Hepatocellular Carcinoma Recurrence Research Articles

Value of high frame rate contrast-enhanced ultrasound in predicting microvascular invasion of hepatocellular carcinoma.

To investigate the value of vascular morphology on high frame rate contrast-enhanced ultrasound (H-CEUS) and CEUS Li-RADS in predicting microvascular invasion (MVI), Ki-67 expression and recurrence of hepatocellular carcinoma (HCC). This retrospective study enrolled 78 patients with single HCC diagnosed by postoperative pathology between January 1, 2021, and June 30, 2022. All patients underwent ultrasound and H-CEUS examination before operation. H-CEUS image features and CEUS Li-RADS were compared in different MVI status and Ki-67 level. Multiple logistic regression analysis was performed to select independent variables for MVI. Differences in recurrence among different H-CEUS image features, MVI status and Ki-67 level were further analyzed. Tumor shape, vascular morphology, LR-M category, necrosis and AFP level were different between the MVI-positive group and MVI-negative group (p < 0.05). Vascular morphology and LR-M category were independent risk factors related to MVI (p < 0.05). Vascular morphology was also different between the high Ki-67 expression group and low Ki-67 expression group (p < 0.05). Vascular morphology, MVI status and Ki-67 expression were different between the recurrence group and no recurrence group (p < 0.05). The vascular morphology of HCC on H-CEUS can indicate the risk of MVI status, Ki-67 expression and recurrence, which provides a feasible imaging technique for predicting the prognosis before operation. H-CEUS shows the different vascular morphology of HCC in arterial phase and indicates the risk of MVI, Ki-67 expression and recurrence, which provides a feasible imaging technique for clinician to judge the risk of MVI pre-operation and adopt appropriate treatment. H-CEUS can clearly show different vascular morphology of HCC in arterial phase. Vascular morphology on H-CEUS is associated with MVI status, Ki-67 expression and HCC recurrence. Preoperative MVI and Ki-67 expression prediction could help surgeons choose a more appropriate treatment plan.

Nomogram for predicting early recurrence of hepatocellular carcinoma with narrow resection margin.

Narrow resection margin hepatocellular carcinoma (NRM-HCC) has a high incidence of early recurrence. Our study was designed to identify prognostic factors in patients with NRM-HCC, establish and validate a nomogram model to predict early recurrence of NRM-HCC patients. We retrospectively analyzed data from 2957 NRM-HCC patients who underwent radical hepatectomy at three medical centers between December 2009 and January 2015. Patients were randomly assigned to a training cohort (n = 2069) and a validation cohort (n = 888). Using univariate and multivariate COX regression to determine early relapse factors in NRM-HCC patients, and used these factors to construct a nomogram. The accuracy of the prediction was evaluated using the C-index, receiver operating characteristic (ROC) and calibration curve. Decision curve analysis (DCA) assessed the predictive value of the models. Finally, the recurrence-free survival of different risks was analyzed using Kaplan-Meier (K-M) method. The nomogram of NRM model contains alpha-fetoprotein (AFP), alkaline phosphatase (ALP), tumor size, tumor number, microvascular invasion (MVI), tumor capsular, and satellite nodules. The model shows good discrimination with C-indexes of 0.71 (95% CI: 0.69-0.72) and 0.72 (95% CI: 0.70-0.75) in the train cohort and test cohort respectively. Decision curve analysis demonstrated that the model is clinically useful and the calibration of our model was favorable. Our model stratified patients into two different risk groups, which exhibited significantly different early recurrence. The web-based tools are convenient for clinical practice. NRM model demonstrated favorable performance in predicting early recurrence in NRM-HCC patients. This novel model will be helpful to guide postoperative follow-up and adjuvant therapy.

ASO Visual Abstract: Comparison of Prognostic Outcomes Between Repeat Liver Resection and Particle Therapy for Patients with Recurrent Hepatocellular Carcinoma.

ASO Visual Abstract: Comparison of Prognostic Outcomes Between Repeat Liver Resection and Particle Therapy for Patients with Recurrent Hepatocellular Carcinoma.

Matching the opposites: liver transplantation from a situs viscerum inversus totalis donor.

