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.

Improvements in advanced hepatocellular carcinoma to repeat implementation of primary protocol after cancer progression occurs following sequential systemic therapy and a clinical trial: A case report.

INTRODUCTION: Systemic therapy is recommended for patients with advanced hepatocellular carcinoma (aHCC). However, drug resistance occurs over time when patients receive systemic therapy, resulting in cancer progression. Due to the lack of relevant clinical trials, optimizing subsequent treatments after cancer progression remains elusive. PATIENT CONCERNS: A 52-year-old male patient presented with epigastric discomfort and fatigue for almost 1 month with a past history of chronic hepatitis B virus infection for 30 years. DIAGNOSIS: Based on the patient's performance status, tumor status assessed by computed tomography, liver function, he was diagnosed with HCC at BCLC stage C. INTERVENTIONS AND OUTCOMES: He first received transarterial chemoembolization (TACE) combined with sintilimab and lenvatinib as first-line treatment and experienced 10-month progression-free survival. After cancer progression, the patient participated in a clinical trial of ABSK-011, a novel fibroblast growth factor receptor 4 inhibitor, with a frustrating result. Then, the patient underwent TACE and received sintilimab plus lenvatinib again. Surprisingly, the tumor had a partial response, and the patient's serum alpha-fetoprotein returned to normal. LESSONS: The combined treatment of TACE plus systemic therapy might be an appropriate subsequent treatment.

[Curative effect of percutaneous microwave ablation therapy on hepatocellular carcinoma survival: a 15-year real-world study].

Objective: To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma. Methods: 2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival. Results: A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P < 0.001, especially for liver cancer 3.1~5.0 cm (P < 0.001). Conclusion: Microwave ablation therapy is a safe and effective method for BCLC stage 0-B, with significantly enhanced technical efficacy and survival rate over time.

[New progress on diagnosis and treatment for indeterminate-phase chronic hepatitis B virus-infected patients].

Authoritative guidelines at home and abroad typically classify chronic hepatitis B virus (HBV) infection into four stages. However, in clinical practice, a considerable number of patients do not meet the guidelines for staging and are called "indeterminate phase" chronic HBV- infected patients. Studies have shown that patients in the indeterminate phase account for about 30%-50% of chronic HBV infection, have significant liver histological changes or even cirrhosis in a large proportion, and are at a higher risk of HCC and death if they do not receive antiviral therapy. Preliminary research shows that patients in the indeterminate phase who receive antiviral treatment have a good virological response and a remarkable reduced HCC risk. To this end, the 2022 publication "Expert Opinions on Expanding Antiviral Treatment for Chronic Hepatitis B" recommends aggressive treatment for patients with an indeterminate phase who have undergone more than a year of follow-up. However, there is still a lack of unified standards to refine the classification, as well as a lack of effective and rapid non-invasive diagnostic methods to identify patients in the indeterminate phase who are at risk for disease progression. This article aims to review the researches on the proportion, clinical characteristics, disease progression, and treatment benefits to further explore how to better manage indeterminate-phase chronic HBV-infected patients.

[Drug research and development and unmet needs for advanced-stage hepatocellular carcinoma].

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is a global health challenge. Radical surgical resection is the most effective method to achieve long-term survival for HCC. Regrettably, the vast majority of HCC patients lose the opportunity for radical resection at the time of diagnosis due to advanced tumors or poor liver reserve capacity. HCC is resistant to conventional chemotherapy, and in the past, there have been no definite and effective systemic therapeutic drugs. Fortunately, over the last decade, the research and development of molecular targeted therapy and immunotherapy drugs for HCC have made rapid progress, and a variety of drugs and combination therapy regimens have been successively approved for clinical use. However, the overall therapeutic effect is still not ideal and needs further improvement.

Prognostic significance of pan-immune-inflammation value in hepatocellular carcinoma treated by curative radiofrequency ablation: potential role for individualized adjuvant systemic treatment.

