Genomic profiling informs therapies and prognosis for patients with hepatocellular carcinoma in clinical practice.

Hepatocellular carcinoma (HCC) genomic research has discovered actionable genetic changes that might guide treatment decisions and clinical trials. Nonetheless, due to a lack of large-scale multicenter clinical validation, these putative targets have not been converted into patient survival advantages. So, it's crucial to ascertain whether genetic analysis is clinically feasible, useful, and whether it can be advantageous for patients. We sequenced tumour tissue and blood samples (as normal controls) from 111 Chinese HCC patients at Qingdao University Hospital using the 508-gene panel and the 688-gene panel, respectively. Approximately 95% of patients had gene variations related to targeted treatment, with 50% having clinically actionable mutations that offered significant information for targeted therapy. Immune cell infiltration was enhanced in individuals with TP53 mutations but decreased in patients with CTNNB1 and KMT2D mutations. More notably, we discovered that SPEN, EPPK1, and BRCA2 mutations were related to decreased median overall survival, although MUC16 mutations were not. Furthermore, we found mutant MUC16 as an independent protective factor for the prognosis of HCC patients after curative hepatectomy. In conclusion, this study connects genetic abnormalities to clinical practice and potentially identifies individuals with poor prognoses who may benefit from targeted treatment or immunotherapy.

Progressive sarcopenia and myosteatosis predict prognosis of advanced HCC patients treated with immune checkpoint inhibitors.

Background: Immunotherapy stands as a pivotal modality in the therapeutic landscape for the treatment of advanced hepatocellular carcinoma, yet responses vary among patients. This study delves into the potential impact of sarcopenia, myosteatosis and adiposity indicators, as well as their changes during immunotherapy, on treatment response and prognosis in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Methods: In this retrospective analysis, 116 patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors were recruited. Skeletal muscle, intramuscular, subcutaneous, and visceral adipose tissue were assessed by computed tomography at the level of the third lumbar vertebrae before and after 3 months of treatment. Sarcopenia and myosteatosis were evaluated by skeletal muscle index and mean muscle density using predefined threshold values. Patients were stratified based on specific baseline values or median values, along with alterations observed during the treatment course. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test and a multifactorial Cox proportional risk model. Results: A total of 116 patients were recruited and divided into two cohorts, 81 patients for the training set and 35 patients for the validating set. In the overall cohort, progressive sarcopenia (P=0.021) and progressive myosteatosis (P=0.001) were associated with objective response rates, whereas progressive myosteatosis (P<0.001) was associated with disease control rates. In the training set, baseline sarcopenia, myosteatosis, and subcutaneous and visceral adipose tissue were not significantly associated with PFS and OS. In multivariate analysis adjusting for sex, age, and other factors, progressive sarcopenia(P=0.002) and myosteatosis (P=0.018) remained independent predictors of PFS. Progressive sarcopenia (P=0.005), performance status (P=0.006) and visceral adipose tissue index (P=0.001) were all independent predictors of OS. The predictive models developed in the training set also had good feasibility in the validating set. Conclusion: Progressive sarcopenia and myosteatosis are predictors of poor clinical outcomes in patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors, and high baseline visceral adiposity is associated with a poorer survival.

The clinical significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib and PD-1 inhibitors.

Background and aim: Sarcopenia has gained considerable attention in the context of hepatocellular carcinoma, as it has been correlated with a poorer prognosis among patients undergoing sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC). The clinical significance of sarcopenia in first-line advanced HCC patients treated with lenvatinib and programmed death-1 (PD-1) inhibitors needs to be clarified. Methods: Sarcopenia was diagnosed using CT (Computed tomography) or MRI (Magnetic Resonance Imaging), with the psoas muscle index (PMI) as the surrogate marker. Patients were grouped based on sarcopenia presences, and a comparative analysis examined characteristics, adverse events, and prognosis. The Cox regression analysis was applied to identify independent prognostic factors for survival, while nomograms were constructed to predict 1-year survival. Results: Among 180 patients, 46 had sarcopenia. Patients with baseline sarcopenia demonstrated significantly inferior median progression-free survival (mPFS) (3.0 vs. 8.3 months) and median overall survival (mOS) (7.3 vs. 21.6 months). The same results for mPFS (3.3 vs. 9.2 months) and mOS (9.4 vs. 24.2 months) were observed in patients who developed sarcopenia after treatment. Furthermore, significantly higher grade 3 or higher adverse events (AEs) (73.91% vs 41.79%, p<0.001) were recorded in the sarcopenia group compared to the non-sarcopenia group. In the multivariate analysis, distant metastasis, elevated PLR and CRP levels, and low PMI remained independent predictive factors for poor OS. Additionally, skeletal muscle loss remained a significant independent risk factor for PFS. We developed a nomogram incorporating these four indicators, which predicted 12-month survival with a C-index of 0.853 (95% CI, 0.791 - 0.915), aligning well with actual observations. Conclusion: The prognosis of patients with HCC and sarcopenia is significantly worse when treated with lenvatinib and PD-1 inhibitors. The combination regimen of lenvatinib plus PD-1 inhibitors should be cautiously recommended due to the inferior prognosis and higher AEs.

Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank.

Nuclear magnetic resonance (NMR)-based plasma fatty acids are objective biomarkers of many diseases. Herein, we aim to explore the associations of NMR-based plasma fatty acids with the risk of hepatocellular carcinoma (HCC) and chronic liver disease (CLD) mortality in 252,398 UK Biobank participants. Here we show plasma levels of n-3 poly-unsaturated fatty acids (PUFA) and n-6 PUFA are negatively associated with the risk of incident HCC [HRQ4vsQ1: 0.48 (95% CI: 0.33-0.69) and 0.48 (95% CI: 0.28-0.81), respectively] and CLD mortality [HRQ4vsQ1: 0.21 (95% CI: 0.13-0.33) and 0.15 (95% CI: 0.08-0.30), respectively], whereas plasma levels of saturated fatty acids are positively associated with these outcomes [HRQ4vsQ1: 3.55 (95% CI: 2.25-5.61) for HCC and 6.34 (95% CI: 3.68-10.92) for CLD mortality]. Furthermore, fibrosis stage significantly modifies the associations between PUFA and CLD mortality. This study contributes to the limited prospective evidence on the associations between plasma-specific fatty acids and end-stage liver outcomes.

Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study.

INTRODUCTION: Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. PATIENTS AND METHODS: The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. RESULTS: The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. CONCLUSION: The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.

Safety, efficacy, and survival of different transarterial chemoembolization techniques in the management of unresectable hepatocellular carcinoma: a comparative single-center analysis.

PURPOSE: Transarterial chemoembolization (TACE) has become the standard of care for the treatment of intermediate-stage hepatocellular carcinoma (HCC). However, current clinical practice guidelines lack consensus on the best selection of a specific TACE technique. This study aims to compare safety, tumor response, and progression-free survival (PFS) of conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE), and degradable starch microsphere TACE (DSM-TACE). METHODS: This retrospective study included n = 192 patients with HCC who underwent first TACE with unbiased follow-up at 4-6 weeks at our center between 2008 and 2021. Eligibility for TACE was BCLC intermediate stage B, bridging/down-staging (B/D) to liver transplantation (LT), or any other stage when patients were not suitable for resection, LT, local ablation, or systemic therapy. Patients were grouped into three cohorts (n = 45 cTACE, n = 84 DEB-TACE, n = 63 DSM-TACE), and further categorized by TACE indication (B/D or palliative). Liver function and adverse events, response assessed by the modified response evaluation criteria in solid tumors (mRECIST) 4-6 weeks post-TACE and PFS were analyzed. RESULTS: There were no significant differences in age, gender distribution, BCLC stage, or etiology of liver disease among the three TACE groups, even in the B/D or palliative subgroups. DEB-TACE induced slight increases in bilirubin in the palliative subgroup and in lactate dehydrogenase in the entire cohort 4-6 weeks post-TACE, and more adverse events in the palliative subgroup. DEB-TACE and DSM-TACE showed significantly higher disease control rates (complete and partial response, stable disease) compared to cTACE, especially in the B/D setting (p < 0.05). There was no significant difference in PFS between the groups [median PFS (months): cTACE, 10.0 vs. DEB, 7.0 vs. DSM, 10.0; p = 0.436]. CONCLUSION: Our study provides valuable perspectives in the decision-making for a specific TACE technique: DEB-TACE and DSM-TACE showed improved tumor response. DEB-TACE showed a prolonged impact on liver function and more side effects, so patients with impaired liver function should be more strictly selected, especially in the palliative subgroup.