Situs viscerum inversus totalis (SIT) is a rare congenital anomaly. Deceased donors with this condition are often declined because of the technical issues in both the organ's procurement and its transplant. Only eight cases of deceased donor organs with SITwere reported to be used for liver transplantation (LT). We herein present a case of LT using a graft from an SIT donor: a modified retroversus piggyback technique was used. A 15year-old female was referred to our institution as a potential donor. An SIT condition was discovered during standard donor evaluation together with the presence of a complex triple arterial pedicle. Procurement operative time was 125min, from skin incision to cross-clamp. Liver extraction occurred 32min after cold flush. The recipient was a 56year-old male affected by recurrent hepatocellular carcinoma (HCC) on hepatitis C related liver cirrhosis. Position and orientation trials of the graft were made and it was decided to implant it with the retroversus technique. Direct duct-to-duct biliary reconstruction was achieved. The postoperative course was uneventful. To our knowledge, this is the first implant with retroversus technique combined to direct biliary reconstruction and the first repetition of that technique. Cases like this highlight how technical complexity can be overcome leading to successful management of difficult scenarios in a safe manner.

ViT-based quantification of intratumoral heterogeneity for predicting the early recurrence in HCC following multiple ablation.

This study aimed to develop a quantitative intratumoral heterogeneity (ITH) model for assessing the risk of early recurrence (ER) in pre-treatment multimodal imaging for hepatocellular carcinoma (HCC) patients undergoing ablation treatments. This multi-centre study enrolled 633 HCC patients who underwent ultrasound-guided local ablation between January 2015 and September 2022. Among them, 422, 85, 57 and 69 patients underwent radiofrequency ablation (RFA), microwave ablation (MWA), laser ablation (LA) and irreversible electroporation (IRE) ablation, respectively. Vision-Transformer-based quantitative ITH (ViT-Q-ITH) features were extracted from the US and MRI sequences. Multivariable logistic regression analysis was used to identify variables associated with ER. A combined model integrated clinic-radiologic and ViT-Q-ITH scores. The prediction performance was evaluated concerning calibration, clinical usefulness and discrimination. The final training cohort and internal validation cohort included 318 patients and 83 patients, respectively, who underwent RFA and MWA. The three external testing cohorts comprised of 106 patients treated with RFA, 57 patients treated with LA and 69 patients who underwent IRE ablation. The combined model showed excellent predictive performance for ER in the training (AUC: .99, 95% CI: .99-1.00), internal validation (AUC: .86, 95% CI: .78-.94), external testing (AUC: .83, 95% CI: .73-.92), LA (AUC: .84, 95% CI: .73-.95) and IRE (AUC: .82, 95% CI: .72-.93) cohorts, respectively. Decision curve analysis further affirmed the clinical utility of the combined model. The multimodal-based model, incorporating clinic-radiologic factors and ITH features, demonstrated superior performance in predicting ER among early-stage HCC patients undergoing different ablation modalities.

Deep learning radiomics based on contrast enhanced MRI for preoperatively predicting early recurrence in hepatocellular carcinoma after curative resection

PurposeTo explore the role of deep learning (DL) and radiomics-based integrated approach based on contrast enhanced magnetic resonance imaging (CEMRI) for predicting early recurrence (ER) in hepatocellular carcinoma (HCC) patients after curative resection.MethodsTotal 165 HCC patients (ER, n = 96 vs. non-early recurrence (NER), n = 69) were retrospectively collected and divided into a training cohort (n = 132) and a validation cohort (n = 33). From pretreatment CEMR images, a total of 3111 radiomics features were extracted, and radiomics models were constructed using five machine learning classifiers (logistic regression, support vector machine, k-nearest neighbor, extreme gradient Boosting, and multilayer perceptron). DL models were established via three variations of ResNet architecture. The clinical-radiological (CR), radiomics combined with clinical-radiological (RCR), and deep learning combined with RCR (DLRCR) models were constructed. Model discrimination, calibration, and clinical utilities were evaluated by receiver operating characteristic curve, calibration curve, and decision curve analysis, respectively. The best-performing model was compared with the widely used staging systems and preoperative prognostic indexes.ResultsThe RCR model (area under the curve (AUC): 0.841 and 0.811) and the optimal radiomics model (AUC: 0.839 and 0.804) achieved better performance than the CR model (AUC: 0.662 and 0.752) in the training and validation cohorts, respectively. The optimal DL model (AUC: 0.870 and 0.826) outperformed the radiomics model in the both cohorts. The DL, radiomics, and CR predictors (aspartate aminotransferase (AST) and tumor diameter) were combined to construct the DLRCR model. The DLRCR model presented the best performance over any model, yielding an AUC, an accuracy, a sensitivity, a specificity of 0.917, 0.886, 0.889, and 0.882 in the training cohort and of 0.844, 0.818, 0.800, and 0.846 in the validation cohort, respectively. The DLRCR model achieved better clinical utility compared to the clinical staging systems and prognostic indexes.ConclusionBoth radiomics and DL models derived from CEMRI can predict HCC recurrence, and DL and radiomics-based integrated approach can provide a more effective tool for the precise prediction of ER for HCC patients undergoing resection.

