Advanced-stage Hepatocellular Carcinoma Research Articles

Comprehensive analysis of radiologic cancer-free (rCF) status through various treatment approaches in advanced-stage hepatocellular carcinoma

Introduction In the realm of oncology, the pinnacle of therapeutic success is achieving a state where the patient is entirely free of cancer, i.e. ‘cancer-free’. This benchmark should not only apply to early-stage malignancies but should also be the standard aim for advanced-stage diseases, including hepatocellular carcinoma (HCC). However, there is a glaring gap in the research landscape concerning the understanding of what cancer-free status truly means for advanced-stage HCC. Our study sheds light on the profound implications of reaching a cancer-free by radiological assessments in patients with advanced-stage HCC. Methods We established a database tracking the full clinical course of all patients with HCC (from 2003–2022). We identified the initial instances of macrovascular invasion or extrahepatic spread. We defined radiologic cancer-free (rCF) as cases in which no recurrence was observed for at least 2 months following curative treatment or complete response to systemic therapies. The frequency of achieving rCF status was investigated, categorised by patients’ background. Results We identified 795 patients with advanced-stage HCC. The rCF rate was 8.7%. Patients who achieved rCF status had significantly better prognoses compared to those who did not (p < 0.001). In the decision tree analysis, the number of tumors ≥8 was the strongest factor making it difficult to achieve rCF status. Analysis of stage progression patterns revealed varying background characteristics at the time of advanced-stage diagnosis, with discrepancies in rCF rates. Conclusions Despite the low rate of achieving rCF status, the prognostic impact was significant. Patients with certain tumor characteristics had a higher likelihood of achieving rCF status. The distribution of tumor conditions varies based on the pattern of progression, which affects the likelihood of achieving a rCF status.

Risk-stratified hepatocellular carcinoma screening according to the degree of obesity and progression to cirrhosis for diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD) in Japan: a cost-effectiveness study.

To evaluate the cost-effectiveness of risk-stratified hepatocellular carcinoma (HCC) screening in diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A state-transition model from a healthcare payer perspective on a lifetime horizon. Japan. A hypothetical cohort of 50-year-old diabetic patients with MASLD risk-stratified according to degree of obesity and progression to cirrhosis. Metabolic dysfunction-associated steatotic liver (MASL), metabolic dysfunction-associated steatohepatitis (MASH) and MASH cirrhosis are progressive manifestations of this specific type of liver disease. Abdominal ultrasound (US), US with alpha-fetoprotein (AFP), US with AFP and lectin-reactive alpha-fetoprotein (AFP-L3), CT, extracellular contrast-media-enhanced MRI (ECCM-MRI), gadoxetic acid-enhanced MRI (EOB-MRI) and no screening. Costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), early-stage HCC cases, advanced-stage HCC cases and HCC-related deaths. EOB-MRI is the most cost-effective screening method for non-obese diabetic patients with MASH cirrhosis and for obese diabetic patients with MASH and MASH cirrhosis. Cost-effectiveness was sensitive to HCC incidence in non-obese diabetic patients with MASH cirrhosis and obese diabetic patients with MASH, and the adherence rate of HCC screening in obese diabetic patients with MASH. When the semiannual HCC incidence was between 0.008 and 0.0138 in non-obese diabetic patients with MASH cirrhosis, US with AFP was more cost-effective than EOB-MRI. Cost-effectiveness acceptability curves showed that EOB-MRI was 50.7%, 96.0% and 99.9% cost-effective in obese diabetic patients with MASH and non-obese diabetic patients with MASH cirrhosis, and obese diabetic patients with MASH cirrhosis at a willingness-to-pay level of $50 000 per QALY gained. Compared with no screening in 100 000 non-obese diabetic patients with MASH cirrhosis and obese diabetic patients with MASH cirrhosis, EOB-MRI reduced total costs by US$69 million and by US$142 million, increased lifetime effectiveness by 12 546 QALYs and by 15 815 QALYs, detected 17 873 and 21 014 early-stage HCC cases, and averted 2068 and 2471 HCC-related deaths, respectively. Of all HCC screening methods for diabetic patients with MASH cirrhosis, EOB-MRI yields the greatest cost-saving with the highest QALYs, detects the greatest number of early-stage HCC cases and averts the greatest number of advanced-stage HCC cases and HCC-related deaths. The findings provide important insights for the precise implementation of risk-stratified HCC surveillance to reduce morbidity and mortality and improve the quality of life in diabetic patients with MASLD.