BACKGROUND: This study aimed to explore the prognostic role of pan-immune-inflammation value (PIV) and develop a new risk model to guide individualized adjuvant systemic treatment following radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Patients with early-stage HCC treated by RFA were randomly divided into training cohort A (n = 65) and testing cohort B (n = 68). Another 265 counterparts were enrolled into external validating cohort C. Various immune-inflammatory biomarkers (IIBs) were screened in cohort A. Prognostic role of PIV was evaluated and validated in cohort B and C, respectively. A nomogram risk model was built in cohort C and validated in pooled cohort D. Clinical benefits of adjuvant anti-angiogenesis therapy plus immune checkpoint inhibitor (AA-ICI) following RFA was assessed in low- and high-risk groups. RESULTS: The cutoff point of PIV was 120. High PIV was an independent predictor of unfavorable recurrence-free survival (RFS) and overall survival (OS). RFS and OS rates of patients with high PIV were significantly lower than those with low PIV both in cohort B (PRFS=0.016, POS=0.011) and C (PRFS<0.001, POS<0.001). The nomogram model based on PIV, tumor number and BCLC staging performed well in risk stratification in external validating cohort C. Adjuvant AA-ICI treatment showed an added benefit in OS (p = 0.011) for high-risk patients. CONCLUSIONS: PIV is a feasible independent prognostic factor for RFS and OS in early-stage HCC patients who received curative RFA. The proposed PIV-based nomogram risk model could help clinicians identify high-risk patients and tailor adjuvant systemic treatment and disease follow-up scheme.

Key findingsHigh pan-immune-inflammation value (PIV) is an independent indicator of unfavorable recurrence-free survival (RFS) and overall survival (OS) for early-stage hepatocellular carcinoma (HCC) patients who received curative radiofrequency ablation (RFA).Adjuvant anti-angiogenesis target therapy plus immune checkpoint inhibitor (AA-ICI) treatment showed added benefit in OS for the high-risk patients defined by a nomogram risk model based on PIV, tumor number and BCLC staging.What is known and what is new?Inflammation and impaired host immunity are associated with carcinogenesis and progression of HCC. Increasing evidences showed that immune-inflammatory biomarkers (IIBs) had prognostic roles in early-stage HCC patients who received RFA. However, prognostic potential of PIV has not been determined in this setting.Herein, high PIV was first reported to be an independent risk factor of poor RFS and OS in early-stage HCC patients treated by curative RFA and helped to discriminate patients between low- and high-risk groups. Adjuvant AA-ICI treatment following RFA was beneficial to OS of patients in the high-risk group.What is the implication, and what should change now?For early-stage HCC with high-risk factors (high PIV, multiple tumor foci and more advanced BCLC stage), intensive follow-up and adjuvant systemic therapy following curative RFA were warranted.

Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration.

Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians' approaches and patient outcomes.

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.

Hepatocellular carcinoma: Advances in systemic therapies.

Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.

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.

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.

Constructing immune and prognostic features associated with ADCP in hepatocellular carcinoma and pan-cancer based on scRNA-seq and bulk RNA-seq.

Aim: Despite the significant therapeutic outcomes achieved in systemic treatments for liver hepatocellular carcinoma (LIHC), it is an objective reality that only a low proportion of patients exhibit an improved objective response rate (ORR) to current immunotherapies. Antibody-dependent cellular phagocytosis (ADCP) immunotherapy is considered the new engine for precision immunotherapy. Based on this, we aim to develop an ADCP-based LIHC risk stratification system and screen for relevant targets. Method: Utilizing a combination of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, we screened for ADCP modulating factors in LIHC and identified differentially expressed genes along with their involved functional pathways. A risk scoring model was established by identifying ADCP-related genes with prognostic value through LASSO Cox regression analysis. The risk scoring model was then subjected to evaluations of immune infiltration and immunotherapy relevance, with pan-cancer analysis and in vitro experimental studies conducted on key targets. Results: Building on the research by Kamber RA et al., we identified GYPA, CLDN18, and IRX5 as potential key target genes regulating ADCP in LIHC. These genes demonstrated significant correlations with immune infiltration cells, such as M1-type macrophages, and the effectiveness of immunotherapy in LIHC, as well as a close association with clinical pathological staging and patient prognosis. Pan-cancer analysis revealed that CLDN18 was prognostically and immunologically relevant across multiple types of cancer. Validation through tissue and cell samples confirmed that GYPA and CLDN18 were upregulated in liver cancer tissues and cells. Furthermore, in vitro knockdown of CLDN18 inhibited the malignancy capabilities of liver cancer cells. Conclusion: We have identified an ADCP signature in LIHC comprising three genes. Analysis based on a risk scoring model derived from these three genes, coupled with subsequent experimental validation, confirmed the pivotal role of M1-type macrophages in ADCP within LIHC, establishing CLDN18 as a critical ADCP regulatory target in LIHC.

