Our study was to compare the therapeutic outcomes of radiofrequency ablation (RFA) with or without conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma (HCC) within Milan criteria in subcapsular versus nonsubcapsular locations by using propensity score matching.

This retrospective study included 171 consecutive HCC patients meeting Milan criteria who initially received RFA with or without cTACE at a tertiary academic center between January 2017 to December 2022. Technical success rate, progression-free survival (PFS) were recorded. Factors predicting PFS after RFA with or without cTACE were investigated through a Cox proportional hazard model.

The cumulative 1-, 3-, and 5-year PFS were 73.9%%, 27.7%%, and 7.7%, respectively. The cumulative PFS rates were 76.1% and 17.3% at 1 and 3 years, respectively, in the subcapsular group and 71.8% and 37.2% in the nonsubcapsular group (p = 0.034). Matching yielded 49 matched pairs of patients. In the matched group, corresponding cumulative PFS rates were 75.6% and 14.6% at 1 and 3 years, respectively, in the subcapsular group and 69.6% and 30.2% in the nonsubcapsular group (p = 0.156). Multivariate analysis confirmed that subcapsular tumor location was not an independent risk factor for PFS. Additionally, differences in technical success rate were not significant between groups.

The differences in PFS rates and technical success rate in HCC patients within the Milan criteria who received RFA with or without cTACE were not significant between the subcapsular and non-subcapsular groups. Future larger prospective multicenter trials are needed to validate these findings.

Sorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned, which strongly correlates with the presence of established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provides valuable information that can facilitate the analysis of other drugs for the development of novel combined treatment strategies based on Sfb therapy.

With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.

Background: Image-guided tumour ablation is a minimally invasive treatment for early stage hepatocellular carcinoma (HCC). Our study reviews the complications and long term outcomes in patients treated at a tertiary referral centre. Methods: Retrospective study. All patients with HCC who underwent microwave ablation (MWA) or radiofrequency ablation (RFA) from 1st January 2014 to 31st December 2022 were identified. Treatment response of target lesion, complications, and survival were recorded. Results: One hundred seventy ablations were performed in 118 patients; 70% MWA, 30% RFA. Median radiological follow-up 21 months (range 3-107). Follow-up imaging was reported using LI-RADS and mRECIST. At first follow-up imaging, 94 patients had complete response (primary efficacy rate 80.3%) while 19.7% (n = 23) had residual disease. Fifteen of these had repeat ablation; 10 had complete response (secondary efficacy rate 85.6%). By end of study duration, 70.5% (n = 79) achieved sustained local complete response from single ablation without documented recurrence. 14.3% (n = 16) required more than one ablation of target lesion. Overall, 84.8% (n = 95) demonstrated long term local complete response to ablation. Complication occurred in 5.9% (n = 10); 40.0% Grade I, 40.0% Grade II, 10.0% Grade III, 10.0% Grade IV as per the CIRSE Classification. 1-, 3-, and 5-year overall survival (OS) rate was 97%, 68%, and 61% respectively. Mean OS was 5.3 years (median 4.7). No difference in OS (P = .7) or local progression free survival (P = .5) between patients treated with MWA versus RFA. Conclusion: This study demonstrates excellent long-term response to TA, with acceptable complication profile. No difference in survival between RFA versus MWA.

The ASAP score, which incorporates age, sex, alpha-fetoprotein (AFP), and protein induced by vitamin K absence-II, has demonstrated promise for early detection of hepatocellular carcinoma (HCC). However, its prognostic value after HCC treatment remains unknown. The current study sought to evaluate the prognostic value of the ASAP score to predict recurrence and survival following curative hepatic resection for HCC.

This study using prospectively collected data included HCC patients who underwent curative-intent hepatic resection. The ASAP score was calculated preoperatively, and X-tile analysis was used to determine the optimal cutoff value. Univariate and multivariate analyses were performed to identify independent risk factors associated with recurrence and overall survival (OS).

Among 1239 patients in the analytic cohort, the optimal ASAP score cutoff was 4.8; patients were divided into low (n = 749) and high (n = 490) ASAP score subgroups. Patients with high ASAP scores had a higher incidence of 5-year recurrence (73.9% vs 51.0%, P < 0.001) and worse OS (31.7% vs 60.1%, P < 0.001) versus individuals with low scores. Multivariate analysis identified ASAP score ≥4.8 as an independent risk factor of both recurrence (hazard ratio [HR] 1.976, 95% confidence interval [CI]: 1.633-2.390, P < 0.001) and OS (HR 1.407, 95% CI 1.170-1.691, P < 0.001) after controlling for established clinicopathological factors.