Prognostic Evaluation of Conversion Therapy Following Hepatic Arterial Infusion Chemotherapy or Immunotherapy in Patients with Advanced or Transarterial Chemoembolization Unsuitable Intermediate-Stage Hepatocellular Carcinoma-A retrospective cohort study.

Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5-15.3 months with a 39.1-42.5% tumor response rate. In comparison, ICIs have a 12-14 month OS rate with a 26-33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes. We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model. Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B vs. A (HR=2.21, p=0.041), BCLC stage C vs. B (HR=4.38, p=0.011), and elevated AFP levels (HR=5.02, p<0.001). Positive responders saw substantial survival benefits (HR=0.26, p=0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p=0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment. Conversion therapy with curative intent following HAIC or ICIs might enhances survival in patients with advanced or TACE-unsuitable intermediate-stage HCC.

Spatial Dynamics of T and B Cell Response Predicts Clinical Outcome of Resectable and Unresectable Hepatocellular Carcinoma.

Immunotherapies have led to a paradigm shift in the treatment of hepatocellular carcinoma (HCC). Studies have revealed the single-cell catalogues of tumor-infiltrating immune cells and the trajectories of their differentiation. Nevertheless, the spatial distribution of these immune cells with distinct phenotypes in tumor microenvironment and their clinicopathological significance in resectable and unresectable HCCs are still largely unclear. We analyzed the spatial dynamics of intratumoral CD4 and CD8 T cells and their association with B and plasma cells using 283 surgically resected HCCs, 58 unresectable HCC samples before combined immunotherapy (atezolizumab plus bevacizumab [Atezo+Bev]), and autopsy specimens from 50 cases of advanced-stage HCCs through multiplex immunohistochemistry combined with transcriptomic and driver gene mutation analysis. Classification based on the spatial dynamics of T and B cell responses (refined immunosubtype) was developed and its clinicopathological significance was analyzed. We found that stem-like CD4 and CD8 T cells were mainly observed in T cell aggregates. Differentiation of T follicular helper cells were associated with the development of tertiary lymphoid structures, whereas differentiation of CD4 TCXCL13 cells with phenotype resembling T peripheral helper cells were associated with the development of lymphoplasmacytic microenvironment. The refined immunosubtype could predict clinical outcomes of resectable HCC after surgery and unresectable HCC after Atezo+Bev therapy. The immune microenvironment of metastatic lesions tended to reflect those of primary lesions. We revealed the spatial dynamics of T and B cell response in HCC, which is closely associated with the clinical outcome after surgical resection or Atezo+Bev therapy.

AAV-mediated combination gene therapy of inducible Caspase 9 and miR-199a-5p is therapeutic in hepatocellular carcinoma.

