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Background. Liver transplantation remains a priority treatment option for hepatocellular carcinoma in the presence of liver cirrhosis; yet precise outcome prediction post-operation continues to be a complex challenge. Existing prognostic model often overlook patient age and donor type. Enhanced models that incorporate these parameters can improve prediction accuracy and treatment efficacy, which is critically important in the dynamically evolving field of transplantation.Objective. The aim of this study is to develop a prognostic model for liver transplantation outcomes in patients with hepatocellular carcinoma and liver cirrhosis.Material and methods. This retrospective study included 69 patients with hepatocellular carcinoma on the background of liver cirrhosis who underwent liver transplantation between May 2010 and December 2022. Of these, 42 patients (61%) received organs from living donors, and 27 (39%) from deceased donors. The study involved analysis of alpha-fetoprotein levels in blood, as well as assessment of radiological (maximum tumor nodule size, number of nodules) and histological parameters (maximum tumor nodule size, number of nodules, presence of vascular invasion). Cox regression model was used to predict recurrence-free survival, and the results for five-year recurrence-free survival, recipient age, and donor type were reused in the Cox model to predict overall survival.Results. Four models for predicting recurrence-free survival and overall survival based on histological and radiological data were developed, demonstrating high prognostic value with C-indexes on training/test data of 0.76/1; 0.73/1; 0.78/0.8; 0.6/0.8 respectively. All models showed recurrence-free survival prediction accuracy comparable to the Milan criteria. The model outcomes are available as a calculator on the website https://nadit.ru/calculate_HCC.Conclusion. The developed prognostic models are vital tools for personalized outcome prediction after liver transplantation for hepatocellular carcinoma. To enhance the accuracy of these models, further amalgamation and validation of data from various medical centers, as well as open scientific collaboration, are necessary.

Obesity is a well-documented risk factor for the development of hepatocellular carcinoma (HCC) in the general population. The applicability of these findings to liver recipients is uncertain, and the results of available data have not been unanimous. The objective of the current study was to investigate the impact of the pre-operative body mass index (BMI) on oncological outcomes of liver transplantation due to HCC. Methods: This observational retrospective study enrolled all patients with histologically confirmed HCC who underwent liver transplantation from a deceased donor in our centre between 2008 and 2018. Results: Overall, 83 patients were enrolled and were subsequently stratified according to their pre-operative BMI into three groups: patients with normal body weight (n = 53), patients with overweight (n = 23), patients with obesity (n = 7). Overall tumour recurrence was 12%. BMI failed to predict the 5-year recurrence-free survival (p = 0.55), risk of tumour recurrence (p = 0.314) and overall 5-year survival (p = 0.19) in liver recipients. Conclusions: BMI was proven to be an unreliable surrogate measure of obesity for predicting oncological outcomes among liver recipients. Other obesity indices should be referenced to assess cancer-related prognosis more accurately in these groups of patients. [ABSTRACT FROM AUTHOR]

Obesity is a well-documented risk factor for the development of hepatocellular carcinoma (HCC) in the general population. The applicability of these findings to liver recipients is uncertain, and the results of available data have not been unanimous. The objective of the current study was to investigate the impact of the pre-operative body mass index (BMI) on oncological outcomes of liver transplantation due to HCC. Methods: This observational retrospective study enrolled all patients with histologically confirmed HCC who underwent liver transplantation from a deceased donor in our centre between 2008 and 2018. Results: Overall, 83 patients were enrolled and were subsequently stratified according to their pre-operative BMI into three groups: patients with normal body weight (n = 53), patients with overweight (n = 23), patients with obesity (n = 7). Overall tumour recurrence was 12%. BMI failed to predict the 5-year recurrence-free survival (p = 0.55), risk of tumour recurrence (p = 0.314) and overall 5-year survival (p = 0.19) in liver recipients. Conclusions: BMI was proven to be an unreliable surrogate measure of obesity for predicting oncological outcomes among liver recipients. Other obesity indices should be referenced to assess cancer-related prognosis more accurately in these groups of patients.

