Therapy For Hepatocellular Carcinoma Patients Research Articles

Long-term posttransplant survival outcome following bridging locoregional therapy in hepatocellular carcinoma patients: A systematic review and meta-analysis.

Liver transplantation (LT) is essential due to its curative efficacy, but liver-graft shortages have limited its widespread application. Bridging locoregional therapy (LRT) before LT has been performed to prevent tumor progression, and a recent literature review revealed that it is associated with a nonsignificant trend toward better survival outcomes. However, much more information on bridging therapy has become available since then. This meta-analysis aimed to compare the posttransplant survival and HCC recurrence between patients with and without pretransplant bridging LRT. Studies were identified in MEDLINE, SCOPUS, and the Cochrane Library. Two independent researchers screened titles and full articles, extracted relevant data, and conducted a parametric survival analysis. Out of 4794 studies, 18 cohort studies were eligible. The 1-, 3-, and 5-year overall survival (OS) rates were 93.1%, 85.0%, and 79.1% for those in the bridging LRT group, while they were 91.8%, 81.1%, and 75.5% for those who did not receive LRT, respectively. There were no differences in overall survival between these groups (HR 0.90; 0.78-1.05, P = 0.17). Interestingly, we discovered that bridging therapy helped prolong survival significantly in a high-risk population with a long waiting time (HR 0.76; 0.60-0.96, P = 0.02). Unfortunately, bridging LRT did not improve disease-free survival (HR 0.98; 0.86-1.11, P = 0.70). The results indicate that bridging LRT does not generally change post-LT outcomes. However, bridging LRT can significantly improve survival in patients with a long waiting time for LT.

Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma.

This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.

Tislelizumab plus sitravatinib as adjuvant therapy for patients with hepatocellular carcinoma at high risk of recurrence after surgical resection: Preliminary analysis of a multi-center, non-randomized, open-label phase 2 study.

e16239 Background: Adjuvant therapy has the potential to prevent or delay recurrence after curative-intent hepatectomy for hepatocellular carcinoma (HCC) patients. IMbrave 050 trial demonstrated improved recurrence-free survival (RFS) for HCC patients at high risk of recurrence when treated with atezolizumab plus bevacizumab, underscoring the promising potential of checkpoint inhibitor-based combination therapy as a strategy in the adjuvant setting. The aim of this study was to evaluate the efficacy and safety of tislelizumab (a PD-1 inhibitor) plus sitravatinib (a selective tyrosine kinase inhibitor) as adjuvant therapy in HCC patients at high risk of recurrence after curative-intent hepatectomy. Here, we reported the preliminary analysis results. Methods: HCC patients confirmed by histopathology or cytology, who had undergone a curative resection and with one or more of the high-risk factors for recurrence, including: a solitary tumor>5 cm, a solitary tumor>2cm and ≤5cm with microvascular invasion, or 2~3 lesions, were eligible. Enrolled patients received tislelizumab (200mg, IV, Q3W) and sitravatinib (100mg, PO, QD), with a maximum treatment duration of one year. The primary endpoint was 2-year RFS rate. Secondary endpoints include RFS, time to recurrence, overall survival (OS), 1-year RFS rate, 1-year and 2-year OS rate, and safety. Results: A total of 22 patients were enrolled, with hepatitis B being the most common (86.4%) etiology, and 36.4% with microvascular invasion. Most patients were at BCLC stage A (86.4%), while stage 0 and stage B accounted for 4.5 and 9.1%, respectively. Till the data cut-off date on Nov. 30th, 2023, the median follow-up duration was 6.0 months (range 0.7-16.2); 2 patients relapsed and 1 patient died. The 1-year RFS rate was 81.3% and the longest RFS (censored) was over 12.5 months. Safety profile indicated that 21 patients (95.5%) experienced treatment-related adverse events (TRAEs), and 8 (36.4%) experienced grade ≥3 TRAEs. Most common (≥10%) grade ≥3 TRAEs were hypertension (13.6%) and palmar-plantar erythrodysesthesia (13.6%). Any grade immune-related adverse events (irAEs) were observed in 12 patients (54.5%) and 3 (13.6%) experienced grade ≥ 3 irAEs. AE leading to tislelizumab delay was observed in 2 patients (9.1%) and sitravatinb delay in 16 patients (72.7%). Dose reduction of sitravatinib occurred in 81.8% of patients due to AE. One patient died due to treatment-related pulmonary infection and biliary fistula. Conclusions: For patients with HCC at high risk of recurrence after curative-intent resection, tislelizumab plus sitravatinib showed preliminarily positive signal in controlling recurrence and had managable safety profile as adjuvant therapy. Further follow-up is needed to validate these findings with more mature data. Clinical trial information: NCT05407519 .