Advanced-stage hepatocellular carcinoma (HCC) remains an untreatable disease with an overall survival of less than one year. One of the critical molecular mediators contributing to increased resistance to therapy and relapse, is increased hypoxia-inducible factor 1α (HIF-1α) levels, leading to metastasis of tumor cells. Several microRNAs are known to be dysregulated and impact HIF-1α expression in HCC. An in silico analysis demonstrated that hsa-miR-199a-5p is downregulated at various stages of HCC and is known to repress HIF-1α expression. Based on this analysis, we developed a combinatorial suicide gene therapy by employing hepatotropic Adeno-associated virus-based vectors encoding an inducible caspase 9 (iCasp9) and miR-199a. The overexpression of miR-199a-5p alone significantly decreased ( ~ 2-fold vs. Mock treated cells, p < 0.05) HIF-1α mRNA levels, with a concomitant increase in cancer cell cytotoxicity in Huh7 cells in vitro and in xenograft models in vivo. To further enhance the efficacy of gene therapy, we evaluated the synergistic therapeutic effect of AAV8-miR-199a and AAV6-iCasp9 in a xenograft model of HCC. Our data revealed that mice receiving combination suicide gene therapy exhibited reduced expression of HIF-1α ( ~ 4-fold vs. Mock, p < 0.001), with a significant reduction in tumor growth when compared to mock-treated animals. These findings underscore the therapeutic potential of downregulating HIF-1α during suicide gene therapy for HCC.

Neoadjuvant atezolizumab plus bevacizumab prior liver transplantation for hepatocellular carcinoma☆

Background & AimsThe combination of atezolizumab and bevacizumab offers a novel approach to immunomodulation, showing efficacy as a primary treatment in advanced hepatocellular carcinoma (HCC). Concerns about graft safety and rejection have limited its exploration in the neoadjuvant setting of liver transplantation (LT).This study investigates the clinical efficacy and the safety profile related to the pre-transplant administration of atezolizumab and bevacizumab for HCC. MethodsProspective assessment of 17 patients with HCC treated with neoadjuvant preoperative atezolizumab and bevacizumab prior to LT for HCC, obtained from December 2020 and December 2023 at seven Western transplant centers. ResultsAmong the 17 patients with HCC included in the study, 16 (94.1%) had a tumor burden outside of Milan Criteria (MC). Neoadjuvant loco-regional therapies along with the administration of atezolizumab plus bevacizumab (median:5 months; discontinued at least 4 weeks prior LT), achieved an ORR 94% (Complete response: 59%), downstaging to within MC (82%) and a pathological response at explant examination of 88%. Grade 3-4 TRAE accounted for 17.6% of cases and were manageable. During the 25 months median follow-up period, 2 cases of mild (RAI ≤ 4), biopsy-proven rejection were reported but no instances of severe allograft rejection or graft loss. The 1-year and 3-year post-LT survival rates were 94.2% and 88.2%, respectively. ConclusionsThis study highlights the favorable oncological and survival outcomes from a multicentric cohort of HCC patients treated with atezolizumab and bevacizumab in the pre-LT setting. This immune-based combination was safe in terms of TRAE, and absence of severe post-transplant rejection or graft loss. These preliminary results could pave the way for expanding transplant eligibility criteria in patients at more advanced HCC stages. Impact and Implications•The combination of atezolizumab and bevacizumab in the neoadjuvant setting prior to liver transplantation for hepatocellular carcinoma (HCC) has been limitedly explored despite its potential to enhance anti-tumor response and downstaging due to raising concerns about its safety profile.•Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within MC, 94% radiological objective response and 88% pathology response, without drop-outs due to TRAEs or graft loss.•The neoadjuvant combination of atezolizumab plus bevacizumab prior liver transplantation in HCC shows an encouraging safety profile and stands out as a promising pre-transplant optimization treatment adjunct, leading to improved oncological outcomes

Mass spectrometry-based multi-omics analysis reveals distinct molecular features in early and advanced stages of hepatocellular carcinoma

Hepatocellular Carcinoma (HCC) is a serious primary solid tumor that is prevalent worldwide. Due to its high mortality rate, it is crucial to explore both early diagnosis and advanced treatment for HCC. In recent years, multi-omics approaches have emerged as promising tools to identify biomarkers and investigate molecular mechanisms of biological processes and diseases. In this study, we performed proteomics, phosphoproteomics, metabolomics, and lipidomics to reveal the molecular features of early- and advanced-stage HCC. The data obtained from these omics were analyzed separately and then integrated to provide a comprehensive understanding of the disease. The multi-omics results unveiled intricate biological pathways and interaction networks underlying the initiation and progression of HCC. Moreover, we proposed specific potential biomarker panels for both early- and advanced-stage HCC by overlapping our data with CPTAC database for HCC diagnosis, and deduced novel insights and mechanisms related to HCC origination and development, such as glucose depletion during tumor progression, ROCK1 deactivation and GSK3A activation.

