Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with transarterial chemoembolisation (TACE) being a primary treatment for intermediate-stage disease. However, post-procedural pain remains a significant challenge due to inconsistent management practices and a lack of standardised protocols. This scoping review synthesises current evidence on pain management strategies in HCC patients undergoing TACE, evaluates their effectiveness, identifies practice gaps, and proposes optimisation strategies. Methods: A comprehensive database search according to the methodological approach given by Arksey and O'Malley with the aid of the PRISMA-ScR guidelines across Cochrane Library, Web of Science, CINAHL, PubMed, and Scopus was performed. The terms associated with pain, TACE, and liver cancer were included in the search strategy. Two independent researchers systematically screened study titles, abstracts, and full texts and extracted key study characteristics and approaches to pain management. Results: Of 1515 identified studies, 29 met the inclusion criteria. Most (72.7%) focused on pharmacological interventions, with dexamethasone and lidocaine being the most frequently investigated agents. Non-pharmacological approaches, including psychological interventions, physical therapies, music therapy, health education, and comprehensive nursing, were also reported. Pain was primarily assessed using the visual analogue scale (VAS) and numeric rating scale (NRS). Conclusions: Pharmacological interventions, particularly dexamethasone and lidocaine, remain the cornerstone of pain management in TACE, yet consensus on their optimal use is lacking. Non-pharmacological strategies provide complementary benefits. standardised, evidence-based pain management protocols integrating both approaches are needed. Future large-scale, multicentre trials are essential to establish the most effective strategies for optimising patient outcomes.

The clinical management of hepatocellular carcinoma (HCC) is strongly influenced by several prognostic factors, mainly tumor stage, patient's health, liver function and specific characteristics of each intervention. The interplay between these factors should be carefully evaluated by a multidisciplinary tumor board. To support this, the novel "multiparametric therapeutic hierarchy" (MTH) concept has been recently proposed. This review will present the main features of available surgical treatments for HCC (liver transplantation, liver resection, ablation). Strengths and weaknesses are reported in the light of clinical decision making and of treatment allocation, with a special focus on the collocation of each treatment in the MTH framework and on how MTH may be useful in supporting clinical decision. Sequential treatments and their role to allow further surgical treatments will also be analyzed.

Transarterial chemoembolization (TACE) is a potential conversion therapeutic strategy for unresectable hepatocellular carcinoma (uHCC). However, therapeutic options following conversion therapy are still controversial.

This study aimed to compare the efficacy and safety of surgical resection (SR) and microwave ablation (MWA) after TACE conversion therapy for uHCC.

A retrospective, multi-institutional study.

From June 2008 to October 2022, 8842 consecutive uHCC patients underwent initial TACE at 15 hospitals were identified. Among them, 1348 eligible patients who received TACE conversion therapy were included. The propensity score matching (PSM) was applied to reduce selection bias. To explore the effect of age on conversion therapy, a therapeutic factor analysis with age change was performed. The overall survival (OS) and disease-free survival (DFS) were compared using the Kaplan-Meier method with the log-rank test.

After PSM 1:1, 542 patients in the MWA group were matched with those in the SR group. SR demonstrated better long-term survival outcomes (median OS, 10.6 vs 5.8 years, HR:1.83, 95% CI: 1.48-2.25, p < 0.001 and median DFS, 3.2 vs 2.5 years, HR: 1.27, 95% CI:1.09-1.49, p = 0.003) than MWA. There was an improvement in the 5-year DFS rate for MWA from 17.1% during 2009-2016 to 37.3% during 2017-2022, becoming comparable to the 40.8% of SR (p = 0.129). When the uHCC patients downstage met Milan criteria, the long-term OS and DFS were comparable between two groups (both, p > 0.05). SR presents an OS advantage over MWA at the age (years) of 45-54 (p = 0.036), 55-65 (p = 0.001), and >65 (p < 0.001), except <45(p = 0.140).

MWA might be acceptable as an alternative to SR in first-line therapeutic scheme after TACE conversion therapy for uHCC, especially, for the aged <45 years cohorts.

To evaluate the efficacy, safety, and clinical course following ablative radioembolization with glass microspheres for hepatocellular carcinoma (HCC) with localized portal vein tumor thrombosis (PVTT) in patients with well-preserved liver function.

This is a prospective, open-label, multi-center, single-arm, phase II trial. Key inclusion criteria are unilobar HCC, PVTT confined to the ipsilateral lobe (Vp1-3), no extrahepatic spread, Child-Pugh class A, and a performance status of ≤ 1. Main exclusion criteria are hepatic venous tumor thrombus, bile duct invasion, and massive arterioportal shunting. Depending on the extent of the tumor and PVTT, patients will undergo radiation segmentectomy, modified radiation lobectomy, or ablative lobar treatment, while adhering to dose limits for the non-tumorous liver and lung. The primary outcome measure is overall survival, with the overall survival rate at two years provided as the summary measurement.

This study will enroll 30 patients to explore the efficacy and safety of ablative radioembolization for HCC with localized PVTT. Efficacy will be evaluated by intention-to-treat and per-protocol populations. Safety will be assessed for all patients who received radioembolization at any dose.

This study aims to address the potential of ablative radioembolization as a definitive or effective downstaging treatment for HCC with localized PVTT, where locoregional treatments may be more beneficial than systemic treatments. The results will help establish treatment outcomes that can serve as a standard for future comparative studies and contribute to the standardization of radioembolization approaches for HCC with localized PVTT.

ClinicalTrials.gov ( https://classic.

gov/ct2/show/NCT06166576 ). Identifier: NCT06166576.