Comparative Outcome Analysis of Lenvatinib Versus Sorafenib for Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in ~17% of patients. We aimed to retrospectively compare the outcomes of patients treated with different tyrosine kinase inhibitors (TKIs) for recurrent HCC post-LT. Patients with recurrent HCC post-LT between 2006 and 2019 were included. The impact of sorafenib and lenvatinib treatment for recurrent disease was assessed using survival analysis with an a priori multivariable Cox regression (alpha-fetoprotein [AFP] at recurrence, recurrence lesion diameter, single-site versus multisite metastases). Seven hundred fifty-four patients underwent LT for HCC, of whom 120 (15.9%) developed recurrence. Of these patients, 56 received TKIs: sorafenib (n = 42) or lenvatinib (n = 14). The median age at LT was 60.8 y (interquartile range, 54.0-66.2); 52 (93%) were men and 26 (46%) were within Milan criteria at listing. Baseline characteristics at recurrence were comparable between the 2 groups, including largest tumor diameter (P = 0.15), receipt of local therapies before TKI (P = 0.33), and single-site recurrence (P = 0.75), and time from interventional treatment to start of TKI (P = 0.44). The AFP at recurrence was higher in the sorafenib group (95.0 versus 3.0 µg/L, P < 0.001). The median overall survival (OS) after initiation of TKI treatment was longer in the lenvatinib group (15.0 mo [95% confidence interval [CI], 11.5-31.5] versus 7.8 mo [95% CI, 4.0-15.4]; P = 0.02) with a 2.3-fold a priori adjusted effect on OS (adjusted hazard ratio 2.32 [95% CI, 1.03-5.20], P = 0.04). Our findings suggest lenvatinib is a valuable treatment option for patients with HCC recurrence after LT.

Advances in Understanding the Complexities of Recurrent HCC Following Liver Transplantation.

Advances in Understanding the Complexities of Recurrent HCC Following Liver Transplantation.

Outcomes of Bridging Therapy in Liver Transplantation for Hepatocellular Carcinoma

Background: Liver transplantation (LT) is a method for treating hepatocellular carcinoma (HCC) with satisfactory outcomes. One of the novel methods for predicting LT outcomes is the Metroticket 2.0 model. The disease in patients initially within the Milan criteria (MC) may progress while on a transplantation waitlist; thus, various transplantation bridging therapy (BT) methods are proposed for patients to stay within the MC and optimize the LT outcome. Methods: We performed a retrospective analysis of patients who underwent LT for HCC at an oncological and transplantation center in northern Poland. Patients who underwent (n = 10) or did not undergo (n = 11) BT were included. The primary endpoints of the study were mortality among the patients, HCC recurrence, and Metroticket 2.0 scores based on LT qualification results and explant pathology outcomes. The median follow-up length was 44.03 months. Results: Patients who underwent BT had significantly lower Metroticket 2.0 scores and greater AFP concentrations at baseline. At LT, there was no significant difference in Metroticket 2.0 scores or AFP concentrations between the groups. Explant Metroticket 2.0 scores were significantly lower in patients who received BT. A complete pathologic response was achieved in 30.0% of patients who underwent BT. The recurrence-free survival rates were 100% and 90.91% in patients who underwent and did not undergo BT, respectively. Overall survival was 80.0% and 81.81% in patients who underwent and did not undergo BT, respectively. Conclusions: BT should be considered only as a means of remaining within the LT criteria. Routine BT does not appear to be justified for LT patients.

New Scenarios in Liver Transplantation for Hepatocellular Carcinoma.

Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.

Combined Bone Mineral Density (BMD) and Monocyte-to-Lymphocyte Ratio (MLR) Predicts Recurrence and Prognosis in Hepatocellular Carcinoma Patients Following Liver Resection.