Preoperative ASAP score was independently associated with recurrence and survival after HCC resection. The clinical utility of the ASAP score may be applicable to both diagnosis and prognosis, potentially improving postoperative surveillance and management strategies for HCC patients.

Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer globally, third most common cause of cancer-related death, and most common primary liver malignancy. Whilst nodular well-defined HCC remains the classical phenotype, presentations with infiltrative phenotype, very large HCC, and complications as tumour rupture provide immense diagnostic and therapeutic challenges. Infiltrative HCC is difficult to distinguish against the background cirrhotic liver. They are ill defined on imaging, have poor vascularity, and aggressive biological behaviour. Vascular invasion, metastasis, and poor response to loco-regional, as well as systemic therapy, leads to dismal prognosis. Very large HCCs have a relatively better prognosis than infiltrative HCC and mandate multimodal therapies to downstage for a curative response including liver transplant. Improvement in interventional radiology techniques, emerging evidence with systemic therapies including immunotherapy, and better understanding of tumour biology have opened newer avenues in the management of such complex cases. HCC rupture is a catastrophic moment in the natural history of HCC which has an exponential increase in mortality. Clinical presentation of pain abdomen, hypotension/syncope, new onset, or sudden increase in ascites mandates a strong suspicion of rupture. Presence of hemoperitoneum on diagnostic tap and contrast extravasation in a computed tomography/magnetic resonance imaging are the diagnostic hallmarks. Emergency surgical intervention, locoregional therapies in the form of bland embolisation, or chemoembolisation forms the management cornerstone. The long-term survival and liver transplant as a curative therapy still needs more data as fear of tumour spread is a possibility. This review summarises the clinical challenges with this advance HCC and provides an algorithmic approach for management.

Hydrogel, as a promising embolic material for hepatocellular carcinoma (HCC), may fully embolize both major vessels and peripheral microvessels. A self-assembling hydrogel composed of chemotherapeutic drugs offers significant clinical benefits without carrier introduction. Herein, we developed a sustained drug-releasing complex hydrogel (RKT@gel), which was fabricated by the self-assembly of raltitrexed chemotherapeutic drugs (R@gel), along with the incorporation of kaempferol and tantalum nanoparticles (Ta NPs). Kaempferol enhances the mechanical strength of R@gel and inhibits hypoxia-induced angiogenesis post-embolization, improving embolization effectiveness. In addition to enabling X-ray-guided transarterial chemoembolization (TACE), Ta NPs enhance radiation sensitivity. These synergistic effects of RKT@gel not only significantly induce immunogenic cell death, thereby enhancing the activation of dendritic cells, but also activate major histocompatibility complex class I (MHC-I)-mediated antitumor immune recognition and cytotoxicity. In vivo, RKT@gel achieves enhanced tumor deposition and sustained drug release, effectively suppressing tumor progression. Additionally, when combined with radiotherapy, RKT@gel achieves efficient antitumor immunoactivation. Overall, this versatile composite hydrogel not only achieves effective embolization therapy but also substantially triggers antitumor immune responses with good biocompatibility. This multifunctional design provides a TACE-based multidisciplinary strategy for HCC.

Real-world data on the variceal bleeding (VB) risk in patients receiving atezolizumab-bevacizumab (Atezo-Bev) treatment remain limited. This study aimed to assess the risk of VB and identify risk factors in patients with advanced hepatocellular carcinoma (HCC) receiving Atezo-Bev treatment.

This retrospective study included 640 patients with HCC who underwent endoscopy before Atezo-Bev treatment at two hospitals in Korea. The primary outcome was the occurrence of VB, with non-VB events considered as competing events.

Of the 640 patients, the mean age was 61.3 years, and 528 (82.5%) patients were male. The main aetiology of HCC was chronic hepatitis B virus (69.5%), and 563 (88.0%) had BCLC stage C. Portal vein invasion (PVI) was present in 313 (48.9%). During a median follow-up of 5.6 months, 45 (7.0%) patients developed VB. The cumulative incidence of VB was 6.3% at 6 months and 7.4% at 12 months. No patient died from VB. Multivariable analysis revealed that the main PVI (subdistribution hazard ratio [SHR]: 3.49, 95% confidence interval [CI]: 1.63-7.44), low platelet count (SHR: 0.994, 95% CI: 0.99-1.00), a history of gastrointestinal (GI) bleeding (SHR: 3.70, 95% CI: 1.49-9.16) and varices needing treatment (VNT; SHR: 2.67, 95% CI: 1.26-5.64) increased the risk of VB.

A low platelet count, main PVI, history of GI bleeding and VNT were significant risk factors for VB in patients receiving Atezo-Bev treatment for HCC. Identifying these factors can guide clinicians in assessing and managing VB risk in clinical settings.