The effects of transarterial chemoembolization (TACE) on the systemic immune in hepatocellular carcinoma (HCC) are not well understood. We aimed to reveal the temporal and spatial changes in the immune profile of peripheral blood and tumor tissues in HCC patients following TACE. Eighty-four HCC patients were included, 20 of whom received TACE with a median follow-up of 28 months. Immune cell proportion within peripheral blood was profiled with flow cytometry, and therapeutic efficacy was evaluated by imaging examinations. Additionally, cell distribution within tumor microenvironment (TME) were compared between the necrotic tumor infiltration zone (N-IZ) and the residual tumor infiltration zone (R-IZ) by multiplex immunofluorescence. Among 20 patients, 25% (5/20) achieved complete response, and 75% (15/20) showed partial response. Fourteen patients received combinational targeted therapy and immunotherapy and the median progression-free survival was 15.5 months. Compared to healthy individuals, HCC exhibited significantly higher proportions of regulatory T cells (Tregs) and programmed death-1 receptor (PD1)+ Tregs within peripheral blood. PD1+ Treg cells, PD1+ CD4+ T cells and PD1+ CD8+ T cells decreased significantly within peripheral blood after TACE. In TME, N-IZ showed significantly lower CD4+ T, CD8+ T and FOXP3+ Tregs, higher PD1+ CD8+/CD8+ and PD1+ CD8+/ PD1+ FOXP3+. Moreover, the spatial distance between CD8+ T cells and the nearest FOXP3+ Tregs in N-IZ was significantly greater than in R-IZ. Our findings demonstrated that TACE could both remodel the immune components in peripheral blood and TME, strengthening the rationale for developing immunotherapy alongside TACE.

Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths globally. Although there have been improvements in identifying treating the disease, patient outcomes are still unfavourable because of the significant variation in HCC. Mitochondrial-related genes (MRGs) are crucial in tumour metabolism, cell death and immune response, emerging as potential therapeutic targets. We analysed 2030 MRGs using TCGA, GEO and HCCDB18 databases. Differentially expressed genes were identified using edgeR and limma, and enrichment analysis was performed via the clusterProfiler package. A prognostic model was built using machine learning algorithms and evaluated using LOOCV. Immune infiltration was assessed with CIBERSORT, EPIC, MCPCounter and TIMER algorithms, and drug sensitivity was analysed using the CTRP and PRISM datasets. MRG expression levels are significantly associated with worse outcomes in HCC patients outperformed conventional clinical indicators in immune response revealed that individuals at high risk exhibited weaker immune responses, characterised by reduced immune scores, and elevated levels of CD8+ T cells and macrophages. Notably, high-risk patients also displayed heightened susceptibility to chemotherapy agents such as paclitaxel and irinotecan. Abnormal MRG expression serves as a significant biomarker for HCC prognosis. The developed model accurately predicts disease progression and can guide personalised treatment, especially for immune and chemotherapeutic therapies. Further validation with broader clinical samples is needed.

Personalized medicine is an emerging field that provides novel approaches to disease's early diagnosis, prevention, treatment, and prognosis based on the patient's criteria in gene expression, environmental factors, lifestyle, and diet. To date, hepatocellular carcinoma (HCC) is a significant global health burden, with an increasing incidence and significant death rates, despite advancements in surveillance, diagnosis, and therapeutic approaches. The majority of HCC lesions develop in patients with liver cirrhosis, carrying the risks of mortality associated with both the tumor burden and the cirrhosis. New therapeutic agents involving immune checkpoint inhibitors and targeted agents have been developed for sequential or concomitant application for advanced HCC but only a tiny percentage of patients benefit from each approach. Moreover, clinicians encounter difficulties determining the most appropriate regimen for each patient. This emphasizes the need for a personalized treatment approach. In other words, patients should no longer undergo treatment based on their tumor's histology but depending on the distinct molecular targets specific to their tumor biology. However, the utilization of precision medicine in managing HCC is still challenging. This review aims to discuss the role of personalized medicine in diagnosing, managing, and defining the prognosis of HCC. We also discuss the role of liquid biopsy and their clinical applications for immunotherapies in HCC. More clinical studies are still necessary to improve the precision of biomarkers used in the treatment decision for patients with HCC.

Laparoscopic microwave ablation (LMWA) has yet to gain a specific place in treatment guidelines for early hepatocellular carcinoma (HCC). This study compared the outcomes of LMWA and trans-arterial chemoembolization (TACE) for early non-resectable patients with HCC, taking percutaneous radiofrequency ablation (PRFA) as the reference treatment.

A retrospective multicenter observational study was conducted, enrolling non-transplantable, non-resectable patients who had early HCC treated with LMWA (n = 658) from Padua and Milan centers, and with PRFA (n = 844), and TACE (n = 425) from the ITA.LI.CA multicenter database. The matching-adjusted indirect comparison (MAIC) method was used to obtain weighted LMWA and TACE populations similar to the reference PRFA population.

Laparoscopic ablation showed an excellent safety profile, and MAIC-weighted early postoperative deaths were comparable among the groups. The MAIC-weighted overall survival was similar between the LMWA (1-, 3-, and 5 year survival of 91.0 %, 67.9 %, 47.0 %, respectively) and PRFA (1-, 3- and 5 year survivals of 90.0 %, 64.7 %, 46.6 %, respectively) groups (p = 0.678) and significantly better for the LMWA group than for the TACE group (1-, 3- and 5 year survivals of 84.7 %, 48.8 %, 33.6 %, respectively) (p < 0.001). Weighted multivariate overall survival analysis and competing risk/subgroup analyses confirmed the non-inferiority of LMWA to PRFA and its superiority to TACE. The LMWA- and PRFA-treated patients had a significantly lower risk of HCC-related death (p = 0.004) than the TACE-treated patients (p = 0.001). Conversely, the groups did not differ significantly in terms of non-HCC-related deaths.

