We investigated the efficacy of quantitative evaluation of tumor signal heterogeneity on gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) to predict prognosis and antitumor immunity in patients with hepatocellular carcinoma (HCC) undergoing liver resection.

A total of 297 patients who underwent curative resection for primary HCC were included. Tumor signal heterogeneity in the hepatobiliary phase (HBP) of EOB-MRI was quantified as the coefficient of variation (CV), calculated as the standard deviation divided by the mean signal intensity. Patients were classified into homogeneous (low CV) and heterogeneous (high CV) groups based on a cutoff value of 0.16 from receiver operating characteristic curve analysis. Tumor-infiltrating CD4+ and CD8+ T cells and PD-L1 expression were assayed by immunohistochemistry, and their associations with tumor signal heterogeneity were evaluated.

Among the 297 patients, 116 (39.1%) were classified into the heterogeneous group. The overall survival (OS) and recurrence-free survival (RFS) rates were significantly lower in the heterogeneous group (p < 0.001 for both). Multivariate analysis identified heterogeneous group as an independent prognostic factor for OS and RFS (p < 0.001 and p = 0.012, respectively). Extrahepatic recurrence was significantly more frequent in the heterogeneous group (18.1% vs. 7.7%, p = 0.024). CD4+ and CD8+ T cells were significantly decreased, and the PD-L1 positivity rate was significantly lower in the heterogeneous group (p < 0.001 for all).

The quantitative evaluation of tumor signal heterogeneity in the HBP of EOB-MRI using CV is useful for predicting postoperative prognosis in patients with HCC. Tumor signal heterogeneity may also reflect impaired local immunity and an immunologically "cold" tumor.

This study aimed to evaluate the prognostic impact of muscle volume changes during atezolizumab-bevacizumab (AB) combination therapy (AB therapy) for unresectable hepatocellular carcinoma (u-HCC). Additionally, we evaluated whether changes in muscle volume relate to prognosis based on treatment response.

The present retrospective, multicenter study included 165 patients with u-HCC treated with AB therapy at eight institutions.

The median albumin-bilirubin score in the entire cohort was -2.42. The objective response rate was 31.5%, and the disease control rate was 80.6%. The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI]: 5.3-8.5). At the first post-treatment computed tomography scan, patients were categorized into two groups: those with a nondecreased psoas muscle area index (PI) (group A) and those with a decreased PI (group B). The median OS was not reached in either group (p = 0.059). The median PFS was 10.5 months in group A and 5.5 months in group B (p = 0.025). Multivariate analysis using the Cox proportional hazards model identified alpha-fetoprotein ≥400 ng/mL (hazard ratio [HR]: 1.68; 95% CI: 1.11-2.54; p = 0.01) and decreased PI (HR: 1.59; 95% CI: 1.07-2.36; p = 0.02) as factors associated with PFS.

Nondecreased muscle volume after initiating AB therapy was associated with improved treatment efficacy and prognosis in patients with u-HCC.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Radiofrequency ablation (RFA) can be utilized in elderly patients and those with cirrhosis with reduced functional liver reserve as it is less invasive. The arfa RFA system is the first system to offer a linear mode. However, the differences in performance between the linear and existing (nonlinear) modes remain unknown.

This retrospective observational study compared the performance of the linear (linear group) and nonlinear RFA modes (nonlinear group) in HCC.

Data of 425 patients with one to three HCC tumors measuring ≤ 3 cm who underwent RFA were analyzed. Recurrence (local and distant), survival, and complication rates between the linear and nonlinear groups were determined.

The intrahepatic distant recurrence rate was lower in the linear group than in the nonlinear group (p < 0.05). Multivariate analysis showed that the high platelet count, low AFP-L3 levels, initial case, and linear mode were independent factors associated with a low intrahepatic distant recurrence rate following RFA. Liver disease-related survival, HCC survival, overall survival of the initial HCC, local recurrence, and complication rates were comparable between the linear and nonlinear groups.

The linear mode of the RFA protocol results in a lower intrahepatic distant recurrence rate compared with the nonlinear protocol.

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.

Liver stiffness measurement (LSM) via vibration-controlled transient elastography accurately assesses fibrosis. We aimed to develop a universal risk score for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis.

We systematically selected predictors and developed the risk prediction model (HCC-LSM) in the hepatitis B virus (HBV) training cohort (n = 2251, median follow-up of 3.2 years). The HCC-LSM model was validated in an independent HBV validation cohort (n = 1191, median follow-up of 5.7 years) and a non-viral chronic liver disease (CLD) extrapolation cohort (n = 1189, median follow-up of 3.3 years). An HCC risk score was then constructed based on a nomogram. An online risk evaluation tool Liver Elastography-Based Hepatocellular Carcinoma Risk Score (LEBER) was developed using ChatGPT4.0.

Eight routinely available predictors were identified, with LSM levels showing a significant dose-response relationship with HCC incidence (P < .001 by log-rank test). The HCC-LSM model exhibited excellent predictive performance in the HBV training cohort (C-index = 0.866) and the HBV validation cohort (C-index = 0.852), with good performance in the extrapolation CLD cohort (C-index = 0.769). The model demonstrated significantly superior discrimination compared to 6 previous models across the 3 cohorts. Cut-off values of 87.2 and 121.1 for the HCC-LSM score categorized participants into low-, medium-, and high-risk groups. An online public risk evaluation tool (LEBER; http://ccra.njmu.edu.cn/LEBER669.html) was developed to facilitate the use of HCC-LSM.

