To develop and validate a comprehensive model for predicting postoperative early recurrence of hepatocellular carcinoma (HCC) based on gadoxetate disodium (Gd-EOB-DTPA)-enhanced MRI.

239 patients with HCC who underwent curative surgical resection were recruited from two centers between April 2017 and December 2022. Radiomics features were extracted from the region of interest (ROI) on preoperative Gd-EOB-DTPA-enhanced MR images, and consistency analysis was performed to select stable radiomics features. Significant variables in the univariate and multivariate logistic regression analysis were included in clinical-radiologic model. Nomograms were constructed by combining the best performing radiologic and clinical-radiologic characteristics. Recurrence-free survival (RFS) comparisons were conducted using the log-rank test based on high versus low model-derived scores.

The radiomics model based on multiple phases MR outperformed all other radiomics models and had the best discrimination for early recurrence, with AUC of 0.799 and 0.743 in the training and validation sets, respectively. In the entire cohort, high-risk patients exhibited significantly lower RFS compared to low-risk patients.

The nomogram integrating Gd-EOB-DTPA enhanced MRI radiomics features and clinical-radiologic characteristics demonstrate superior predictive performance with postoperative early recurrence in patients with HCC. The model can identify patients at high risk and provide support for individualized treatment planning.

The high recurrent rate after surgery hinders the survival of patients with hepatocellular carcinoma (HCC). This prospective cohort study aimed to evaluate the efficacy and safety of lenvatinib plus transarterial chemoembolization (TACE) as an adjuvant therapy in HCC patients with high risk of recurrence.

Patients were enrolled from eight hepatobiliary centers in China. The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS) and safety. Additionally, propensity score matching (PSM) and other three propensity score analyses were performed to balance the potential baseline bias to validate the conclusion. The adverse events (AEs) were recorded throughout the study. The study was registered at ClinicalTrials.gov (NCT03838796).

A total of 297 patients were enrolled, with 147 in the LEN + TACE group and 150 in the TACE group. Before PSM, the LEN + TACE group achieved significantly better DFS than the TACE group (19.0 vs. 10.0 months, P = 0.011). PSM analysis identified 111 matched pairs. After PSM, the LEN + TACE group also showed better DFS (19.0 vs. 9.0 months, P = 0.018). Other three propensity score analyses yielded similar DFS benefit tendency. Furthermore, favorable OS was also obtained in the LEN + TACE group before PSM. Lenvatinib related AEs of grade 3 or 4 occurred in 28.6% of the patients in the LEN + TACE group.

Adjuvant lenvatinib plus TACE might be a promising adjuvant approach for HCC patients with high risk of recurrence, which could significantly prolong DFS and potentially OS with a manageable safety profile.

To develop and externally validate an MRI-based diagnostic model for microvascular invasion (MVI) or Edmondson-Steiner G3/4 (i.e., high-risk histopathology) in solitary BCLC 0/A hepatocellular carcinoma (HCC) ≤ 5 cm and to assess its performance in predicting adjuvant therapy benefits.

This multicenter retrospective cohort study included 577 consecutive adult patients who underwent contrast-enhanced MRI and subsequent curative resection or ablation for solitary BCLC 0/A HCC ≤ 5 cm (December 2011 to January 2024) from four hospitals. For resection-treated patients, a diagnostic model integrating clinical and 50 semantic MRI features was developed against pathology with logistic regression analyses on the training set (center 1) and externally validated on the testing dataset (centers 2-4), with its utilities in predicting posttreatment recurrence-free survival (RFS) and adjuvant therapy benefit evaluated by Cox regression analyses.

Serum α-fetoprotein > 100 ng/mL (odds ratio (OR), 1.94; p = 0.006), non-simple nodular growth subtype (OR, 1.69; p = 0.03), and the VICT2 trait (OR, 4.49; p < 0.001) were included in the MVI or high-grade (MHG) trait, with testing set AUC, sensitivity, and specificity of 0.832, 74.0%, and 82.5%, respectively. In the multivariable Cox analysis, the MHG-positive status was associated with worse RFS (resection testing set HR, 3.55, p = 0.02; ablation HR, 3.45, p < 0.001), and adjuvant therapy was associated with improved RFS only for the MHG-positive patients (resection HR, 0.39, p < 0.001; ablation HR, 0.30, p = 0.005).