The non-inferiority of LMWA to PRFA, its superiority to TACE, and its applicability to a wide range of presentations with few contraindications support its inclusion among radical therapies for treating early-HCC patients.

Accurate multi-classification is a prerequisite for appropriate management of focal liver lesions (FLLs). Ultrasound is the most common imaging examination but lacks accuracy. Contrast-enhanced ultrasound (CEUS) offers better performance but is highly dependent on operator experience. Therefore, we aimed to develop a CEUS-based artificial intelligence (AI) model for FLL multi-classification and evaluate its performance in multicenter clinical tests.

Since January 2017 to December 2023, CEUS videos, immunohistochemical biomarkers and clinical information on solid FLLs >1 cm in adults were collected from 52 centers to build and test the model. The model was developed to classify FLLs into six types: hepatocellular carcinoma, hepatic metastasis, intrahepatic cholangiocarcinoma, hepatic hemangioma, hepatic abscess and others. First, Module-Disease, Module-Biomarker and Module-Clinic were built in training set A and a validation set. Then, three modules were aggregated as Model-DCB in training set B and an internal test set. Model-DCB performance was compared with CEUS and MRI radiologists in three external test sets.

In total 3,725 FLLs from 52 centers were divided into training set A (n = 2,088), the validation set (n = 592), training set B (n = 234), the internal test set (n = 110), and external test sets A (n = 113), B (n = 276) and C (n = 312). In external test sets A, B and C, Model-DCB achieved significantly better performance (accuracy from 0.85 to 0.86) than junior CEUS radiologists (0.59-0.73), and comparable performance to senior CEUS radiologists (0.79-0.85) and senior MRI radiologists (0.82-0.86). In multiple subgroup analyses on demographic characteristics, tumor characteristics and ultrasound devices, its accuracy ranged from 0.79 to 0.92.

CEUS-based Model-DCB provides accurate multi-classification of FLLs. It holds promise for a wide range of populations, especially those in remote areas who have difficulty accessing MRI.

NCT04682886.

Ultrasound is the most common imaging examination for screening focal liver lesions (FLLs), but it lacks accuracy for multi-classification, which is a prerequisite for appropriate clinical management. Contrast-enhanced ultrasound (CEUS) offers better diagnostic performance but relies on the experience of radiologists. We developed a CEUS-based model (Model-DCB) that can help junior CEUS radiologists to achieve comparable diagnostic ability as senior CEUS radiologists and senior MRI radiologists. The combination of an ultrasound device, CEUS examination and Model-DCB means that even patients in remote areas can be accurately diagnosed through examination by junior radiologists.

Stereotactic body radiation therapy (SBRT) is an emerging treatment for hepatocellular carcinoma (HCC), which provides excellent local control (LC) and prolongs overall survival (OS). However, in current guidelines, transcatheter arterial chemoembolization (TACE) has been proposed as a key treatment option for patients with early- and intermediate-stage HCC, whereas SBRT is not. Therefore, we performed a systematic review and meta-analysis of randomized controlled trials and retrospective studies using the propensity score (PS) to compare the outcomes of SBRT and TACE for HCC in a balanced manner. We systematically searched the PubMed, Cochrane, EMBASE, and Web of Science databases to identify randomized controlled trials and studies comparing SBRT and TACE using PS analysis. The hazard ratios (HRs) for OS and LC were pooled. The heterogeneity between the data collected from these studies was also assessed. SBRT led to a comparable OS (HR: 0.83; 95 % confidence interval (CI): 0.52-1.34; p = 0.44) to TACE, and significantly improved LC (HR: 0.25; 95 % CI: 0.09-0.67; p = 0.006). Considerable heterogeneity was observed in the HR of OS and LC. Although there was no significant difference in the rate of grade 3 or higher toxicities between TACE and SBRT, or between studies, liver toxicity was identified as a common adverse event associated with both SBRT and TACE. Compared to TACE, SBRT showed a comparable OS and improved LC without serious toxicity. Therefore, SBRT should be considered an effective treatment option for various stages of HCC, depending on the tumor factors and pretreatment liver function.

Transarterial chemoembolization (TACE) is an effective and safe downstaging therapy for hepatocellular carcinoma (HCC). However, the selection of sequential therapeutic modalities is still controversial.

This study compared the effectiveness and safety of surgical resection (SR) and thermal ablation (TA) after patients with HCC underwent TACE downstaging therapy.

A retrospective, multi-institutional study.

From June 2008 to October 2022, a total of 4782 consecutive patients with HCC beyond the initial Milan criteria underwent TACE at 12 hospitals. Among them, 609 patients who received successful downstaging therapy were retrospectively reviewed. Among them, 209 patients underwent an SR, and 390 patients received TA after TACE. The propensity score matching (PSM) method was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan-Meier method with the log-rank test.

After PSM 1:1 (n = 185 in both groups), the cumulative 1-, 3-, 5-, and 10-year OS rates were 98.8%, 89.3%, 82.9%, and 64.4%, respectively, in the SR group and 99.5%, 88.4%, 75.3%, and 53.9%, respectively, in the TA group; these two groups were not significantly different (HR: 1.22; 95% CI: 0.78-1.89; p = 0.381). The cumulative 1-, 3-, 5-, and 10-year PFS rates were 88.5%, 69.2%, 58.8%, and 32.2%, respectively, in the SR group and 90.6%, 71.4%, 53.1%, and 32.0%, respectively, in the TA group, revealing no significant difference between the two groups (HR: 0.97; 95% CI: 0.71-1.32; p = 0.855).