The accessible, reliable risk score based on LSM accurately predicted HCC development in patients with chronic hepatitis, providing an effective risk assessment tool for HCC surveillance strategies.

This multicentre study investigated the dynamics of thrombospondin 2 (TSP2) levels during direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV) infected patients and evaluated TSP2's potential as a predictive marker for hepatocellular carcinoma (HCC). All 134 participants achieved sustained virological response at 12 weeks (SVR12) with DAA therapy, and serum TSP2 levels significantly decreased from before and after treatment (p < 0.001). During the median follow-up period of 6.0 years, HCC after DAA therapy was observed in 16 patients (11.9%). Patients with serum TSP2 High (≥ 32 ng/mL) at SVR12 had a significantly higher cumulative occurrence of HCC than did those without (26.5% vs. 7.0%, p = 0.0033). A multivariate Cox proportional hazards model identified male gender (HR 4.84, p = 0.005), HCC history (HR 4.61, p = 0.017) and TSP2 High (HR 3.93, p = 0.009) as significant independent predictors of HCC occurrence after DAA therapy. The model had a high concordance index of 0.878. Additionally, combining TSP2 High and FIB-4 High (≥ 3.538) at SVR12 yielded high specificity and negative predictive value (0.941 and 0.917, respectively) for predicting HCC. Kaplan-Meier analysis showed a higher HCC incidence in the TSP2 High + FIB-4 High group (log-rank p < 0.0001). In conclusion, TSP2 may be a promising biomarker for personalised HCC surveillance in DAA-treated hepatitis C patients.

Currently, only tumors classified as LR-5 are considered definitive hepatocellular carcinoma (HCC), and no further pathologic confirmation is required to initiate therapy. Previous studies have shown that the sensitivity of LR-5 is modest, and lesions enhanced by gadoxetic acid (Gd-EOB-DTPA) may exhibit lower sensitivity than those enhanced by Gd-DTPA.

To identify malignant ancillary features (AFs) that can independently and significantly predict HCC in Liver Imaging Reporting and Data System version 2018, and to develop modified LR-5 criteria to improve diagnostic performance on Gd-EOB-DTPA - enhanced magnetic resonance imaging.

Imaging data from patients with HCC risk factors who underwent abdominal Gd-EOB-DTPA - enhanced magnetic resonance imaging were collected. Univariate and multivariate logistic regression analyses were performed to determine AFs that could independently and significantly predict HCC. The modified LR-5 criteria involved reclassifying LR-4/LR-3 lesions based on major features combined with independently significant AFs for HCC, or by substituting threshold growth with significant AFs. McNemar's test was used to compare the diagnostic performance of the modified LR-5 criteria.

A total of 244 lesions from 216 patients were included. Transitional phase hypointensity, mild - moderate T2 hyperintensity, and fat in mass (more than adjacent liver) were identified as significant independent predictors of HCC. Using the modified LR-5 criteria (e.g., LR-5-M1: LR-4 + transitional phase hypointensity; LR-5-M4: LR-5 by transitional phase hypointensity instead of threshold growth; LR-5-M5: LR-5 by mild - moderate T2 hyperintensity instead of threshold growth; LR-5-M8: LR-3/LR-4 + any two features of transitional phase hypointensity/mild - moderate T2 hyperintensity/fat in mass), sensitivities were significantly increased (88.5%-89.1%) compared to the standard LR-5 (60.6%; all P values < 0.05), while specificities (84.8%-89.9%) remained largely unchanged (93.7%; all P values > 0.05). The LR-5-M8 criterion achieved the highest sensitivity.

Mild - moderate T2 hyperintensity, transitional phase hypointensity, and fat in mass are independent and significant predictors of HCC malignant AFs. The modified LR-5 criteria can improve sensitivity without significantly reducing specificity.

While the value of Des-γ-carboxy prothrombin in hepatocellular carcinoma diagnosis has been widely acknowledged, whether or how Des-γ-carboxy prothrombin could be used in recurrence evaluation remains largely unexplored.

We performed a multicenter retrospective analysis including an Exploration Cohort (1074 patients, 5133 Des-γ-carboxy prothrombin measurements) and a Validation Cohort (263 patients, 612 Des-γ-carboxy prothrombin measurements) to investigate whether Des-γ-carboxy prothrombin could evaluate patients' prognosis. We introduced the Des-γ-carboxy prothrombin dynamic rate as a normalized quantitative measurement of Des-γ-carboxy prothrombin dynamic change. Des-γ-carboxy prothrombin dynamic rates were further applied in a high-risk liver cirrhosis patient cohort (PreCar Cohort, 542 liver cirrhosis patients, 2023 Des-γ-carboxy prothrombin measurements).