Characterization of a predictive signature for tumor microenvironment and immunotherapy response in hepatocellular carcinoma involving neutrophil extracellular traps

Neutrophil extracellular traps (NETs) and other factors play a significant role in impacting the prognosis of patients with Hepatocellular carcinoma (HCC). Nevertheless, further research is warranted to fully elucidate the prognostic implications of NETs in patients with HCC. We employed a hierarchical clustering technique to examine the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) data and identified subtypes associated with NETs. Subsequently, we utilized LASSO regression analysis to identify a distinct gene expression pattern within these subtypes. The strength of this signature was further validated through analysis of TCGA-LIHC and International Cancer Genome Consortium-Liver Cancer (ICGC-LIRI-JP) data. Our findings resulted in the construction of a six-gene signature related to NETs, which can predict survival outcomes in HCC patients. To enhance the predictive accuracy of our tool, we developed a nomogram that integrates the NETs signature with clinicopathological characteristics. We validated the significance of NETs in HCC patients using qRT-PCR and immunohistochemistry assays, along with in vitro experiments targeting high-risk genes. Furthermore, our exploration of the immune microenvironment uncovered augmented immune-specific metrics within the low-risk cohort, implying potential disparities in immune-related attributes between the high-risk and low-risk contingents. In summary, the NETs signature we discovered serves as a valuable biomarker and provides guidance for personalized therapy in HCC patients.

Statin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and accounts for more than 90% of primary liver cancer. The advent of immune checkpoint inhibitor (ICI)-related therapies combined with angiogenesis inhibition has revolutionized the treatment of HCC in late-stage and unresectable HCC, as ICIs alone were disappointing in treating HCC. In addition to the altered immune microenvironment, abnormal lipid metabolism in the liver has been extensively characterized in various types of HCC. Stains are known for their cholesterol-lowering properties and their long history of treating hypercholesterolemia and reducing cardiovascular disease risk. Apart from ICI and other conventional therapies, statins are frequently used by advanced HCC patients with dyslipidemia, which is often marked by the abnormal accumulation of cholesterol and fatty acids in the liver. Supported by a body of preclinical and clinical studies, statins may unexpectedly enhance the efficacy of ICI therapy in HCC patients through the regulation of inflammatory responses and the immune microenvironment. This review discusses the abnormal changes in lipid metabolism in HCC, summarizes the clinical evidence and benefits of stain use in HCC, and prospects the possible mechanistic actions of statins in transforming the immune microenvironment in HCC when combined with immunotherapies. Consequently, the use of statin therapy may emerge as a novel and valuable adjuvant for immunotherapies in HCC.

TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.

Predictive Biomarkers of Immune Checkpoint Inhibitor-Based Mono- and Combination Therapies for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most frequent and deadly human cancers worldwide. It has been shown that interaction between immune checkpoint receptors and ligands plays a crucial role in inhibition of T cell-mediated anti-tumor immune responses, thereby assisting tumor cells to evade the host immune surveillance. Therefore, several immune checkpoint inhibitors (ICIs) that selectively block immune checkpoint receptors or ligands have been developed as clinically effective and safe immunotherapeutic agents for treating HCC, including the inhibitors targeting cytotoxic T lymphocyte-associated antigen 4, programmed death 1, and programmed death ligand 1. In addition, various combinations of ICIs and other ICIs or tyrosine kinase inhibitors or vascular endothelial growth factor inhibitors have also emerged as clinically beneficial treatments for HCC. However, the overall response rates of ICI mono-therapy and combination therapy in HCC patients remain unsatisfied, highlighting the urgent need for discovering valuable predictive biomarkers to achieve personalized therapy. This review comprehensively summarizes the literature-based evidence validating a variety of biomarkers with predictive significance for treatment responses and outcomes in HCC patients receiving various ICI-based mono- and combination therapies.