Background: Highly active hepatitis B virus (HBV) is known to be associated with poor outcomes in patients with hepatocellular carcinoma (HCC). This study aims to investigate the relationship between HBV status and HCC recurrence after liver transplantation. Methods: The study retrospectively analyzed HCC patients undergoing liver transplantation in two centres between January 2015 and December 2020. The authors reviewed post-transplant HBV status and its association with outcomes. Results: The prognosis of recipients with hepatitis B surface antigen (HBsAg) reappearance (n = 58) was poorer than those with HBsAg persistent negative (n = 351) and positive (n = 53). In HBsAg persistent positive group, recipients with HBV DNA reappearance or greater than 10-fold increase above baseline had worse outcomes than those without (P < 0.01). HBV reactivation was defined as (a) HBsAg reappearance or (b) HBV DNA reappearance or greater than 10-fold increase above baseline. After propensity score matching, the 5-year overall survival rate and recurrence-free survival rate after liver transplantation in recipients with HBV reactivation were significantly lower than those without (32.0% vs. 62.3%; P < 0.01, and 16.4% vs. 63.1%; P < 0.01, respectively). Moreover, HBV reactivation was significantly related to post-transplant HCC recurrence, especially lung metastasis. Cox regression analysis revealed that beyond Milan criteria, microvascular invasion and HBsAg-positive graft were independent risk factors for post-transplant HBV reactivation, and a novel nomogram was established accordingly with a good predictive efficacy (area under the time-dependent receiver operating characteristic curve = 0.78, C-index = 0.73). Conclusions: Recipients with HBV reactivation had worse outcomes and higher tumour recurrence rates than those without. The nomogram could be used to evaluate the risk of post-transplant HBV reactivation effectively. [ABSTRACT FROM AUTHOR]

Many end-stage liver disease etiologies are attributed to robust inflammatory cell recruitment. Neutrophils play an important role in inflammatory infiltration and neutrophil phagocytosis, oxidative burst, and degranulation. It has also been suggested that neutrophils may release neutrophil extracellular traps (NETs) to kill pathogens. It has been proven that neutrophil infiltration within the liver contributes to an inflammatory microenvironment and immune cell activation. Growing evidence implies that NETs are involved in the progression of numerous complications of liver transplantation, including ischemiareperfusion injury, acute rejection, thrombosis, and hepatocellular carcinoma recurrence. NETs are discussed in this comprehensive review, focusing on their effects on liver transplantation complications. Furthermore, we discuss NETs as potential targets for liver transplantation therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Complement component(C7) gene has been shown to influence the prognosis in Hepatocellular carcinoma (HCC) patients. The association between C7 and HCC recurrence after orthotopic liver transplantation (OLT), however, is still unknown. The purpose of this study was to evaluate whether the donor and recipient C7 gene polymorphisms are related to HCC recurrence after OLT in the Han Chinese population. Methods A total of 73 consecutive patients with HCC who had undergone OLT, both donors and recipients, were involved in this research. A single nucleotide polymorphism of C7, rs9292795, was genotyped using Sequenom MassARRAY in the cohort. The expression of C7 and the association between C7 gene polymorphisms and HCC recurrence following OLT were analyzed by bioinformatics and statistical analysis, respectively. Results As shown in database, the expression of C7 was higher in HCC tissues than that in normal tissues, and represented a worse prognosis. We also found that recipient C7 rs9292795 polymorphism, rather than the donor, was significantly associated with HCC recurrence after OLT. Multivariate logistic regression analysis confirmed that TNM stage (P = 0.001), Milan criteria (P = 0.000) and recipient rs9292795 genotype (TT vs AA/AT, P = 0.008) were independent risk factors for HCC recurrence. Furthermore, the recipient carrying AA/AT showed higher recurrence-free survival (RFS) and overall survival (OS) than that carrying TT (P

New strategies to decrease risk of relapse after surgery are needed for improving 5‐year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound‐targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti‐PD‐L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface‐coated with platelet membrane (PM) to achieve surgical site targeting in a self‐amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti‐PD‐L1 antibody on the PM surface. The resulting nano‐formulation, abbreviated as a‐PM‐S‐MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a‐PM‐S‐MSNP generate potent anti‐HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti‐HCC immunity and anti‐angiogenesis effect at tumor sites. More importantly, microscopic inspection of a‐PM‐S‐MSNP treated mice shows that 2 out 6 are histologically tumor‐free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a‐PM‐S‐MSNP can efficiently inhibit post‐surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug. [ABSTRACT FROM AUTHOR]

Abstract New strategies to decrease risk of relapse after surgery are needed for improving 5‐year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound‐targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti‐PD‐L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface‐coated with platelet membrane (PM) to achieve surgical site targeting in a self‐amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti‐PD‐L1 antibody on the PM surface. The resulting nano‐formulation, abbreviated as a‐PM‐S‐MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a‐PM‐S‐MSNP generate potent anti‐HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti‐HCC immunity and anti‐angiogenesis effect at tumor sites. More importantly, microscopic inspection of a‐PM‐S‐MSNP treated mice shows that 2 out 6 are histologically tumor‐free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a‐PM‐S‐MSNP can efficiently inhibit post‐surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.

