A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma

Noncoding RNAs instruct the Cas9 nuclease to site speifillyl cleave DNA in the CRISPR/Cas9 system.Despite the high incidence of hepatocellular carcinoma(HCC),the patient's outcome is poor.As a result of the emergence of therapeutic resistance in HCC patients,dlinicians have faced difficulties in treating such tumor.In addition,CRISPR/Cas9 screens were used to identify genes that improve the dlinical response of HCC patients.It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer,with a particular emphasis on HCC as part of the current state of knowledge.Thus,in order to locate recent developments in oncology research,we examined both the Scopus database and the PubMed database.The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs.Drug resistance can be overcome with the help of the CRISPR/Cas9 system.HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening although this method is not without limitations.It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy.CRISPR and its applications to tumor research,particularly in HCC,are examined in this study through a review of the literature.

Precision targeting in hepatocellular carcinoma:Exploring ligandreceptor mediated nanotherapy

Hepatocellular carcinoma(HCC)is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality.Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages,but it is often ineffective and suffers from problems such as multidrug resistance,rapid drug clearance,nonspecific targeting,high side effects,and low drug accumulation in tumor cells.In response to these limitations,recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC.This review focuses on recent advances in nanoparticle-based targeted drug delivery systems,with special attention to various receptors overexpressed on HCC cells.These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC.We comprehensively summarize the current understanding of these receptors,their role in nanoparticle targeting,and the impact of such targeted therapies on HCC.By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies,more effective and precise treatment of HCC can be achieved.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

New insights into mechanisms and interventions of locoregional therapies for hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization(TACE)being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors(TKIs) and immune checkpoint inhibitors(ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.

Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic liver.The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis.Notwithstanding the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical challenge.Emergent systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of HCC.This review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent.We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent.Finally,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

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.

Adjuvant therapy for hepatocellular carcinoma:Dilemmas at the start of a new era

Approximately 50%-70%of patients with hepatocellular carcinoma experience recurrence within five years after curative hepatic resection or ablation.As a result,many patients receive adjuvant therapy after curative resection or ablation in order to prolong recurrence-free survival.The therapy recommended by national guidelines can differ,and guidelines do not specify when to initiate adjuvant therapy or how long to continue it.These and other unanswered questions around adjuvant therapies make it difficult to optimize them and determine which may be more appropriate for a given type of patient.These questions need to be addressed by clinicians and researchers.

Perioperative remedial antiviral therapy in hepatitis B virus-related hepatocellular carcinoma resection:How to achieve a better outcome

BACKGROUND Although the benefits of antiviral therapy for hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC)have been proven,researchers have not con-firmed the differences in patient outcomes between patients who received preoperative antiviral therapy for a period of time(at least 24 wk)and patients who received remedial antiviral therapy just before radical resection for HBV-related HCC.AIM To investigate the efficacy of perioperative remedial antiviral therapy in patients with HBV-related HCC.METHODS A retrospective study of patients who underwent radical resection for HBV-related HCC at the First Affiliated Hospital of Xi’an Jiaotong University from January 2016 to June 2019 was conducted.Considering the history of antiviral therapy,patients were assigned to remedial antiviral therapy and preoperative antiviral therapy groups.RESULTS Kaplan–Meier analysis revealed significant differences in overall survival(P<0.0001)and disease-free survival(P=0.035)between the two groups.Multivariate analysis demonstrated that a history of preoperative antiviral treatment was independently related to improved survival(hazard ratio=0.27;95%confidence interval:0.08-0.88;P=0.030).CONCLUSION In patients with HBV-related HCC,it is ideal to receive preoperative long-term antiviral therapy,which helps patients tolerate more extensive hepatectomy;however,remedial antiviral therapy,which reduces preoperative HBV-DNA levels to less than 4 Log10 copies DNA/mL,can also result in improved outcomes.