The MHG trait effectively predicted high-risk histopathology, RFS and adjuvant therapy benefit among patients receiving curative resection or ablation for solitary BCLC 0/A HCC ≤ 5 cm.

Question Despite being associated with increased recurrence and potential benefit from adjuvancy in HCC, microvascular invasion or Edmondson-Steiner grade 3/4 are hardly assessable noninvasively. Findings We developed and externally validated an MRI-based model for predicting high-risk histopathology, post-resection/ablation recurrence-free survival, and adjuvant therapy benefit in solitary HCC ≤ 5 cm. Clinical relevance Among patients receiving curative-intent resection or ablation for solitary HCC ≤ 5 cm, noninvasive identification of high-risk histopathology (MVI or high-grade) using our proposed MRI model may help improve individualized prognostication and patient selection for adjuvant therapies.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in China. The rapid progress in systemic therapies has led to the approval of many therapeutic methods that have quickly changed clinical guidelines and practices. Because of the high heterogeneity of HCC, there are still some gaps between the guidelines and real-world clinical practice. The present study surveyed experts in China to investigate the current treatment concepts and clinical practice regarding HCC.

A questionnaire survey on the treatment concepts and clinical practice of HCC was administered to 310 experts with senior professional titles in 2020 and 312 experts in 2021. The results were analyzed and compared.

For treating patients with resectable HCC, 28% of hepatobiliary surgeons indicated neoadjuvant therapy, and 7% chose systemic therapy ± locoregional therapy as 1 L therapy in 2021 compared with 20% and 1% in 2020. More experts chose adjuvant treatment within 1 month in 2021 compared with 2020, and 6 months and 12 months were the leading choices for the duration of adjuvant treatment. In 2021, 79% of surgeons and 19% of interventionalists were willing to conduct downstaging/conversion therapy for patients with potentially resectable HCC, and 78% chose tyrosine kinase inhibitors (TKI) + immunotherapy (IO) + locoregional therapy for cases in which R0 resection could not be achieved. For completely unresectable HCC, more experts preferred TKI + IO-based therapy as 1 L therapy in 2021 compared with 2020 (78% vs. 55%). The proportion of experts who indicated TKI + IO-based therapy as 2 L therapy increased from 32% in 2020 to 40% in 2021.

The survey results indicated that in 2021, compared with 2020, more experts opted to administer IO + TKI for the treatment of liver cancer, and more experts and patients were willing to participate in clinical research.

The risk of hepatocellular carcinoma (HCC) recurrence following surgical resection remains high, approaching 50%-70% at 5 years, with the highest risk occurring in the first year after resection. This study aimed to evaluate the efficacy and safety of lenvatinib as adjuvant therapy for HCC.

In this open-label, single-arm, prospective, multicenter Phase II clinical study, a total of 51 hCC patients with China Liver Cancer (CNLC) stage IIb/IIIa (ie tumor number ≥ 4 or vascular invasion, equivalent to BCLC B/C) who underwent R0 resection 4-6 weeks after curative surgery were enrolled. Patients received lenvatinib for up to 12 months, at a dose of 8 mg/day for body weight < 60 kg, or 12 mg/day for ≥ 60 kg. Patients were followed up every 2 months for a median of 24.1 months.

The median recurrence-free survival (RFS) was 16.1 months, with a 12-month RFS rate of 60.4%, exceeding the historical rate of under 50% in similar high-risk populations. The 12-month overall survival (OS) rate was 93.6%, while median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 88.0% of patients, with ≥ grade 3 TRAEs in 14.0%, including thrombocytopenia and proteinuria in 6.0% of patients each, and leukopenia, neutropenia, elevated aspartate aminotransferase, and elevated alanine aminotransferase in 2.0% of patients each. AEs leading to the interruption of lenvatinib occurred in 6.0% of patients, and dose reduction was required in 18% of patients. No deaths were observed.

Lenvatinib may be an effective adjuvant therapy for patients with CNLC stage IIb/IIIa HCC after R0 hepatectomy. However, the findings are limited by the single-arm design and small patient cohort, necessitating larger randomized controlled trials for validation.