Background: High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer. Methods: Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice. Findings: Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner. Interpretation: TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.

Aim: It remains unclear how direct‐acting antiviral (DAA) treatments influence hepatocellular carcinoma (HCC) recurrence and survival in comparison with interferon (IFN). Methods: In total, 338 patients with chronic hepatitis C virus (HCV) infection and previous HCC treatments who initiated IFN (N = 88, IFN group) or DAA treatment (N = 250, DAA group) from January 2005 to November 2017 at 23 hospitals and achieved sustained virologic response (SVR) were analyzed. Cumulative HCC recurrence and survival rates were compared between the two groups using propensity score (PS) matching. Results: After PS matching, 63 patients were selected for each group. The cumulative HCC recurrence rates at 1 and 3 years were 20.6% and 34.6% in the IFN group and 19.2% and 43.0% in the DAA group, respectively; the difference in cumulative HCC recurrence rates between the two groups was not significant (P = 0.332). No significant differences in HCC recurrence patterns were observed between the two groups. Overall survival rates at 1 and 3 years were 100% and 96.6% in the IFN group and 100% and 96.4% in the DAA group, respectively; the difference in overall survival rates between the two groups was not significant (P = 0.132). No significant differences in HCC recurrence and overall survival rates were observed between the two groups in subgroup analyses of patients receiving curative treatment (liver resection or radiofrequency ablation) for the most recent HCC before HCV treatment. Conclusions: The recurrence rates and patterns of HCC and overall survival rates do not differ between SVR patients receiving IFN and DAA treatments. [ABSTRACT FROM AUTHOR]

To investigate whether the measurement of liver stiffness (LSM) using fibroscan and the serum Cancer Stem Cells (CSC): Ep-CAM and cytokeratin-19, could predict the recurrence of hepatocellular carcinoma (HCC) and their impact on clinical outcome and overall survival. This is a prospective study, including 179 HCV-related HCC patients. All patients were treated following the BCLC guidelines. All HCC patients had transient elastography, measurements of Ep-CAM and cytokeratin-19 before and six months post-treatment. We looked for predictors of recurrence and performed a survival analysis using Kaplan-Meier estimates. TACE was the most common procedure (77.1%), followed by microwave ablation (15.6%). Complete ablation was achieved in 97 patients; 55 of them developed HCC recurrence. After treatment, LSM increased significantly with a significant reduction in CSCs levels in complete and partial response groups. The median time to observe any recurrence was 14 months. LSM increased significantly post-treatment in patients with recurrence versus no recurrence. Higher levels of CSCs were recorded at baseline and post-treatment in patients with recurrence but without statistical significance. We used univariate analysis to predict the time of recurrence by determining baseline CK-19 and platelet levels as the key factors, while the multivariate analysis determined platelet count as a single factor. The univariate analysis for prediction of overall survival included several factors, LSM and EpCAM (baseline and post-ablation) among them, while multivariate analysis included factors such as Child score B and incomplete ablation. Dynamic changes were observed in LSM and CSCs levels in response to HCC treatment and tumour recurrence. Child score and complete ablation are factors that significantly affect survival. [ABSTRACT FROM AUTHOR]