Hepatocellular carcinoma arises in the setting of cirrhosis in most cases, requiring multidisciplinary input to define resectability. In this regard, more precise surgical management considers patient factors and anatomical states, including resection margins, tumour biology, and perioperative therapy. Together with advances in surgical techniques, this integrated approach has resulted in considerable improvements in patient morbidity and oncological outcomes. Despite this, recurrence rates in hepatocellular carcinoma remain high. As the systemic treatment landscape in hepatocellular carcinoma continues to evolve and locoregional options are increasingly used, we review current and future opportunities to individualise the surgical management of patients with hepatocellular carcinoma.

To develop an MRI-based score that enables individualized predictions of the survival benefit of wide over narrow resection margins.

This single-center retrospective study (December 2011 to May 2022) included consecutive patients who underwent curative-intent resection for single Barcelona Clinic Liver Cancer (BCLC) 0/A HCC and preoperative contrast-enhanced MRI. In patients with narrow resection margins, preoperative demographic, laboratory, and MRI variables independently associated with early recurrence-free survival (RFS) were identified using Cox regression analyses, which were employed to develop a predictive score (named "MARGIN"). Survival outcomes were compared between wide and narrow resection margins in a propensity-score matched cohort for the score-stratified low- and high-risk groups, respectively.

Four hundred nineteen patients (median age, 54 years; 361 men) were included, 282 (67.3%) undergoing narrow resection margins. In patients with narrow resection margins, age, alpha-fetoprotein (AFP) > 400 ng/mL, protein induced by vitamin K absence or antagonist-II (PIVKA-II) > 200 mAU/mL, radiological involvement of liver capsule, and infiltrative appearance were associated with early RFS (p values, 0.002-0.04) and formed the MARGIN score with a testing dataset C-index of 0.75 (95% CI: 0.65-0.84). In the matched cohort, wide resection margin was associated with improved early RFS rate for the high-risk group (MARGIN score ≥ - 1.3; 71.1% vs 41.0%; p = 0.02), but not for the low-risk group (MARGIN score < - 1.3; 79.7% vs 76.1%; p = 0.36).

In patients with single BCLC 0/A HCC, the MARGIN score may serve as promising decision-making to indicate the need for wide resection margins.

The MARGIN score has the potential to identify patients who would benefit more from wide resection margins than narrow resection margins, improving the postoperative survival of patients with single BCLC 0/A hepatocellular carcinoma (HCC).

Age, AFP, PIVKA-II, radiological involvement of liver capsule, and infiltrative appearance were associated with early RFS and formed the MARGIN score. The MARGIN score achieved a testing dataset C-index of 0.75. Wide resection margins were associated with improved early RFS for the high-risk group, but not for the low-risk group.

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.

Solitary hepatocellular carcinoma measuring ≤3 cm represents approximately 30% of hepatocellular carcinoma cases, yet treatment guidelines lack robust evidence. This study compares oncologic outcomes after ablation, liver resection, and liver transplantation for solitary, small hepatocellular carcinoma.

We systematically searched databases up to 7 February 2022, for studies including adults with solitary hepatocellular carcinoma ≤3 cm treated by any ablation, liver resection, or liver transplantation. We excluded non-hepatocellular carcinoma cancers, recurrent/metastatic diseases, and alternative therapies. A frequentist network meta-analysis assessed 5-year overall survival and recurrence-free survival using only adjusted effect estimates while accounting for bias risk.

We identified 80 studies (4 randomized controlled trials, 72 retrospectives, and 4 prospective cohorts) with 28,211 patients. In the network meta-analysis for 5-year overall survival (26 studies), liver transplantation was associated with the lowest mortality hazard (hazard ratio, 0.47; 95% confidence interval, 0.31-0.73, referenced to liver resection), followed by liver resection (reference), whereas ablation had the greatest mortality hazard (hazard ratio, 1.32; 95% confidence interval, 1.16-1.49, referenced to liver resection). For 5-year recurrence-free survival (19 studies), liver transplantation had the best outcome (hazard ratio, 0.36; 95% confidence interval, 0.20-0.63, referenced to liver transplantation), followed by liver resection (reference), with ablation showing the least favorable outcome (hazard ratio, 1.67; 95% confidence interval, 1.45-1.93, referenced to liver resection).

This network meta-analysis provides the evidence for comparing treatment modality outcomes for solitary, small (≤3 cm) hepatocellular carcinoma. LT emerges as the superior choice for achieving a better 5-year OS, followed by liver resection, then ablation. When feasible to preserve liver function, liver resection can be prioritized. Ablation with close surveillance should be reserved for individuals unfit for surgery.

