Transarterial radioembolization (TARE) is an established treatment method for non-resectable liver tumors. One of the challenges of the approach is the accurate prediction of the microsphere biodistribution in the liver. We propose to use ultrasound contrast microbubbles as holmium microsphere precursors, which allows real-time prediction of the microsphere trajectories and biodistribution using dynamic contrast-enhanced ultrasound (DCE-US). The immediate goal in this in vitro study was to investigate the predictive capabilities of microbubbles as microsphere precursors. The study was conducted in an experimental in vitro model which represents the bifurcating right branch of the hepatic artery. A controlled injection of experimental BR-14 ultrasound contrast microbubbles and non-radioactive holmium-165 microspheres was performed in separate consecutive experiments in an arterial flow phantom. The microbubbles and microspheres were collected separately at the outlets of the phantom and counted using a Coulter counter to determine their distribution over the different outlets. The flow profile, the injection velocity, and the catheter position were monitored during the measurements to ensure stability. The results showed a good correlation between the microbubble and the microsphere distributions (p = 0.0038, r = 0.88) measured at the outlets. Differences in the distributions could be attributed to the characteristics of microbubbles and microspheres alone (e.g. particle size and concentration), since critical parameters were kept stable between the two experiments. The current in vitro study provides confidence that the microsphere biodistribution can be predicted using contrast microbubbles. The comparison provided by this study forms a foundation for the development of a DCE-US guided TARE treatment.

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.

Increased intratumoral pressure and stiffening of the extracellular matrix are biophysical barriers to effective drug delivery in hepatocellular carcinoma (HCC). Local thermal interventions alter these biophysical characteristics of the tumor.

To characterize time-dependent and thermal dose-related effects of radiofrequency hyperthermic (RFHT) interventions on intratumoral pressure and tumor stiffness.

Two treatment protocols (high input power > 1 W and low input power < 1 W) were investigated using a computational modeling approach and a syngeneic rat HCC tumor model with a customized monopolar RFHT system. Intratumoral pressure and stiffness were assessed using piezo-electric sensors and ultrasound shear wave elastography (SWE), respectively, across three groups (untreated tumors, tumors treated with high and low RFHT) and time points (immediately after treatment, at 24 h, and 48 h).

The developed RFHT system maintained electrode-tip temperatures of 74.1 ± 5.2 °C (high RFHT) and 45.9 ± 1.6 °C (low RFHT) for 15 min. Histological analysis confirmed larger necrotic areas in the high RFHT group compared with low RFHT (p < 0.01) and control groups (p < 0.001). The initial intratumoral hypertension significantly decreased in both treated groups at 24 h and 48 h (p < 0.01 high RFHT, p < 0.05 low RFHT). Tumor stiffness significantly decreased (p < 0.05) only in the low RFHT group at the end of treatment. This change was spatially-dependent within the tumor and a recovery toward initial conditions was observed at 48 h (p < 0.01).

Local RFHT induces time- and heating profile-dependent alterations in intratumoral pressure and stiffness in a rat model of HCC, suggesting that RFHT interventions may modulate tumor biophysics and influence drug delivery.

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.

Hepatocellular carcinoma (HCC) remains a health concern characterized by heterogeneity and high mortality. Surgical resection, radiofrequency ablation, trans-arterial chemoembolization, and liver transplantation offer potentially curative treatments for early-stage disease, but recurrence remains high. Most patients present with advanced-stage HCC, where locoregional therapies are less effective, and systemic treatments-primarily multi-kinase inhibitors and immune checkpoint inhibitors-often yield limited responses. Precision medicine aims to tailor therapy to molecular and genetic profiles, yet its adoption in HCC is hindered by inter-/intra-tumoral heterogeneity and limited biopsy availability. Advances in molecular diagnostics support reintroducing tissue sampling to better characterize genetic, epigenetic, and immunological features. Liquid biopsy offers a minimally invasive method for capturing real-time tumor evolution, overcoming spatial and temporal heterogeneity. Artificial intelligence and machine learning are revolutionizing biomarker discovery, risk stratification, and treatment planning by integrating multi-omics data. Immunological factors such as tumor-infiltrating lymphocytes, natural killer cells, macrophages, and fibroblasts have emerged as determinants of HCC progression and treatment response. Conversion therapy-combining systemic agents with locoregional treatments-has showndemonstrated promise in downstaging unresectable HCC. Ongoing efforts to refine biomarker-driven approaches and optimize multi-modality regimens underscore precision medicine's potential to improve outcomes. PubMed (January 2002-February 2025) was searched for relevant studies.

Esophagogastric variceal bleeding, especially first variceal hemorrhage, represents a challenging complication in the management of patients with hepatocellular carcinoma (HCC), and its presence significantly herald poor patient prognosis. The stratification system for the risk of first variceal hemorrhage and mortality has not been validated in patients with HCC. We aimed to develop and validate a simple score for the prediction of initial variceal bleeding and mortality in patients with HCC.

This multicenter retrospective-prospective study included HCC patients at three tertiary hospitals in China from January 2016 to December 2023. The bleeding following endoscopy for hepatocellular carcinoma (BFE-HCC) score was constructed by the least absolute contraction and selection operator (LASSO) regression combined with multivariate logistic regression analysis. The performance of the score model was evaluated using the receiver operating characteristic (ROC) curve, the calibration curve, and the decision curve analysis (DCA). Finally, the of the results was further verified in an independent external cohort.