Despite the improvements in surgical and medical therapy for hepatocellular carcinoma (HCC), recurrence still represents a major issue. Up to 70% of patients can experience HCC recurrence after liver resection (LR), as well as 20% of them even after liver transplantation (LT). The patterns of recurrence are different according to both the time and the location. Similarly, the risk factors and the management can change not only according to these patterns, but also according to the underlying liver condition and to the first treatment performed. Deep knowledge of such correlation is fundamental, since prevention and effective management of recurrence are undoubtedly the most important strategies to improve the outcomes of HCC treatment. Without adjuvant therapy, maintaining very close monitoring during the first 2 years in order to diagnose curable recurrence and continue this monitoring beyond 5 years because late recurrences exist, remains our only possibility today. Surgery represents the cornerstone treatment for HCC, including both LT and LR. However, new interesting therapeutic opportunities are coming from immunotherapy that has shown encouraging results also in the adjuvant setting. In such a complex and evolutionary scenario, the aim of this review is to summarize current strategies for the management of HCC recurrence, focusing on the different possible scenarios, as well as on future perspectives., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-579/coif). B.G. and F.P. serve as the unpaid editorial board members of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2024 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: With advent of direct-acting antiviral agents (DAA), hepatitis C virus (HCV) treatment is dramatically increasing. Although few studies reported rates of hepatocellular carcinoma (HCC) recurrence following DAA treatment, there have been no studies that followed sufficient number of DAA-treated patients after successful HCC treatment to examine HCC recurrence.Methods: We conducted a cohort study of HCV+ patients who had successfully treated HCC before initiating DAAs. We conducted medical record reviews to confirm HCC diagnosis, treatment, and remission prior to DAA initiation, and subsequent HCC recurrence. We calculated HCC recurrence rate and examined the recurrent tumor characteristics. We used Cox proportional hazard model to identify factors associated with HCC recurrence.Results: We identified 264 HCV+ patients who received DAAs after an average of 30.9 (20.6) months following HCC treatment. HCC recurred in 26.1% patients during 23.3 (9.8) months follow-up, at a rate of 0.38 [0.30, 0.48] per 1000 person-month. Most (82.3%) recurrent HCC were early stage. Receiving non-curative treatment for HCC was associated with a higher risk of recurrence than curative treatment (HRadj = 2.06, [1.24, 3.40]). The risk of HCC recurrence decreased with longer duration between HCC treatment completion and DAA initiation (HRadj = 0.97, [0.95, 0.99] per additional month). Compared with patients who achieved sustained virological response (SVR), those without SVR had significantly increased risk of HCC recurrence (HRadj = 4.17, [1.48, 11.75]).Conclusions: We conclude that most HCV+ patients with HCC benefit from DAA treatment; however, timing of DAA initiation after HCC treatment should be carefully considered. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Predictive factors for early and late recurrence of HCC are different. • Early recurrence of HCC is associated with underlying primary HCC and surgical techniques and strategies. • Late recurrence is associated with the degree of portal hypertension assessed by spleen stiffness measurement. Background & Aims Hepatocellular carcinoma (HCC) is a frequent complication of liver disease. When feasible, hepatic resection is the first-choice therapy. However, tumor recurrence complicates at least 2/3 hepatic resections at 5 years. Early recurrences are mainly tumor or treatment-related, but predictors of late recurrences are undefined. We aimed to evaluate the factors related to HCC recurrence after curative resection, with liver and spleen stiffness measurement (LSM and SSM) as markers of severity and duration of the underlying liver disease. Methods We enrolled patients with chronic liver disease and primary HCC suitable for hepatic resection. We followed up patients for at least 30 months or until HCC recurrence. We performed uni- and multivariate analyses to evaluate the predictive role of tumor characteristics, laboratory data, LSM and SSM for both early and late recurrence of HCC. Results We prospectively enrolled 175 patients. Early HCC recurrence at multivariate analysis was associated with viral etiology, HCC grading (3 or 4), resection margins <1 cm and being beyond the Milan criteria. HCC late recurrence at univariate analysis was associated with esophageal varices (hazard ratio [HR] 3.321, 95% CI 1.564–7.053), spleen length (HR 3.123, 95% CI 1.377–7.081), platelet/spleen length ratio if <909 (HR 2.170, 95% CI 1.026–4.587), LSM (HR 1.036, 95% CI 1.005–1.067), SSM (HR 1.046, 95% CI 1.020–1.073). HCC late recurrence at multivariate analysis was independently associated only with SSM (HR 1.046, CI 1.020–1.073). Late HCC recurrence-free survival was significantly different according to the SSM cut-off of 70 kPa (p = 0.0002). Conclusions SSM seems to be the only predictor of late HCC recurrence, since it is directly correlated with the degree of liver disease and portal hypertension, both of which are involved in carcinogenesis. Lay summary The main result of this study is that spleen stiffness measurement, evaluated by transient elastography, seems to be the only predictor of the late recurrence of hepatocellular carcinoma, defined as recurrence after 24 months from liver resection. Indeed, spleen stiffness measurement is directly correlated with the degree of liver disease and portal hypertension, which are both involved in carcinogenesis. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • There was no significant difference in the early HCC recurrence rate and pattern between IFN-based and DAA therapy. • High AFP-L3, short recurrence-free period, and history of multiple HCC treatments were risk factors for early recurrence. • Eradication of HCV after curative HCC treatments could preserve liver function, regardless of antiviral therapy regimen. Background & Aims It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C. Methods We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C). Results The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70). Conclusions HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy. Lay summary We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy. [ABSTRACT FROM AUTHOR]