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.

Patients with recurrent hepatocellular carcinoma after liver resection can often receive curative treatment, including repeat hepatic resection and local ablative therapy. However, recurrence typically becomes increasingly aggressive during the clinical course, characterized by cycles of recurrence and repeated treatment, ultimately resulting in noncurative patterns.

Noncurative recurrence was defined as the presence of ≥4 liver nodules, macroscopic vascular invasion, and extrahepatic lesions. First, this study investigated the incidence of noncurative recurrence and survival after noncurative recurrence. Subsequently, this study examined survival after the initial recurrence in patients with curative and noncurative recurrences and compared them. Finally, this study investigated whether the time to noncurative recurrence serves as a surrogate for overall survival (OS) in 266 patients who underwent initial curative hepatectomy.

The 3-year cumulative incidences of noncurative recurrence were 15.6%, 6.0%, and 11.0% for ≥4 liver nodules, macroscopic vascular invasion, and extrahepatic lesions, respectively. The median postrecurrence survival estimates after these noncurative recurrences were 21, 17, and 8 months, respectively (P =.006). When analyzed exclusively in patients developing initial recurrence, the 3-year postrecurrence survival rates were 68.3% and 27.8% for patients with curative and noncurative recurrences, respectively (P =.003). The 3-year survival rate without noncurative recurrences was 71.9%, and the recurrence-free survival (RFS) and OS rates were 49.2% and 87.9%, respectively. The concordance index with OS was higher for time to noncurative recurrence than for RFS (0.88 vs 0.67, respectively).

Our findings suggest that the time to noncurative recurrence is a more suitable surrogate for OS than RFS.

To retrospectively evaluate the long-term outcomes of patients treated with liver transplantation after neoadjuvant or induction transarterial chemoembolization using doxorubicin-eluting superabsorbent polymer microspheres and to assess risk factors associated with disease recurrence and death after transplantation.

Between January 2006 and April 2021, 286 patients underwent liver transplantation related to cirrhosis and early hepatocellular carcinoma (HCC). Demographic, angiographic imaging, and clinical follow-up data were collected from patients' electronic medical records. Kaplan-Meier method was used to estimate disease-free survival. The prognostic effect of patient and disease characteristics on HCC recurrence was analyzed using logistic regression models.

Fifty-three out of 286 patients (19%) underwent neoadjuvant or induction chemoembolization with doxorubicin-eluting superabsorbent polymer microspheres as bridging (n = 36) or as downstaging (n = 17) treatment. Time between diagnosis and liver transplantation was 311 days (range:225-440). Post-transplant follow-up revealed HCC recurrence in n = 1 (3%) and n = 4 (23.5%) patients in the bridging and downstaging groups, respectively, and disease-free survival at 5 years of 86% and 65% (p < 0.05) in the bridging and downstaging groups, respectively. Prognostic factors for post-transplant HCC recurrence include number of HCC lesions (p = 0.0088) and total tumor size (p = 0.0188) at diagnosis, as well as number of lesions (p = 0.0181) and largest tumor size (p = 0.0179) at explant analysis.

Neoadjuvant or induction chemoembolization with doxorubicin-eluting superabsorbent polymer microspheres is associated with a low incidence of post-transplant HCC recurrence; number and total size of HCC lesions at diagnosis and at explant analysis are risk factors for post-transplant HCC recurrence.

Posttransplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent diseases are needed. In this retrospective study across 6 centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. The efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. In our study, 431 of 3349 (14%) patients with HCC who underwent transplantation developed recurrence within a median interval of 18 (IQR: 9-32) months. One hundred forty-seven (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with a median survival of 45 (95% CI: 36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving noncurative treatments (median: 11 [95% CI: 10-13] mo, 1/3/5-y survival of 46%/10%/7%, log-rank p < 0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over the previous era (HR 0.64 [95% CI: 0.47-0.86]). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR: 3.5 [95% CI: 2.7-4.6]), recurrence within 1 year (HR: 1.7 [95% CI: 1.3-2.1]), poor tumor differentiation (HR: 1.5 [95% CI: 1.1-1.9]), RETREAT score ≥3 (HR: 1.4 [95% CI: 1.1-1.8]), and alpha-fetoprotein at recurrence ≥400 ng/mL (HR: 1.4 [95% CI: 1.1-1.9]). These factors contributed to a prognostic scoring system (0-9) that stratified patients into 3 prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. Curative-intent treatments should be advocated for patients with posttransplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past 5 years.