For HCC patients beyond the Milan criteria who received TACE downstaging therapy, TA might be acceptable as an alternative to SR in the first-line sequential treatment scheme.

The management of hepatocellular carcinoma (HCC) is undergoing transformational changes due to the emergence of various novel immunotherapies and their combination with image-guided locoregional therapies. In this setting, immunotherapy is expected to become one of the standards of care in both neoadjuvant and adjuvant settings across all disease stages of HCC. Currently, more than 50 ongoing prospective clinical trials are investigating various end points for the combination of immunotherapy with both percutaneous and catheter-directed therapies. This review will outline essential tumor microenvironment mechanisms responsible for disease evolution and therapy resistance, discuss the rationale for combining locoregional therapy with immunotherapy, summarize ongoing clinical trials, and report on developing imaging end points and novel biomarkers that are relevant to both diagnostic and interventional radiologists participating in the management of HCC.

Background and Objectives: Hepatic resection offers promising outcomes for patients with hepatocellular carcinoma (HCC) but can be constrained by factors like patient suitability. Continuous advancements in laparoscopic and robotic technologies have made minimally invasive hepatectomies (MIHs) a viable alternative to open hepatectomies with benefits in terms of recovery and complications. Materials and Methods: We completed a retrospective review on 138 HCC patients who underwent OH or MIH between 2010 and 2020 at the Hume-Lee Transplant Center. Univariate and multivariate analyses were completed on demographic, clinical, and tumor-specific data to assess the impact of these variables on overall and disease-free survival at 1, 3, and 5 years. Preoperative metrics like length of hospital stay (LOS) and operation duration were also evaluated. Results: Of the 109 OH and 29 MIH patients, MIH patients demonstrated shorter LOS and operative times. However, overall survival (OS) and disease-free survival (DFS) were similar between groups, with no significant variations in 1-, 3-, and 5-year survival rates. Age > 60 years and a lack of preoperative transcatheter arterial chemoembolization (TACE) were significant predictors of inferior OS and DFS in multivariate analyses. Conclusions: MIH is an efficient substitute for OH with comparable survival, even in older patients. The reduced LOS and operation time enhance its feasibility, and older patients previously denied for curative resection may qualify for MIH. Preoperative TACE also enhances survival outcomes, emphasizing its general role in managing resectable HCCs. Both robotic and laparoscopic hepatectomies offer acceptable short- and long-term clinical outcomes, highlighting MIH as the standard choice for HCC patients.

In recent years, significant progress has been made in treatment strategies for intermediate-stage hepatocellular carcinoma (HCC), which is a highly heterogeneous patient population requiring tailored therapies based on tumor characteristics.

We conducted a comprehensive review of treatment approaches for intermediate-stage HCC, highlighting the evolution of treatment options over time. While chemoembolization remains the standard therapy for many patients, it has advanced to include combinations with systemic therapies, known as combination therapy, which is becoming the new standard of care for this group.

Based on our clinical and research experience, combination therapy is increasingly recognized as the preferred first-line treatment for intermediate-stage HCC patients. This approach allows most patients to be candidates for subsequent curative-intent treatments, while a smaller number will require palliative care.

Accurate staging is necessary for predicting hepatocellular carcinoma (HCC) prognosis and guiding patient management. The Barcelona Clinic Liver Cancer (BCLC) staging system has limitations due to heterogeneity observed among patients in BCLC stages B and C. In contrast, the Hong Kong Liver Cancer (HKLC) staging system offers more aggressive treatment strategies.

To compare the prognostic performance of HKLC and BCLC staging systems in Egyptian patients with HCC.

We conducted a retrospective study at the National Liver Institute, Menoufia University, Egypt, on 1015 HCC patients. Data was collected from patients' medical records over 10 years (from 2008 to 2018). The BCLC and HKLC stages were identified, and Kaplan-Meier survival analysis was used to compare patients' overall survival rates within each staging system. Additionally, we evaluated the comparative prognostic performance of the two staging systems.

Hepatitis C was identified as the underlying etiology in 799 patients (78.7%), hepatitis B in 12 patients (1.2%), and non-viral causes in 204 patients (20.1%). The survival analysis demonstrated significant differences across the various stages within both the BCLC and HKLC systems. The receiver operating characteristic (ROC) curves indicated a marginally superior performance of the HKLC system in predicting survival at 1, 2, and 3 years compared to the BCLC system. Furthermore, the HKLC staging provided a slightly enhanced prognostic capability, particularly for patients classified under BCLC stages B and C, suggesting a potential survival benefit.

HKLC classification had a slightly better prognostic performance than BCLC staging system and may offer a survival advantage for certain patients with HCC in BCLC stage B and C HCC cases.

Surgical resection (SR) following transarterial chemoembolization (TACE)-based downstaging is a promising treatment for unresectable hepatocellular carcinoma (uHCC), and identification of patients at high-risk of postoperative recurrence may assist individualized treatment.

To develop and externally validate preoperative and postoperative prognostic models integrating multimodal CT and digital subtraction angiography features as well as clinico-therapeutic-pathological features for predicting disease-free survival (DFS) after TACE-based downstaging therapy.