We recruited 351 patients from three centers (median age 56 years, 85.5% male and 83.5% with cirrhosis), 56.6% patients presented high-risk (HR) varices, and 35% patients experienced variceal bleeding. Multivariate logistic analysis revealed that the presence of cirrhosis, a history of acute variceal bleeding (AVB), Child-Pugh score, ALBI score, tumor size and portal vein tumor thrombosis (PVTT) Vp4 were independent predictors of HR varices. The BFE-HCC is composed of six variables: white blood cell count, HR varices, Child-Pugh score, HCC therapy modality, Vp4, and tumor stage. The area under the curve (AUC) of BFE-HCC was 0.82, and the calibration plots and decision curve analysis exhibited outstanding performance compared with the MELD, ALBI, and Child-Pugh scores. In addition, Patients with BFE-HCC ≥ 4 were at increased risk of mortality (P<0.01).

The BFE-HCC score is hopeful to predict initial variceal bleeding and mortality in patients with HCC, offering a promising tool for prognostic assessment and treatment decisions.

Many patients with hepatocellular carcinoma (HCC) present with advanced-stage disease or multifocal tumors which make them unsuitable for radical treatment options. In such cases, locoregional therapy (LRT) such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE) can be used as a bridge to liver transplantation or to downstage borderline tumors. However, post treatment response assessment can be very difficult, especially in the case of TARE. The recently updated Liver Imaging Reporting and Data System treatment response algorithm (LI-RADS TRA) 2024 guidelines has included ancillary features of mild-moderate T2 signal intensity and diffusion restriction into the assessment algorithm. Diffusion-weighted imaging (DWI) would be particularly important in post-TARE assessment as early response assessment using traditional size and enhancement criteria can be challenging following TARE. However, the interpretation of restricted diffusion in post-treatment imaging can be challenging as DWI can be affected by various factors such as inflammatory changes, haemorrhage, or T2-relaxation time of the surrounding parenchyma. In this review article, we provide an overview of the advantages and challenges in the use of DWI to interpret treatment response after LRT.

Transhepatic arterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, a significant proportion of patients are non-responders or poor responders to TACE. Therefore, our aim is to identify the targets of TACE responders or non-responders. GSE104580 was utilized to identify differentially expressed genes (DEGs) in TACE responders and non-responders. Following the protein-protein interaction (PPI) analysis, hub genes were identified using the MCC and MCODE plugins in Cytoscape software, as well as LASSO regression analysis. Gene set enrichment analysis (GSEA) was performed to investigate potential mechanisms. Subsequently, the hub genes were validated using data from The Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and The Human Protein Atlas (HPA) database. To evaluate the clinical significance of the hub genes, Kaplan-Meier (KM) survival and Cox regression analysis were employed. A total of 375 DEGs were identified, with 126 remaining following PPI analysis, and TTK, a dual-specificity protein kinase associated with cell proliferation, was ultimately identified as the hub gene through multiple screening methods. Data analysis from TCGA, CCLE, and HPA databases revealed elevated TTK expression in HCC tissues. GSEA indicated that the cell cycle, farnesoid X receptor pathway, PPAR pathway, FOXM1 pathway, E2F pathway, and ferroptosis could be potential mechanisms for TACE non-responders. Analysis of immune cell infiltration showed a significant correlation between TTK and Th2 cells. KM and Cox analysis suggested that HCC patients with high TTK expression had a worse prognosis. TTK may play a pivotal role in HCC patients' response to TACE therapy and could be linked to the prognosis of these patients.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and the sixth most prevalent cancer worldwide. However, most patients with HCC are at an advanced stage at the time of clinical diagnosis, making surgery impossible. In the past, targeted therapeutic drugs such as sorafenib and lenvatinib were the main treatments. With recent breakthroughs in medicine, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has garnered interest and has been extensively studied for clinical treatment. In addition to single-agent therapies, combination regimens involving ICIs have also been developed. Despite this progress, not all patients with HCC benefit from immunotherapy. Therefore, to improve the treatment response rates, it is crucial to identify patients with HCC who are suitable for immunotherapy. The exploration and validation of markers to predict the outcomes of immunotherapeutic treatments in patients with HCC are of clinical importance. In this article, we provide a comprehensive review of research progress in immunotherapy, particularly ICIs and combination therapies, for HCC. Furthermore, we summarize the clinical indicators and tumor markers discovered in recent years to forecast immunotherapy outcomes in patients with HCC. We also outline predictive markers for the occurrence of immune-related adverse events in patients with HCC receiving immunotherapy and discuss future research directions in the immunotherapeutic treatment landscape.

Since its introduction in 1977, transarterial chemoembolization (TACE) has widely been accepted treatment for unresectable intermediate stage hepatocellular carcinoma (HCC). Conventional TACE (c-TACE) uses an emulsion of chemotherapeutic agent and ethiodized oil with subsequent embolization of the feeding artery using gelatin sponge. Drug eluting beads (DEB) were introduced in clinical practice in the 2000s and have since been used as an alternative to c-TACE with better outcomes, especially in larger tumors. Considering the widespread use of TACE in HCC, it is important to revisit the current knowledge and the advances that have developed for better safety and efficacy. This article aims to emphasize on the current knowledge and importance of TACE, touch upon the technical aspects including post-TACE care, response assessment, and discontinuation strategies and highlight the recent advances in the technology, catheters, and embolization particles. Thus, despite a rapid change in treatment algorithms and availability of newer drugs for HCC, TACE will remain an integral part of HCC treatment alone or in combination with other therapies.