Highlights • Solitary adrenal recurrence of HCC after LDLT is extremely rare. • Strict follow up protocol is necessary to allow early detection of tumor recurrence. • Curative surgical resection of solitary recurrent HCC is a safe option. • It is associated with low morbidity and expected to have a good long-term survival. Abstract Introduction The adrenal gland is a rare site for hepatocellular carcinoma (HCC) recurrence after living-donor liver transplantation (LDLT). Solitary adrenal recurrence can be managed by surgical excision, with expected better survival outcomes. We describe a rare case of successful left adrenalectomy of solitary recurrent HCC in the left adrenal gland 5 years after LDLT. Presentation 59 years male patient with HCC complicating chronic HCV infection received a right hemi-liver graft from his son. The actual graft weight was 1208 g and GRWR was 1.5. The patient started oral direct acting antiviral drugs for recurrent HCV 2 years after LDLT. A left adrenal mass was detected on follow up radiology. No other metastatic lesions were detected on metastatic workup. Left adrenalectomy was done by an anterior approach. The postoperative course was uneventful and was discharged a week after operation. Postoperative pathological and immune-histochemical examinations confirmed the metastatic HCC nature of the mass. The patient is under regular follow up with no recurrences 6 month after resection. Discussion There is no consensus regarding the management of HCC recurrence after LDLT. Most patients had multi-organ recurrences and usually offered palliative or supportive care. Solitary HCC recurrence offers a better chance for more aggressive therapy, offering better prognosis. Conclusion Solitary adrenal recurrence of HCC after LDLT is extremely rare. Strict follow up protocol is necessary to allow early detection of tumor recurrence. Curative surgical resection is a safe option associated with low morbidity and expected to have a good long-term survival. [ABSTRACT FROM AUTHOR]

Objective The primary objective of this study was to compare between liver resection (LR) and radiofrequency ablation (RFA) in the management of early hepatocellular carcinoma (HCC). We are trying to provide an update that can be valuable in clinical practice for determining the most suitable first-line management option for early HCC. Patients and methods The study included 80 patients with early HCC according to the Barcelona Clinic Liver Cancer staging system. Patients were divided into two groups: group A included 40 (50%) patients treated through LR, whereas group B included 40 (50%) patients managed through percutaneous RFA. In this study, we used the alternation method as an allocation process in this study. Procedures in both groups were done according to conventional principles. Percutaneous RFA technique was done under the guidance of ultrasonography (US) in complete aseptic conditions. Collected data included procedure time, intraoperative bleeding, postoperative complications, pain score, ICU, and the total hospital stay days. After procedures, patients were monitored every three months throughout the follow-up period. Results A total of 80 patients with early HCC underwent treatment with LR (N=40) and with RFA (N=40). There is a significant difference between both groups regarding the mean time of the procedure: 145±19.8 versus 40.6±7.8 min for LR and RFA, respectively. Rates of recurrence significantly (P<0.05) correlated with age and tumor size in both groups. No significant difference was observed in rates of recurrence or the time of recurrence (P>0.05) between LR and RFA groups. However, the recurrence percentage was slightly higher among patients treated by RFA compared with LR group. Conclusion Our prospective comparative study offers evidence that RFA provides a novel treatment for early HCC, and it shows survival and tumor relapse rates comparable to LR. [ABSTRACT FROM AUTHOR]