Deciphering the immune modulation through deep transcriptomic profiling and therapeutic implications of DNA damage repair pattern in hepatocellular carcinoma

AimsDNA damage repair (DDR) plays a pivotal role in hepatocellular carcinoma (HCC), driving oncogenesis, progression, and therapeutic response. However, the mechanisms of DDR mediated immune cells and immuno-modulatory pathways in HCC are yet ill-defined. MethodsOur study introduces an innovative deep machine learning framework for precise DDR assessment, utilizing single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data. Single-cell RNA sequencing data were obtained and in total 85,628 cells of primary or post-immunotherapy cases were analyzed. Large-scale HCC datasets, including 1027 patients in house together with public datasets, were used for 101 machine-learning models and a novel DDR feature was derived at single-cell resolution (DDRscore). Druggable targets were predicted using the reverse phase protein array (RPPA) proteomic profiling of 169 HCC patients and RNA-seq data from 22 liver cancer cell lines. ResultsOur investigation reveals a dynamic interplay of DDR with natural killer cells and B cells in the primary HCC microenvironment, shaping a tumor-promoting immune milieu through metabolic programming. Analysis of HCC post-immunotherapy demonstrates elevated DDR levels that induces epithelial-mesenchymal transition and fibroblast-like transformation, reshaping the fibrotic tumor microenvironment. Conversely, attenuated DDR promotes antigen cross-presentation by dendritic cells and CD8+ T cells, modulating the inflammatory tumor microenvironment. Regulatory network analysis identifies the CXCL10-CXCR3 axis as a key determinant of immunotherapeutic response in low DDR HCC, potentially regulated by transcription factors GATA3, REL, and TBX21. Using machine learning techniques by combining bulk RNA-seq data in house together with public datasets, we introduce DDRscore, a robust consensus DDR scoring system to predict overall survival and resistance to PD-1 therapy in HCC patients. Finally, we identify BRAF as a potential therapeutic target for high DDRscore patients. ConclusionOur comprehensive findings advance our understanding of DDR and the tumor microenvironment in HCC, providing insights into immune regulatory mechanisms mediated via DDR pathways.

Integrated bulk and single-cell transcriptomes reveal pyroptotic signature in prognosis and therapeutic options of hepatocellular carcinoma by combining deep learning.

Although some pyroptosis-related (PR) prognostic models for cancers have been reported, pyroptosis-based features have not been fully discovered at the single-cell level in hepatocellular carcinoma (HCC). In this study, by deeply integrating single-cell and bulk transcriptome data, we systematically investigated significance of the shared pyroptotic signature at both single-cell and bulk levels in HCC prognosis. Based on the pyroptotic signature, a robust PR risk system was constructed to quantify the prognostic risk of individual patient. To further verify capacity of the pyroptotic signature on predicting patients' prognosis, an attention mechanism-based deep neural network classification model was constructed. The mechanisms of prognostic difference in the patients with distinct PR risk were dissected on tumor stemness, cancer pathways, transcriptional regulation, immune infiltration and cell communications. A nomogram model combining PR risk with clinicopathologic data was constructed to evaluate the prognosis of individual patients in clinic. The PR risk could also evaluate therapeutic response to neoadjuvant therapies in HCC patients. In conclusion, the constructed PR risk system enables a comprehensive assessment of tumor microenvironment characteristics, accurate prognosis prediction and rational therapeutic options in HCC.

Identification and development of TP53 mutation-associated Long non-coding RNAs signature for optimized prognosis assessment and treatment selection in hepatocellular carcinoma.