HCC ranks as the third leading cause of cancer-related death, yet current surveillance strategies miss over one-third of cases at an early stage. SerpinB3-PD (SB3-PD), a polymorphic isoform of a serine-protease inhibitor involved in tumorigenesis and fibrogenesis, has been related to a more rapid cirrhosis decompensation. This study investigates the prognostic role of SB3-PD in patients with HCC.

SB3-PD polymorphism was assessed in 140 patients with HCC, followed up in our outpatient Clinic. Cell invasion analysis was conducted on HepG2 cells either overexpressing the SB3 wild-type (HepG2/SB3WT) or the PD isoform (HepG2/SB3PD). The effect of recombinant SB3-WT or SB3-PD on the production of molecules that impair immunosurveillance was also assessed in the THP-1 monocytic cell line.

Patients carrying SB3-PD polymorphism showed worse tumour characteristics, associated with significantly lower survival and SB3-PD was an independent predictor of mortality. HepG2/SB3PD cells had a significantly higher invasion capacity than the HepG2/SB3WT. In THP-1 cells recombinant SB3-PD induced higher levels of PDL1 and IL-13 than SB3-WT.

SB3-PD isoform is associated with worse clinical prognosis in patients with HCC. These findings were supported in vitro by increased cellular invasion and higher production of molecules impairing immunosurveillance.

Despite increasing interest, prospective data on the use of degradable starch microsphere-transarterial chemoembolization (DSM-TACE) in the management of patients with unresectable HCC are still scarce. The objective of the HepaStar study was to collect prospective safety and effectiveness data in a prospective multicenter observational study.

Between January 2017 and December 2022, consecutive participants with unresectable or recurrent HCC treated with DSM-TACE as standard of care at 6 participating centers in Europe were enrolled. Tumor response was evaluated according to the mRECIST criteria. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were assessed by using Kaplan-Meier analysis and Common Terminology Criteria for Adverse Events, version 5. Liver function deterioration was assessed by monitoring changes in liver blood tests during the follow-up.

Seventy-nine participants (median age, 69 years (IQR, 51-87 years); 67 men (85%)) were enrolled and treated. The median follow-up time was 18 months (IQR 9.5-38.0 months). The estimated median OS and PFS for the entire cohort was 32 months (CI, 95% 21-NaN) and 9 months (CI, 95% 7-NaN), respectively. Eleven (13.9%) participants experienced at least one grade 3 or 4 AE. The most frequent grade 3-4 AE was elevated bilirubin (2.2%, 5 of 79). Deterioration of bilirubin, AST, ALT, and albumin were observed in 24.1%, 23.7%, 19%, and 24% of participants, respectively.

DSM-TACE achieves promising survival in patients with unresectable or recurrent HCC. This technique shows a favorable safety profile both in terms of treatment-related AEs and liver function deterioration.

Question Although degradable starch microspheres transarterial chemoembolization is widely used in clinical practice across Europe, prospective data on its application in hepatocellular carcinoma patients remains limited. Findings Degradable starch microspheres transarterial chemoembolization results in promising survival rates, good tumor response rates, and low rates of treatment-related adverse events. Clinical relevance In patients with unresectable hepatocellular carcinoma, degradable starch microspheres transarterial chemoembolization represents a safe and effective alternative to more well-established chemoembolization techniques like conventional transarterial chemoembolization and drug-eluting beads transarterial chemoembolization.

Morphologic criteria, such as the Barcelona Clinic Liver Cancer staging system often fail to accurately predict long-term survival among patients undergoing liver resection for hepatocellular carcinoma. We sought to develop a continuous risk score that incorporates established markers of tumor biology and liver function to improve the prediction of overall survival.

Data from a multi-institutional database were used to identify patients who underwent curative-intent hepatectomy for hepatocellular carcinoma. A predictive score for overall survival was developed using weighted beta-coefficients from a multivariable Cox regression model.

Among 850 patients, 595 (70.0%) were assigned to the training cohort, and 255 (30.0%) to the test cohort. In the training cohort, multivariable analysis identified the Model of End-Stage Liver Disease (hazard ratio, 1.04; 95% confidence interval, 1.01-1.07), log-transformed alpha-fetoprotein (hazard ratio, 1.07; 95% confidence interval, 1.02-1.13), and tumor burden score (hazard ratio, 1.07; 95% confidence interval, 1.03-1.11) as independent predictors of worse overall survival. The Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score, based on the Cox model, stratified patients into low-risk (n = 466, 78.3%) with a 5-year OS of 70.5% and high-risk (n = 129, 21.7%) with a 5-year OS of 47.0% (P < .001). In the test cohort, the Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score demonstrated superior discriminative accuracy (C-index: 0.72, time-dependent area under the curve 1-year: 0.80, 3-year 0.76, 5-year 0.70) compared with the Barcelona Clinic Liver Cancer staging system (C-index: 0.53, time-dependent area under the curve 1-year: 0.61, 3-year 0.55, 5-year 0.56). An online tool was made accessible at https://jk-osu.shinyapps.io/MELD_AFP_TBS/.

The Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score provides a novel, accurate tool for prognostic stratification of patients with hepatocellular carcinoma, identifying high-risk patients who may benefit from alternative treatments to improve outcomes.

Racial and ethnic minority populations are disproportionately impacted by HCC due to more advanced tumor burden and underuse of treatments. We explored racial and ethnic differences in medical mistrust, barriers to treatment, and health literacy among patients with HCC.

We conducted a multicenter survey among patients with newly diagnosed HCC between September 2018 and July 2023 at 4 large U.S. health systems. The survey assessed medical mistrust [Group-Based Medical Mistrust Scale (GBMMS)], health literacy (CHEW Assessment of Health Literacy), and barriers to HCC treatment. We performed multivariable logistic regression to evaluate associations between race and ethnicity and survey measures.

Of 1245 eligible patients, 833 (66.9%) completed the survey (45.9% Hispanic, 35.9% White, and 14.2% Black). A higher proportion of Black and Hispanic patients had high medical mistrust than White patients (14.2% and 3.3% vs. 0.7%, respectively; p<0.001). In multivariable analysis, Black race (OR: 19.2, 95% CI: 4.2-87.7) but not Hispanic ethnicity (OR: 3.72, 95% CI: 0.80-17.2) was significantly associated with high mistrust. Compared to White patients, Black and Hispanic patients both reported greater barriers to HCC treatment, with the most common barriers being concerns about pain (41.6%), financial burden (37.6%), and time commitment (31.1%). Limited health literacy was reported by 38.1% of patients (46.8% Hispanic, 41.0% Black, 26.2% White; p<0.001).

Medical mistrust, barriers to treatment, and limited health literacy are prevalent among Black and Hispanic patients with HCC. Understanding the interplay between race, ethnicity, and these factors is essential to address HCC disparities.

Several prognostic gene signatures have been proposed as predictors of the prognosis of hepatocellular carcinoma (HCC), yet none are implemented in the clinical setting. We aimed to validate two gene scores previously derived from European cohorts.

The patients who underwent liver resection for HCC at Copenhagen University Hospital, Rigshospitalet from 2014 to 2018 were included. RNA sequencing determined the expression of genes in the '5-gene score' (HN1, RAN, RAMP3, KRT19, TAF9B) and 'HepatoPredict' (CLU, DPT, SPRY2, CAPSN1). Univariable Cox regression assessed associations with overall and disease-free survival. These parameters were also analyzed in the The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) (n = 359) and National Institute of Health (NIH) (n = 178) cohorts.

Among 51 patients (88% male), 59% had no underlying liver disease and 25% had cirrhosis. No individual genes were significantly associated with overall survival in the Danish cohort. In the TCGA-LIHC cohort, CLU was linked to better overall survival, and in the NIH cohort, high expression of SPRY2 was associated with poorer overall survival. In the TCGA-LIHC cohort, HN1, RAN, and TAF9B were associated with poorer overall survival, while RAMP3 was linked to better overall survival. No genes were associated with disease-free survival.

Few individual genes significantly predicted survival in the larger cohorts, and none in the Danish cohort. However, the clinical implication of this needs further investigation.

To analyze the efficacy and safety of balloon-occluded transarterial chemoembolization (B-TACE) of hepatocellular carcinoma (HCC).

We searched English databases, assessed the quality of the selected studies, analyzed the extracted data, tested heterogeneity of data, explored the resources of heterogeneity, and tested publication bias.

After inclusion and exclusion criterion, totally 7 studies included in our analysis. The numbers of complete response (CR) in B-TACE were significantly more than in Non B-TACE (P = 0.003). There were no significant difference in partial response (PR), stable disease (SD) and progressive disease (PD) between B-TACE and Non B-TACE. Moderate heterogeneity existed in CR and PR (I2 = 60%). Low heterogeneity existed in SD (I2 = 36%). Heterogeneity did not exist in PD (I2 = 0%). The numbers of treatment effect (TE) 4-1 in B-TACE were significantly more than in Non B-TACE, respectively (P = 0.000007, P < 0.00001). Heterogeneity did not exist in TE4 (I2 = 0%). Low heterogeneity existed in T3 - 1 (I2 = 48%). The numbers of post embolization syndrome(PES) in B-TACE were significantly more than in Non B-TACE, respectively(P = 0.000007, P < 0.00001). There were no significant difference in adverse events (AEs) of grade 3 and 2 between B-TACE and Non B-TACE, respectively(P = 0.57, 0.12). High heterogeneity existed in PES (I2 = 76%). Moderate heterogeneity existed in AEs of grade 2(I2 = 57%). Heterogeneity did not exist in AEs of grade 3(I2 = 0%).

B-TACE was safe. It showed promising efficacy in achieving higher CR rates in short term compared to Non B-TACE.

The association between preoperative imaging and postoperative pathological tumor size disparity, and cancer-specific survival (CSS) among patients undergoing hepatectomy for hepatocellular carcinoma (HCC) remains unclear. We sought to evaluate this association and identify predictors of size disparity.