Efficacy of hepatic arterial infusion chemotherapy and its combination strategies for advanced hepatocellular carcinoma:A network meta-analysis

BACKGROUND With the rapid progress of systematic therapy for hepatocellular carcinoma(HCC),therapeutic strategies combining hepatic arterial infusion chemotherapy(HAIC)with systematic therapy arised increasing concentrations.However,there have been no systematic review comparing HAIC and its combination strategies in the first-line treatment for advanced HCC.AIM To investigate the efficacy and safety of HAIC and its combination therapies for advanced HCC.METHODS A network meta-analysis was performed by including 9 randomized controlled trails and 35 cohort studies to carry out our study.The outcomes of interest comprised overall survival(OS),progression-free survival(PFS),tumor response and adverse events.Hazard ratios(HR)and odds ratios(OR)with a 95% confidence interval(CI)were calculated and agents were ranked based on their ranking probability.RESULTS HAIC outperformed Sorafenib(HR=0.55,95%CI:0.42-0.72;HR=0.51,95%CI:0.33-0.78;OR=2.86,95%CI:1.37-5.98;OR=5.45,95%CI:3.57-8.30;OR=7.15,95%CI:4.06-12.58;OR=2.89,95%CI:1.99-4.19;OR=0.48,95%CI:0.25-0.92,respectively)and transarterial chemoembolization(TACE)(HR=0.50,95%CI:0.33-0.75;HR=0.62,95%CI:0.39-0.98;OR=3.08,95%CI:1.36-6.98;OR=2.07,95%CI:1.54-2.80;OR=3.16,95%CI:1.71-5.85;OR=2.67,95%CI:1.59-4.50;OR=0.16,95%CI:0.05-0.54,respectively)in terms of efficacy and safety.HAIC+lenvatinib+ablation,HAIC+ablation,HAIC+anti-programmed cell death 1(PD-1),and HAIC+radiotherapy had the higher likelihood of providing better OS and PFS outcomes compared to HAIC alone.HAIC+TACE+S-1,HAIC+lenvatinib,HAIC+PD-1,HAIC+TACE,and HAIC+sorafenib had the higher likelihood of providing better partial response and objective response rate outcomes compared to HAIC.HAIC+PD-1,HAIC+TACE+S-1 and HAIC+TACE had the higher likelihood of providing better complete response and disease control rate outcomes compared to HAIC alone.CONCLUSION HAIC proved more effective and safer than sorafenib and TACE.Furthermore,combined with other interventions,HAIC showed improved efficacy over HAIC monotherapy according to the treatment ranking analysis.

Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo

Exosomes,the smallest extracellular vesicles,have gained significant attention as key mediators in intercellular communication,influencing both physiological and pathological processes,particularly in cancer progression.A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes,with a focus on the origin from which exosomes derive.If information about the mechanisms for delivering exosomes to specific cells is incorporated,the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

Comparative effectiveness of several adjuvant therapies after hepatectomy for hepatocellular carcinoma patients with microvascular invasion

BACKGROUND For resectable hepatocellular carcinoma(HCC),radical hepatectomy is commonly used as a curative treatment.However,postoperative recurrence significantly diminishes the overall survival(OS)of HCC patients,especially with microva-scular invasion(MVI)as an independent high-risk factor for recurrence.While some studies suggest that postoperative adjuvant therapy may decrease the risk of recurrence following liver resection in HCC patients,the specific role of adju-vant therapies in those with MVI remains unclear.AIM To conduct a network meta-analysis(NMA)to evaluate the efficacy of various adjuvant therapies and determine the optimal adjuvant regimen.METHODS A systematic literature search was conducted on PubMed,EMBASE,and Web of Science until April 6,2023.Studies comparing different adjuvant therapies or comparing adjuvant therapy with hepatectomy alone were included.Hazard ratios(HRs)with 95%confidence intervals were used to combine data on recurrence free survival and OS in both pairwise meta-analyses and NMA.RESULTS Fourteen eligible trials(2268 patients)reporting five different therapies were included.In terms of reducing the risk of recurrence,radiotherapy(RT)[HR=0.34(0.23,0.5);surface under the cumulative ranking curve(SUCRA)=97.7%]was found to be the most effective adjuvant therapy,followed by hepatic artery infusion chemotherapy[HR=0.52(0.35,0.76);SUCRA=65.1%].Regarding OS improvement,RT[HR:0.35(0.2,0.61);SUCRA=93.1%]demonstrated the highest effectiveness,followed by sorafenib[HR=0.48(0.32,0.69);SUCRA=70.9%].INTRODUCTION Hepatocellular carcinoma(HCC)is the sixth most common malignant tumor in the world and ranks third in terms of worldwide malignant tumor mortality rates in 2020[1].Curative treatments for HCC include ablation,radical hepatectomy,and liver transplantation.However,ablation is suitable only for early-stage HCC patients,who represent a small percentage of the overall HCC population.Although liver transplantation serves as the optimal treatment for HCC patients,the scarcity of donor organs restricts the availability of this procedure.Therefore,hepatectomy is the most commonly employed curative treatment for resectable HCC.Unfortunately,the 5-year recurrence rate for patients who undergoing hepatectomy ranges from 50%to 70%[2,3].Recurrence of HCC is associated with several risk factors[4],including single nodule>5 cm,vascular invasion,and multiple nodules.Among these factors,microvascular invasion(MVI)is an independent risk factor for recurrence.MVI is defined as the presence of cancer cells in the lumen of endothelium-lined vessels,typically in the small branches of the portal and hepatic veins of the paracancerous liver tissue,visible only under the microscope[5].Previous studies have shown that among HCC patients who underwent hepatectomy,those with MVI had a higher risk of recurrence and shorter overall survival(OS)than those without MVI[6].Several studies have indicated that adjuvant therapy following curative hepatectomy can prevent recurrence and improve OS in HCC patients with MVI.These postoperative adjuvant therapies include transarterial chemoembolization(TACE)[7],sorafenib[8],hepatic artery infusion chemotherapy(HAIC)[9],and radiotherapy(RT)[10].However,the existing studies mostly compare individual adjuvant therapy with hepatectomy alone.Direct or indirect comparisons between the various adjuvant therapies are lacking.Therefore,we performed the network meta-analysis(NMA)to compare the relative efficacy of each adjuvant therapy to determine the optimal treatment.