The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma -CLEAP 004 study.

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Does depressurization of the portal vein before liver transplantation affect the recurrence of HCC? A nested case-control study.

BACKGROUND: Portal hypertension (PHT) has been proven to be closely related to the development of hepatocellular carcinoma (HCC). Whether PHT before liver transplantation (LT) will affect the recurrence of HCC is not clear. METHODS: 110 patients with depressurization of the portal vein (DPV) operations (Transjugular Intrahepatic Portosystemic Shunt-TIPS, surgical portosystemic shunt or/and splenectomy) before LT from a HCC LT cohort, matched with 330 preoperative non-DPV patients; this constituted a nested case-control study. Subgroup analysis was based on the order of DPV before or after the occurrence of HCC. RESULTS: The incidence of acute kidney injury and intra-abdominal bleeding after LT in the DPV group was significantly higher than that in non-DPV group. The 5-year survival rates in the DPV and non-DPV group were 83.4% and 82.7% respectively (P = 0.930). In subgroup analysis, patients in the DPV prior to HCC subgroup may have a lower recurrence rate (4.7% vs.16.8%, P = 0.045) and a higher tumor free survival rate (88.9% vs.74.4%, P = 0.044) after LT under the up-to-date TNMI-II stage, while in TNM III stage, there was no difference for DPV prior to HCC subgroup compared with the DPV after HCC subgroup or the non-DPV group. CONCLUSION: Compared with DPV after HCC, DPV treatment before HCC can reduce the recurrence rate of HCC after early transplantation (TNM I-II). DPV before LT can reduce the recurrence of early HCC.

Identification of PANoptosis-related subtypes, construction of a prognosis signature, and tumor microenvironment landscape of hepatocellular carcinoma using bioinformatic analysis and experimental verification.

Background: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. PANoptosis is a recently unveiled programmed cell death pathway, Nonetheless, the precise implications of PANoptosis within the context of HCC remain incompletely elucidated. Methods: We conducted a comprehensive bioinformatics analysis to evaluate both the expression and mutation patterns of PANoptosis-related genes (PRGs). We categorized HCC into two clusters and identified differentially expressed PANoptosis-related genes (DEPRGs). Next, a PANoptosis risk model was constructed using LASSO and multivariate Cox regression analyses. The relationship between PRGs, risk genes, the risk model, and the immune microenvironment was studies. In addition, drug sensitivity between high- and low-risk groups was examined. The expression profiles of these four risk genes were elucidate by qRT-PCR or immunohistochemical (IHC). Furthermore, the effect of CTSC knock down on HCC cell behavior was verified using in vitro experiments. Results: We constructed a prognostic signature of four DEPRGs (CTSC, CDCA8, G6PD, and CXCL9). Receiver operating characteristic curve analyses underscored the superior prognostic capacity of this signature in assessing the outcomes of HCC patients. Subsequently, patients were stratified based on their risk scores, which revealed that the low-risk group had better prognosis than those in the high-risk group. High-risk group displayed a lower Stromal Score, Immune Score, ESTIMATE score, and higher cancer stem cell content, tumor mutation burden (TMB) values. Furthermore, a correlation was noted between the risk model and the sensitivity to 56 chemotherapeutic agents, as well as immunotherapy efficacy, in patient with. These findings provide valuable guidance for personalized clinical treatment strategies. The qRT-PCR analysis revealed that upregulated expression of CTSC, CDCA8, and G6PD, whereas downregulated expression of CXCL9 in HCC compared with adjacent tumor tissue and normal liver cell lines. The knockdown of CTSC significantly reduced both HCC cell proliferation and migration. Conclusion: Our study underscores the promise of PANoptosis-based molecular clustering and prognostic signatures in predicting patient survival and discerning the intricacies of the tumor microenvironment within the context of HCC. These insights hold the potential to advance our comprehension of the therapeutic contribution of PANoptosis plays in HCC and pave the way for generating more efficacious treatment strategies.

Assessment of safety and efficacy of transarterial chemoembolization combined with camrelizumab and donafenib in patients with hepatocellular carcinoma at BCLC stage C: A study of 20 cases.