Here, we show a post-operative decrease of Des-γ-carboxy prothrombin in the Exploration Cohort, making the Des-γ-carboxy prothrombin threshold in diagnosis unsuitable for prognosis, while Des-γ-carboxy prothrombin dynamic rates significantly associate with recurrence risk. Categorizing patients based on Des-γ-carboxy prothrombin dynamic rates and final concentrations shows that patients negative for both exhibit the best median recurrence-free survival and patients positive for both show the worst median recurrence-free survival. Patients with consistently positive status have a significantly lower median recurrence-free survival compared to those whose status reverted to negative. These findings are validated in the Validation Cohort. Furthermore, the Des-γ-carboxy prothrombin dynamic rates in the PreCar Cohort can identify an additional 28% of cirrhosis patients progressing to hepatocellular carcinoma.

These results expand on the clinical utilization of the hepatocellular carcinoma diagnosis biomarker, Des-γ-carboxy prothrombin, by proposing a quantification measurement of Des-γ-carboxy prothrombin dynamics to monitor hepatocellular carcinoma recurrence. This measurement is not limited in prognosis but can also improve the sensitivity of early hepatocellular carcinoma screening.

Maximum diameter and number are the main parameters of tumor burden in hepatocellular carcinoma (HCC). Tumor burden score (TBS) shows its distinguished ability to stratify patients with HCC undergoing transcatheter arterial chemoembolization (TACE). However, the prognostic accuracy of TBS in HCC undergoing liver resection and its association with the BCLC stage has not been well evaluated.

A total of 3044 treatment-naïve HCC patients from six independent medical centers undergoing liver resection were retrospectively analyzed. Survival analyses were conducted by plotting Kaplan-Meier curves and the Log rank test. We further investigated whether the tumor burden score was a feasible subclassification criterion across the BCLC stage. Then, we also used TBS to identify HCC patients beyond BCLC criteria who could benefit most from surgical resection. Finally, univariate and multivariate cox analysis was used to determine independent prognostic predictors.

About 44.2% (n=1343) of patients had low TBS, 38.8% (n=1182) had intermediate TBS and 17% (n=519) had high TBS. Overall survival (OS) and recurrence-free survival deteriorated incrementally with increasing TBS (P<0.0001). Subgroup analysis indicated that there was a significant survival difference among the three TBS groups across the BCLC stage (P<0.0001). Low TBS group of patients beyond BCLC criteria reported acceptable outcomes compared to intermediate TBS group patients within BCLC criteria, even better than high TBS group (5-year OS: 64.3%, 69.8%, and 56.3%). Finally, low TBS was identified as an independent protective prognostic factor.

Tumor burden score is a feasible and reliable prognostic tool for prognosis prediction and clinical decisions.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with advanced stages posing significant treatment challenges. Although hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising modality for treating advanced HCC, particularly in Asian clinical practice, its adoption in Western medicine remains limited due to a lack of large-scale randomized controlled trials. This editorial reviews and comments on the meta-analysis conducted by Zhou et al, which evaluates the efficacy and safety of HAIC and its combination strategies for advanced HCC. The authors performed a comprehensive meta-analysis of various clinical trials and cohort studies comparing HAIC and its combinations to other first-line treatments, such as sorafenib and transarterial chemoembolization (TACE). In this work, HAIC showed significantly better results regarding overall survival and progression-free survival compared to sorafenib or TACE alone and their combination. HAIC in combination with lenvatinib, ablation, programmed cell death 1 inhibitors, and radiotherapy further enhanced patient outcomes, indicating a synergistic effect. This editorial focuses on the critical role of multimodal treatment strategies in managing advanced HCC. It advocates for a paradigm shift towards integrated treatment approaches to enhance survival rates and improve the quality of life in patients with advanced HCC.

We investigated the impact of proteinuria on the therapeutic effect before lenvatinib administration as second-line treatment after atezolizumab-bevacizumab.

We examined 64 patients who were administered lenvatinib as second-line treatment after discontinuation of atezolizumab and bevacizumab. Proteinuria assessed before lenvatinib administration was considered severe if the qualitative value test (QV) was 3+ or the urine protein/creatinine ratio (UPCR) was ≥ 2.0 (group A, n = 13) and non-severe if the UPCR was < 2.0 or the QV was ≤ 2+ (group B, n = 51).

In the entire cohort, the modified albumin-bilirubin grades were grades 1, 2a, 2b, and 3 in 12, 21, 26, and 5 patients, respectively. Regarding the Barcelona Clinic of Liver Cancer stage, 2, 22, and 40 patients had stages A, B, and C, respectively. The objective response rate (ORR) was 14.0% and the disease control rate (DCR) was 59.3%. The median survival time and progression free survival after administration of lenvatinib was 14.8 (95% confidence interval [CI], 11.3-18.4) and 5.5 (95% CI, 3.6-7.5) months, respectively. The ORR and DCR were 0% and 38.4% for group A (n = 13) and 17.6% and 64.7% for group B (n = 51), respectively. The median time to treatment failure was 2.2 months in group A and 4.2 months in group B (p = 0.120).

Severe proteinuria before lenvatinib as a second-line therapy after atezolizumab-bevacizumab treatment may affect the duration of lenvatinib administration and treatment efficacy.

Hepatocellular carcinoma (HCC) frequently recurs after radical resection, resulting in a poor prognosis. This study assessed the prognostic value of Mac-2 binding protein glycosylation isomer (M2BPGi) for early recurrence (ER) in patients with HCC.

Patients who underwent radical resection for HCC between 2015 and 2021. HCC recurrence within one year after curative resection was defined as ER.