The TP53 gene is estimated to be mutated in over 50% of tumors, with the majority of tumors exhibiting abnormal TP53 signaling pathways. However, the exploration of TP53 mutation-related LncRNAs in Hepatocellular carcinoma (HCC) remains incomplete. This study aims to identify such LncRNAs and enhance the prognostic accuracy for Hepatoma patients. Differential gene expression was identified using the "limma" package in R. Prognosis-related LncRNAs were identified via univariate Cox regression analysis, while a prognostic model was crafted using multivariate Cox regression analysis. Survival analysis was conducted using Kaplan-Meier curves. The precision of the prognostic model was assessed through ROC analysis. Subsequently, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were executed on the TCGA dataset via the TIDE database. Fractions of 24 types of immune cell infiltration were obtained from NCI Cancer Research Data Commons using deconvolution techniques. The protein expression levels encoded by specific genes were obtained through the TPCA database. In this research, we have identified 85 LncRNAs associated with TP53 mutations and developed a corresponding signature referred to as TP53MLncSig. Kaplan-Meier analysis revealed a lower 3-year survival rate in high-risk patients (46.9%) compared to low-risk patients (74.2%). The accuracy of the prognostic TP53MLncSig was further evaluated by calculating the area under the ROC curve. The analysis yielded a 5-year ROC score of 0.793, confirming its effectiveness. Furthermore, a higher score for TP53MLncSig was found to be associated with an increased response rate to immune checkpoint blocker (ICB) therapy (p = .005). Patients possessing high-risk classification exhibited lower levels of P53 protein expression and higher levels of genomic instability. The present study aimed to identify and validate LncRNAs associated with TP53 mutations. We constructed a prognostic model that can predict chemosensitivity and response to ICB therapy in HCC patients. This novel approach sheds light on the role of LncRNAs in TP53 mutation and provides valuable resources for analyzing patient prognosis and treatment selection.

Concomitant Irradiation to Checkpoint Inhibitor Therapy of Hepatocellular Carcinoma Patients: A Systematic Retrospective, Single-Center Analysis

Introduction: Immunotherapy has been established as the standard treatment option for patients with advanced hepatocellular carcinoma (aHCC). Despite the increased efficacy, disease progression occurs in a relevant proportion of patients even after an objective response. Combination concepts with locoregional therapy are currently under investigation for hepatic disease but are also in discussion for the control of distant metastasis. Radiotherapy is a highly effective treatment modality for local tumor control. It is also thought to increase the efficacy of checkpoint inhibition and sensitize distant lesions to the effects of immunotherapy, but may potentially increase adverse effects. In our center, few patients with aHCC treated with immune checkpoint inhibitors (ICIs) received concomitant radiotherapy for symptom or disease control. The aim of this study was to retrospectively analyze adverse effects and efficacy of concomitant radiotherapy in patients with aHCC treated with checkpoint inhibition. Methods: To this aim, patients who received a combination of ICI and radiotherapy in our institution were retrospectively considered for analysis. The predefined inclusion criterion was radiotherapy after initiated checkpoint inhibition and continuation of ICI therapy for at least 8 weeks. Adverse effects and efficacy measurements were performed according to local standards. Results: The database search of 2016–2021 revealed six consecutive patients fulfilling the predefined criteria for concomitant ICI and radiotherapy. Three patients received high-dose-rate brachytherapy (15 Gy) to treat progredient hepatic lesions. Two patients received stereotactic body radiotherapy (SBRT) (25–30 Gy) for symptom control, and 1 patient received brachytherapy and SBRT to treat metastases. No severe adverse events were reported in the period (<6 months) after concomitant radiotherapy. In 5 out of 6 cases, long-term tumor control could be achieved by this therapeutic combination. Conclusion: A good efficacy of concomitant radiotherapy and checkpoint inhibition has been achieved with no safety concerns. Further investigations should evaluate the safety, appropriate clinical context, and efficacy of this promising approach.