Camrelizumab, donafenib, and transarterial chemoembolization (TACE) are recommended for advanced hepatocellular carcinoma (HCC), but their combined efficacy remains unclear. From July 2021 to January 2023, 20 Barcelona Clinic Liver Cancer stage C HCC patients were prospectively enrolled. Inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, Child-Pugh Score ≤ 7, and Barcelona Clinic Liver Cancer B or C. Surgical candidates were excluded. The treatment included TACE, camrelizumab, and donafenib. Endpoints were median overall survival, progression-free survival, and adverse events (AEs) related to donafenib. Among 20 patients, 85% experienced AEs from targeted therapy and programmed cell death protein-1, with 40% having grade 3 AEs. No grade 4 or 5 AEs occurred. Median follow-up was 9 months, with 15% achieving complete response, 65% partial response, and 15% stable disease. Disease control rate was 90%. Median progression-free survival and overall survival were 9 and 14 months, respectively. TACE, camrelizumab, and donafenib combination therapy in Chinese advanced HCC patients show effectiveness in extending survival with low severe AEs incidence.

Beneficial effects of maintaining liver function during hepatic arterial infusion chemotherapy combined with tyrosine kinase and programmed cell death protein-1 inhibitors on the outcomes of patients with unresectable hepatocellular carcinoma.

BACKGROUND AND AIM: Combination therapy is the primary treatment for unresectable hepatocellular carcinoma (u-HCC). The hepatic functional reserve is also critical in the treatment of HCC. In this study, u-HCC was treated with combined hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKIs), and programmed cell death protein-1 (PD-1) inhibitors to analyze the therapeutic response, progression-free survival (PFS), and safety. METHODS: One hundred sixty-two (162) patients with u-HCC were treated by combination therapy of HAIC, TKIs, and PD-1 inhibitors. PFS was assessed by Child-Pugh (CP) classification subgroups and the change in the CP score during treatment. RESULTS: The median PFS was 11.7 and 5.1 months for patients with CP class A (CPA) and CP class B (CPB), respectively (p = 0.013), with respective objective response rates of 61.1 and 27.8% (p = 0.002) and conversion rates of 16 and 0% (p = 0.078). During treatment, the CP scores in patients with CPA worsened less in those with complete and partial response than in those with stable and progressive disease. In the CP score 5, patients with an unchanged CP score had longer PFS than those with a worsened score (Not reached vs. 7.9 months, p = 0.018). CPB was an independent factor negatively affecting treatment response and PFS. Patients with CPA responded better to the combination therapy and had fewer adverse events (AEs) than those with CPB. CONCLUSIONS: Thus, triple therapy is more beneficial in patients with good liver function, and it is crucial to maintain liver function during treatment.

Comparative Study of the Short-Term Efficacy and Safety between DEB-TACE and C-TACE in the Treatment of Unresectable Hepatocellular Carcinoma, a Retrospective Study.

Background: This is a retrospective study aimed at comparing the clinical efficacy and safety between drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE) and conventional TACE (C-TACE) in the treatment of unresectable hepatocellular carcinoma. Methods: From July 2019 to April 2021, we enrolled 282 patients with unresectable hepatocellular carcinoma who were admitted to our hospital, of which 179 and 103 were in the DEB-TACE and C-TACE groups, respectively. General information was collected, and treatment effects were evaluated following the modified Response Evaluation Criteria in Solid Tumors. To compare the indexes of liver and kidney function, routine blood and coagulation were collected before treatment, and 1 day, 1 month, 3 months, and 6 months postoperatively. Postoperative adverse reactions (ie, fever, nausea, vomiting, anorexia, abdominal pain) were recorded to evaluate the safety of treatment. The two groups' progression-free survival and overall survival were also calculated to assess the treatment effect. Results: Preoperatively, the bilirubin, transaminase, and absolute neutrophil values between the two groups were not statistically significant (P > .05). At 1 month postoperatively, the absolute neutrophil values were significantly higher in the DEB-TACE group than those in the C-TACE group (P < .05). At 3 months postoperatively, AST, total bilirubin, and direct bilirubin levels were significantly elevated in the DEB-TACE group (P < .05), compared with the C-TACE group. However, at 6 months postoperatively, total and direct bilirubin levels in the C-TACE group were higher than those in the DEB-TACE group, showing a statistically significant difference (P < .05). For patients undergoing DEB-TACE, the survival risk was lower compared to those undergoing C-TACE. The survival risk of patients undergoing DEB-TACE was lower than that of C-TACE within 20 months postoperatively. The survival risk of patients undergoing DEB-TACE was lower than that of patients undergoing C-TACE. Conclusion: DEB-TACE may be superior to C-TACE in terms of safety and efficacy in the treatment of unresectable hepatocellular carcinoma.