Background: The effects of postoperative adjuvant therapy for high-risk recurrent hepatocellular carcinoma (HCC) in immunotherapy are still under investigation. This study evaluated the preventive effects and safety of postoperative adjuvant therapy, including atezolizumab, and bevacizumab, against the early recurrence of HCC with high-risk factors., Methods: The complete data of HCC patients who underwent radical hepatectomy with or without postoperative adjuvant therapy after two-year follow-up were analyzed retrospectively. The patients were divided into high-risk or low-risk groups based on HCC pathological characteristics. High-risk recurrence patients were divided into postoperative adjuvant treatment and control groups. Due to the difference in approaches in postoperative adjuvant therapies, they were divided into transarterial chemoembolization (TACE), atezolizumab, and bevacizumab (T + A), and combination (TACE+T + A) groups. The two-year recurrence-free survival rate (RFS), overall survival rate (OS), and associated factors were analyzed., Results: The RFS in the high-risk group was significantly lower than that in the low-risk group (P = 0.0029), and the two-year RFS in the postoperative adjuvant treatment group was significantly higher than that in the control group (P = 0.040). No severe complications were observed in those who received atezolizumab and bevacizumab or other therapy., Conclusion: Postoperative adjuvant therapy was related to two-year RFS. TACE, T + A, and the combination of these two approaches were comparable in reducing the early recurrence of HCC without severe complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

Aim Recurrence of hepatocellular carcinoma (HCC) is observed frequently, even after curative treatments. The aim of this study is to elucidate the risk factors for recurrence of HCC after radiofrequency ablation (RFA), focusing on the carcinogenic potential of the liver assessed by α-fetoprotein (AFP). Methods We enrolled 357 consecutive patients who underwent complete ablation by RFA for primary HCC (≤3 cm, ≤3 tumors) and analyzed the correlation between 17 critical parameters, including AFP and HCC recurrence. Results Recurrence was observed in 236 patients during a mean observation period of 54.3 months. Multivariate analysis revealed that multiple tumors (risk ratio [RR] = 1.70, 95% confidence interval [CI] = 1.27-2.26, P < 0.001), high AFP (>10 ng/mL, RR = 1.45, 95% CI = 1.09-1.94, P < 0.001) and high des-γ-carboxyprothrombin (>40 mAU/mL, RR = 1.52, 95% CI = 1.13-2.02, P < 0.005) were significantly correlated with recurrence. AFP was selected as a significant factor even when the cut-off level was set lower (≤5 ng/mL). The risk of recurrence increased linearly according to the increase of the lowest AFP level after RFA and the adjusted ratios relative to AFP less than 5 ng/mL were 1.56, 2.14, 2.57 and 3.13 in AFP 5-10 ng/mL, 10-20 ng/mL, 20-50 ng/mL and over 50 ng/mL, respectively. In addition, the recurrence rate was predicted by the AFP level after RFA, regardless of the level before the treatment. Conclusion AFP less than 5 ng/mL after curative RFA was an important predictor of a better prognosis and was considered to indicate the low carcinogenic potential of the non-cancerous liver. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CNIs) have been associated in a dose-dependent fashion with an increased risk of post-transplant hepatocellular carcinoma (HCC) recurrence. The mammalian target of rapamycin inhibitors (mTORi) (sirolimus/everolimus) might represent an alternative immunosuppressive regimen with antineoplastic effect. In the present systematic review, the association between mTORi and HCC recurrence after liver transplantation (LT) was evaluated and compared against that of CNIs-treated patients. In total, 3666 HCC liver transplant recipients from 42 studies met the inclusion criteria. Patients under CNIs developed HCC recurrence significantly more frequently, compared with patients under mTORi (448/3227 or 13.8% vs. 35/439 or 8%, P < 0.001), although patients treated with CNIs had a higher proportion of HCC within Milan criteria (74% vs. 69%) and lower rates of microvascular invasion, compared with mTORi-treated patients (22% vs. 44%) (P < 0.05). Patients on everolimus had significantly lower recurrence rates of HCC, compared with those on sirolimus or CNIs (4.1% vs. 10.5% vs. 13.8%, respectively, P < 0.05), but everolimus-treated recipients had shorter follow-up period (13 vs. 30 vs. 43.2 months, respectively) and more frequently been transplanted for HCC within Milan criteria (84% vs. 60.5% vs. 74%, respectively, P < 0.05). Our findings favor the use of mTORi instead of CNIs to control HCC recurrence after LT, but comparative studies with longer follow-up are needed for final conclusions. [ABSTRACT FROM AUTHOR]