The 150 patients were divided into two groups: non-ER (116, 77.3%) and ER (34, 22.7%). The ER group had a lower overall survival rate (p < 0.0001) and significantly higher levels of M2BPGi (1.06 vs. 2.74 COI, p < 0.0001) than the non-ER group. High M2BPGi levels (odds ratio [OR] 1.78, 95% confidence interval [CI] 1.31-2.41, p < 0.0001) and a large tumor size (OR 1.31, 95% CI, 1.05-1.63; p = 0.0184) were identified as independent predictors of ER. M2BPGi was the best predictor of ER according to a receiver operating characteristic (ROC) analysis (area under the ROC curve 0.82, p < 0.0001).

M2BPGi can predict ER after surgery and is useful for risk stratification in patients with HCC.

Postsustained virologic response (SVR) screening following clinical guidelines does not address individual risk of hepatocellular carcinoma (HCC). Our aim is to provide tailored screening for patients using machine learning to predict HCC incidence after SVR.

Using clinical data from 1,028 SVR patients, we developed an HCC prediction model using a random survival forest (RSF). Model performance was assessed using Harrel's c-index and validated in an independent cohort of 737 SVR patients. Shapley additive explanation (SHAP) facilitated feature quantification, whereas optimal cutoffs were determined using maximally selected rank statistics. We used Kaplan-Meier analysis to compare cumulative HCC incidence between risk groups.

We achieved c-index scores and 95% CIs of 0.90 (0.85 to 0.94) and 0.80 (0.74 to 0.85) in the derivation and validation cohorts, respectively, in a model using platelet count, gamma-glutamyl transpeptidase, sex, age, and ALT. Stratification resulted in four risk groups: low, intermediate, high, and very high. The 5-year cumulative HCC incidence rates and 95% CIs for these groups were as follows: derivation: 0% (0 to 0), 3.8% (0.6 to 6.8), 26.2% (17.2 to 34.3), and 54.2% (20.2 to 73.7), respectively, and validation: 0.7% (0 to 1.6), 7.1% (2.7 to 11.3), 5.2% (0 to 10.8), and 28.6% (0 to 55.3), respectively.

The integration of RSF and SHAP enabled accurate HCC risk classification after SVR, which may facilitate individualized HCC screening strategies and more cost-effective care.

We aimed to develop a preoperative model to predict overall survival (OS) in patients with hepatoma undergoing liver resection (LR).

Patients who underwent LR for Barcelona Clinic Liver Cancer (BCLC) stage 0, A, or B hepatoma were enrolled. Tumor burden score (TBS) scores were determined using the following equation: TBS (Pinna et al., 2018) 2 = (largest tumor size [in cm])(Pinna et al., 2018) 2 ​+ ​(tumor number) (Pinna et al., 2018) 22. The cutoff values for radiographic TBS were based on our recently published paper: low, <2.6; medium, 2.6-7.9; high, >7.9.

Multivariate analysis showed that radiographic TBS (low: referent; medium: HR ​= ​2.89; 95 ​% CI: 1.60-5.21; p ​< ​0.001; high, HR ​= ​7.60; 95 ​% CI: 3.80-15.2; p ​< ​0.001), AFP (<400 ​ng/mL: referent; ≧400 ​ng/mL: HR ​= ​1.67, 95 ​% CI: 1.11-2.52, p ​= ​0.014), and cirrhosis (absence: referent; presence: HR ​= ​1.88, 95 ​% CI: 1.30-2.72, p ​< ​0.001) were associated with OS. A simplified risk score was superior to BCLC system in concordance index (0.688 vs. 0.623).

We have developed a preoperative model that performs better in predicting OS than the BCLC system.

The impact of hepatitis C virus (HCV) eradication via direct-acting antiviral (DAA) therapy on overall mortality, particularly non-liver-related mortality, is understudied.

We recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non-SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all-cause mortality, including non-liver-related diseases, were investigated.

Of the 4180 patients, 592 died during the follow-up period. In the SVR group, the mortality rates from liver-related and non-liver-related diseases were 16.5% and 83.5%, respectively. Compared to the non-SVR group, mortality rates from liver-related and non-liver-related diseases were 50.1% and 49.9%, respectively (p < .001). In non-cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver-related (hazard ratio [HR], .251; 95% confidence interval [CI], .092-.686) and non-liver-related (HR, .641; 95% CI, .415-.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver-related mortality (HR, .151; 95% CI, .081-.279). In propensity score-matched patients, the eradication of HCV (SVR group) decreased both liver-related (p < .001) and non-liver-related mortality (p = .008) rates compared to persistent HCV infection (non-SVR group).

The elimination of HCV via DAA therapy reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV.

Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics.

This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX.

The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis.

A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.

In hepatocellular carcinoma (HCC), postoperative recurrence remains high. This study aimed to evaluate the recurrence patterns and prognosis of HCC after curative hepatectomy.

Among 352 patients with primary HCC who underwent initial hepatectomy between January 2002 and December 2022, 151 with recurrence were assessed for the relationship between recurrence pattern and prognosis.