The treatment of early stage hepatocellular carcinoma (HCC) has become increasingly complex. This study evaluates the effectiveness of radiofrequency ablation (RFA) versus laparoscopic liver resection (LLR) for treating solitary hepatocellular carcinoma (HCC) ≤ 3 cm, with a focus on tumor location and depth.

We conducted a retrospective analysis of patients treated for solitary HCC ≤ 3 cm in the right liver lobe from 2004 to 2022. Tumor depth was categorized into three zones based on proximity to portal vein branches: Zone I (near first-order branches), Zone II (adjacent to second-order branches), and Zone III (near third-order branches). Outcomes were measured using overall survival (OS) and recurrence-free survival (RFS) rates.

Of the 662 patients, for Zone I, II, and III, 240 (65 LLR, 175 RFA); 174 (100 LLR, 74 RFA); and, 248 patients were treated (244 LLR, 4 RFA), respectively. Statistically significant differences in the treatment outcomes based on the tumor depth were observed. For Zone I, LLR demonstrated superior OS (p = 0.043) and RFS rates (p = 0.030) than did RFA. For Zone II, both treatments had comparable survival outcomes, with no statistically significant differences in the OS (p = 0.460) and RFS (p = 0.358). For Zone III, LLR was principally favored, due to easier surgical access and cleaner margins.

This study highlighted the importance of including tumor location and depth, in addition to the tumor size and liver function, in the management of early stage HCC. A multidisciplinary approach is essential for treatment planning and optimizing survival outcomes.

The role of PET-CT with [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluorocholine ([18F]FCH) in staging hepatocellular carcinoma and treatment decisions has, to our knowledge, never been prospectively assessed.

We conducted a multicentre prospective study (PET-HCC01) in nine hospitals in France, including patients aged 18 years or older with a first diagnosis of hepatocellular carcinoma classified as Barcelona Clinic Liver Cancer (BCLC) classification A to C (without metastasis). At study inclusion, patients underwent contrast-enhanced liver MRI and liver, chest, and pelvis CT scans. Patients subsequently underwent [18F]FCH and [18F]FDG PET-CT. A first tumour staging and treatment decision was recorded by the multidisciplinary tumour board at each centre using morphological imaging, blind to the results of the PET-CTs. After the results of the PET-CTs were revealed, a second tumour staging and treatment decision was recorded. The primary endpoint was the proportion of patients whose treatment was modified by PET-CTs. Analyses were done in the intention-to-image population, consisting of all patients who had undergone at least one PET-CT and were discussed by the multidisciplinary tumour board. This study was registered with ClinicalTrials.gov, NCT04391348.

Between July 20, 2020, and April 27, 2023, 230 patients were enrolled. Among the 215 patients included in the intention-to-image population, the median age was 66·0 years (IQR 60·0-71·5), 193 (90%) were male, and 155 (73%) had cirrhosis. Hepatocellular carcinoma was classified as BCLC stage A in 140 (65%) patients, B in 48 (22%), and C without metastasis in 27 (13%) on the basis of morphological imaging. Potential new lesions were identified in 19 (9%) patients by PET-CT (eight by both tracers, six by [18F]FCH only, and five by [18F]FDG only) and in six of these patients, follow-up confirmed the diagnosis of hepatocellular carcinoma (one lesion in the adrenal gland, two in bones, two in the lymph node, and one intrahepatic). PET-CT modified BCLC stage in ten patients: disease stage for two patients moved from BCLC A to B, from BCLC A to C for two patients, from BCLC B to C for two patients, and from BCLC C without metastasis to BCLC C with metastasis for four patients. Planned treatment was modified for four patients (2% [95% CI 1-5]), below the prespecified threshold of clinical significance (10%).

[18F]FDG and [18F]FCH-PET-CTs should not be systematically performed for staging a first diagnosis of hepatocellular carcinoma, as they modified treatment decisions only in a minority of patients.

Programme Hospitalier de Recherche Clinique Inter-regional-PHRC-I2018 (Ministère de la Santé).