Patients undergoing curative-intent hepatectomy for HCC (2000-2023) were identified from an international, multi-institutional database. Size ratio was defined as the ratio of pathological to imaging tumor size. Patients with a size ratio of 0.5-1.5 were classified as "without size disparity," while patients outside this range were considered "with size disparity." Multivariable Cox regression was used to identify predictors of CSS, while logistic regression was utilized to determine factors associated with size disparity. For variables identified as significant in multivariable analyses, further evaluation including cutoff determination, were performed using receiver operating characteristic (ROC) analysis.

Among 833 patients, median size ratio was 1.02, with a strong correlation between imaging and pathological tumor sizes (r = 0.87). Size disparity was present in 106 patients (12.7 %); in general, patients had smaller median imaging sizes (2.85 vs. 4.80 cm; p < 0.001) while size on pathology was noted to be larger(both 4.50 cm; p = 0.370). Patients with size disparity had worse 5-year CSS (60.1% vs. 79.0 %; p < 0.001). Multivariable Cox regression identified higher ALBI score (HR:2.56 [1.50-4.37]; p < 0.001), larger pathological tumor size (HR:1.09 [1.03-1.15]; p = 0.001), and size disparity (HR:2.53 [1.37-4.66]; p = 0.002) as independent predictors of CSS. Logistic regression demonstrated that cirrhosis (OR: 2.68 [1.43-5.02]; p = 0.002) and log alpha-fetoprotein (AFP) (OR:1.11 [1.01-1.22]; p = 0.030) were associated with an increased likelihood of size disparity. Cirrhosis and log AFP could be used to stratify patients relative to probability of a size disparity (low-risk:9.9 %, medium-risk:12.2 %, high-risk:17.7 %). The optimal AFP cutoff value was 3928 ng/mL for non-cirrhotic (AUC:0.90) versus 28.9 ng/mL for cirrhotic (AUC:0.74) patients.

Tumor size disparity was associated with worse CSS among patients with HCC undergoing hepatectomy. Size disparity could be predicted preoperatively using cirrhosis status and AFP level, which may help identify high-risk patients who may benefit from more detailed imaging assessments.

Liver cancer, a malignant tumor of the digestive system, is a leading cause of cancer‑related mortality globally. Numerous genetic mutations associated with tumorigenesis have been identified, stemming from genomic instability. However, the clinical implications and therapeutic relevance of these mutations remain poorly understood. The present study evaluated the prognostic significance of titin (TTN) mutations in liver cancer by analyzing the mutation landscape of liver cancer tissues from The Cancer Genome Atlas (TCGA) database. The association between TTN mutations and drug susceptibility was subsequently examined using the OncoPredict algorithm and Cell Counting Kit‑8 (CCK‑8) assays. Furthermore, the impact of TTN mutations on hepatoma cell biology both in vivo and in vitro were assessed by reverse transcription‑quantitative PCR, protein stability assays, colony formation assays, tumor spheroid formation assays and subcutaneous tumor transplantation in BALB/c nude mice. Genetic analysis of the TCGA database revealed that TTN mutations are among the most frequent mutations in liver cancer. Patients with TTN mutations exhibited worse prognoses compared with those with the wild‑type allele. The OncoPredict algorithm and CCK‑8 assays revealed that TTN mutations are associated with altered drug sensitivity, particularly to GSK1904529A, nilotinib, 5‑fluorouracil (5‑FU) and sapitinib. Additionally, TTN mutations were shown to enhance TTN protein stability, decrease intracellular ferrous ion levels and significantly decrease liver cancer sensitivity to 5‑FU both in vitro and in vivo. The findings indicated that TTN mutations increase protein stability and lower intracellular ferrous ion levels, thereby suppressing ferroptosis and contributing to resistance to 5‑FU in hepatoma cells. These results suggest that TTN mutations are associated with poor prognosis in liver cancer and could serve as a predictive biomarker for liver cancer progression, prognosis and drug resistance.

Prior to the commencement of treatment, it is essential to establish an objective method for accurately predicting the prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). In this study, we aimed to develop a machine learning (ML) model to predict the response of HCC patients to TACE based on CT images analysis.

Public dataset from The Cancer Imaging Archive (TCIA), uploaded in August 2022, comprised a total of 105 cases, including 68 males and 37 females. The external testing dataset was collected from March 1, 2019 to July 1, 2022, consisting of total of 26 patients who underwent TACE treatment at our institution and were followed up for at least 3 months after TACE, including 22 males and 4 females. The public dataset was utilized for ResNet50 transfer learning and ML model construction, while the external testing dataset was used for model performance evaluation. All CT images with the largest lesions in axial, sagittal, and coronal orientations were selected to construct 2.5D images. Pre-trained ResNet50 weights were adapted through transfer learning to serve as a feature extractor to derive deep features for building ML models. Model performance was assessed using area under the curve (AUC), accuracy, F1-Score, confusion matrix analysis, decision curves, and calibration curves.

The AUC values for the external testing dataset were 0.90, 0.90, 0.91, and 0.89 for random forest classifier (RFC), support vector classifier (SVC), logistic regression (LR), and extreme gradient boosting (XGB), respectively. The accuracy values for the external testing dataset were 0.79, 0.81, 0.80, and 0.80 for RFC, SVC, LR, and XGB, respectively. The F1-score values for the external testing dataset were 0.75, 0.77, 0.78, and 0.79 for RFC, SVC, LR, and XGB, respectively.

The ML model constructed using deep features from 2.5D images has the potential to be applied in predicting the prognosis of HCC patients following TACE treatment.