The early recurrence group (within 6 months postoperatively; n = 38) had significantly higher serum alpha-fetoprotein (p = 0.002), des-γ-carboxyprothrombin (DCP; p = 0.004) levels and Barcelona Clinic Liver Cancer (BCLC) stage (p < 0.001), larger tumor size (p < 0.001), higher incidence of multiple tumors (p = 0.002) and lower overall survival (OS) (p < 0.001) than the late recurrence group (> 6 months postoperatively; n = 113). The tumor size (p = 0.013) and BCLC stage (p = 0.001) were independent risk factors for early recurrence within 6 months in multivariate analysis. The multiple recurrence group (intrahepatic multinodular recurrence or distant metastasis; n = 89) had significantly lower prognostic nutritional index (p = 0.026), larger tumor size (p = 0.017), lower incidence of liver cirrhosis (p = 0.03) than the single recurrence group (single nodule recurrence; n = 62). The multiple recurrence group, especially patients with ≥ three intrahepatic nodules and distant metastases, had lower postoperative OS (p < 0.001) and shorter time to recurrence (p < 0.001) than the single recurrence group. When the patients were classified into three groups: late recurrence with one or two tumors (Group A; n = 74), early recurrence or three or more tumors or distant metastasis (Group B; n = 54), and early recurrence with three or more tumors or distant metastasis (Group C; n = 23), OS was significantly lower in Groups B and C than Group A (p < 0.001).

Patients with early recurrence within 6 months after surgery and three or more recurrence nodule or distant metastasis exhibited poor prognosis after initial recurrence, and they should be carefully followed up.

The aim of the study was to evaluate chemerin levels as a potentially useful marker in diagnosing early-stage hepatocellular carcinoma (HCC) as well as in HCC staging.

The cohort comprised 76 patients: 45 people with cirrhosis and HCC (including 13 with a single HCC lesion in the liver and 32 with metastatic lesions/spread of HCC in the liver) and 21 people with isolated cirrhosis. The control group included 10 clinically healthy people.

The degree of liver failure in the whole cohort was assessed using the Child-Turcotte-Pugh (CTP) score (class A - 34, class B - 28, class C - 4) and using the MELD score (≤ 12 points - 45 and > 12 points - 21 people). Serum chemerin level in patients with liver cirrhosis only was 53.30 ng/ml, in patients with a single HCC lesion 77.01 ng/ml, and in patients with disseminated HCC 83.58 ng/ml. In the control group, the chemerin level was 82.20 μg/ml. When patients with cirrhosis and with/without HCC were divided according to their CTP scores, the level of chemerin was as follows: class A - 83.90 μg/ml, class B - 61 μg/ml, class C - 30.10 μg/ml. For MELD scores ≤ and > 12 it was 75 μg/ml and 58 μg/ml, respectively. For BCLC staging the results were as follows: A - 20.10 μg/ml, B - 20.20 μg/ml, C -19.44 μg/ml.

Chemerin increases with the number of neoplastic lesions and decreases with the progression of liver failure as assessed using the CTP score.

Combined hepatocellular cholangiocarcinoma is a rare and challenging primary liver malignancy that lacks any established standard treatments for unresectable cases. We herein present the first known case of a 49-year-old woman diagnosed with unresectable combined hepatocellular-cholangiocarcinoma, who underwent novel chemotherapy involving durvalumab plus tremelimumab combination therapy. The treatment was temporarily discontinued owing to immune-related adverse events, such as rash, and the patient was subsequently managed with systemic steroid therapy; however, the disease progressed after two courses of this treatment. Further studies are needed to validate the efficacy and safety of immune checkpoint inhibitors such as durvalumab and tremelimumab for the treatment of unresectable combined hepatocellular cholangiocarcinoma.

Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume. However, in patients with huge HCC, high lung absorbed dose often prevents them from receiving SIRT.

A 35-year-old man was admitted because of emaciation and pain in the hepatic region for about 1 month. The computed tomography scan showed a 20.2 cm × 19.8 cm tumor located in the right lobe-left medial lobes with right portal vein and right hepatic vein invasion. After the pathological type of HCC was confirmed by biopsy, two conversions were presented. The first one was drug-eluting bead transarterial chemoembolization plus hepatic arterial infusion chemotherapy and lenvatinib and sintilimab, converted to SIRT, and the second one was sequential SIRT with continued systemic treatment. The tumor size significantly decreased from 20.2 cm × 19.8 cm to 16.2 cm × 13.8 cm, then sequentially to 7.8 cm × 6.8 cm. In the meantime, the ratio of spared volume to total liver volume increased gradually from 34.4% to 55.7%, then to 62.9%. Furthermore, there was visualization of the portal vein, indicating regression of the tumor thrombus. Finally, owing to the new tumor in the left lateral lobe, the patient underwent LT instead of resection without major complications.

Patients with inoperable huge HCC with PVTT could be converted to SIRT first and accept surgery sequentially.

To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532-1.450-2.361 (p for trend 0.037), 1.057-1.691-3.364 (p for trend 0.004), 1.176-0.686-0.281 (p for trend 0.002), 0.639-0.759-1.820 (p for trend 0.462), 1.030-0.959-0.147 (p for trend 0.011), and 0.697-0.609 (p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592-1.073-2.811 (p for trend 0.255), 1.161-1.282-4.324 (p for trend 0.03), 0.965-0.781-0.655 (p for trend 0.095), 0.737-0.623-2.147 (p for trend 0.153), 1.061-0.832-0.800 (p for trend 0.391), and 1.412-0.560 (p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) has shown efficacy for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). However, whether DEB-TACE is superior to conventional TACE (cTACE) remains unclear.