The primary curative therapies for hepatocellular carcinoma are resection or liver transplantation. For patients requiring downstaging or who are unresectable at presentation, the landscape of local treatment options has vastly changed over the past decades. This change is partly due to the paucity of high-level evidence to guide the selection of liver-directed therapies, where physician preference and treatment patterns have historically resulted in relegating external-beam radiation therapy (EBRT) to a secondary option in the treatment of hepatocellular carcinoma in cases where arterially directed therapies or thermal ablations were not possible. However, technology advancements have substantially improved the ability to treat liver malignancies with high doses of radiation therapy and to minimise doses to uninvolved hepatic parenchyma and other nearby organs. These advancements have enabled safe treatment of hepatocellular carcinoma with EBRT, with low risk of toxicity. Recent randomised trials support the role of EBRT in the treatment of hepatocellular carcinoma from early to advanced stages. These trials identified that EBRT improved several key patient-centred outcomes, including overall survival when using stereotactic body radiotherapy and sorafenib compared with sorafenib alone in unresectable hepatocellular carcinoma, recurrence-free survival with the use of adjuvant EBRT in select patients after hepatocellular carcinoma resection, and quality of life for patients with painful hepatocellular carcinoma masses treated with palliative EBRT. With emerging high-quality evidence, hepatocellular carcinoma therapeutic guidelines should include the growing role of EBRT in improving the quality and quantity of life for patients with liver cancer.

The albumin-bilirubin (ALBI) score, used for predicting outcomes after hepatocellular carcinoma (HCC) resection, does not directly capture liver cell damage or biliary obstruction. Gamma-glutamyl transferase (GGT), which reflects hepatic oxidative stress and inflammation, may complement the ALBI score. We sought to develop the ALBI-GGT score, a composite prognostic tool, and evaluate its performance to predict long-term outcomes among patients undergoing HCC resection.

Patients undergoing curative-intent HCC resection (2000-2023) were identified from an international, multi-institutional database. The cohort was divided into training (65%) and testing cohorts (35%). Multivariable Cox analysis examined the association of ALBI-GGT score with overall survival (OS).

Among 759 patients, the median ALBI score was -2.78 (-3.02 to -2.48), and the median GGT was 55.0 U/L (31.0-93.0). On multivariable analysis, ALBI score (hazard ratio [HR], 1.473 [1.112-1.950]; P =.007) and GGT (HR, 1.007 [1.004-1.010]; P <.001) were predictors of overall mortality, alongside tumor burden score (HR, 1.051 [1.015-1.090]; P =.006) and American Society of Anesthesiologists class >2 (HR, 1.473 [1.005-2.161]; P =.047). There was a near-linear correlation between increasing ALBI scores and GGT and higher hazards of death. The ALBI-GGT score demonstrated the highest predictive accuracy in the testing set (concordance index, 0.68 [0.58-0.72]), outperforming the ALBI score (0.62 [0.56-0.69]) and GGT (0.65 [0.58-0.72]). The ALBI-GGT achieved the lowest Akaike and Bayesian information criteria. Time-dependent area under the curve (AUC) analysis demonstrated consistent superiority over 0 to 60 months. At 1-, 3-, and 5-years, the ALBI-GGT score had AUCs of 0.782, 0.725, and 0.688, respectively, outperforming ALBI score and GGT. The ALBI-GGT score was able to stratify patients into distinct prognostic groups (5-year OS, low ALBI-GGT [85.0%] vs intermediate ALBI-GGT [65.8%] vs high ALBI-GGT [56.8%]; P <.001).

ALBI score alone may be insufficient to prognostically stratify patients with HCC. Combining ALBI score with GGT was a superior tool to stratify patients relative to long-term survival.

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.

To compare the prognostic power of commonly used staging systems of hepatocellular carcinoma (HCC) for predicting overall survival after transarterial chemoembolization (TACE).

This retrospective single center study included patients with HCC who underwent TACE between 2008 and 2019 in a single tertiary care center. After initial screening of 408 consecutive patients, 317 patients with HCC treated with conventional or drug-eluting beads-TACE were included. Five HCC staging systems (Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, Japan Integrated Staging, Cancer of the Liver Italian Program and Okuda) were compared using Kaplan Meier survival analysis and a log-rank test with overall survival (OS) as the study endpoint. Uni- and multivariate analyses of system-specific variables were applied to stratify outcomes and compare the ability to predict OS of patients after TACE. Four different measures were used to assess the homogeneity (Likelihood ratio:LR), discriminatory ability (linear trend:LT and C-index) and explanatory ability (Akaike Information Criterion:AIC).

The OS of the total cohort was 29.8 months. In terms of prognostic stratification, the BCLC staging system had the best performance (LT: 8.209, LR: 26.639, AIC: 317, c-index: 0.818) compared to HKLC (LT: 10.919, LR: 25.802, AIC: 443, c-index: 0.835), JIS (LT: 4.611, LR: 16.880, AIC: 449, c-index: 0.548), CLIP (LT: 6.738, LR: 13.109, AIC: 501, c-index: 0.782), and Okuda (LT: 7.185, LR: 0.760. LR: 16.356, AIC: 487, c-index: 0.760).

Across five commonly utilized international staging systems, the BCLC staging system demonstrated the greatest prognostic accuracy with respect to predicting OS of patients undergoing TACE.