Liver Regeneration Following Radiation Therapy in Hepatocellular Carcinoma Patients: Insights from Functional Liver Imaging

A critical need for hepatocellular carcinoma (HCC) patients is understanding how the liver recovers following radiation therapy (RT). While liver regeneration after hepatic resection has been well-studied, liver recovery following RT is less understood. We have previously studied 99mTc-sulphur colloid (SC) single photon emission tomography (SPECT)/CT to spatially and quantitatively analyze liver function. The purpose of this study was to assess both volumetric and functional liver changes following RT. Patients with HCC had liver function assessed with SC SPECT/CT before and after definitive RT. Patients received 30-67.5 Gy in 4-15 fractions. Anatomic and functional liver metrics were assessed before and after treatment. The anatomic liver volume (ALV) was drawn on CT imaging. Liver function was measured as the functional volume encompassing 30% of maximum uptake (FLV) and mean liver-to-spleen uptake ratio (L/S). Changes in liver size and function were compared to clinical characteristics, including Child-Pugh (CP) score. Parametric t-tests were used to analyze the data. Of 23 evaluable patients (proton RT, n = 16 or photon RT, n = 7), 15 patients had CP-A5/6, 7 had CP-B7/8, and 1 had CP-C10 scores. The mean interval of SC SPECT was 67 days following RT (range, 44 to 113 days). The mean PTV was 272 cc (range 22-802 cc). Regarding baseline liver status, mean pre-treatment ALV was 1584 cc (range 810-2749 cc) with no significant difference in ALV between CP-A and B/C patients (p = 0.285). Pre-treatment mean liver function as assessed with L/S was 1.06 ± 0.43 with significantly greater function in CP-A compared to CP-B/C patients (1.27 vs 0.66, respectively, p<0.001). Mean pre-treatment FLV was 1351 ± 430.8 cc with no significant difference in FLV between CP-A and B/C patients (1422 ± 441 cc vs 1220 ± 436 cc, respectively, p = 0.31). When evaluating change following RT, the mean change in ALV was 0.9% (range, -29% to 23%) with no significant difference between CP-A and CP-B/C patients (-1.5% vs 5.4%, respectively, p = 0.19). In contrast, change in liver function following RT was larger; mean change in FLV was -20% (range, -55% to 33%) and mean change in L/S was -16% (range, -66% to 105%). While change in FLV was not significantly different between CP-A and CP-B/C patients, CP-B/C patients had significantly greater decline in mean liver function (L/S) than CP-A patients (-40 ± 18% vs -3.6 ± 36%, respectively, p = 0.018). There was no association between change in liver volume and change in L/S, p = 0.543. Functional liver imaging metrics reveal different information about the potential functional reserve of irradiated livers compared to anatomic measurements. These data imply that functional liver imaging may more accurately assess the regenerative potential of irradiated and non-irradiated volumes of liver, which may be useful in clinical scenarios where assessment of the function of future liver remnants become critical.

The Role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in Treating Portal Hypertension in Patients with Hepatocellular Carcinoma.

Liver cancer is very frequent, and hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases. Its growing incidence has been greatly affected by the increasing prevalence of metabolic-associated fatty liver disease (MAFLD). The latter is a new epidemic in our era. In fact, HCC is often generated from noncirrhotic liver and its treatment benefits from surgical and nonsurgical approaches, potentially bridged by transjugular intrahepatic portosystemic shunt (TIPS) use. TIPS use is an effective treatment for portal hypertension complications, but its application in patients with HCC and clinically significant portal hypertension (CSPH) remains controversial due to concerns about tumor rupture, dissemination, and increased toxicity. The technical feasibility and safety of TIPS use in HCC patients have been evaluated in several studies. Despite concerns about intraprocedural complications, retrospective studies have shown high success rates and low complication rates in TIPS placement for HCC patients. TIPS use in combination with locoregional treatments, such as transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), has been explored as a treatment option for HCC patients with portal hypertension. These studies have shown improved survival rates in patients undergoing TIPS in combination with locoregional treatments. However, the efficacy and toxicity of TACE in combination with TIPS use require careful evaluation, as changes in venous and arterial flow can affect treatment outcomes and complications. The results from studies evaluating the impact of TIPS on systemic therapy and surgical options are also promising. In conclusion, the TIPS is a sufficiently safe, useful item available for physicians treating complications of portal hypertension. Moreover, a TIPS can be used in combination with locoregional therapy in HCC patients. Systemic chemotherapy can also benefit of the use of TIPS placement. A complex interplay affects TIPS use with surgery. The latter needs further data. The TIPS is a useful and safe add-on treatment, changing the natural course of HCC progression. Its use is regulated by a sophisticated physiologic and pathophysiologic flow of evidence.