Many end-stage liver disease etiologies are attributed to robust inflammatory cell recruitment. Neutrophils play an important role in inflammatory infiltration and neutrophil phagocytosis, oxidative burst, and degranulation. It has also been suggested that neutrophils may release neutrophil extracellular traps (NETs) to kill pathogens. It has been proven that neutrophil infiltration within the liver contributes to an inflammatory microenvironment and immune cell activation. Growing evidence implies that NETs are involved in the progression of numerous complications of liver transplantation, including ischemia-reperfusion injury, acute rejection, thrombosis, and hepatocellular carcinoma recurrence. NETs are discussed in this comprehensive review, focusing on their effects on liver transplantation complications. Furthermore, we discuss NETs as potential targets for liver transplantation therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Yan, Bin, Qin and Wu.)

Background: It is still unknown whether laparoscopic liver resection is suitable for recurrent hepatocellular carcinoma (HCC) after previous curative hepatic resection. Method: The perioperative outcomes of 40 patients treated with second surgery for recurrent HCC by partial hepatectomy were studied retrospectively. The second surgery was performed under laparotomy in 20 patients (laparotomy group) and under laparoscopy in 20 patients (laparoscopy group). Results: Intraoperative blood loss ( p < 0.0001) and the incidence of postoperative complications ( p = 0.0004) were lower in the laparoscopy group than in the laparotomy group. The incidence rates of surgical site infection and intractable ascites were significantly higher in the laparotomy group than in the laparoscopy group ( p = 0.0202, p = 0.0436, respectively). The proportion of patients classified as Clavien grade IIIa was higher in the laparotomy group than in the laparoscopy group ( p = 0.0033). The duration of the postoperative hospital stay was significantly shorter in the laparoscopy group than in the laparotomy group ( p < 0.0001). Conclusions: Postoperative morbidity has been decreased by the introduction of laparoscopic liver resection in patients with recurrent HCC after curative hepatic resection. As a result, the duration of the postoperative stay is shorter. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, the rate of hepatocellular carcinoma (HCC) recurrence (HCC-R) after hepatitis C virus eradication by direct-acting antiviral (DAA) treatment was relatively high, corresponding to 63.8% (83/130) of the studied cases. The patients who electively received palliative treatment before DAA treatment and showed a shorter interval period between the last treatment for HCC and DAA initiation, also displayed a significant increase in alpha-fetoprotein during follow-up after therapy, relative to cases without HCC-R. Overall, the survival was comparable in both groups because of the improvement in liver function tests after the DAA therapy, and thus no differences in survival rates were observed between patients with or without HCC-R. The results of this study indicate that interferon (IFN)-free DAA treatment after treatment for HCC could be recommended to improve prognosis in this subset of cases. However, it remains imperative to observe the timing, i.e., at least 9–12 months after the last treatment for HCC, before proposing DAA therapy. There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924–8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016–1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered. [ABSTRACT FROM AUTHOR]

The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as "seeds" in peripheral blood, then reach the target organ as dormant cells which could be subsequently "awakened" and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The aim of the study was to determine factors influencing hepatocellular carcinoma (HCC) recurrence in a cohort of patients who underwent liver transplantation (LT) at a large, tertiary-care medical center., Methods: A total of 132 patients with the diagnosis of HCC at time of transplant were evaluated for HCC recurrence over a 7-year period. Nine patients were found to have HCC recur post-LT., Results: No significant demographic values were found to indicate recurrence. Pre-LT factors potentially influencing HCC recurrence rates included number of days between HCC diagnosis and date of LT (P = 0.015), caudate lobe involvement (P = 0.019), increased use of radiation therapies pre-LT (P = 0.011), and total number of locoregional therapies (LRT) pre-LT (P < 0.001). Post-transplant outcomes demonstrated a significant difference in deep venous thrombosis (DVT) in the recurrent vs. non-recurrent groups (P = 0.035)., Conclusions: The prevalence of HCC recurrence in this study was lower than the national average, yet difficulty still exists in predicting pre-LT factors which may influence HCC recurrence rates., Competing Interests: None to declare., (Copyright 2021, Zucker et al.)