Primary liver cancer ranks as the sixth most prevalent malignant tumor and stands as the second leading cause of cancer-related mortality globally, posing a significant threat to public health. Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Surgical resection remains the cornerstone treatment for achieving radical cure and prolonged survival in HCC patients. Contrary to Western countries, the majority of HCC patients in China present with hepatitis B virus infection and consequent liver cirrhosis, with most cases diagnosed at an intermediate or advanced stage. This complexity results in a poor prognosis. Recent advancements in local therapeutic techniques and the introduction of systemic therapies, including targeted and immunotherapy agents, have provided new avenues for both clinical and basic conversion therapy for advanced HCC. Integrating multi-dimensional local and systemic therapies, multi-modal sequential, and comprehensive multidisciplinary approaches into the management of HCC patients has demonstrated promising conversion success rates. This holistic management strategy involves combining multiple treatment modalities vertically and coordinating various disciplines horizontally. However, significant challenges remain, including the precise selection of patients eligible for conversion therapy, the optimal choice of conversion therapy regimens, and the accurate determination of surgical timing post-conversion therapy. Addressing these challenges is crucial for hepatobiliary surgeons. High-quality, randomized controlled trials are urgently needed to generate robust evidence for clinical practice. This review aims to synthesize the latest research developments both in China and internationally and examines key issues in the realm of HCC conversion therapy.

The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

After the global approval of atezolizumab plus bevacizumab and chemotherapy as first-line metastatic nonsquamous non-small-cell lung cancer (nsqNSCLC) treatment, the IMpower151 ( NCT04194203 ) trial was conducted in China to address regional differences. Chemotherapy-naive patients with metastatic nsqNSCLC (N = 305) were randomized 1:1 to receive either atezolizumab, bevacizumab, carboplatin and paclitaxel or pemetrexed (ABCPem/Pac; n = 152) or placebo plus bevacizumab, carboplatin and pemetrexed or paclitaxel (BCPem/Pac; n = 153). The primary endpoint was investigator-assessed progression-free survival (INV-PFS); secondary endpoints included subgroup analyses of INV-PFS, independent review facility-assessed PFS, overall survival, and investigator-assessed objective response rate and duration of response per RECIST v.1.1. Most patients (97%) received pemetrexed, and 53% had EGFR+ tumors. Median INV-PFS for ABCPem/Pac versus BCPem/Pac was 9.5 versus 7.1 months (stratified hazard ratio: 0.84; 95% confidence interval: 0.65, 1.09; P = 0.184). INV-PFS across subgroups and independent review facility-assessed PFS were consistent with INV-PFS in the intention-to-treat population. Median overall survival was 20.7 versus 18.7 months in the ABCPem/Pac versus BCPem/Pac arms, respectively (stratified hazard ratio: 0.93; 95% confidence interval: 0.67, 1.28). Confirmed objective response rate with ABCPem/Pac versus BCPem/Pac was 48% versus 50%, respectively; median duration of response was 11.3 versus 8.3 months. Adverse events of special interest for atezolizumab were observed in 68% (grades 3 and 4: 11%) and 71% (grades 3 and 4: 7%) of patients receiving ABCPem/Pac and BCPem/Pac, respectively. The most common adverse events of special interest for atezolizumab in the ABCPem/Pac and BCPem/Pac arms were hepatitis (driven by laboratory abnormalities; mostly low grade), hypothyroidism and rash. Overall, IMpower151 did not meet its primary endpoint (INV-PFS) in metastatic nsqNSCLC. ABCPem/Pac was generally well tolerated, with no new safety signals. Trial registration number: ClinicalTrials.gov, NCT02366143.

Investigative work in the treatment of hepatocellular carcinoma is rapidly growing with the advent of immunotherapy. Nonetheless, trial endpoints and, more importantly, clinically meaningful endpoints need to be accurately chosen depending on the phase of trial and the patient population studied. We provide a scoping review focusing on trial endpoints on the use of immunotherapy in hepatocellular carcinoma.

We searched PubMed and Google Scholar for prospective phase II and III trials using immunotherapy, whether in the neoadjuvant, adjuvant, bridging, downstaging, or palliative settings, while discussing the clinical implications of trial endpoints.

The field of immune oncology is rapidly progressing and has become the standard of care in advanced hepatocellular carcinoma. However, the role of immunotherapy in the treatment of early and intermediate stage hepatocellular carcinoma is yet to be defined. Prospective trials for all stages of disease must strive for endpoints that are not only statistically significant but also clinically consequential. Whereas overall response rate may be a reasonable trial endpoint in phase II trials, phase III trials should rather aim for the improvement of overall survival or quality of life to have clinically meaningful impacts.