This randomized controlled trial aimed to compare the efficacy and safety of DEB-TACE versus cTACE in treating HCC with PVTT.

The study was conducted at a tertiary care center in Southeast China. HCC patients with PVTT were randomized at a 1:1 ratio into the DEB-TACE or cTACE groups. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and the incidence of adverse events (AEs). An independent review committee assessed the radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). AEs were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Systemic therapies were not restricted.

Between September 2018 and July 2020, 163 patients were randomized to undergo DEB-TACE ( n =82) or cTACE ( n =81). Nine patients were excluded, and 154 patients were included in the final analysis; the median age was 55 years (range, 24-78 years), and 140 (90.9%) were male. The median PFS in the DEB-TACE group was 6.0 months (95% CI, 5.0-10.0) versus 4.0 months (95% CI, 3.0-5.0) in the cTACE group (hazard ratio, 0.63; 95% CI, 0.42-0.95; P =0.027). The DEB-TACE group showed a higher response rate [51 (66.2%) vs. 36 (46.8%); P =0.0015] and a longer median OS [12.0 months (95% CI, 9.0-16.0) vs. 8.0 months (95% CI, 7.0-11.0), P =0.039] than the cTACE group. Multivariate analysis showed that the treatment group, ALBI score, distant metastasis and additional TKIs were the four independent prognostic factors correlated with PFS. In addition, the treatment group, PVTT group and combination with surgery were independently associated with OS. AEs were similar in the two groups, and postembolization syndrome was the most frequent AE.

DEB-TACE is superior to cTACE in treating HCC patients with PVTT, demonstrating improved PFS and OS with an acceptable safety profile, and may thus emerge as a promising treatment strategy for HCC patients with PVTT.

Chinese Clinical Trial Registry ChiCTR1800018035.

The triple combination of programmed cell death protein-1 (PD-1) inhibitors plus anti-angiogenesis tyrosine kinase inhibitors (TKIs) with or without transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) enhance the effect of treatment for unresectable hepatocellular carcinoma (uHCC). The present study compared the efficacy and safety of PD-1 plus TKI with or without transarterial chemo(embolization) for uHCC.

The meta-analysis was conducted using data acquired from PubMed, EMBASE, the Cochrane Library, Ovid, Web of Science, and Clinical Trials.gov from the inception date to December 2023. All clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CIs) were used to measure the pooled effect. In addition, subgroup analysis was conducted to determine the specific patient population that benefited.

The OS (HR = 0.47; 95% CI: 0.39-0.56, P <  0.05), PFS (HR = 0.52; 95% CI: 0.45-0.60, P < 0.05), and ORR (RR = 1.94; 95% CI: 1.60-2.35, P < 0.05) were significantly better in TACE/HAIC+TKI+PD-1(TACE/HAIC TP) group than TKI+PD-1(TP) group. The incidence of AEs was acceptable.

The triple therapy of TACE/HAIC TP had better efficacy for uHCC than TP, with acceptable security.

PROSPERO, identifier CRD42023475953.

Percutaneous ultrasound-guided radiofrequency ablation (RFA) is a well-studied treatment option for locally non-advanced hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLMs). Sedation is of crucial interest as it enables safe and pain-free procedures. Whether the type of sedation has an impact on procedural outcome is still not well investigated.

We retrospectively collected data on patients undergoing liver RFA for various oncological conditions. Procedures were conducted in a non-operating room anesthesia (NORA) setting. Procedural-related complications and short-term oncological outcomes were analyzed.

Thirty-five patients (mean age 71.5 y, 80% male) were treated for HCC (26), CRLM (6) and gastric cancer metastases (3). Mean lesion size was 21 mm (SD ± 10.1 mm), and the most common tumor localization was the right hepatic lobe. RFA was performed in a step-up sedation approach, with subcutaneous lidocaine injection prior to needle placement and subsequent deep sedation during ablation. No anesthesia-related early or late complications occurred. One patient presented with pleural effusion due to a large ablation zone and was treated conservatively. Local tumor-free survival after 1 and 6 months was 100% in all cases where a curative RFA approach was intended.

NORA for liver RFA comes with high patient acceptance and tolerance, and optimal postoperative outcomes and oncologic results.

In many Asian hepatocellular carcinoma (HCC) guidelines, resection is an option for multiple HCCs. It is difficult to compare small but multiple tumors vs. fewer large tumors in terms of the traditional tumor burden definition. We aimed to evaluate the role of liver resection for multiple HCCs and determine factors associated with survival benefits.

We reviewed 160 patients with multiple HCCs who underwent liver resection between July 2003 and December 2018. The risk factors for tumor recurrence were assessed using Cox proportional hazards modeling, and survival was analyzed using the Kaplan-Meier method.