From March 2008 to August 2022, 488 consecutive patients with Barcelona Clinic Liver Cancer (BCLC) A/B uHCC receiving TACE-based downstaging therapy and subsequent SR were included from four tertiary-care hospitals. All CT and digital subtraction angiography images were independently evaluated by two blinded radiologists. In the derivation cohort ( n =390), the XGBoost algorithm was used for feature selection, and Cox regression analysis for developing nomograms for DFS (time from downstaging to postoperative recurrence or death). In the external testing cohort ( n =98), model performances were compared with five major staging systems.

The preoperative nomogram included over three tumors [hazard ratio (HR), 1.42; P =0.003], intratumoral artery (HR, 1.38; P =0.006), TACE combined with tyrosine kinase inhibitor (HR, 0.46; P <0.001) and objective response to downstaging therapy (HR, 1.60; P <0.001); while the postoperative nomogram included over three tumors (HR, 1.43; P =0.013), intratumoral artery (HR, 1.38; P =0.020), TACE combined with tyrosine kinase inhibitor (HR, 0.48; P <0.001), objective response to downstaging therapy (HR, 1.69; P <0.001) and microvascular invasion (HR, 2.20; P <0.001). The testing dataset C-indexes of the preoperative (0.651) and postoperative (0.687) nomograms were higher than all five staging systems (0.472-0.542; all P <0.001). Two prognostically distinct risk strata were identified according to these nomograms (all P <0.001).

Based on 488 patients receiving TACE-based downstaging therapy and subsequent SR for BCLC A/B uHCCs, the authors developed and externally validated two nomograms for predicting DFS, with superior performances than five major staging systems and effective survival stratification.

The aim of this study was to assess the efficacy of boosted dose yttrium-90 radioembolization (TARE) as a modality for conversion therapy to transplant or surgical resection in patients with unresectable hepatocellular carcinoma (HCC).

In this single-center retrospective study, all patients with a diagnosis of HCC who were treated with boosted dose TARE (>190 Gy) between January 2013 and December 2023 were reviewed. Treatment response and decrease in tumor size were assessed with the RECIST v1.1 and mRECIST criteria. Milan and University of California, San Francisco (UCSF), criteria were used to determine transplant eligibility, and Barcelona Clinic Liver Cancer (BCLC) surgical resection recommendations were used to evaluate tumor resectability.

Thirty-eight patients with primary HCC who were treated with boosted dose TARE were retrospectively analyzed. The majority of the patients were Child-Pugh A (n = 35; 92.1%), BCLC C (n = 17; 44.7%), and ECOG performance status 0 (n = 25; 65.8%). The mean sum of the target lesions was 6.0 cm (standard deviation; SD = 4.0). The objective response rate (ORR) was 31.6% by RECIST and 84.2% by mRECIST. The disease control rate (DCR) was 94.7% by both RECIST and mRECIST. Among patients outside of Milan or UCSF, 13/25 (52.0%, Milan) and 9/19 (47.4%, UCSF) patients were successfully converted to within transplant criteria. Of patients who were initially unresectable, conversion was successful in 7/26 (26.9%) patients.

This study provides further real-world data demonstrating that boosted-dose TARE is an effective modality for conversion of patients with unresectable HCC to transplant or resection.

The 2022 Barcelona Clinic Liver Cancer algorithm currently discourages liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules that are each 3 cm or smaller.

To compare the efficacy of liver resection (LR), percutaneous radiofrequency ablation (PRFA), and transarterial chemoembolization (TACE) in patients with multinodular HCC.

This cohort study is a retrospective analysis conducted using data from the HE.RC.O.LE.S register (n = 5331) for LR patients and the ITA.LI.CA database (n = 7056) for PRFA and TACE patients. A matching-adjusted indirect comparison (MAIC) method was applied to balance data and potential confounding factors between the 3 groups. Included were patients from multiple centers from 2008 to 2020; data were analyzed from January to December 2023.

LR, PRFA, or TACE.

Survival rates at 1, 3, and 5 years were calculated. Cox MAIC-weighted multivariable analysis and competing risk analysis were used to assess outcomes.

A total of 720 patients with early multinodular HCC were included, 543 males (75.4%), 177 females (24.6%), and 350 individuals older than 70 years (48.6%). There were 296 patients in the LR group, 240 who underwent PRFA, and 184 who underwent TACE. After MAIC, LR exhibited 1-, 3-, and 5-year survival rates of 89.11%, 70.98%, and 56.44%, respectively. PRFA showed rates of 94.01%, 65.20%, and 39.93%, while TACE displayed rates of 90.88%, 48.95%, and 29.24%. Multivariable Cox survival analysis in the weighted population showed a survival benefit over alternative treatments (PRFA vs LR: hazard ratio [HR], 1.41; 95% CI, 1.07-1.86; P = .01; TACE vs LR: HR, 1.86; 95% CI, 1.29-2.68; P = .001). Competing risk analysis confirmed a lower risk of cancer-related death in LR compared with PRFA and TACE.

For patients with early multinodular HCC who are ineligible for transplant, LR should be prioritized as the primary therapeutic option, followed by PRFA and TACE when LR is not feasible. These findings provide valuable insights for clinical decision-making in this patient population.

Intra-arterial conversion therapy (ICT) is a promising option for patients with unresectable hepatocellular carcinoma (uHCC). However, the selection of sequential therapeutic modalities is still controversial. This study compared the efficacy and safety of surgical resection (SR) versus thermal ablation (TA) after patients with uHCC received ICT.