Significant advances have occurred in the locoregional and systemic therapy landscape for hepatocellular carcinoma (HCC), with the most notable being the introduction of immune checkpoint inhibitor (ICI) combinations. ICI combinations have significantly improved the overall survival of patients with unresectable HCC, affording median survival over 2 years and long-term survival exceeding 5 years in a subset of patients. Accordingly, there has been increased interest in the earlier application of systemic therapies, including (neo)adjuvant therapy in the perioperative setting or in combination with intra-arterial therapies. However, recent data failed to demonstrate improved recurrence-free survival with use of adjuvant ICI therapy. Conversely, 2 trials showed improved progression-free survival when ICI therapies were combined with transarterial chemoembolization, although data regarding the impact on overall survival are still immature. These improved outcomes raise several new questions, including which patients with liver-localized HCC should receive systemic therapy, how should this be sequenced or combined with other available therapies, and how to manage those patients with marked responses, including consideration of liver transplantation. These questions are often determined on a case-by-case basis and best made in a multidisciplinary manner considering several factors, including tumor burden, degree of liver dysfunction, performance status, and patient's long-term goals of care.

The purpose of this study was to demonstrate the impact of postoperative adjuvant transarterial chemoembolization (TACE) on the prognosis of patients with macrotrabecular-massive hepatocellular carcinoma (MTM-HCC).

This retrospective study used the clinical records of patients with resected MTM-HCC with/without adjuvant TACE at three centers between January 2015 and December 2022. The primary end point was recurrence free survival (RFS). The secondary end points were overall survival (OS) and safety.

A total of 559 eligible patients were classified into the adjuvant TACE group and the observation group. After propensity score matching analysis, both RFS (HR 0.62 [95% CI, 0.48 to 0.80]; P < 0.001) and OS (HR 0.59 [95% CI, 0.42 to 0.84]; P = 0.013) in the adjuvant TACE group were significantly better than the observation group. By Cox regression models, mALBI grade, types of hepatectomy, number, satellite lesion, without adjuvant TACE were identified as independent risk factors for RFS, and mALBI grade, number, maximum tumor size, satellite lesion, microvascular invasion, high AFP level, without adjuvant TACE were identified as independent risk factors for OS. The incidence of surgery-related adverse events (AEs) had no significant difference between the two groups (P = 0.609). The majority of AEs associated with adjuvant TACE were grade I (84.4%), and no treatment-related deaths occurred in either group.

Adjuvant TACE significantly improved the RFS and OS of patients with resected MTM-HCC with acceptable toxicity.

Hepatocellular carcinoma is the most common primary liver tumor and is strongly related to underlying liver cirrhosis. Common etiologies include viral hepatitis, elevated alcohol consumption and metabolic diseases, all of which result in liver inflammation and scarring. Previously, systemic therapies for locally advanced or metastatic disease were limited to tyrosine kinase inhibitors with poor efficacy and rare cures. Recent advances have harnessed the power of the immune system to combat disease, resulting in improved outcomes and occasional cures. Here, we describe the recent clinical trials in immunotherapies for the treatment of hepatocellular carcinoma as first- and second-line therapies and in combination with other drug classes.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally, owing to its high recurrence rate of 50 to 70% within five years. Despite known associations of certain DNA damage and repair (DDR) genes with tumor recurrence and drug resistance, a comprehensive understanding of DDR pathways' role in predicting HCC recurrence and therapeutic responses remains elusive. Addressing this gap could offer significant advancements in prognostic and therapeutic strategies for HCC. This study used 769 RNA sequencing samples from public datasets and 53 samples from Xiangya Hospital for DDR model training and validation. It came out that DDR pathways were significantly enriched in samples with P53 mutations. Next, among the 173 combinations of algorithms and parameters, CoxBoost + RSF, Lasso [fold = 10] + RSF, and Lasso [fold = 50] + RSF demonstrated the best performance. The average AUC values of 1 to 5 years and the average concordance index (C-index) value were around 0.7. The risk scores were increased in tumors with recurrence, P53 mutation, and higher TNM stages. High-risk groups, characterized by enriched DDR pathways, exhibited lower CD8 + T cell infiltration and poorer responses to immunotherapy using atezolizumab and bevacizumab, emphasizing the potential of DDR signatures as valuable prognostic and therapeutic biomarkers. In conclusion, the DDR signatures associated with P53 mutations can predict recurrence and therapeutic response in HCC, highlighting their potential as prognostic and therapeutic biomarkers.

Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.

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.

Relapse after radical treatment remains a major concern in hepatocellular carcinoma (HCC), affecting 50-75 % of early-stage cases within 5 years. Early recurrence prediction is a clinical unmet need. Circulating blood biomarkers could provide a minimally invasive approach to detect minimal residual disease (MRD) post-intervention. Although alpha-fetoprotein has been the primary biomarker in this setting, its MRD sensitivity is limited to 50-70 %. This systematic review aims to summarize available evidence regarding the clinical validity and potential utility of emerging circulating blood biomarkers for MRD detection in HCC patients.

We searched PubMed and Embase for peer-reviewed articles and abstracts published up to 2025, and ClinicalTrials.gov for ongoing trials on circulating blood biomarkers for MRD in HCC.

A total of 91 studies (74 with results and 17 ongoing, out of 2,386) were retrieved. We evaluated various blood biomarkers, including circulating DNA (cDNA, N = 24), circulating tumor cells (CTCs, N = 20), circulating RNA (cRNA, N = 8), and other miscellaneous (N = 22) for MRD detection in HCC. These biomarkers demonstrated encouraging results, albeit with notable heterogeneity. In particular, circulating tumor DNA (ctDNA) and CTCs stand as the most robust novel approaches, with 50-80 % sensitivity and specificity up to 94 %. Nonetheless, none of the 17 ongoing studies involve biomarker-driven intervention to prove clinical utility.

Novel circulating blood biomarkers are mature for MRD detection in HCC. However, variability in methodologies and results highlights the need for further validation. We encourage the investigation of CTCs and/or ctDNA in interventional trials to assess clinical utility. This biomarker-driven approach may enhance adjuvant treatment effectiveness in MRD-positive cases while minimizing toxicity in MRD-negative patients.

Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.

The clinical effectiveness of classic anatomical resection (CAR) of the liver for hepatocellular carcinoma (HCC) has been controversial. Laparoscopic Portal Territory fluorescence navigation-guided anatomical liver resection (LPTAR) has been increasingly applied in clinical practice. However, evidence on the safety and efficacy of LPTAR is lacking.

A retrospective cohort study of patients who underwent laparoscopic hepatectomy from December 2018 to December 2022 was conducted. Propensity score matching (PSM) was employed to match patients who underwent LPTAR with patients who underwent CAR. Differences in recurrence-free survival (RFS), overall survival (OS), and perioperative data were evaluated between the LPTAR and CAR groups. Cox regression models were used for univariate and multivariate analyses, as well as subgroup analyses.

Of the 234 patients included in this study, 70 underwent LRTAR, and 164 underwent CAR. After 1:1 PSM, each group contained 59 patients, and perioperative parameters were better in the LPTAR group. Specifically, the LPTAR group had wider resection margins (13.00 cm vs. 11.00 cm, P = 0.023), less blood loss (200 ml vs. 320 ml, P = 0.010), and fewer postoperative complications (33.90% vs. 57.62%, P = 0.016) than did the CAR group. The RFS rates of patients with HCC was also increased by LPTAR. The 1-, 3-, and 5-year RFS rates of the LPTAR group were significantly higher than those of the CAR group (P = 0.002).

Accurate preoperative planning and standardized LPTAR technical criteria prolonged RFS in HCC patients, improved the safety of surgery, and reduced surgical stress.

The study has been prospective registered at Chinese Clinical Trial Registry (https://www.chictr.org.cn/, ChiCTR2400087661).

In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.

Recent advances in the systemic treatment of advanced hepatocellular carcinoma (HCC) with immunotherapy have once again reignited discussion over the role of combined therapy in earlier stages. This year, different international meetings have presented recent results from clinical trials on adjuvant therapy alone (IMBrave-050) and combined with transarterial chemoembolization (EMERALD-1 and LEAP-12). Increased enthusiasm for the use of adjuvant and neoadjuvant therapy for liver transplantation, surgery, and local-regional treatment of HCC has been shown. However, the initial results from these trials should be interpreted cautiously as we wait for final analyses and effects on overall survival. In this position paper from the special interest group from the Latin American Association for the Study of Liver Diseases (ALEH), we underline the caveats of the applicability of these potential treatments in our region, explore points of agreement, and highlight areas of uncertainty. Moreover, we underscore the role of hepatologists in the clinical decision-making process and management of these patients.

