis, both RFS and DSS exhibited significantly worse prognoses in the presence of more advanced fibrosis. There was a significantly higher incidence of multiple recurrences in the F4 group than the F1–3 group, and a number of recurrences were observed both in the same hepatic segment as the resected side and in the contralateral lobe in F4 group. Discussion/Conclusion: The hazard and recurrence pattern of HCC signifies that the prognosis could potentially be poor, as the hepatic fibrosis likely owing to a higher hepatocarcinogenic potential, even in the absence of progression to cirrhotic condition. The risk of de novo recurrence may also increase with the progression of this fibrosis.

Revolutionising hepatocellular carcinoma surveillance: Harnessing contrast-enhanced ultrasound and serological indicators for postoperative early recurrence prediction.

This study aimed to develop a noninvasive predictive model for identifying early postoperative recurrence of hepatocellular carcinoma (within 2 years after surgery) based on contrast-enhanced ultrasound and serum biomarkers. Additionally, the model's validity was assessedthrough internal and external validation. Clinical data were collected from patients who underwent liver resection at the First Hospital of Quanzhou and Mengchao Hepatobiliary Hospital. The data included general information, contrast-enhanced ultrasound parameters, Liver Imaging Reporting and Data System (LI-RADS) classification, and serum biomarkers. The data from Mengchao Hospital were divided into 2 groups, with a ratio of 6:4, to form the modeling and internal validation sets, respectively. On the other hand, the data from the First Hospital of Quanzhou served as the external validation group. The developed model was named the Hepatocellular Carcinoma Early Recurrence (HCC-ER) prediction model. The predictive efficiency of the HCC-ER model was compared with other established models. The baseline characteristics were found to be well-balanced across the modeling, internal validation, and external validation groups. Among the independent risk factors identified for early recurrence, LI-RADS classification, alpha-fetoprotein, and tumor maximum diameter exhibited hazard ratios of 1.352, 1.337, and 1.135 respectively. Regarding predictive accuracy, the HCC-ER, Tumour-Node-Metastasis, Barcelona Clinic Liver Cancer, and China Liver Cancer models demonstrated prediction errors of 0.196, 0.204, 0.201, and 0.200 in the modeling group; 0.215, 0.215, 0.218, and 0.212 in the internal validation group; 0.210, 0.215, 0.216, and 0.221 in the external validation group. Using the HCC-ER model, risk scores were calculated for all patients, and a cutoff value of 50 was selected. This cutoff effectively distinguished the high-risk recurrence group from the low-risk recurrence group in the modeling, internal validation, and external validation groups. However, the calibration curve of the predictive model slightly overestimated the risk of recurrence. The HCC-ER model developed in this study demonstrated high accuracy in predicting early recurrence within 2 years after hepatectomy. It provides valuable information for developing precise treatment strategies in clinical practice and holds considerable promise for further clinical implementation.

MRI Features for Predicting Microvascular Invasion and Postoperative Recurrence in Hepatocellular Carcinoma Without Peritumoral Hypointensity.

To identify MRI features of hepatocellular carcinoma (HCC) that predict microvascular invasion (MVI) and postoperative intrahepatic recurrence in patients without peritumoral hepatobiliary phase (HBP) hypointensity. One hundred and thirty patients with HCC who underwent preoperative gadoxetate-enhanced MRI and curative hepatic resection were retrospectively reviewed. Two radiologists reviewed all preoperative MR images and assessed the radiological features of HCCs. The ability of peritumoral HBP hypointensity to identify MVI and intrahepatic recurrence was analyzed. We then assessed the MRI features of HCC that predicted the MVI and intrahepatic recurrence-free survival (RFS) in the subgroup without peritumoral HBP hypointensity. Finally, a two-step flowchart was constructed to assist in clinical decision-making. Peritumoral HBP hypointensity (odds ratio, 3.019; 95% confidence interval: 1.071-8.512; P=0.037) was an independent predictor of MVI. The sensitivity, specificity, positive predictive value, negative predictive value, and AUROC of peritumoral HBP hypointensity in predicting MVI were 23.80%, 91.04%, 71.23%, 55.96%, and 0.574, respectively. Intrahepatic RFS was significantly shorter in patients with peritumoral HBP hypointensity (P<0.001). In patients without peritumoral HBP hypointensity, the only significant difference between MVI-positive and MVI-negative HCCs was the presence of a radiological capsule (P=0.038). Satellite nodule was an independent risk factor for intrahepatic RFS (hazard ratio,3.324; 95% CI: 1.733-6.378; P<0.001). The high-risk HCC detection rate was significantly higher when using the two-step flowchart that incorporated peritumoral HBP hypointensity and satellite nodule than when using peritumoral HBP hypointensity alone (P<0.001). In patients without peritumoral HBP hypointensity, a radiological capsule is useful for identifying MVI and satellite nodule is an independent risk factor for intrahepatic RFS.