Uncovering gene expression signatures and diagnostic – Biomarkers in hepatocellular carcinoma through multinomial logistic regression analysis

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and classifying the developmental stages of HCC can help with early prognosis and treatment. This study aimed to investigate diagnostic and prognostic molecular signatures underlying the progression of HCC, including tumor initiation and growth, and to classify its developmental stages based on gene expression levels. We integrated data from two cancer systems, including 78 patients with Edmondson-Steiner (ES) grade and 417 patients with TNM stage cancer. Functional profiling was performed using identified signatures. Using a multinomial logistic regression model (MLR), we classified controls, early-stage HCC, and advanced-stage HCC. The model was validated in three independent cohorts comprising 45 patients (neoplastic stage), 394 patients (ES grade), and 466 patients (TNM stage). Multivariate Cox regression was employed for HCC prognosis prediction. We identified 35 genes with gradual upregulation or downregulation in both ES grade and TNM stage patients during HCC progression. These genes are involved in cell division, chromosome segregation, and mitotic cytokinesis, promoting tumor cell proliferation through the mitotic cell cycle. The MLR model accurately differentiated controls, early-stage HCC, and advanced-stage HCC across multiple cancer systems, which was further validated in various independent cohorts. Survival analysis revealed a subset of five genes from TNM stage (HR: 3.27, p < 0.0001) and three genes from ES grade (HR: 7.56, p < 0.0001) that showed significant association with HCC prognosis. The identified molecular signature not only initiates tumorigenesis but also promotes HCC development. It has the potential to improve clinical diagnosis, prognosis, and therapeutic interventions for HCC. This study enhances our understanding of HCC progression and provides valuable insights for precision medicine approaches.

Clinical Characteristics and Prognosis of Early-Onset Hepatocellular Carcinoma: A Retrospective Cohort Study Based on Population Data.

The incidence of young patients diagnosed with hepatocellular carcinoma (HCC) is projected to rise. This study aimed to investigate the distinctive characteristics of adolescent and young adult (AYA) patients with HCC and identify the risk factors that impact their survival. This study included 1005 AYA patients and 55,435 older adult (OA) patients with HCC, using data from the Surveillance, Epidemiology, and End Results database. Propensity score matching was used to adjust for baseline differences in patient characteristics. The Kaplan-Meier curve and log-rank test are utilized to compare the overall survival between the two groups. The Cox proportional hazards regression model was used for subgroup analysis to identify risk factors for overall survival in AYA patients. AYA patients exhibited a higher proportion of advanced clinical stage (49.15% vs 37.57%, P < 0.001) and fibrolamellar hepatocellular carcinoma (14.13% vs 0.09%, P < 0.001), but a lower incidence of alpha-fetoprotein positivity (32.04% vs 45.32%, P < 0.001) and cirrhosis (8.86% vs 18.32%, P < 0.001). The subgroup analysis results indicated that AYA patients had a more favorable prognosis than OA patients in most subgroups. Undifferentiated carcinoma emerged as the predominant risk factor for AYA patients (Hazard Ratio [HR], 6.08 [2.53-14.62]), whereas partial hepatectomy was determined to be the most advantageous factor (HR, 0.29 [0.23-0.37]). AYA patients with HCC exhibit more aggressive characteristics but demonstrate a better prognosis compared to the OA group, necessitating personalized surveillance and treatment.