Hepatocellular carcinoma (HCC) is increasing in prevalence globally, and cure remains limited with non-operative treatment. Surgical intervention, through resection or transplantation, offers a potential for cure for select patients. However, many patients present with advanced or unresectable disease, and recurrence rates remain high. Recent advances in systemic therapies, particularly immune checkpoint inhibitors, have demonstrated promise in treating unresectable HCC and as adjuvant therapy. Evidence from adjuvant trials highlights the synergistic potential of combined liver-directed and systemic therapies. These findings have ignited growing interest in neoadjuvant therapy across various scenarios: (1) as a bridging strategy while awaiting transplantation, (2) for downstaging disease to enable transplantation, (3) for converting unresectable disease to a resectable state, or (4) as neoadjuvant treatment in operable cases. Early-stage trials of neoadjuvant therapy in resectable HCC have reported promising outcomes. To realize the potential of neoadjuvant treatment for HCC, thoughtfully designed, adequately powered, multi-center clinical trials are essential.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HCC treatment is challenging; surgical resection is the primary curative treatment for early-stage disease, but recurrence rates are high. Immune checkpoint inhibitors (ICIs) are a promising neoadjuvant treatment that can reduce recurrence rates and mortality after surgery and achieve complete/partial responses. Clinical trials provide strong evidence for the efficacy and safety of ICI monotherapy for neoadjuvant HCC treatment.

The incidence and mortality rates of liver cancer in China remain elevated. Although early-stage liver cancer is amenable to surgical resection, a significant proportion of patients are diagnosed at advanced stages. Currently, in addition to surgical resection for hepatocellular carcinoma, the primary treatment modalities predominantly include chemotherapy. The widespread use of chemotherapy, which non-selectively targets both malignant and healthy cells, often results in substantial immunosuppression. Simultaneously, the accumulation of chemotherapeutic agents can readily induce drug resistance upon reaching the physiological threshold, thereby diminishing the efficacy of these treatments. Besides chemotherapy, there exist targeted therapy, immunotherapy and other therapeutic approaches. Nevertheless, the development of drug resistance remains an inevitable challenge. To address these challenges, we turn to nanomedicine, an emerging and widely utilized discipline that significantly influences medical imaging, antimicrobial strategies, drug delivery systems, and other related areas. Stable and safe nanomaterials serve as effective carriers for delivering anticancer drugs. They enhance the precision of drug targeting, improve bioavailability, and minimize damage to healthy cells. This review focuses on common nanomaterial carriers used in hepatocellular carcinoma (HCC) treatment over the past five years. The following is a summary of the three drugs: Sorafenib, Gefitinib, and lenvatinib. Each drug employs distinct nanomaterial delivery systems, which result in varying levels of bioavailability, drug release rates, and therapeutic efficacy.

Hepatocellular carcinoma (HCC), a prevalent malignancy, is often diagnosed at advanced stages. Recent advances have integrated immunotherapy with targeted therapy, significantly improving treatment outcomes. This study provides a bibliometric overview of these therapeutic combinations, evaluating their development and impact.

A rigorous selection process was applied to relevant literature from Web of Science, followed by in-depth bibliometric analyses- including timeline visualization, burst detection, and co-occurrence analysis-using CiteSpace and VOSviewer. This approach offered insights into the contributions of countries, institutions, authors, journals, references, and key terms within the field.

A total of 506 studies published between 2014 and 2023 were included, with all articles in English. Mainland China dominated the publication output, contributing 40% (N = 202), followed by significant contributions from the United States and Japan. Kindai University led institutional contributions, accounting for 7.9% of the total (N = 40). The authors Kudo Masatoshi and Hatanaka Takeshi were the most prolific, each with nine publications. The journal Cancers emerged as the top publisher, with 48 relevant articles and an Impact Factor of 5.2 in 2022. A co-citation network analysis traced the evolution of immunotherapy and targeted therapy combinations in HCC treatment. Early research primarily focused on angiogenesis, dendritic cells, and expression markers, while recent trends have shifted towards phase III trials, adverse reactions, and checkpoint inhibitors, underscoring the field's dynamic progression.