The introduction of immune checkpoint inhibitor (ICI) based therapies has significantly improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the variable treatment response and the uncertain benefit in patients with advanced liver cirrhosis emphasise the urgent need for prognostic and predictive biomarkers guiding patient selection. The soluble urokinase plasminogen activator receptor (suPAR) is strongly associated with inflammation, liver cirrhosis and various types of cancer. In this study, we investigated suPAR as a potential novel biomarker in patients with unresectable HCC.

This multicenter retrospective study, conducted at three German tertiary care centers, included 90 patients with unresectable HCC and suPAR measurements prior to and during atezolizumab/bevacizumab therapy. Patients with liver cirrhosis without HCC (n = 235) and non-cirrhotic patients with other gastrointestinal tumours (n = 155) were selected as control cohorts.

Median suPAR levels were significantly higher in patients with liver cirrhosis compared to non-cirrhotic cancer patients. A strong association with parameters of liver function, but not with HCC characteristics, was observed. In patients with HCC receiving atezolizumab/bevacizumab, suPAR was the most accurate independent predictor of hepatic decompensation and overall survival (OS). In addition, suPAR was able to stratify the risk of hepatic decompensation within the different Child-Pugh classes.

SuPAR represents a promising novel biomarker in patients with HCC treated with ICI-based therapies and bears the potential to guide the selection of antitumoral systemic therapies in patients with advanced liver cirrhosis.

Hepatocellular carcinoma (HCC) is a common malignancy with high mortality. Liver resection (LR) is a curative treatment for early-stage HCC, but the prognosis of HCC patients after LR is unsatisfactory because of tumor recurrence. Prognostic prediction models with great performance are urgently needed. The present study aimed to establish a novel prognostic nomogram to predict tumor recurrence in HCC patients after LR.

We retrospectively analyzed 726 HCC patients who underwent LR between October 2011 and December 2016. Patients were randomly divided into the training cohort (n = 508) and the testing cohort (n = 218). The protein expression of 14 biomarkers in tumor tissues was assessed by immunohistochemistry. The nomogram predicting recurrence-free survival (RFS) was established by a multivariate Cox regression analysis model and was evaluated by calibration curves, Kaplan-Meier survival curves, time-dependent areas under the receiver operating characteristic (ROC) curves (AUCs), and decision curve analyses in both the training and testing cohorts.

Alpha-fetoprotein [hazard ratio (HR) = 1.013, P = 0.002], portal vein tumor thrombosis (HR = 1.833, P < 0.001), ascites (HR = 2.024, P = 0.014), tumor diameter (HR = 1.075, P < 0.001), E-cadherin (HR = 0.859, P = 0.011), EMA (HR = 1.196, P = 0.022), and PCNA (HR = 1.174, P = 0.031) immunohistochemistry scores were found to be independent factors for RFS. The 1-year and 3-year AUCs of the nomogram for RFS were 0.813 and 0.739, respectively. The patients were divided into the high-risk group and the low-risk group by median value which was generated from the nomogram, and Kaplan-Meier analysis revealed that the high-risk group had a shorter RFS than the low-risk group in both the training (P < 0.001) and testing cohorts (P < 0.001).

Our newly developed nomogram integrated clinicopathological data and key gene expression data, and was verified to have high accuracy in predicting the RFS of HCC patients after LR. This model could be used for early identification of patients at high-risk of postoperative recurrence.

To evaluate the effectiveness of combined portal vein embolization (PVE) and hepatic vein embolization (HVE) compared with that of PVE alone in cirrhotic and noncirrhotic swine.

Sixteen Yorkshire pigs were included in this study. In the cirrhotic group (n = 8) and noncirrhotic group (n = 8), subjects underwent embolization according to established protocols. Computed tomography (CT) scans were acquired before and at 2- and 4-week intervals following the embolization. Liver volumes were segmented in the portal venous phase. Student t test with a significance level at P < .05 was used.

Across all swine, the future liver remnant (FLR) was significantly larger after PVE + HVE than after PVE at 2 weeks (24.12% [95% CI, 15.36%-32.88%] vs 12.75% [95% CI, 7.43%-18.07%]; P = .021) and 4 weeks (23.23% [95% CI, 15.79%-33.47%] vs 15.08% [95% CI, 9.98%-20.87%]; P = .043) after embolization. In the cirrhotic group, the FLR increase was greater following PVE + HVE than after PVE at 2 weeks (20.85% [95% CI, 14.40%-27.30%] vs 8.66% [95% CI, 6.47%-10.86%]; P = .0089) and 4 weeks (19.27% [95% CI, 17.87%-20.67%] vs 13.33% [95% CI, 9.23%-13.33%]; P = .0003) after embolization.

PVE + HVE resulted in greater FLR hypertrophy than PVE alone, indicating that cirrhotic livers may benefit from the addition of HVE.

The outcome of patients with HCC who achieved complete response (CR) to immune-checkpoint inhibitor (ICI)-based systemic therapies is unclear.

Retrospective study of patients with HCC who had CR according to modified Response Evaluation Criteria in Solid Tumors (CR-mRECIST) to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based noncurative systemic therapies, 174 (4.4%) achieved CR-mRECIST, and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; Barcelona-Clinic Liver Cancer-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95% CI: 29.9-34.4) months. One- and 3-year overall survival rates were 98% and 86%. One- and 3-year recurrence-free survival rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after the first mRECIST CR had a longer recurrence-free survival than those who discontinued immunotherapy earlier ( p =0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathological CR (CR-RECISTv1.1, n= 2/2; CR-mRECIST-only, n= 6/7).