Efficacy and safety of transarterial chemoembolization alone compared to its combination with anlotinib among patients with intermediate or advanced stage hepatocellular carcinoma: a phase II randomized controlled trial.

Anlotinib hydrochloride is a potent oral multitargeted tyrosine kinase inhibitor that targets VEGFR1-3, FGFR1-4, and PDGFR α/β, demonstrating significant antiangiogenic activity. Transcatheter arterial chemoembolization (TACE) is considered the effective treatment for intermediate/advanced hepatocellular carcinoma (HCC), which remains a major global health challenge. This study evaluated the relative efficacy and safety of combining anlotinib with TACE against the standard TACE monotherapy among patients with intermediate or advanced HCC. This phase II randomized controlled trial included 38 patients diagnosed with intermediate or advanced HCC. Patients were randomly assigned to receive either TACE in combination with anlotinib or TACE alone. The primary endpoint of the study was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. This trial aimed to determine whether the addition of anlotinib could extend PFS and improve other clinical outcomes compared to TACE alone. The median PFS for patients treated with TACE and anlotinib was significantly longer at 11.04 months compared to 6.87 months in the TACE-alone group [hazard ratio (HR) 0.46; P=0.02], indicating a robust enhancement in disease management. Although the median OS was not reached at the time of analysis, early trends suggest potential improvement. Both treatment groups had comparable ORR and DCR, demonstrating effective disease control. The safety profile of the combined treatment was manageable, with side effects similar in nature to those observed with TACE alone but not significantly more severe, thus maintaining patient quality of life. The addition of anlotinib to TACE appears to provide a safe and effective therapeutic benefit for patients with intermediate or advanced-stage HCC. However, longer follow-up is needed for a more comprehensive efficacy assessment. ClinicalTrials.gov NCT04066543.

Drug Repurposing Approach to Identify Candidate Drug Molecules for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, with a high mortality rate due to the limited therapeutic options. Systemic drug treatments improve the patient's life expectancy by only a few months. Furthermore, the development of novel small molecule chemotherapeutics is time-consuming and costly. Drug repurposing has been a successful strategy for identifying and utilizing new therapeutic options for diseases with limited treatment options. This study aims to identify candidate drug molecules for HCC treatment through repurposing existing compounds, leveraging the machine learning tool MDeePred. The Open Targets Platform, UniProt, ChEMBL, and Expasy databases were used to create a dataset for drug target interaction (DTI) predictions by MDeePred. Enrichment analyses of DTIs were conducted, leading to the selection of 6 out of 380 DTIs identified by MDeePred for further analyses. The physicochemical properties, lipophilicity, water solubility, drug-likeness, and medicinal chemistry properties of the candidate compounds and approved drugs for advanced stage HCC (lenvatinib, regorafenib, and sorafenib) were analyzed in detail. Drug candidates exhibited drug-like properties and demonstrated significant target docking properties. Our findings indicated the binding efficacy of the selected drug compounds to their designated targets associated with HCC. In conclusion, we identified small molecules that can be further exploited experimentally in HCC therapeutics. Our study also demonstrated the use of the MDeePred deep learning tool in in silico drug repurposing efforts for cancer therapeutics.

Hepatic arterial infusion chemotherapy-based conversion hepatectomy in responders versus nonresponders with hepatocellular carcinoma: A multicenter cohort study.