The T Cell Receptor (TCR) significantly contributes to tumor immunity, whereas the intricate interplay with the Hepatocellular Carcinoma (HCC) microenvironment and clinical significance remains largely unexplored. Here, we aimed to examine the function of TCR signaling in tumor immunity and its clinical significance in HCC. Our objective was to employ TCR signaling genes and a machine learning-based integrative methodology to construct a prognostic prediction system termed the TCR score. Herein, we revealed that the TCR score serves as an independent risk factor for overall survival in HCC patients, demonstrating stable and robust performance. The accuracy of the TCR score significantly exceeds that of traditional clinical variables and published signatures. Additionally, the immune infiltration was abundant in patients with low TCR scores. Single-cell cohort analysis further demonstrates that patients with low TCR scores possess an immune-active tumor microenvironment (TME), with T/NK cells enhancing interactions with myeloid cells through signaling networks such as MIF, MK, and SPP1. In response to these changes in the TME, patients with high TCR scores exhibit poorer outcomes and shorter survival in immunotherapy cohorts. In vitro experiments demonstrated that the key TCR signaling biomarker SOS1 knockdown significantly suppresses the HCC cells' capability to proliferate, invade, and migrate while enhancing tumor cell apoptosis. The TCR score could function as a robust and potential tool to predict immune activity and improve clinical outcomes for HCC patients.

In recent years, new systemic therapies have been developed for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the prognosis of patients with unresectable HCC treated with R0 hepatectomy after systemic therapy.

Data from 27 patients who underwent hepatectomy for HCC after systemic therapy at six facilities were analyzed retrospectively. Cancer-specific survival (CSS) and recurrence-free survival (RFS) after hepatectomy were investigated using Kaplan-Meier curves. We examined the prognostic value of the oncological criteria of resectability for HCC reported by the Japanese Expert Consensus 2023.

R0 resection was performed in 24 of the 27 patients. Using the Response Evaluation Criteria in Solid Tumors, 0 patient had a complete response, 16 had a partial response, 6 had stable disease, and 2 had progressive disease. Median CSS was not evaluated, but the median RFS was 17.8 months. Patients with resectable and borderline resectable (BR) 1 cancers had a better prognosis than those with BR2 cancers. The group whose oncological criteria were improved by systemic therapy had a lower recurrence rate than the group whose oncological criteria were maintained, but no difference was observed in CSS.

The findings of this study suggest that hepatectomy after systemic therapy may improve the prognosis of HCC patients.

Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in ~17% of patients. We aimed to retrospectively compare the outcomes of patients treated with different tyrosine kinase inhibitors (TKIs) for recurrent HCC post-LT.

Patients with recurrent HCC post-LT between 2006 and 2019 were included. The impact of sorafenib and lenvatinib treatment for recurrent disease was assessed using survival analysis with an a priori multivariable Cox regression (alpha-fetoprotein [AFP] at recurrence, recurrence lesion diameter, single-site versus multisite metastases).

Seven hundred fifty-four patients underwent LT for HCC, of whom 120 (15.9%) developed recurrence. Of these patients, 56 received TKIs: sorafenib (n = 42) or lenvatinib (n = 14). The median age at LT was 60.8 y (interquartile range, 54.0-66.2); 52 (93%) were men and 26 (46%) were within Milan criteria at listing. Baseline characteristics at recurrence were comparable between the 2 groups, including largest tumor diameter ( P  = 0.15), receipt of local therapies before TKI ( P  = 0.33), and single-site recurrence ( P  = 0.75), and time from interventional treatment to start of TKI ( P  = 0.44). The AFP at recurrence was higher in the sorafenib group (95.0 versus 3.0 µg/L, P  < 0.001). The median overall survival (OS) after initiation of TKI treatment was longer in the lenvatinib group (15.0 mo [95% confidence interval [CI], 11.5-31.5] versus 7.8 mo [95% CI, 4.0-15.4]; P  = 0.02) with a 2.3-fold a priori adjusted effect on OS (adjusted hazard ratio 2.32 [95% CI, 1.03-5.20], P  = 0.04).

Our findings suggest lenvatinib is a valuable treatment option for patients with HCC recurrence after LT.

Immune checkpoint inhibitors (ICIs) are playing a significant role in the treatment of hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of alpha-fetoprotein (AFP) and initial tumor shape irregularity in patients treated with ICIs.

In this retrospective, multi-center study, 296 HCC patients were randomly divided into the training set and the validation set in a 3:2 ratio. The training set was used to evaluate prognostic factors and to develop an easily applicable ATSI (AFP and Tumor Shape Irregularity) score, which was verified in the validation set.