Bone mineral density (BMD) and monocyte-to-lymphocyte ratio (MLR) were recently identified as novel risk factors for patients with several malignancies. The objective of this study was to validate the role of preoperative BMD/MLR as a potential prognostic biomarker in patients with hepatocellular carcinoma (HCC) undergoing liver resection. This investigation enrolled 442 adult patients diagnosed with HCC who underwent liver resection. The patients were classified into high- and low-BMD/MLR groups based on the median, and forward stepwise logistic regression was employed to identify independent predictors for early HCC recurrence. To mitigate the impact of confounding factors, a propensity score matching (PSM) analysis was conducted between patients in the high- and low-BMD/MLR groups. The Kaplan-Meier method was employed to assess and compare the disease-free survival (DFS) and overall survival (OS) between the two cohorts. The study categorized patients into high-BMD/MLR and low-BMD/MLR groups. Forward stepwise logistic regression analysis revealed that low BMD/MLR (P < 0.001), tumor size > 50 mm (P < 0.001), and AFP > 200 ug/L (P = 0.001) were significantly associated with the early recurrence of HCC. Moreover, the results suggested that DFS and OS were significantly shorter in the low-BMD/MLR group compared to the high-BMD/MLR group, both before and after PSM (P < 0.05). Preoperative BMD/MLR held promise as a prognostic biomarker for early recurrence and prognosis in patients with HCC who underwent liver resection. Furthermore, the integration of tumor size, AFP level, and BMD/MLR demonstrated a robust predictive capacity for early recurrence within this patient population.

Self-supervised multi-modal feature fusion for predicting early recurrence of hepatocellular carcinoma

Self-supervised multi-modal feature fusion for predicting early recurrence of hepatocellular carcinoma

Construction of a 2.5D Deep Learning Model for Predicting Early Postoperative Recurrence of Hepatocellular Carcinoma Using Multi-View and Multi-Phase CT Images

Construction of a 2.5D Deep Learning Model for Predicting Early Postoperative Recurrence of Hepatocellular Carcinoma Using Multi-View and Multi-Phase CT Images

Prognostic factors for hepatocellular carcinoma recurrence after liver transplantation or resection – single-center experience.

Prognostic factors for hepatocellular carcinoma recurrence after liver transplantation or resection – single-center experience.

ZNF143-mediated upregulation of MEX3C promotes hepatocellular carcinoma progression

BackgroundMicrovascular invasion is strongly associated with aggressive tumor behavior and recurrence in hepatocellular carcinoma (HCC) patients. Zinc finger protein 143(ZNF143) is a transcription factor involved in a wide variety of physiological and developmental processes. This study primarily focuses on the exact biological role and mechanism of ZNF143 in HCC migration and invasion. MethodsThe expression and prognosis of ZNF143 in HCC patients were analyzed. The levels of ZNF143, mex-3 RNA binding family member C (MEX3C) were quantified by western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell migration ability was detected by wound- healing assay. Matrigel transwell assay was conducted to evaluate the invasion of HCC cells. The differential expression genes of ZNF143 overexpression and knockdown were screened by mRNA profiling analysis. Dual luciferase assay was performed to determine the promoter activity of MEX3C. The enrichment of ZNF143 at MEX3C promoter was determined by chromatin immunoprecipitation (ChIP). ResultsZNF143 is overexpressed in HCC tissues and that its overexpression is correlated with poorer prognosis, especially in HCC patients with higher tumor grades and microvascular invasion. Gain- and loss-of function experiments showed that ZNF143 promotes migration and invasion in HCC cells. mRNA profiling showed that ZNF143 significantly upregulates MEX3C. ZNF143 was positively correlated with MEX3C expression in HCC tissue. ZNF143 activates MEX3C transcription by directly binding to its promoter. MEX3C knockdown inhibited migration and invasion induced by ZNF143 overexpression in HCC cells. ConclusionZNF143 promotes HCC cell migration and invasion by binding to MEX3C promoter and activating its expression.

Recurrence of HCC after living donor liver transplantation, retrospective cohort study of a single centre experience.

Recurrence of HCC after living donor liver transplantation, retrospective cohort study of a single centre experience.

Extracellular vesicles in hepatocellular carcinoma: unraveling immunological mechanisms for enhanced diagnosis and overcoming drug resistance.