Hepatic arterial infusion chemotherapy (HAIC) has shown satisfactory therapeutic efficacy in unresectable hepatocellular carcinoma (HCC) and is regarded as an important conversion treatment. However, limited information is available regarding the optimal timing of HAIC-based conversion hepatectomy. This study aims to determine the optimal timing for HAIC-based conversion surgery in patients with HCC. Data from a retrospective cohort of patients who underwent HAIC-based conversion hepatectomy were reviewed. Oncological outcomes, surgical information, and risk factors were comparatively analyzed. In total, 424 patients with HCC who underwent HAIC-based conversion hepatectomy were included and were divided into responder (n=312) and nonresponder (n=112) groups. The overall survival (OS) and recurrence-free survival (RFS) rates of both the whole responder cohort and patients who achieved a response after 4-6 cycles of HAIC were significantly better than those of the nonresponder cohort. Higher OS and RFS were observed in responders than in nonresponders with advanced-stage HCC. Patients in the responder group had a shorter occlusion duration and less intraoperative blood loss than those in the nonresponder group. There were no significant differences in other surgical information or postoperative complications between the two groups. Tumor response, differentiation, postoperative alpha-fetoprotein level, postoperative protein induced by vitamin K absence or antagonist-II level, age, microvascular invasion, pre-HAIC neutrophil-to-lymphocyte ratio, and preoperative systemic inflammatory response index were independent risk factors for poor long-term survival. Conversion surgery should be considered when tumor response is achieved. Our findings may be useful in guiding surgeons and patients in decision-making regarding HAIC-based conversion hepatectomy.

Evaluation and Management of Unresectable Hepatocellular Carcinoma: Multidisciplinary Indian Consensus Statements from a Delphi Panel

Background India, like many parts of Asia, likely faces a high burden of hepatocellular carcinoma (HCC), though large-scale data on etiology, presentation, and outcomes are lacking. There appears to be a predominance of unresectable, advanced-stage HCC at presentation in India with variable level of expertise in India to manage these scenarios. This publication summarizes the latest evidence with cognizance of the unique challenges faced in India by treating clinicians. Methods A multidisciplinary panel of medical oncologists, gastroenterologists, hepatologists, interventional radiologists, and hepatobiliary surgical oncologists held a meeting in June 2022 and reviewed the evidence available for management of HCC. The meeting concentrated on the recognition and management of HCC not amenable to surgical approaches in the Indian context. A literature review of these aspects of management was conducted and consensus statements with level of evidence and grades of recommendation were prepared by individual specialists in each field. Statements were evaluated by the modified Delphi method. Key Content and Findings The panel comprising 22 experts formulated 40 consensus statements with regard to defining unresectable HCC, optimization of underlying conditions prior to management, rationale use of various liver-directed therapies (LDTs) in unresectable HCC, and systemic therapeutic options in this group of patients. Conclusion Our consensus statements offer practical, yet evidence-based management guidelines for treating unresectable HCC in the Indian context. There is an emphasis on the crucial need for combining available approaches for LDT, even if less well studied though possibly effective, with standard systemic therapy.

Interleukin-1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma-induced increase in intra-hepatic immune cells.

Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC. Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1β levels in human and mouse serum were assessed. Interleukin-1β levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1β levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1-/-) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1β concentration. IL-1R1-/- mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver. Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.

Targeted redox-responsive peptide for arterial chemoembolization therapy of orthotropic hepatocellular carcinoma

ObjectiveTranscatheter Arterial Chemoembolization (TACE) is the first choice for the treatment of advanced-stage hepatocellular carcinoma (HCC). However, TACE suffers from a lack of specificity and rapid drug release. Herein, a targeted redox-responsive peptide (TRRP) was synthesized and used as a carrier of doxorubicin (DOX) to enhance the efficacy of TACE through tumor cells targeting and controlled drug release.MethodsTRRP has a high loading capacity of DOX and a sensitive drug release behavior at high glutathione (GSH) concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models.ResultsTRRP has a high loading capacity of DOX and a sensitive drug release behavior at GSH concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models.ConclusionsThis study demonstrated that TRRP was a promising therapeutic agent for enhancing TACE therapy for HCC treatment.Graphical abstract

Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies.

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.