Single-cell profiling reveals the metastasis-associated immune signature of hepatocellular carcinoma.

AIM: Metastasis is the leading cause of mortality in hepatocellular carcinoma (HCC). The metastasis-associated immune signature in HCC is worth exploring. METHODS: Bioinformatic analysis was conducted based on the single-cell transcriptome data derived from HCC patients in different stages. Cellular composition, pseudotime state transition, and cell-cell interaction were further analyzed and verified. RESULTS: Generally, HCC with metastasis exhibited suppressive immune microenvironment, while HCC without metastasis exhibited active immune microenvironment. Concretely, effector regulatory T cells (eTregs) were found to be enriched in HCC with metastasis. PHLDA1 was identified as one of exhaustion-specific genes and verified to be associated with worse prognosis in HCC patients. Moreover, A novel cluster of CCR7+ dendritic cells (DCs) was identified with high expression of maturation and migration marker genes. Pseudotime analysis showed that inhibition of differentiation occurred in CCR7+ DCs rather than cDC1 in HCC with metastasis. Furthermore, interaction analysis showed that the reduction of CCR7+ DCs lead to impaired CCR7/CCL19 interaction in HCC with metastasis. CONCLUSIONS: HCC with metastasis exhibited upregulation of exhaustion-specific genes of eTregs and inhibition of CCL signal of a novel DC cluster, which added new dimensions to the immune landscape and provided new immune therapeutic targets in advanced HCC.

A multi-parametric prognostic model based on clinicopathologic features: vessels encapsulating tumor clusters and hepatic plates predict overall survival in hepatocellular carcinoma patients.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) is a newly described vascular pattern that is distinct from microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). Despite its importance, the current pathological diagnosis report does not include information on VETC and hepatic plates (HP). We aimed to evaluate the prognostic value of integrating VETC and HP (VETC-HP model) in the assessment of HCC. METHODS: A total of 1255 HCC patients who underwent radical surgery were classified into training (879 patients) and validation (376 patients) cohorts. Additionally, 37 patients treated with lenvatinib were studied, included 31 patients in high-risk group and 6 patients in low-risk group. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to establish a prognostic model for the training set. Harrell's concordance index (C-index), time-dependent receiver operating characteristics curve (tdROC), and decision curve analysis were utilized to evaluate our model's performance by comparing it to traditional tumor node metastasis (TNM) staging for individualized prognosis. RESULTS: A prognostic model, VETC-HP model, based on risk scores for overall survival (OS) was established. The VETC-HP model demonstrated robust performance, with area under the curve (AUC) values of 0.832 and 0.780 for predicting 3- and 5-year OS in the training cohort, and 0.805 and 0.750 in the validation cohort, respectively. The model showed superior prediction accuracy and discrimination power compared to TNM staging, with C-index values of 0.753 and 0.672 for OS and disease-free survival (DFS) in the training cohort, and 0.728 and 0.615 in the validation cohort, respectively, compared to 0.626 and 0.573 for TNM staging in the training cohort, and 0.629 and 0.511 in the validation cohort. Thus, VETC-HP model had higher C-index than TNM stage system(p < 0.01).Furthermore, in the high-risk group, lenvatinib alone appeared to offer less clinical benefit but better disease-free survival time. CONCLUSIONS: The VETC-HP model enhances DFS and OS prediction in HCC compared to traditional TNM staging systems. This model enables personalized temporal survival estimation, potentially improving clinical decision-making in surveillance management and treatment strategies.

Options and survival benefits of conversion therapy for unresectable hepatocellular carcinoma.