Current research is focused on utilizing EVs as a biopsy tool to improve the diagnostic accuracy of HCC, reduce surgical risk, and explore their potential in modulating drug resistance and advancing immunotherapeutic strategies. Extracellular vesicles (EVs) have been increasingly recognized as important non-invasive biomarkers in hepatocellular carcinoma (HCC) due to the presence of a variety of biomolecules within them, such as proteins and RNAs, etc. EVs play a key role in the early detection, diagnosis, treatment, and prognostic monitoring of HCC. These vesicles influence the development of HCC and therapeutic response in a variety of ways, including influencing the tumor microenvironment, modulating drug resistance, and participating in immune regulatory mechanisms. In addition, specific molecules such as miRNAs and specific proteins in EVs are regarded as potential markers for monitoring treatment response and recurrence of HCC, which have certain research space and development prospects. In this paper, we summarize the aspects of EVs as HCC diagnostic and drug resistance markers, and also discuss the questions that may be faced in the development of EVs as markers.

Influence of recipient KRAS gene rs712 polymorphisms on the overall survival rate of hepatocellular carcinoma after hepatic transplantation

Hepatocellular carcinoma (HCC) recurrence appears commonly after liver transplantation (LT), and it severely affected the long-term survival of patients. Previous studies have proved that Rap1A is involved in hepatocarcinogenesis and metastasis, and demonstrated the significant association between KRAS rs712 polymorphism and HCC. However, the relationship between KRAS rs712 polymorphism and HCC recurrence after LT remained unclear. A total of 93 HCC patients who underwent LT from March 2008 to Dec 2015 was analyzed. The genotypes of both donors and recipients had been confirmed as KRAS rs712. The independent risk factors that associated with HCC recurrence were investigated with univariate and multivariate logistic regression analysis. The recurrence-free (RFS) and overall survival (OS) were calculated with Cox regression analysis. The KRAS rs712 genotype frequencies were determined using the Χ2 test and the minor allele frequencies (MAFs) of KRAS rs712 genotypes were calculated by Hardy–Weinberg equilibrium. We found that the recipient KRAS rs712 polymorphism was significantly associated with HCC recurrence after LT. Moreover, the Milan criteria, microvascular invasion and recipient KRAS rs712 genotype were proved to be independent risk factors for HCC recurrence after LT. Patients with donor TG/TT genotypes had a significantly higher RFS and OS than TT genotype. The TNM stage, microvascular invasion, Milan criteria, treatment and recipient KRAS rs712 genotype were independent factors for the RFS of LT patients. Recipient KRAS rs712 polymorphism is associated with HCC recurrence after liver transplantation and plays as a promising bio-predictor of overall survival rate of HCC risks after hepatic transplantation.

ASO Author Refections: The potential role of particle therapy as a therapeutic option for patients with recurrent hepatocellular carcinoma after liver resection.

ASO Author Refections: The potential role of particle therapy as a therapeutic option for patients with recurrent hepatocellular carcinoma after liver resection.

Comparison of Prognostic Outcomes Between Repeat Liver Resection and Particle Therapy for Patients with Recurrent Hepatocellular Carcinoma.

Particle therapy (PT) as an initial hepatocellular carcinoma (HCC) treatment has been reported to be effective; however, its efficacy for the treatment of recurrent HCC remains unclear. This study aimed to evaluate the efficacy of PT compared with repeat liver resection for treating recurrent HCC after initial LR, with a focus on prognostic outcomes. Between 2005 and 2019, 89 and 49 patients underwent repeat LR and PT for recurrent HCC after initial LR, respectively. The 5-year overall survival (OS) and recurrence-free survival (RFS) were evaluated using propensity score matching. Treatment-related complications were scored using the National Institute Common Terminology Criteria for Adverse Events (CTCAE) and were compared between the repeat LR and PT groups. In the entire cohort, the 5-year OS was significantly better in the repeat LR group than in the PT group (75% vs. 48%; p=0.0003), and the 5-year RFS was comparable in both groups (22% vs. 13%; p=0.088). Propensity score matching created 34 pairs of patients; no significant differences in the 5-year OS (65% vs. 48%; p=0.310) and RFS (21% vs. 8%; p=0.271) were observed between the repeat LR and PT groups. The proportion of CTCAE grade ≥3 complications was 8.8% and 5.9% in the repeat LR and PT groups, respectively (p=0.641). After initial LR, the prognosis and treatment-related complications in patients with recurrent HCC were comparable between the repeat LR and PT groups in the matched cohort; therefore, PT may remain one of the multidisciplinary treatment options for recurrent HCC.