From May 2008 to November 2021, 3553 consecutive patients were reviewed and 791 patients were downstaged to receive TA or SR. Among them, 340 patients received SR, and 451 received TA after ICTs. The propensity score matching (PSM) method was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan-Meier method with the log-rank test. The occurrence of complications and adverse events (AEs) were compared using chi-square test.

After PSM 1:1 (n = 185 in both groups), the 10-year OS and PFS rates for patients who underwent SR were comparable to those of patients who underwent TA (OS: 45.2% vs. 36.1%; p = 0.190; PFS: 19.3% vs. 15.9%; p = 0.533). A total of 237 (29.9%) patients (203 males; mean age:57.1 ± 11.0 years) received downstaging therapy, and long-term OS and PFS remained comparable between the two groups (p = 0.718, 0.636, respectively). However, the cumulative OS and PFS rates in the downstaged cohort were significantly higher than those in the nondownstaged cohort (both ps < 0.001). Additionally, there was no difference in major complications between the two groups (SR: 6.3% vs. TA: 8.6%; p = 0.320).

TA might be an acceptable first-line alternative to SR after patients with uHCC receive ICT, especially patients unsuitable for SR. Better long-term survival was observed among patients in the downstaged cohort compared to those who failed to downstage.

Despite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients.

We analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared.

A total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms' concordance indices in the training cohort were 0.777 (95% confidence interval 0.759-0.800) and 0.719 (95% confidence interval 0.697-0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts.

We developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.

Evaluating the pathological response and the survival outcomes of combined thermal ablation (TA) and transarterial chemoembolization (TACE) as a bridge or downstaging for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) > 3 cm.

A retrospective review encompassed 36 consecutive patients who underwent combined TA-TACE as bridging or downstaging before LT. Primary objectives included necrosis of the target lesion at explant pathology, post-LT overall survival (OS) and post-LT recurrence-free survival (RFS). For OS and RFS, a comparison with 170 patients subjected to TA alone for nodules <3 cm in size was also made.

Out of the 36 patients, 63.9% underwent TA-TACE as bridging, while 36.1% required downstaging. The average node size was 4.25 cm. All cases were discussed in a multidisciplinary tumor board to assess the best treatment for each patient. Half received radiofrequency (RF), and the other half underwent microwave (MW). All nodes underwent drug-eluting beads (DEB) TACE with epirubicin. The mean necrosis percentage was 65.9% in the RF+TACE group and 83.3% in the MW+TACE group (p-value = 0.099). OS was 100% at 1 year, 100% at 3 years and 94.7% at 5 years. RFS was 97.2% at 1 year, 94.4% at 3 years and 90% at 5 years. Despite the different sizes of the lesions, OS and RFS did not show significant differences with the cohort of patients subjected to TA alone.

The study highlights the effectiveness of combined TA-TACE for HCC>3 cm, particularly for bridging and downstaging to LT, achieving OS and RFS rates significantly exceeding 80% at 1, 3 and 5 years.

This study aims to investigate α-fetoprotein (AFP) trajectories for prediction of survival outcomes after hepatic arterial infusion chemotherapy (HAIC) treatment in large hepatocellular carcinoma (HCC).

From May 2014 to June 2020, 889 eligible patients with large HCC underwent HAIC were retrospectively enrolled from five hospitals. A latent class growth mixed (LCGM) model was applied to distinguish potential AFP level dynamic changing trajectories. Inverse-probability-of-treatment weighted (IPTW) analyses were performed to eliminate unmeasured confounders through marginal structural models. Multivariate Cox proportional hazard regression analyses were used to determine the overall survival (OS) in patients with large HCC. Performance of these serum markers for survival prediction was compared by areas under receiver operating characteristic analysis with the Delong test.

The median follow-up time was 23.7 (interquartile range, 3.8-115.3). A total of 1009 patients with large HCC, who underwent HAIC with AFP repeatedly measured 3-10 times, were enrolled in the study. Three distinct trajectories of these serum AFP were identified using the LCGM model: high stable (37.0%; n = 373), low stable (15.7%; n = 159), and sharp-falling (47.3%; n = 477). Multivariate Cox proportional hazard regression analyses found that ALBI stage 2-3, BCLC-C stage and high-stable AFP trajectories were associated with OS. AFP trajectories yield the optimal predictive performance in all risk factors.

The AFP trajectories based on longitudinal AFP change showed outstanding performance for predicting survival outcomes after HAIC treatment in large HCC, which provide a potential monitoring tool for improving clinical decision-making.

Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.

In this Expert Opinion, we thoroughly analyse the Barcelona Clinic Liver Cancer (BCLC) staging and treatment algorithm for hepatocellular carcinoma (HCC) that, since 1999, has standardised HCC management, offering a structured approach for the prognostic evaluation and treatment of patients with HCC. The first part of the article presents the strengths and evolutionary improvements of the BCLC staging system. Nevertheless, both patient characteristics and available treatments have changed in the last two decades, limiting the role of the BCLC criteria for treatment allocation in a growing number of patients. As therapeutic options expand and become more effective, the stage-linked treatment decision-making algorithm may lead to undertreatment and suboptimal outcomes for patients with disease beyond early-stage HCC. Consequently, strict adherence to BCLC criteria is limited in expert centres, particularly for patients diagnosed beyond early-stage HCC. Although the BCLC system remains the benchmark against which other therapeutic frameworks must be judged, the era of precision medicine calls for patient-tailored therapeutic decision-making (by a multidisciplinary tumour board) rather than stage-dictated treatment allocation. Acknowledging this conceptual difference in clinical management, the second part of the article describes a novel "multiparametric therapeutic hierarchy", which integrates a comprehensive assessment of clinical factors, biomarkers, technical feasibility, and resource availability. Lastly, considering the increasing efficacy of locoregional and systemic treatments, the concept of "converse therapeutic hierarchy" is introduced. These treatments can increase the feasibility (conversion approach) and effectiveness (adjuvant approach of systemic therapy) of potentially curative approaches to greatly improve clinical outcomes.