A retrospective study of the efficacy and safety of donafenib combined with TACE as adjuvant therapy in patients with high-risk recurrence factors after hepatocellular carcinoma surgery.

e16121 Background: Surgical resection is the most important treatment for patients with hepatocellular carcinoma (HCC) to obtain long-term survival. However, the 5-year recurrence rate after hepatectomy is as high as 40%-60% and above. Reducing the postoperative recurrence rate is the key to improve the overall efficacy of HCC. This study aimed to evaluate the efficacy and safety of donafenib combined with TACE as adjuvant therapy in HCC patients with high-risk recurrence factors after surgical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high-risk recurrence factors who underwent surgical resection at Shanghai Eastern Hepatobiliary Surgery Hospital from April 2021 to October 2022. High-risk recurrence factors included: the number of tumors ≥ 3, tumor diameter ≥ 5 cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. Patients received adjuvant therapy of donafenib combined with TACE after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 40 patients were enrolled with a median age of 55.5 years (21-78), 39 patients (97.5%) in BCLC stage B and 1 patient (2.5%) in BCLC stage C. 33 patients (82.5%) were co-infected with HBV. All 40 patients had ECOG PS scores of 0 and Child-Pugh scores of A. A total of 34 patients (85%) with MVI were pathologically reported after surgery, 23 patients (57.5%) with tumor diameter ≥5cm, 9 patients (22.5%) with portal vein cancer thrombus, and 6 patients (15%) with satellite lesions. All patients received at least one TACE treatment after surgery, 31 patients (77.5%) received the TACE treatment one month after surgery, and 9 patients (22.5%) received the TACE treatment within one month after surgery. The initial dose of donafenib was 200mg/day. As of the cut-off date of data collection, the median follow-up time was 9 months (95%CI: 7.73-10.27), 4 patients relapsed and 2 patients died. The median RFS was 18 months (95% CI: 13.673-22.327), the one-year RFSR was 83.3% (95% CI: 61.9%-93.8%), and the one-year OS rate was 95.8% (95% CI: 75.2%-99.6%). 21 patients (52.5%) had combined treatment-related adverse events (TRAE), of which 4 patients (10%) had Grade 3 TRAE and no grade 4 or 5 TRAE were reported. Common adverse events included hand-foot skin reaction (9 patients, 22.5%), diarrhea (9 patients, 22.5%), rash (5 patients, 12.5%), hypertension, and gastrointestinal reactions (2 patients each, 5%). Conclusions: Donafenib combined with TACE was used for adjuvant therapy in patients with high-risk recurrence of HCC, which has a high one-year recurrence-free survival rate and was well tolerated.

TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study.

The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT. The authors retrospectively reviewed data of HCC patients with PVTT treated with combination therapy (TACE-hepatic artery infusion chemotherapy with tyrosine kinase inhibitors and PD-1 inhibitors) or TACE alone in SYSUCC from 2011 to 2020. The overall survival (OS), progression-free survival, and overall response rate were compared. Propensity score matching was used to minimize confounding bias. A total of 743 HCC patients with PVTT received combination therapy ( n =139) or TACE alone ( n =604). After propensity score matching, the overall response rate was significantly higher in the combination group than in the TACE group [42.1% vs. 5.0%, P < 0.001 (response evaluation criteria in solid tumours); 53.7% vs. 7.8%, P < 0.001 (modified response evaluation criteria in solid tumours)]. The combination group showed significantly better OS than the TACE group (median OS not reached vs. 10.4 months, P < 0.001). The median progression-free survival of the combination and TACE groups was 14.8 and 2.3 months ( P < 0.001), respectively. Tumour downstaging followed by salvage liver resection was significantly more common for the combination therapy group than for TACE group (46.3% vs. 4.5%, P < 0.001). After salvage liver resection, 31.6% (30/95) and 1.7% (3/179) of the patients achieved a pathological complete response in the combination and TACE groups, respectively ( P < 0.001). The grade 3/4 adverse events rates were similar between the two groups (28.1% vs. 35.9%, P =0.092). Compared with TACE alone, combination therapy was safe enough and resulted in survival benefits. This is a promising treatment option for HCC patients with PVTT.