The ATSI score was developed from two independent prognostic risk factors: baseline AFP ≥ 400 ng/ml (HR 1.73, 95% CI 1.01-2.96, P = 0.046) and initial tumor shape irregularity (HR 1.94, 95% CI 1.03-3.65, P = 0.041). The median overall survival (OS) was not reached (95% CI 28.20-NA) in patients who met no criteria (0 points), 25.8 months (95% CI 14.17-NA) in patients who met one criterion (1 point), and 17.03 months (95% CI 11.73-23.83) in patients who met two criteria (2 points) (P = 0.001). The median progression-free survival (PFS) was 10.83 months (95% CI 9.27-14.33) for 0 points, 8.03 months (95% CI 6.77-10.57) for 1 point, and 5.03 months (95% CI 3.83-9.67) for 2 points (P < 0.001). The validation set effectively verified these results (median OS, 37.43/24.27/14.03 months for 0/1/2 points, P = 0.028; median PFS, 13.93/8.30/4.90 months for 0/1/2 points, P < 0.001).

The ATSI score can effectively predict prognosis in HCC patients receiving ICIs.

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.

To report outcomes in hepatocellular carcinoma (HCC) patients with lobar and segmental vascular invasion treated with resin Yttrium-90 transarterial radioembolization (Y90-TARE) with single-compartment MIRD (Medical Internal Radiation Dose) model.

This was a retrospective IRB approved study of patients with a diagnosis of HCC with vascular invasion undergoing resin Y90-TARE from 2014 to 2022 (n = 61). Patients with Body Surface Area dosimetry (n = 20), main portal vein invasion (n = 6) and patients with an ECOG of > 2 were excluded (n = 1) with a final cohort of 34 patients.

Study population consisted of 34 patients, median age 62 years [60-71], tumor size 4.2 (2.8-7.4) cm, and 82% male. The median prescribed dose was 170 (126-200) Gy. The objective response rate at 6 months was 67% and disease control rate was 72%. The median survival was 18 months, median progression-free survival was 9.8 months. The 1- and 3-year survival rates were 76% and 57% in patients prescribed > 180 Gy, compared to 29% and 15% in patients with < 180 Gy (p = 0.01). Five of 15 Childs-Pugh A, ECOG < 1 patients (33%) were downstaged to resection, with complete pathologic necrosis in 40%, and 1 and 3-year survival rates of 100%. Grade-3 adverse events were seen in only 5/34 (15%), with no grade-4 or 5 adverse events.

Resin Y90-TARE using single compartment MIRD model for HCC with segmental and lobar vascular invasion can result in downstaging to resection in 33% of patients and higher prescribed doses (> 180 Gy) result in improved survival.

Curative surgery for hepatocellular carcinoma (HCC) includes liver resection (LR) and orthotopic liver transplantation (OLT). Due to the obesity epidemic, metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent HCC aetiology that often coincides with increased alcohol consumption, termed MetALD, or even alcohol-associated liver disease (ALD).

Patients undergoing LR or OLT for HCC at Charité-Universitätsmedizin Berlin (2010-2020) were included in this retrospective cohort study investigating disease aetiology, time to recurrence (TTR), overall survival (OS) and CT-based body composition.

Out of 579 patients with HCC, 417 underwent LR and 162 OLT. Tumour aetiologies were viral n = 191 (33.0%), MASLD n = 158 (27.3%), MetALD n = 51 (8.8%), ALD n = 68 (11.7%) and other/cryptogenic n = 111 (19.2%). Patients with MASLD and MetALD had more intramuscular (p < 0.001, p = 0.015) and visceral fat (both p < 0.001) than patients with non-metabolic dysfunction aetiologies. Patients with MASLD-HCC had comparable TTR (median 26 months, [95% CI: 23-31] vs. 30 months [95% CI: 4-57], p = 0.425) but shorter OS than patients with other HCC aetiologies (63 months [95% CI: 42-84] vs. 80 months [95% CI: 60-100], hazard ratio: 1.53 [95% CI: 1.050-2.229], p = 0.026) after LR. Multivariate analysis confirmed MASLD aetiology, portal vein thrombosis and MELD score ≥ 10 as independent prognostic factors for OS in LR (adjusted p = 0.021,p < 0.001,p = 0.003), even after excluding in-hospital mortality (adjusted p = 0.016,p = 0.002,p = 0.002). Causes of death were similar in MASLD and non-MASLD aetiology.

Patients with HCC undergoing LR and meeting the new MASLD criteria have significantly shorter OS. This study provides empirical prognostic evidence for the novel MASLD/MetALD classification in a large European cohort of patients undergoing curative-intent HCC therapy.