Epidemiological, Diagnostic and Therapeutic Aspects of Hepatocellular Carcinoma in Morocco: A Case Series and Review of Literature.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common primary liver tumor. It is considered a global public health problem given its incidence and high mortality rate. Epidemiological studies on hepatocellular carcinoma in our Moroccan and North African contexts are rare. Hence, our study aims to determine the epidemiological, clinical, paraclinical, etiological and therapeutic aspects of this pathology in our context. MATERIALS AND METHODS: We conducted a descriptive retrospective study on patients with HCC treated by the Hepato-gastroenterology department of the university hospital of Mohammed VI in Marrakech over a period of 7 years spread between 01/01/2015 and 31/12/2021. The epidemiological characteristics, diagnostic methods and therapeutic management of HCC in these patients have been described and analyzed. RESULTS: 100 patients with HCC were identified and included in our study. The average age was 63.3 ± 12.63 years with a male predominance. The predominant etiology was cirrhosis (87% of cases) then viral hepatitis C (35%) and B (27%) and of unknown origin in 29% of cases. HCC revealed cirrhosis in 41% and was diagnosed during cirrhosis surveillance in 36% of cases. The functional signs were dominated by abdominal pain (68%), deterioration of general condition (58%) and abdominal distension (43%). Alfa-fetoprotein was elevated in 73% of cases and was above 400ng/ml in 41% of cases. The diagnosis was mainly radiological in 92% and histological in 8% of cases. The radiological aspects of HCC were dominated by mononodular form (58%), a right lobar location (80%), a diameter greater than 5 cm (58%), a typical vascular aspect (86%) with portal thrombosis in 24% and metastases in 36% of cases, especially in lymph nodes. The majority of cirrhosis in our series was classified as Child-Pugh stage B (46%) at the time of diagnosis and most patients had an advanced stage of HCC with 31% at BCLC C and 28% at BCLC D. 72% of patients received palliative treatment, and only 6% received curative treatment. At the end of the study, 48% of patients had died with an overall survival of 6.5 months. CONCLUSION: Our study achieved its main objective by providing a snapshot of HCC in our context and confirmed that HCC remains with poor prognosis since its diagnosis is often late, limiting the therapeutic choices with a very short median survival. It also noted that the viral etiology remains the main cause of HCC in our population. Therefore, prevention remains the best therapeutic approach against HCC and the need for a national or at least a regional HCC registry in our country is essential in order to develop targeted preventive measures adapted to our context and to improve the diagnostic and therapeutic approaches for our patients.

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.

Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review).

Hepatocellular carcinoma (HCC), one of the leading causes of cancer­related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi­tyrosine kinase inhibitors approved for first­line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non­apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

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.

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.

Nanoparticle/Engineered Bacteria Based Triple-Strategy Delivery System for Enhanced Hepatocellular Carcinoma Cancer Therapy.

Background: New treatment modalities for hepatocellular carcinoma (HCC) are desperately critically needed, given the lack of specificity, severe side effects, and drug resistance with single chemotherapy. Engineered bacteria can target and accumulate in tumor tissues, induce an immune response, and act as drug delivery vehicles. However, conventional bacterial therapy has limitations, such as drug loading capacity and difficult cargo release, resulting in inadequate therapeutic outcomes. Synthetic biotechnology can enhance the precision and efficacy of bacteria-based delivery systems. This enables the selective release of therapeutic payloads in vivo. Methods: In this study, we constructed a non-pathogenic Escherichia coli (E. coli) with a synchronized lysis circuit as both a drug/gene delivery vehicle and an in-situ (hepatitis B surface antigen) Ag (ASEc) producer. Polyethylene glycol (CHO-PEG2000-CHO)-poly(ethyleneimine) (PEI25k)-citraconic anhydride (CA)-doxorubicin (DOX) nanoparticles loaded with plasmid encoded human sulfatase 1 (hsulf-1) enzyme (PNPs) were anchored on the surface of ASEc (ASEc@PNPs). The composites were synthesized and characterized. The in vitro and in vivo anti-tumor effect of ASEc@PNPs was tested in HepG2 cell lines and a mouse subcutaneous tumor model. Results: The results demonstrated that upon intravenous injection into tumor-bearing mice, ASEc can actively target and colonise tumor sites. The lytic genes to achieve blast and concentrated release of Ag significantly increased cytokine secretion and the intratumoral infiltration of CD4/CD8+T cells, initiated a specific immune response. Simultaneously, the PNPs system releases hsulf-1 and DOX into the tumor cell resulting in rapid tumor regression and metastasis prevention. Conclusion: The novel drug delivery system significantly suppressed HCC in vivo with reduced side effects, indicating a potential strategy for clinical HCC therapy.