In the study by Wu et al, patients with unresectable hepatocellular carcinoma were subjected to transarterial chemoembolization (TACE) as a conversion therapy in order to render their tumors suitable for resection. A nomogram was devised and shown to be effective in predicting the survival of these patients. Generalization of the results, however, is questionable since the study subjects consisted of patients who had resection after TACE while excluding patients with the same disease but not suitable for TACE. Immunotherapy can be considered to be an option for conversion therapy. However, markers for determining responses to a conversion therapy and for guiding the decision between TACE and sequential immunotherapy have been lacking. The question of whether effective conversion therapy can truly enhance overall survival remains unanswered.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and PD-1 inhibitors for advanced hepatocellular carcinoma with macrovascular invasion.

BACKGROUND AND AIMS: The prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion(MaVI)is poor, and the treatment is limited. This study aims to explore the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC), combined with lenvatinib and programmed cell death-1(PD-1) inhibitor in the first-line treatment of HCC with MaVI. METHODS: From July 2020 to February 2022, we retrospectively analyzed consecutive patients with HCC with MaVI who received hepatic arterial infusion FOLFOX(oxaliplatin, 5-fluorouracil, and leucovorin)combined with lenvatinib and PD-1 inhibitor. The efficacy was evaluated by RECIST 1.1. Kaplan-Meier was used to explore the overall survival and progression-free survival (PFS), and the COX regression model was used to analyze the risk factors of PFS. Adverse events (AEs) were evaluated according to CTCAE5.0. RESULTS: Thirty-two patients with HCC complicated with MaVI were recruited from the Second Affiliated Hospital of Nanchang University. Among the patients treated with HAIC combined with lenvatinib and PD-1 inhibitor, ten patients (31.25%) got partial response, eighteen patients (56.25%) maintained stable disease and four patients (12.50%) suffered progressive disease during follow-up; and objective response rate was 31.25%, and disease control rate was 87.5%. The median PFS was 179 days. Univariate and multivariate Cox analysis showed that the extrahepatic metastases and Child-Pugh score were independent prognostic factors of PFS. Twenty-two (68.75%) patients suffered adverse reactions. The main AEs were elevated transaminase (46.87%), thrombocytopenia (40.63%), hypoalbuminemia (28.13%), nausea and vomiting (21.88%), leukopenia (18.76%), abdominal pain (15.63%), hypertension (15.63%) and fever (15.63%). There were seven cases (21.88%) that had grade 3 or above AEs; Among them, two cases with elevated transaminase (6.25%), leukopenia, thrombocytopenia, nausea and vomiting, abdominal pain, and diarrhea occurred in one case respectively. Moreover, no treatment-related death was observed. CONCLUSIONS: Hepatic arterial infusion of FOLFOX combined with lenvatinib and PD-1 inhibitor as the first-line treatment for HCC complicated with MaVI is effective, and adverse reactions are tolerable.

Predictive nomograms based on gamma-glutamyl transpeptidase to prealbumin ratio for prognosis of hepatocellular carcinoma patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) presents a significant threat to individuals and healthcare systems due to its high recurrence rate. Accurate prognostic models are essential for improving patient outcomes. Gamma-glutamyl transpeptidase (GGT) and prealbumin (PA) are biomarkers closely related to HCC. This study aimed to investigate the predictive value of the GGT to PA ratio (GPR) and to construct prognostic nomograms for HCC patients without microvascular invasion. METHODS: We retrospectively analyzed data from 355 HCC patients who underwent radical hepatectomy at Shengjing Hospital of China Medical University between December 2012 and January 2021. Patients were randomly assigned to a training cohort (n = 267) and a validation cohort (n = 88). The linearity of GPR was assessed using restricted cubic spline (RCS) analysis, and the optimal cut-off value was determined by X-tile. Kaplan-Meier survival curves and log-rank tests were used to investigate the associations between GPR and both progression-free survival (PFS) and overall survival (OS). Cox multivariate regression analysis identified independent risk factors, enabling the construction of nomograms. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the accuracy of the nomograms. Decision curve analysis (DCA) assessed the predictive value of the models. RESULTS: Patients were categorized into GPR-low and GPR-high groups based on a GPR value of 333.33. Significant differences in PFS and OS were observed between the two groups (both P < 0.001). Cox multivariate analysis identified GPR as an independent risk factor for both PFS (OR = 1.80, 95% CI: 1.24-2.60, P = 0.002) and OS (OR = 1.87, 95% CI: 1.07-3.26, P = 0.029). The nomograms demonstrated good predictive performance, with C-index values of 0.69 for PFS and 0.76 for OS. Time-dependent ROC curves and calibration curves revealed the accuracy of the models in both the training and validation cohorts, with DCA results indicating notable clinical value. CONCLUSIONS: GPR emerged as an independent risk factor for both OS and PFS in HCC patients without microvascular invasion. The nomograms based on GPR demonstrated relatively robust predictive efficiency for prognosis.