In all 160 patients, 133 (83.1%) exceeded the Milan criteria. Total tumor volume (TTV) > 275 cm3 and serum alpha-fetoprotein (AFP) level > 20 ng/mL were associated with disease-free survival. Patients beyond the Milan criteria were grouped into three risk categories: no risk (TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL, n = 39), one risk (either TTV > 275 cm3 or AFP > 20 ng/mL, n = 76), and two risks (TTV > 275 cm3 and AFP > 20 ng/mL, n = 18). No-risk group had comparable disease-free survival (p = 0.269) and overall survival (p = 0.215) to patients who met the Milan criteria.

Patients with TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL can have good outcomes even exceed the Milan criteria.

This editorial comments on the study by Ma et al, which delves into the efficacy and predictive factors associated with the combination of transarterial chemoembolization, lenvatinib, and programmed cell death protein-1 inhibition for the management of unresectable hepatocellular carcinoma. Analysing data from a retrospective study involving 102 patients, the treatment showcased a median overall survival (OS) of 26.43 months and a median progression-free survival (PFS) of 10.07 months. Notably, the objective response rate and disease control rate reached 61.76% and 81.37%, respectively. Specific factors such as Barcelona Clinic Liver Cancer (BCLC) Classification B-stage, early neutrophil-to-lymphocyte ratio response, and early alpha-fetoprotein response (> 20% decrease) correlated with superior OS and PFS. The triple therapy exhibited promising efficacy, particularly in BCLC B-stage disease, with prognostic markers aiding in patient stratification. Acknowledging the retrospective nature of the study design, future research should address this limitation and incorporate longer follow-up periods for a comprehensive evaluation of long-term outcomes.

Neoadjuvant transcatheter arterial chemoembolization (TACE) for large tumors is controversial, especially in the minimally invasive surgery era. The aim of this study was to compare features between groups treated with neoadjuvant TACE followed by surgery (TACE + surgery) or upfront surgery for hepatocellular carcinoma >5 cm.

In this exploratory, multicenter, randomized phase I study, the primary measure was 2-year disease-free survival (DFS). Secondary measures were resection rate, necrosis rate by TACE, 2-year overall survival, and site of recurrence. A total of 30 patients were randomly allocated to each arm.

The two arms did not differ in patient characteristics. The median time to surgery from randomization was 48 days for TACE + surgery and 29 for surgery only (p < 0.001). Postoperative morbidities did not differ between arms. The 2-year DFS, overall survival, and resection rates were 56.7%, 80.0%, and 93.3%, respectively, in the TACE + surgery arm, and 56.1%, 89.9%, and 90.0% in the upfront surgery arm. Minimally invasive surgery was carried out in 35.7% in the TACE + surgery arm and in 29.6% in the upfront surgery arm. The median necrosis rate by TACE was 90.0%. In resected specimens, invasion to the hepatic vein was less with TACE + surgery (3.6% vs. 22.2%, p = 0.0380). In cases of 100% necrosis with TACE, 2-year DFS was 100%. Site of recurrence did not differ between groups.

Neoadjuvant TACE did not improve 2-year DFS, and neoadjuvant TACE allowed delay of surgical treatment without increased morbidity and cancer progress.

UMIN: 000005241.

This investigation seeks to elucidate the role of the Granulocyte Colony-Stimulating Factor (G-CSF) in the progression of hepatocellular carcinoma (HCC), as well as the impact of the substance on related signaling pathways within the disease matrix.

Nude mouse tumor-bearing assay was used to detect tumor progression. Levels of Mannose/CD68 and CD34/Mannose within these samples and the concentrations of Mannose and inducible Nitric Oxide Synthase (iNOS) in macrophages were quantified using immunofluorescence techniques. The angiogenic capability was assessed via tube formation assays, and protein expressions of G-CSF, Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor-beta (TGF-β), Matrix Metalloproteinases 2 and 9 (MMP2/9), SH2-containing protein tyrosine phosphatase-2 (SHP-2), phosphorylated PI3K/total PI3K (P-PI3K/t-PI3K), phosphorylated AKT/total AKT (P-AKT/t-AKT), and phosphorylated mTOR/total mTOR (P-mTOR/t-mTOR) were measured through Western Blot analysis in both tumor tissues and macrophages.

Administration of G-CSF resulted in a marked augmentation of tumor volume. Macrophage Mannose expression was significantly elevated upon G-CSF treatment, while iNOS levels were conspicuously diminished. G-CSF substantially enhanced the secretion of VEGF, TGF-β, and MMPs in tumor tissues. Macrophage parameters, following incubation in G-CSF pre-treated conditioned medium, indicated enhanced tube-forming capabilities relative to the control, an effect mitigated by the introduction of specific inhibitors. Furthermore, the G-CSF group exhibited a notable reduction in SHP-2 expression, alongside a substantial elevation in the phosphorylation levels of the PI3K/AKT/mTOR pathway proteins across all tumor-bearing paradigms.

G-CSF ostensibly facilitates the advancement of hepatocellular carcinoma by activating the PI3K/AKT/mTOR signaling cascade within Tumor-Associated Macrophages (TAM).

Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development.

A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n = 1169) and post-DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed.

Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P < 0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P < 0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P = 1.0).

The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients.

The recognition of arterial phase hyperenhancement (APHE) and washout during the late phase is key for correct diagnosis of hepatocellular carcinoma (HCC) with contrast-enhanced ultrasound (CEUS). This meta-analysis was conducted to compare SonoVue®-enhanced and Sonazoid®-enhanced ultrasound in the assessment of HCC enhancement and diagnosis.