Overall survival and recurrence-free survival of patients with CR-mRECIST-only and CR-RECISTv1.1 were excellent, and 6 of 7 patients with CR-mRECIST-only who underwent surgical conversion therapy had pathological CR. Despite potential limitations, these findings support the use of mRECIST in the context of immunotherapy for clinical decision-making. When considering ICI discontinuation, treatment for at least 6 months beyond CR seems advisable.

Severe postoperative complications still occur following hepatectomy among patients with hepatocellular carcinoma (HCC). There is a need to identify high-risk patients for severe complications to enhance patient safety. We sought to evaluate the combined impact of pre- and postoperative albumin-bilirubin (ALBI) score and Fibrosis-4 (FIB-4) index trends to predict severe complications after HCC resection.

Patients with HCC undergoing curative-intent hepatectomy (2000-2023) were identified from an international, multi-institutional database. The cohort was divided into training (n = 439) and testing (n = 651) sets. ALBI score and FIB-4 index trends from preoperative to postoperative days 1, 3, and 5 were used for K-means clustering (K = 3). A logistic regression model was developed using the training set, and its performance was evaluated using the area under the receiver operating characteristic curve (AUC) in both cohorts.

Severe complications (Clavien-Dindo Grade ≥ IIIa) occurred in 118 patients (10.8 %); 43 (9.8 %) in training and 75 (11.5 %) in testing set (p = 0.42). K-means clustering identified three groups: Cluster1 (low), Cluster2 (intermediate), and Cluster3 (high), which was associated with a progressively increasing risk of complications (p < 0.01). On multivariable logistic regression, patients in ALBI Cluster1 had 76 % decreased odds (odds ratio[OR] 0.24, 95 % CI 0.07-0.83, p = 0.02) of postoperative complications relative to Cluster3 patients. Individuals categorized into FIB-4 Cluster1 had 85 % decreased odds (OR 0.15, 95 % CI 0.02-1.24, p = 0.07) versus patients in FIB-4 Cluster3. A new prediction model incorporating ALBI and FIB-4 index clusters achieved an AUC of 0.71, outperforming models based on preoperative data. A tool was made available at https://nm49jf-miho-akabane.shinyapps.io/HCC_ALBI/.

A dynamic ALBI score and FIB-4 index trend tool improved risk stratification of patients undergoing resection of HCC relative to severe complications.

To compare concordance of radiologic and pathologic response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE), percutaneous ablation, and multimodal treatment using radiologic-pathologic correlation.

This single-center retrospective study analyzed 56 treatment-naive patients (male, 75%; Barcelona Clinic Liver Cancer Stage A, 63%) with 81 HCC tumors (mean diameter, 2.1 cm [SD ± 0.9]) who underwent locoregional therapy (LRT) (TACE, n = 44; ablation, n = 10; TACE + ablation, n = 27) prior to liver transplantation (LT) between 2010 and 2019. Immediate pre-LT cross-sectional imaging was used to assess modified Response Evaluation Criteria in Solid Tumours (mRECIST) response. Explant liver pathology was reviewed for percent pathologic necrosis (PN). Associations between imaging and pathologic observations were statistically characterized using the chi-square and Kruskal-Wallis tests.

Median time from imaging to LT was 37 days (range, 2-191 days). Across all LRT types, 68% (55/81), 19% (15/81), and 13% (11/83) of tumors displayed mRECIST complete response (CR), partial response (PR), and stable disease. The mean percent PN (%PN) in CR tumors (89% [SD ± 21]) was significantly higher than those in PR (68% [SD ± 34], P = .005) and stable disease (67% [SD ± 36], P = .009) tumors. Sixty percent (33/55) of CR tumors showed 100% complete PN (CPN), whereas only 20% (3/15) of PR tumors and 18% (2/11) of stable disease tumors showed CPN (P = .002). There was no association between %PN and CPN across different LRT modalities and radiologic response categories, indicating consistent performance between treatments. Sensitivity and specificity for radiologic CR to predict 100% PN were 87% and 49%, respectively.

Herein, radiologic-pathologic outcomes suggest that radiologic response criteria are associated with PN, with no differences across treatment modalities. However, the imperfect predictive capacity of imaging for PN supports surveillance of treated tumors before LT.

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

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

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

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

Hepatobiliary malignancies encompass a spectrum of invasive carcinomas arising in the liver [hepatocellular carcinoma (HCC), bile ducts [intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (EHC)] and the gallbladder. These malignancies represent a growing global health burden, with rising incidence and mortality rates and their overall prognosis remains poor because many patients present with advanced unresectable disease at diagnosis. In recent years, significant advancements in understanding HCC immunogenicity have reshaped the therapeutic scenario of advanced HCC with the immunotherapy revolutionizing the current HCC treatment landscape and patients' prognosis. Moreover, the addition of immunotherapy to chemotherapy has recently established a new standard of care first-line treatment for patients with biliary tract cancers (BTCs) who had historically few therapeutic options. Currently, immunotherapy and immune checkpoint inhibitor (ICI)-based regimens stand as a valuable and practice-changing options in both HCC and BTC management. The mounting recent evidence supporting immunotherapy's survival benefit demands clinicians to stay updated with a rapidly evolving treatment landscape as well as gain knowledge about patient selection, response rate compared with other systemic treatments and immune-mediated adverse events (imAEs) management. A panel of international Experts, comprising hepatologists and oncologists, gathered to explore the challenges in effectively integrating immunotherapy in routine clinical practice. The aim of this review is to present the Experts' insights to inform treatment choice in HCC and BTC with a special emphasis on the role of currently available ICI-based therapies in shifting treatment paradigms and potentially reversing the natural course of these two deadly malignancies.