Systemic therapeutic strategies for hepatocellular carcinoma: current status and prospects

Hepatocellular carcinoma (HCC) is a common type of poorly prognosticated malignant tumor. Surgical resection is the preferred treatment method for early-stage HCC. However, at the time of the initial diagnosis, fewer than 30% of patients with liver cancer are suitable for radical therapy. Systemic therapy plays an important role in the treatment process of patients with intermediate- to advanced-stage HCC, as it can effectively extend patients' survival time. With an emphasis on the status and role of systemic therapy for comprehensive management of HCC, this article summarizes the latest progress at home and abroad in the past five years, including first-line combined immunotherapy for advanced-stage HCC, second-line therapy selection, perioperative systemic therapy application, and combined therapy of systemic and local. Currently, the treatment model combined with local therapy has already become a new research hotspot in the treatment of advanced-stage HCC. Nevertheless, in the future, individualized and precise systemic therapeutic strategies will need further exploration.

Multidisciplinary approach to the treatment of a patient with hepatocellular carcinoma against the background of liver cirrhosis of viral (hepatitis C) etiology. Cinical case

The article presents a clinical case of a multidisciplinary approach to the treatment of 55‑years‑old patient with hepatocellular carcinoma (HCC) against the background of liver cirrhosis of viral (hepatitis C) etiology. A focal liver lesion was accidentally detected during an ultrasound examination in an asymptomatic patient. Further radiological studies (CT and MRI of the liver with contrast) revealed numerous focal lesions of the liver against the background of its cirrhotic alterations. One of the foci in S7 with dimensions 62x68 mm, had LIRADS 5 signs, so it did not require histological verification. According to the Barcelona guidelines, the patient met criteria for advanced HCC (stage B). Treatment options in this case were liver transplantation or locoregional therapy to reduce the HCC stage. The preserved portal blood flow and the preserved functional status of the patient made it possible to conduct successful transarterial chemoembolisation of the focus in S7. After two months, radiological control recorded stabilization of the focus with necrosis and absence of distant metastatic lesions. Moreover, patient had a recurrence of viral hepatitis C, which required administration of the scheme sofosbuvir + glecaprevir/pibrentasvir. After reviewing the patient’s clinical status and evaluating his radiological and serological dynamics, the possibility of liver transplantation was considered. On April 20, 2023, a successful orthotopic liver transplantation was performed. Pathomorphological findings confirmed HCC G2 in the S7 focus. Three months after transplantation, the patient developed a clinical picture of acute cellular rejection of mild severity, which was confirmed by pathomorphological examination. Appropriate correction of immunosuppressive therapy stabilized the patient’s clinical condition and liver function tests. In the future, the patient needs dynamic monitoring with careful control of laboratory parameters and radiological examinations.

Drug-eluting bead transarterial chemoembolization as neoadjuvant therapy pre-liver transplantation for advanced-stage hepatocellular carcinoma.