Studies were included in the analysis if they reported data for HCC enhancement in the arterial phase and late phase for SonoVue® or in the arterial phase and Kupffer phase (KP) for Sonazoid®. Forty-two studies (7502 patients) with use of SonoVue® and 30 studies (2391 patients) with use of Sonazoid® were identified. In a pooled analysis, the comparison between SonoVue® and Sonazoid® CEUS was performed using chi-square test. An inverse variance weighted random-effect model was used to estimate proportion, sensitivity, and specificity along with 95% confidence interval (CI).

In the meta-analysis, the proportion of HCC showing APHE with SonoVue®, 93% (95% CI 91-95%), was significantly higher than the proportion of HCC showing APHE with Sonazoid®, 77% (71-83%) (p < 0.0001); similarly, the proportion of HCC showing washout at late phase/KP was significantly higher with SonoVue®, 86% (83-89%), than with Sonazoid®, 76% (70-82%) (p < 0.0001). The sensitivity and specificity for the detection of APHE plus late-phase/KP washout detection in HCC were also higher with SonoVue® than with Sonazoid® (sensitivity 80% vs 52%; specificity 80% vs 73% in studies within unselected patient populations).

APHE and late washout in HCC are more frequently observed with SonoVue® than with Sonazoid®. This may affect the diagnostic performance of CEUS in the diagnosis of HCCs.

Meta-analysis data show the presence of key enhancement features for diagnosis of hepatocellular carcinoma is different between ultrasound contrast agents, and arterial hyperenhancement and late washout are more frequently observed at contrast-enhanced ultrasound with SonoVue® than with Sonazoid®.

• Dynamic enhancement features are key for imaging-based diagnosis of HCC. • Arterial hyperenhancement and late washout are more often observed in HCCs using SonoVue®-enhanced US than with Sonazoid®. • The existing evidence for contrast-enhanced US may need to be considered being specific to the individual contrast agent.

The study aims to develop a novel predictive model including the fibrosis (FIB)-3 index for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) who achieved sustained virological response (SVR) with direct-acting antiviral (DAA) therapy.

This study included 2529 patients in whom HCV was eradicated with DAA therapy. The after DAA recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used to predict HCC development. We developed a modified ADRES (mADRES) score, in which the FIB-4 index was replaced by the FIB-3 index, and evaluated its usefulness in predicting HCC development compared with the ADRES score.

In the training set (n = 1770), multivariate analysis with Cox proportional hazards modeling showed that male sex (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.48-3.01), FIB-3 index (HR, 1.36; 95% CI, 1.28-1.45), and α-fetoprotein (HR, 1.05; 95% CI, 1.03-1.07) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES or mADRES score in multiple comparisons. Univariate Cox proportional hazards models showed that compared with the mADRES score 0 group, the HR for HCC development was 2.07 (95% CI, 1.02-4.19) for the mADRES score 1 group, 11.37 (95% CI, 5.80-22.27) for the mADRES score 2 group, and 21.95 (95% CI, 10.17-47.38) for the mADRES score 3 group. Similar results were obtained for mADRES score but not for ADRES score in the validation set (n = 759).

The mADRES score is useful for predicting HCC development after SVR.

Unresectable recurrence after curative treatments for hepatocellular carcinoma (HCC) is a life-limited event. Although the IMbrave050 trial (IM050) showed a favorable reduction in recurrence with adjuvant immune-combination chemotherapy, inclusion criteria of the radiofrequency ablation (RFA) group were lower risk than that of the resection group. This study aimed to elucidate the clinical features of patients treated with RFA, which really need adjuvant-chemotherapy.

From 2000 to 2022, 528 patients with Child-Pugh A and HCC within the Milan criteria (MC), who met the IM050 criteria for RFA and undergone resection or RFA, were enrolled (71 years, HCV:HBV:HBV/HCV:alcohol:others = 337:44:5:53:89, multi-tumor = 138, RFA:resection = 309:219). Unresectable recurrence was defined as beyond the MC. Risk factors for recurrence beyond the MC were retrospectively evaluated.

Multivariate Cox-hazard analysis showed HCV-positive (HR 1.49), AFP-L3 > 10% (HR 1.75), and DCP > 100 mAU/mL (HR1.80) as significant prognostic factors for recurrence beyond the MC (each P < 0.05). Summing of positive factors (1 point for each) was used for scoring (AD-ON score), which showed increased positive rates for micro-hepatic vein invasion (score 0:1:2:3 = 0%:1.1%:6.6%:15.8%), micro-portal vein invasion (0:1:2:3 = 2.0%:12.1%:14.1%:31.6%), and poor differentiation (0:1:2:3 = 6.0%:6.7%:15.3%:15.8%) in the resection group associated with a greater score (each P < 0.01). In patients treated with RFA, those with greater AD-ON scores showed shorter time to recurrence beyond the MC, recurrence-free time, and overall survival (score 0:1:2:3 = no-estimation:97:66:23 months, 35:27:20:12 months, and 91:82:67:52 months, respectively, each P < 0.05).

HCC patients treated by RFA and with a high AD-ON score (≧2) should be considered for aggressive adjuvant-chemotherapy to prolong the period of recurrence beyond the MC.