This review explores the evolution of cancer staging, focusing on intermediate hepatocellular carcinoma (HCC), and the challenges faced by physicians. The Barcelona Clinic Liver Cancer (BCLC) staging system, introduced in 1999, was designed to address the limitations associated with providing accurate prognostic information for HCC and allocating specific treatments, to avoid overtreatment. However, criticism has emerged, particularly regarding the intermediate stage of HCC (BCLC-B) and its heterogeneous patient population. To overcome this limitation, various subclassification systems, such as the Bolondi and Kinki criteria, have been proposed. These systems are aimed at refining categorizations within the intermediate stage and have demonstrated varying degrees of success in predicting outcomes through external validation. This study discusses the shift in treatment paradigms, emphasizing the need for a more personalized approach rather than strictly adhering to cancer stages, without dismissing the relevance of staging systems. It assesses the available treatment options for intermediate-stage HCC, highlighting the importance of considering surgical and nonsurgical options alongside transarterial chemoembolization for optimal outcomes. In conclusion, the text advocates for a paradigm shift in staging systems prioritizing treatment suitability over cancer stage. This reflects the evolving landscape of HCC management, where a multidisciplinary approach is crucial for tailoring treatments to individual patients, ultimately aiming to improve overall survival.

Minimally invasive liver surgery (MILS) has been slowly introduced in the past two decades and today represents a major weapon in the fight against HCC, for several reasons. This narrative review conveys the major emerging concepts in the field. The rise in metabolic-associated steatotic liver disease (MASLD)-related HCC means that patients with significant cardiovascular risk will benefit more profoundly from MILS. The advent of efficacious therapy is leading to conversion from non-resectable to resectable cases, and therefore more patients will be able to undergo MILS. In fact, resection outcomes with MILS are superior compared to open surgery both in the short and long term. Furthermore, indications to surgery may be further expanded by its use in Child B7 patients and by the use of laparoscopic ablation, a curative technique, instead of trans-arterial approaches in cases not amenable to radiofrequency. Therefore, in a promising new approach, multi-parametric treatment hierarchy, MILS is hierarchically superior to open surgery and comes second only to liver transplantation.

Circular RNAs (circRNAs) represent a subset of non-coding RNAs implicated in the regulation of diverse biological processes, including tumorigenesis. However, the expression and functional implications of circ0060467 in hepatocellular carcinoma (HCC) remain elusive. In this study, we aimed to elucidate the role of circ0060467 in modulating the progression of HCC.

Differentially expressed circRNAs in HCC tissues were identified through circRNA microarray assays. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays revealed the upregulation of circ0060467 in both HCC cell lines and tissues. Various assays were conducted to investigate the roles of circ0060467 in HCC progression. Additionally, RNA immunoprecipitation (RIP) assays and luciferase assays were carried out to assess the interactions between circ0060467, microRNA-6085 (miR-6085), apoptosis-inducing factor mitochondria-associated 2 (AIFM2), and glutathione peroxidase 4 (GPX4) in HCC.

Microarray and qRT-PCR analyses demonstrated a marked elevation of circ0060467 in HCC tissues and cell lines. Knockdown of circ0060467 suppressed HCC cell proliferation. Luciferase reporter and RIP assays confirmed the binding of circ0060467, AIFM2, and GPX4 to miR-6805. Subsequent experiments revealed that circ0060467 competes with AIFM2 and GPX4, thereby inhibiting cancer cell ferroptosis by binding to miR-6085 and promoting hepatocellular carcinoma progression.

Collectively, circ0060467 modulates the levels of AIFM2 and GPX4, crucial regulators of tumor cell ferroptosis, by acting as a sponge for miR-6085 in HCC. Thus, circ0060467 may represent a novel diagnostic marker and therapeutic target for HCC.

The effectiveness of adjuvant immunotherapy to diminish recurrence and improve long-term prognosis following curative-intent surgical resection for hepatocellular carcinoma (HCC) is of increased interest, especially among individuals at high risk of recurrence. The objective of the current study was to investigate the impact of adjuvant immunotherapy on long-term recurrence and survival after curative resection among patients with intermediate/advanced HCC.

Using a prospectively-collected multicenter database, patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC were identified. Propensity score matching (PSM) analysis was used to compare recurrence-free survival (RFS) and overall survival (OS) between patients treated with and without adjuvant immune checkpoint inhibitors (ICIs). Multivariate Cox-regression analysis further identified independent factors of RFS and OS.

Among the 627 enrolled patients, 109 patients (23.3%) received adjuvant immunotherapy. Most ICI-related adverse reactions were grading I-II. PSM analysis created 99 matched pairs of patients with comparable baseline characteristics between patients treated with and without adjuvant immunotherapy. In the PSM cohort, the median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) were better among patients who received adjuvant immunotherapy versus patients who did not. After adjustment for other confounding factors on multivariable analyzes, adjuvant immunotherapy remained independently associated with favorable RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyzes identified potentially prognostic benefits of adjuvant immunotherapy among patients with intermediate-stage and advanced-stage HCC.