Future research will expand on the pathological mechanisms underlying these therapies and novel interventions and combination strategies. Addressing adverse events and treatment discontinuation will remain central to advancing clinical applications.

Cytokine-induced killer (CIK) cell immunotherapy has shown promise in reducing recurrence and improving survival outcomes in hepatocellular carcinoma (HCC). We evaluated the efficacy and safety of CIK cell therapy in a real-world clinical setting.

A retrospective analysis was conducted on 49 patients who received CIK cell therapy after curative resection or radiofrequency ablation, compared with 49 matched control patients via 1:1 propensity score matching. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS).

The median follow-up durations were 19.1 months for the immune cell group and 67.7 months for the control group. In univariable analysis, the immune cell group demonstrated a prolonged RFS than the control group (hazard ratio [HR], 0.32; 95% CI, 0.15-0.71; log-rank p = 0.001). The median RFS was not reached in the immune cell group but was 48.62 months in the control group. A multivariable Cox regression model identified CIK cell therapy as a significant factor associated with a reduced risk of HCC recurrence (adjusted HR, 0.32; 95% CI, 0.15-0.71; p = 0.005). The median OS was not reached in either group; no significant differences in OS were observed between the immune cell and control groups (log-rank p = 0.082). The overall incidence of adverse events was low, and no Grade 3 or 4 events were reported.

Adjuvant CIK cell immunotherapy after curative treatment significantly prolongs RFS in early-stage HCC patients. Further research regarding the broader applications of CIK cell immunotherapy in HCC is warranted.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. While liver transplantation (LT) provides the best long-term survival, it is constrained by organ scarcity and strict criteria. Liver resection (LR) is often the initial treatment for patients with solitary tumors and preserved liver function. The high recurrence rates associated with LR has prompted the exploration of sequential living donor liver transplantation (seqLDLT) after LR as a strategy for HCC patients with high-risk of recurrence.

We analyzed data from 27 adult patients who underwent seqLDLT after LR for HCC at Kaohsiung Chang Gung Memorial Hospital (KCGMH) between June 1994 and December 2023. Patients were selected based on high-risk histopathological features post-LR or as part of downstaging strategy. Outcomes measured included overall survival (OS) and disease-free survival (DFS).

Among 765 HCC patients who underwent LDLT, 204 received LR before LDLT, and 27 underwent seqLDLT. Five patients (19%) underwent living donor liver transplantation (LDLT) following LR as a downstaging strategy while the rest received seqLDLT as a preemptive strategy. The median age was 53.5 years with 85% males. Chronic hepatitis B was the predominant underlying disease (74%). The 1-, 3-, and 5-year OS and DFS rates were 100%, 96.0%, 96.0% and 100%, 96.2%, 96.2%, respectively, with two patients experiencing HCC recurrence. One patient died from HCC recurrence. High-risk histopathological features included microvascular invasion (52%), satellite nodules (15%), multiple tumors (26%), tumors > 5 cm (19%), and a total tumor diameter > 10 cm (7%).

SeqLDLT offers a promising, tailored approach for managing HCC with adverse histopathologic features. Combining seqLDLT, downstaging strategies, and multidisciplinary treatments can achieve satisfactory OS and DFS in carefully selected patients, highlighting the need for refined criteria to identify the best candidates.

Hepatocellular carcinoma (HCC) persists as a leading cause of cancer-related mortality, often diagnosed at advanced stages with limited treatment options. Locoregional therapies (LRTs) are crucial in HCC management, playing significant roles in neoadjuvant and palliative treatments, among others. However, the unique disease background of HCC necessitates multidisciplinary and integrated treatment strategies. The therapeutic landscape for advanced HCC has been significantly broadened by the advent of combined therapies, presenting multiple approaches aimed at improving long-term survival, which remains a critical challenge. This review offers a comprehensive overview of major LRTs for HCC, highlighting recent technological advancements and exploring the challenges and limitations in their application, and presents the latest developments in combination therapies, including combinations between different LRTs and their integration with systemic treatments. Additionally, we outline future directions for the development of integrated treatment modalities for advanced HCC.