To develop habitat and deep learning (DL) models from multi-phase contrast-enhanced magnetic resonance imaging (CE-MRI) habitat images categorized using the K-means clustering algorithm. Additionally, we aim to assess the predictive value of identified regions for early evaluation of the responsiveness of hepatocellular carcinoma (HCC) patients to treatment with transarterial chemoembolization (TACE) plus molecular targeted therapies (MTT) and anti-PD-(L)1.

A total of 102 patients with HCC from two institutions (A, n = 63 and B, n = 39) who received TACE plus systemic therapy were enrolled from September 2020 to January 2024. Multiple CE-MRI sequences were used to outline 3D volumes of interest (VOI) of the lesion. Subsequently, K-means clustering was applied to categorize intratumoral voxels into three distinct subgroups, based on signal intensity values of images. Using data from institution A, the habitat model was built with the ExtraTrees classifier after extracting radiomics features from intratumoral habitats. Similarly, the Crossformer model and ResNet50 model were trained on multi-channel data in institution A, and a DL model with Transformer-based aggregation was constructed to predict the response. Finally, all models underwent validation at institution B.

The Crossformer model and the habitat model both showed high area under the receiver operating characteristic curves (AUCs) of 0.869 and 0.877 (training cohort). In validation, AUC was 0.762 for the Crossformer model and 0.721 for the habitat model.

The habitat model and DL model based on CE-MRI possesses the capability to non-invasively predict the efficacy of TACE plus systemic therapy in HCC patients, which is critical for precision treatment and patient outcomes.

Despite advances in surgical treatment, high recurrence after surgery remains a challenge for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the association between compliance to regular follow-up and long-term oncological outcomes among patients undergoing curative resection for HCC.

This multicenter study included patients who underwent curative resection for early-stage HCC between January 2012 and December 2021 at 12 liver surgery centers. Patients were stratified into a regular follow-up group (follow-up every 2-3 months for the first 2 years and every 3-6 months thereafter) and an irregular/no follow-up group. Overall survival (OS), time to recurrence (TTR), and post-recurrence survival (PRS) were compared between the two groups.

Among 1544 patients, 786 (50.9%) underwent regular follow-up during postoperative follow-up. The regular follow-up group had better OS (median: 113.4 vs. 94.5 months, P = 0.010) and PRS (median: 37.9 vs. 16.3 months, P < 0.001) than the irregular/no follow-up group, although TTR was comparable (median: 61.4 vs. 66.2 months, P = 0.161). Furthermore, patients in the regular follow-up group had a lower incidence of tumor beyond the Milan criteria at recurrence (41.6% vs. 50.4%, P = 0.013) and were more likely to receive curative treatments for recurrence (56.1% vs. 49.3%, P = 0.061). On multivariate analysis, compliance to regular follow-up was an independent factor associated with better OS [hazard ratio (HR) = 0.777, 95% confidence interval (CI): 0.663-0.910, P = 0.002] and PRS (HR = 0.523, 95% CI: 0.428-0.638, P < 0.001).

Compliance to regular follow-up improved OS and PRS after curative resection for HCC, highlighting the importance of postoperative regular follow-up for early detection of recurrence and timely intervention.

This study evaluates the prognostic value of tumor response on CT at 3 months, assessed by Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and Liver Imaging Reporting and Data System Treatment Response Algorithm (LR-TRA) in patients with hepatocellular carcinoma (HCC) treated with selective internal radiation therapy (SIRT).

A retrospective analysis was conducted on 102 HCC patients treated with SIRT between 2018 and 2020. RECIST, mRECIST, and LR-TRA were assessed at 3 months post-SIRT. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier analysis and Cox proportional-hazards models.

The median age was 71 years, and most patients (90%) had advanced-stage tumors (Barcelona Clinic Liver Cancer-C). After a median follow-up of 32.0 months (95% CI: 16.8-60.9), 60/102 patients died (59%), and 90/102 patients showed tumor progression (88%). Median OS was 20.4 months (95% CI: 15.4-33.0), and median PFS was 14.5 months (95% CI: 6.5-24.5); 1-year OS and PFS rates were 65.6% and 50.7%. Multivariable analysis revealed that early response according to RECIST 1.1 (HR 1.66, p = 0.30), mRECIST (HR 1.40, p = 0.215), and LR-TRA (HR 0.67, p = 0.30) were not predictors of OS. Disease progression evaluated by RECIST (HR 2.55, p < 0.001) and mRECIST (HR 2.53, p < 0.001), bilirubin levels (HR 1.03, p < 0.001), and prothrombin time (HR 0.98, p = 0.005) were predictors of OS. For PFS, neither RECIST nor mRECIST response, disease progression, nor LR-TRA viability were predictors.