Adjuvant transarterial chemoembolization with sorafenib for patients with hepatocellular carcinoma with portal vein tumor thrombus after surgery: A phase III, multicenter, randomized, controlled trial.

493 Background: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization (SOR-TACE) versus sorafenib alone as postoperative adjuvant therapy for hepatocellular carcinoma (HCC) patients with portal vein thrombus (PVTT). Methods: This was a phase III, multicenter, randomized, control clinical trial. Eligible HCC patients with PVTT were included and randomly assigned (1:1) to receive SOR-TACE or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400mg twice a day. In the SOR-TACE group, TACE was performed one day after the administration of sorafenib. The primary endpoint was recurrence-free survival (RFS). Results: From October 2019 to March 2022, a total of 158 HCC patients with PVTT from China were enrolled and randomized. After a median follow-up duration of 28.4 months, the median RFS was significantly longer in the SOR-TACE group (16.8 vs. 12.6 months; hazard ratio, 0.57; P = 0.002). The median overall survival (OS) was also significantly longer with SOR-TACE than with sorafenib (30.4 vs. 22.5 months; hazard ratio, 0.57; P = 0.017). Multivariable analysis indicated SOR-TACE treatment was an independent risk factor for both RFS and OS. The SOR-TACE group did not show additional toxicity compared with the sorafenib alone group. Conclusions: The combination of sorafenib and TACE as postoperative adjuvant therapy in HCC patients with PVTT resulted in longer RFS and OS compared to sorafenib alone and was well tolerated. Clinical trial information: NCT04143191 .

Circulating MiRNA-373 as a Predictor of Response to Super-selective Transarterial Chemoembolization Bridging Therapy in Hepatocellular Carcinoma Patients Awaiting Liver Transplantation.

Super selective transarterial chemoembolization (TACE) has emerged as a bridging therapy for early hepatocellular carcinoma (HCC) patients awaiting liver transplantation. This study aimed at assessing the expression profiles of circulating MiR-210 and MiR-373 as potential predictors of response to TACE bridging therapy in a group of Egyptian HCC cases on top of chronic hepatitis-C infection, awaiting liver transplantation. Fifty-three HCC cases awaiting liver transplantation referred for TACE, were followed up for three months, resulting in forty-five responders and eight non-responders based on modified response evaluation criteria in solid tumors (mRECIST). Circulating pre TACE MiR-210 and MiR-373 expressions were determined using reverse transcription quantitative polymerase chain reaction. Circulating pre TACE MiR-373, but not MiR-210, was significantly higher in non-responders than responders. Receiver operating characteristics (ROC) curve analysis of MiR-373, pre-TACE tumor volume, inflammatory score, and albumin bilirubin (ALBI) grade revealed highest sensitivity for pre-TACE tumor volume (cutoff>11.49 cm3) and highest specificity for pre-TACE MiR-373 (cutoff>1.46-fold change). Multivariate logistic regression revealed pre TACE MiR-373 as a significant independent predictor of TACE response after adjusting for pre TACE tumor volume. Circulating pre-TACE MiR-373 could assist as a noninvasive predictor marker of response to TACE bridging therapy in early HCC patients awaiting liver transplantation.

Efficacy and safety of anlotinib as an adjuvant therapy in hepatocellular carcinoma patients with a high risk of postoperative recurrence.