This real-world observational study demonstrated that adjuvant immunotherapy was associated with improved RFS and OS following curative-intent resection of intermediate/advanced HCC. Future randomized controlled trials are warranted to establish definitive evidence for this specific population at high risks of recurrence.

The 2022 Barcelona Clinic Liver Cancer (BCLC) algorithm does not recommend liver resection (LR) in BCLC A patients with oligo-nodular (two or three nodules ≤3 cm) hepatocellular carcinoma (HCC). This sharply contrasts with the therapeutic hierarchy concept, implying a precise treatment order exists within each BCLC stage. This study aimed to compare the outcomes of LR versus radiofrequency ablation (RFA) or trans-arterial chemoembolization (TACE) in BCLC A patients.

A meta-analysis adhering to PRISMA guidelines and the Cochrane Handbook was performed. All RCT, cohort and case-control studies that compared LR versus RFA or TACE in oligo-nodular BCLC A HCC published between January 2000 and October 2023 were comprehensively searched on PubMed, Embase, the Cochrane Library and China Biology Medicine databases. Primary outcomes were overall survival (OS) and disease-free survival (DFS) at 3 and 5 years. Risk ratio (RR) was computed as a measure of treatment effect (OS and DFS benefit) to calculate common and random effects estimates for meta-analyses with binary outcome data.

2601 patients from 14 included studies were analysed (LR = 1227, RFA = 686, TACE = 688). There was a significant 3- and 5-year OS benefit of LR over TACE (RR = 0.55, 95% c.i. 0.44 to 0.69, P < 0.001 and RR 0.57, 95% c.i. 0.36 to 0.90, P = 0.030, respectively), while there was no significant 3- and 5-year OS benefit of LR over RFA (RR = 0.78, 95% c.i. 0.37 to 1.62, P = 0.452 and RR 0.74, 95% c.i. 0.50 to 1.09, P = 0.103, respectively). However, a significant 3- and 5-year DFS benefit of LR over RFA was found (RR = 0.70, 95% c.i. 0.54 to 0.93, P = 0.020 and RR 0.82, 95% c.i. 0.72 to 0.95, P = 0.015, respectively). A single study comparing LR and TACE regarding DFS showed a significant superiority of LR. The Newcastle-Ottawa Scale quality of studies was high in eight (57%) and moderate in six (43%).

In BCLC A oligo-nodular HCC patients, LR should be preferred to RFA or TACE (therapeutic hierarchy concept). Additional comparative cohort studies are urgently needed to increase the certainty of this evidence.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses.

This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed.

HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients.

In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

The advantages of the robotic approach in minimally invasive liver surgery (MILS) are still debated. This study compares the short-term outcomes between laparoscopic (LLR) and robotic (RLR) liver resections in propensity score matched cohorts.

Data regarding minimally invasive liver resections in two liver surgery units were retrospectively reviewed. A propensity score matched analysis (1:1 ratio) identified two groups of patients with similar characteristics. Intra- and post-operative outcomes were then compared. The difficulty of MILS was based on the IWATE criteria.

Two hundred sixty-nine patients underwent MILS between January 2014 and December 2021 (LLR = 192; RLR = 77). Propensity score matching identified 148 cases (LLR = 74; RLR = 74) consisting of compensated cirrhotic patients (100%) underwent non-anatomic resection of IWATE 1-2 class (90.5%) for a solitary tumor < 5 cm in diameter (93.2%). In such patients, RLRs had shorter operative time (227 vs. 250 min, p = 0.002), shorter Pringle's cumulative time (12 vs. 28 min, p < 0.0001), and less blood loss (137 vs. 209 cc, p = 0.006) vs. LLRs. Conversion rate was nihil (both groups). In RLRs compared to LLRs, R0 rate (93 vs. 96%, p > 0.71) and major morbidity (4.1 vs. 5.4%, p > 0.999) were similar, without post-operative mortality. Hospital stay was shorter in the robotic group (6.2 vs. 6.6, p = 0.0001).

This study supports the non-inferiority of RLR over LLR. In compensated cirrhotic patients underwent resection of low-to-intermediate difficulty for a solitary nodule < 5 cm, RLR was faster, with less blood loss despite the shorter hilar clamping, and required shorter hospitalization compared to LLR.

Despite second-line transplant(SLT) for recurrent hepatocellular carcinoma(rHCC) leads to the longest survival after recurrence(SAR), its real applicability has never been reported. The aim was to compare the SAR of SLT versus repeated hepatectomy and thermoablation(CUR group).

Patients were enrolled from the Italian register HE.RC.O.LE.S. between 2008 and 2021. Two groups were created: CUR versus SLT. A propensity score matching (PSM) was run to balance the groups.

743 patients were enrolled, CUR = 611 and SLT = 132. Median age at recurrence was 71(IQR 6575) years old and 60(IQR 53-64, p < 0.001) for CUR and SLT respectively. After PSM, median SAR for CUR was 43 months(95%CI = 37 - 93) and not reached for SLT(p < 0.001). SLT patients gained a survival benefit of 9.4 months if compared with CUR. MilanCriteria(MC)-In patients were 82.7% of the CUR group. SLT(HR 0.386, 95%CI = 0.23 - 0.63, p < 0.001) and the MELD score(HR 1.169, 95%CI = 1.07 - 1.27, p < 0.001) were the only predictors of mortality. In case of MC-Out, the only predictor of mortality was the number of nodules at recurrence(HR 1.45, 95%CI= 1.09 - 1.93, p = 0.011).

It emerged an important transplant under referral in favour of repeated hepatectomy or thermoablation. In patients with MC-Out relapse, the benefit of SLT over CUR was not observed.