The objectives of this study were to assess the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) as neoadjuvant therapy before liver transplantation (LT) for advanced-stage hepatocellular carcinoma (HCC) and to analyze the prognostic factors. To determine whether DEB-TACE before LT is superior to LT for advanced-stage HCC. A total of 99 individuals diagnosed with advanced HCC were studied retrospectively. The participants were categorized into the following two groups based on whether they had received DEB-TACE before LT: DEB-TACE group (n = 45) and control group (n = 54). The participants were further divided into two subgroups based on the presence or absence of segmental portal vein tumor thrombus (PVTT). The DEB-TACE group consisted of two subgroups: Group A (n = 31) without PVTT and group B (n = 14) with PVTT. The control group also had two subgroups: Group C (n = 37) without PVTT and group D (n = 17) with PVTT. Data on patient demographics, disease characteristics, therapy response, and adverse events (AEs) were collected. The overall survival (OS) and recurrence-free survival (RFS) rates were assessed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were conducted to determine the parameters that were independently related to OS and RFS. The DEB-TACE group exhibited an overall response rate of 86.6%. Following therapy, there was a significant decrease in the median alpha-fetoprotein (AFP) level (275.1 ng/mL vs 41.7 ng/mL, P < 0.001). The main AE was post-embolization syndrome. The 2-year rates of RFS and OS were significantly higher in the DEB-TACE group than in the control group (68.9% vs 38.9%, P = 0.003; 86.7% vs 63.0%, P = 0.008). Within the subgroups, group A had higher 2-year rates of RFS and OS compared to group C (71.0% vs 45.9%, P = 0.038; 83.8% vs 62.2%, P = 0.047). The 2-year RFS rate of group B was markedly superior to that of group D (64.3% vs 23.5%, P = 0.002). Results from multivariate analyses showed that pre-LT DEB-TACE [hazard ratio (HR) = 2.73, 95% confidence interval (CI): 1.44-5.14, P = 0.04], overall target tumor diameter ≤ 7 cm (HR = 1.98, 95%CI: 1.05-3.75, P = 0.035), and AFP level ≤ 400 ng/mL (HR = 2.34; 95%CI: 1.30-4.19, P = 0.009) were significant risk factors for RFS. Additionally, pre-LT DEB-TACE (HR = 3.15, 95%CI: 1.43-6.96, P = 0.004) was identified as a significant risk factor for OS. DEB-TACE is a safe and efficient therapy for advanced-stage HCC and also enhances patient survival after LT.

Meta-analysis of transarterial chemoembolization combined with cryoablation vs transarterial chemoembolization alone for ≥ 5 cm hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks sixth globally in cancer incidence and third in mortality rates. Unfortunately, over 70% of HCC patients forego the opportunity for curative surgery or liver transplantation due to inadequate physical examinations, poor physical condition, and limited organ availability upon diagnosis. Clinical guidelines endorse transarterial chemoembolization (TACE) as the frontline treatment for intermediate to advanced-stage HCC. Cryoablation (CRA) is an emerging local ablative therapy increasingly used in HCC management. Recent studies suggest that combining CRA with TACE offers complementary and synergistic effects, potentially improving long-term survival rates. However, the superiority of combined TACE + CRA therapy over TACE alone for HCC lesions equal to or exceeding 5 cm requires further investigation. To compare the efficacy and safety of TACE combined with CRA vs TACE alone in the treatment of HCC with a diameter of ≥ 5 cm. PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, and VIP databases were searched to retrieve all relevant studies on TACE and CRA up to July 2022. Meta-analysis was performed using RevMan 5.3 software. After screening according to the inclusion and exclusion criteria, 6 articles were included, including 2 randomized controlled trials and 4 nonrandomized controlled trials, with a total of 575 patients included in the meta-analysis. The results showed that the objective response rate [odds ratio (OR) = 2.56, 95% confidence interval (CI):1.66-3.96, P < 0.0001), disease control rate (OR = 3.03, 95%CI: 1.88-4.89, P < 0.00001), 1-year survival rate (OR = 3.79, 95%CI: 2.50-5.76, P < 0.00001), 2-year survival rate (OR = 2.34, 95%CI: 1.43-3.85, P = 0.0008), and 3-year survival rate (OR = 3.34, 95%CI: 1.61-6.94, P = 0.001) were all superior to those of the control group; the postoperative decrease in alpha-fetoprotein value (OR = 295.53, 95%CI: 250.22-340.85, P < 0.0001), the postoperative increase in CD4 value (OR = 10.59, 95%CI: 8.78-12.40, P < 0.00001), and the postoperative decrease in CD8 value (OR = 6.47, 95%CI: 4.44-8.50, P < 0.00001) were also significantly higher than those in the TACE-alone treatment group. Compared with TACE-alone treatment, TACE + CRA combined treatment not only improves the immune function of HCC patients with a diameter of ≥ 5 cm, but also enhances the therapeutic efficacy and long-term survival rate, without increasing the risk of complications. Therefore, TACE + CRA combined treatment may be a more recommended treatment for patients with HCC with a diameter of ≥ 5 cm.