Hepatocellular carcinoma (HCC) has a high rate of postoperative recurrence and lacks an effective treatment to prevent recurrence. This study aims to investigate the efficacy and safety of anlotinib in postoperative adjuvant therapy for HCC patients with high-risk recurrence factors. For this multicenter, retrospective study, we recruited 63 HCC patients who received either anlotinib (n=27) or transcatheter arterial chemoembolization (TACE) (n=36) from six research centers in China between March 2019 and October 2020. The primary endpoint was disease-free survival (DFS) and the secondary endpoints were overall survival (OS) and safety. In this study, the median follow-up time was 25.9 and 26.8 months in the anlotinib and TACE groups, respectively. There was no significant difference in the median DFS between the anlotinib [26.8 months, 95% confidence interval (95% CI): 6.8-NE] and TACE groups (20.6 months, 95% CI: 8.4-NE). The 12-month OS rates in the anlotinib and TACE groups were 96.3% and 97.2%, respectively. In the anlotinib group, 19 of 27 patients (70.4%) experienced treatment-emergent adverse events, with the most common events (≥10%) being hypertension (22.2%) and decreased platelet count (22.2%). The results indicate that anlotinib, as a new, orally administered tyrosine kinase inhibitor, has the same efficacy as TACE, and side effects can be well controlled.

Safety and tolerability of radiotherapy in combination with systemic targeted therapies for treatment of hepatocellular carcinoma: a narrative review.

Palliative radiotherapy (RT) and systemic immuno- or targeted therapy both play significant roles in the treatment of advanced hepatocellular carcinoma (HCC). Concurrent application of these therapies is increasing, however, no guidelines exist regarding the combination of systemic therapy with RT. This narrative review summarises the existing literature reporting toxicity observed after concurrent treatment with RT and immuno- or targeted therapeutic agents commonly used in HCC. The PubMed database was searched for studies published between 2011 and 2023 reporting toxicity data on patients treated concurrently with RT and targeted agents used in HCC. Due to the paucity of relevant literature in HCC, the inclusion criteria were expanded to include non-HCC cohorts treated with targeted therapies commonly used in advanced HCC. Sixty-seven articles were included in this review. Twenty-two articles reported combined RT with sorafenib, one with regorafenib, 22 with bevacizumab, three with lenvatinib and 19 with immune checkpoint inhibitors. Significant findings include a high rate severe hepatotoxicity with combination RT and sorafenib, ranging from 0-19% with liver stereotactic body radiotherapy (SBRT) and 3-18% with conventionally fractionated liver RT. Severe gastrointestinal (GI) toxicities including perforation and ulceration were seen with combination bevacizumab and RT, ranging from 0-27% in the acute setting and 0-23% in the late setting. The safety profile of combination immune checkpoint blockade agents and RT was similar to that seen in monotherapy. Existing data suggests that combination RT and targeted therapy given the risk of severe adverse events including hepatotoxicity and GI toxicity. There is an urgent need for future studies specifically examining the impact of combination therapy in HCC patients to guide clinical decision-making in the evolving landscape of immune- and targeted therapies.

Dickkopf-1 drives tumor immune evasion by inducing PD-L1 expression in hepatocellular carcinoma

Understanding the mechanisms regulating PD-L1 expression in hepatocellular carcinoma (HCC) is important to improve the response rate to PD-1/PD-L1 blockade therapy. Here, we show that DKK1 expression is positively associated with PD-L1 expression and inversely correlated with CD8+ T cell infiltration in human HCC tumor specimens. In a subcutaneous xenograft tumor model, overexpression of DKK1 significantly promotes tumor growth, tumoral PD-L1 expression, but reduces tumoral CD8+ T cell infiltration; whereas knockdown of DKK1 has opposite effects. Moreover, enforced expression of DKK1 dramatically promotes PD-L1 expression, Akt activation, β-catenin phosphorylation and total protein expression in HCC cells. By contrast, knockdown of DKK1 inhibits all, relative to controls. In addition, CKAP4 depletion, Akt inhibition, or β-catenin depletion remarkably abrogates DKK1 overexpression-induced transcriptional expression of PD-L1 in HCC cells. Reconstituted expression of the active Akt1 largely increased PD-L1 transcriptional expression in HCC cells. Similarly, expression of WT β-catenin, but not the phosphorylation-defective β-catenin S552A mutant, significantly promotes PD-L1 expression. Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-β-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/β-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.