The role of adjuvant transcatheter arterial chemoembolization following repeated curative resection/ablation for hepatocellular carcinoma with early recurrence: a propensity score matching analysis.

BACKGROUND: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. METHODS: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). RESULTS: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6-16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. CONCLUSION: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort.

Effect of cytokines on advanced hepatocellular carcinoma prognosis receiving radiotherapy and tislelizumab plus anlotinib: a single-center phase II clinical trial.

The purpose of this study was to investigate the relationship between circulating cytokines and liver function and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with radiotherapy combined with tislelizumab and anlotinib. The liver function indexes and pre-treatment levels of cytokines in 47 patients were measured by chemical method and flow cytometry. The median follow-up was 23.1 months. The objective response and the disease control rates were 46.8% and 68.1%, while overall survival (OS) and progression-free survival (PFS) were 12.6 and 11.4 months, respectively. Adverse events (2.1%) were grade 3-4. In addition to stage, intrahepatic metastasis and Child-Pugh score, pre-treatment interleukin-6 (IL-6) was the main cytokine affecting OS and PFS (p < 0.05). The OS (14.63 pg/mL as cutoff value) and PFS (9.85 pg/mL as cutoff value) of patients with low IL-6 levels exceeded those with high levels (21.0 and 6.9, 15.8 and 10.0 months, respectively). The risks of death and disease progression were reduced by 63.0% (HR = 0.37, 95% CI: 0.19-0.72) and 43.0% (HR = 0.57, 95% CI: 0.22-1.47), respectively. Pre-treatment IL-6 levels may be a simple and effective prognostic indicator for patients with advanced HCC treated with radiotherapy combined with immunotargeted therapy.

Efficacy and safety of transarterial chemoembolization combined with targeted therapy and immunotherapy versus with targeted monotherapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The application of transarterial chemoembolization (TACE) in combination with targeted therapy and immunotherapy (TACE-T-I) for unresectable hepatocellular carcinoma (HCC) has gained increasing attention. However, there are variations in the efficacy and safety outcomes between TACE-T-I versus TACE combined with targeted drugs (TACE-T). This study aims to systematically evaluate the efficacy and safety of TACE-T-I versus TACE-T in unresectable HCC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to August 21, 2023, for comparative studies on TACE-T-I versus TACE-T for unresectable HCC. Outcome measures included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the incidence of treatment-related adverse events (TRAEs). OS was the primary outcome of this study. Weighted mean difference (WMD) or hazard ratio (HR) was used as the pooled statistic for OS and PFS. Relative risk (RR) was employed as the pooled statistic for ORR, DCR and the incidence of TRAEs. And 95% confidence intervals (CIs) were calculated for all effect measures. Data analysis was conducted using Stata 14.0 software. RESULTS: The meta-analysis included 14 studies with 2144 patients. The pooled results showed that compared with patients in the TACE-T group, patients in the TACE-T-I group had higher ORR (RR = 1.61; 95%CI: 1.38-1.89) and DCR (RR = 1.17; 95%CI: 1.09-1.26). Patients in the TACE-T-I group experienced prolonged PFS (WMD = 3.08; 95%CI: 2.63-3.53) and OS (WMD = 5.76; 95%CI: 4.68-6.84). And the risk of disease progression (HR = 0.45; 95%CI: 0.37-0.55) and death (HR = 0.43; 95%CI: 0.38-0.49) was lower in the TACE-T-I group. Common TRAEs included fever, pain, abdominal pain, nausea, vomiting, elevated ALT, elevated AST, hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence and severity of TRAEs in the TACE-T-I group were similar to those in the TACE-T group, with no significant differences (P > .05). CONCLUSION: Current evidence suggests that, on the basis of TACE combined with targeted therapy, the addition of immunotherapy provides better clinical efficacy and survival benefits for unresectable HCC patients, with good tolerability.