Background: Although it has now been excluded that direct-acting antivirals (DAA) are associated with a significant risk of hepatocellular carcinoma (HCC) in HCV-infected patients, a possible effect of DAA on tumor growth is still a subject of debate. We performed a blind comparison of the kinetics of HCC recurrence in patients after HCV treatment with or without DAA to evaluate the potential aggressiveness of HCC after DAA treatment., Basic Procedures: Thirty-nine HCV-infected patients from the AFEF/ANRS CO22 Hepather cohort who experienced HCC recurrence after so-called curative treatment were evaluated. Contrast-enhanced CT and/or MR images were read blindly 6 months before HCC recurrence and during the follow-up period. Seventeen patients who received DAA (DAA+) before HCC recurrence were compared to the 22 who did not receive (DAA-), according to the LiRads and mRECIST criteria., Main Findings: There were 28 men and 11 women, median age 62 years old, 37 (95%) with cirrhosis. DAA+ patients had a lower median MELD score (8±2 vs. 10±4, P=0.0286) than DAA- patients. The median time to HCC recurrence (time from the date of curative treatment to the diagnosis of recurrence) was not different (20 vs. 18 months) (P=0.73) between the two groups. There was no difference between the 2 groups in the overall survival and/or transplantation-free survival (P=0.71) and for the mRECIST time to progression (P=0.25)., Conclusion: This blinded analysis of HCC recurrence after HCC treatment does not support any negative impact of DAA therapy on the severity or progression of recurrent HCC., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer., Methods: Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice., Findings: Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner., Interpretation: TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC), a malignant form of cancer, is frequently treated with surgical resections, which have relatively high recurrence rates. Effective recurrence predictions enable physicians' timely detections and adequate therapeutic measures that can greatly improve patient care and outcomes. Toward that end, predictions of early versus late HCC recurrences should be considered separately to reflect their distinct onset time horizons, clinical causes, underlying clinical etiology, and pathogenesis. We propose a novel Bayesian network-based method to predict different HCC recurrence outcomes by considering the respective recurrence evolution paths. Typical patient information obtained in early stages is insufficiently informative to predict recurrence outcomes accurately, due to the lack of subsequent patient progression information. Our method alleviates such information deficiency constraints by incorporating an independent latent variable, dominant recurrence type, to regulate recurrence outcome predictions (early, late, or no recurrence). We use a real-world HCC data set to evaluate the proposed method, relative to three prevalent benchmark techniques. Overall, the results show that our method consistently and significantly outperforms all the benchmark techniques in terms of accuracy, precision, recall, and F-measures. For increased robustness, we use another data set to perform an out-of-sample evaluation and obtain similar results. This study thus contributes to HCC recurrence research and offers several implications for clinical practice. [ABSTRACT FROM AUTHOR]

Background and Aim: The meta-analysis aimed to quantify and summarize the contribution of serum hepatitis B virus (HBV) DNA load in the carcinogenesis and prognosis of hepatocellular carcinoma (HCC)., Results: Nine independent studies with a total of 1162 cases and 9365 participants on risk of HCC and seventeen studies with 1342 cases and 2891 participants on recurrence of HCC were finally included. The non-liner dose-response association between HBV DNA level and HCC risk was observed, with P value equal to 0.02 for linear test. Compared with 2 log10copies/ml HBV DNA level carriers, the summary relative risk of HCC were 1.65(95% CI: 0.94-2.92) for 4.5 log10copies/ml, 2.20(95% CI: 1.00-4.85) for 5.5 log10copies/ml, 3.06(95% CI: 1.11-8.44) for 6.5 log10copies/ml. Moreover, individuals with high viral load (HBV DNA levels > 105copies/ml) presented significant association with increased risk of HCC recurrence, with the pooled RR of 1.69 (95% CI: 1.49-1.92)., Materials and Methods: Pertinent studies were identified by searching PubMed, Embase and ISI Web of science databases up to January 2016 and by reviewing the references of retrieved articles. The dose-response meta-analysis was precisely performed to calculate the summary relative risks (RRs) by quantizing the association between HBV load and risk of HCC. Besides, the contribution of HBV load on recurrence of HCC was further clarified by general meta-analysis., Conclusions: These findings indicated a non-linear dose-response relationship between serum HBV DNA level and risk of HCC, and confirmed the significant contribution of serum HBV DNA level in the prognosis of HCC., Competing Interests: The authors disclose no conflicts of interest.