Impact of baseline hepatitis B virus viral load on the long-term prognosis of advanced hepatocellular carcinoma treated with immunotherapy

BACKGROUND Although the combination of lenvatinib and PD-1 inhibitors has become the standard regimen for the treatment of advanced hepatocellular carcinoma(HCC),real data on the impact of baseline hepatitis B virus(HBV)-DNA levels on the clinical efficacy of this regimen is still limited.AIM To evaluate the effectiveness of camrelizumab combined with lenvatinib in patients with HCC at varying levels of HBV-DNA.METHODS One hundred and twenty patients with HCC who received camrelizumab and lenvatinib treatment were categorized into two cohorts:HBV-DNA≤2000(n=66)and HBV-DNA>2000(n=54).The main outcomes measured were overall survival(OS)and progression-free survival(PFS),while additional outcomes included the rate of objective response rate(ORR),disease control rate(DCR),and any negative events.Cox proportional hazards regression analysis revealed independent predictors of OS,leading to the creation of a nomogram incorporating these variables.RESULTS The median PFS was 8.32 months for the HBV-DNA≤2000 group,which was similar to the 7.80 months observed for the HBV DNA>2000 group(P=0.88).Likewise,there was no notable variation in the median OS between the two groups,with durations of 13.30 and 14.20 months respectively(P=0.14).The ORR and DCR were compared between the two groups,showing ORR of 19.70%vs 33.33%(P=0.09)and DCR of 72.73%vs 74.07%(P=0.87).The nomogram emphasized the importance of antiviral treatment as the main predictor of patient results,with portal vein tumor thrombus and Barcelona Clinic Liver Cancer staging following closely behind.CONCLUSION The clinical outcomes of patients with HBV-associated HCC treated with camrelizumab in combination with lenvatinib are not significantly affected by HBV viral load.

Predicting the prognosis of hepatic arterial infusion chemotherapy in hepatocellular carcinoma

Hepatic artery infusion chemotherapy(HAIC)has good clinical efficacy in the treatment of advanced hepatocellular carcinoma(HCC);however,its efficacy varies.This review summarized the ability of various markers to predict the efficacy of HAIC and provided a reference for clinical applications.As of October 25,2023,51 articles have been retrieved based on keyword predictions and HAIC.Sixteen eligible articles were selected for inclusion in this study.Comprehensive literature analysis found that methods used to predict the efficacy of HAIC include serological testing,gene testing,and imaging testing.The above indicators and their combined forms showed excellent predictive effects in retrospective studies.This review summarized the strategies currently used to predict the efficacy of HAIC in middle and advanced HCC,analyzed each marker's ability to predict HAIC efficacy,and provided a reference for the clinical application of the prediction system.

Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy

Advanced hepatocellular carcinoma(HCC)is a severe malignancy that poses a serious threat to human health.Owing to challenges in early diagnosis,most patients lose the opportunity for radical treatment when diagnosed.Nonetheless,recent advancements in cancer immunotherapy provide new directions for the treatment of HCC.For instance,monoclonal antibodies against immune check-point inhibitors(ICIs)such as programmed cell death protein 1/death ligand-1 inhibitors and cytotoxic t-lymphocyte associated antigen-4 significantly improved the prognosis of patients with HCC.However,tumor cells can evade the immune system through various mechanisms.With the rapid development of genetic engineering and molecular biology,various new immunotherapies have been used to treat HCC,including ICIs,chimeric antigen receptor T cells,engineered cytokines,and certain cancer vaccines.This review summarizes the current status,research progress,and future directions of different immunotherapy strategies in the treatment of HCC.

Conversion therapy of a giant hepatocellular carcinoma with portal vein thrombus and inferior vena cava thrombus:A case report and review of literature

BACKGROUND The prognosis of hepatocellular carcinoma(HCC)combined with portal and hepatic vein cancerous thrombosis is poor,for unresectable patients the combination of targeted therapy and immune therapy was the first-line recommended treatment for advanced HCC,with a median survival time of only about 2.7-6 months.In this case report,we present the case of a patient with portal and hepatic vein cancerous thrombosis who achieved pathologic complete response after conversion therapy.CASE SUMMARY In our center,a patient with giant HCC combined with portal vein tumor thrombus and hepatic vein tumor thrombus was treated with transcatheter arterial chemoembolization(TACE),radiotherapy,targeted therapy and immunotherapy,and was continuously given icaritin soft capsules for oral regulation.After 7 months of conversion therapy,the patient's tumor shrank and the tumor thrombus subsided significantly.The pathology of surgical resection was in complete remission,and there was no progression in the postoperative follow-up for 7 months,which provided a basis for the future strategy of combined conversion therapy.CONCLUSION In this case,atezolizumab,bevacizumab,icaritin soft capsules combined with radiotherapy and TACE had a good effect.For patients with hepatocellular carcinoma combined with hepatic vein/inferior vena cava tumor thrombus,adopting a high-intensity,multimodal proactive strategy under the guidance of multidisciplinary team(MDT)is an important attempt to break through the current treatment dilemma.

Epidemiology,therapy and outcome of hepatocellular carcinoma between 2010 and 2019 in Piedmont,Italy

BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver malignancy and the second leading cause of cancer deaths worldwide.It is often diagnosed at an advanced stage and therefore its prognosis remains poor with a low 5-year survival rate.HCC patients have increasingly complex and constantly changing characteristics,thus up-to-date and comprehensive data are fundamental.AIM To analyze the epidemiology and main clinical characteristics of HCC patients in a referral center hospital in the northwest of Italy between 2010 and 2019.METHODS In this retrospective study,we analyzed the clinical data of all consecutive patients with a new diagnosis of HCC recorded at"Santa Croce e Carle"Hospital in Cuneo(Italy)between 1 January 2010 and 31 December 2019.To highlight possible changes in HCC patterns over the 10-year period,we split the population into two 5-year groups,according to the diagnosis period(2010-2014 and 2015-2019).RESULTS Of the 328 HCC patients who were included(M/F 255/73;mean age 68.9±11.3 years),154 in the first period,and 174 in the second.Hepatitis C virus infection was the most common HCC risk factor(41%,135 patients).The alcoholic etiology rate was 18%,the hepatitis B virus infection etiology was 5%,and the non-viral/non-alcoholic etiology rate was 22%.The Child-Pugh score distribution of the patients was:class A 75%,class B 21%and class C 4%.The average Mayo end-stage liver disease score was 10.6±3.7.A total of 55 patients(17%)were affected by portal vein thrombosis and 158(48%)by portal hypertension.The average nodule size of the HCC was 4.6±3.1 cm.A total of 204 patients(63%)had more than one nodule<3,and 92%(305 patients)had a non-metastatic stage of the disease.The Barcelona Clinic Liver Cancer(BCLC)staging distribution of all patients was:4%very early,32%early,23%intermediate,34%advanced,and 7%terminal.Average survival rate was 1.6±0.3 years.Only 20%of the patients underwent treatment.Age,presence of ascites,BCLC stage and therapy were predictors of a better prognosis(P<0.01).A comparison of the two 5-year groups revealed a statistically significant difference only in global etiology(P<0.05)and alpha-fetoprotein(AFP)levels(P<0.01).CONCLUSION In this study analyzing patients with a new diagnosis of HCC between 2010-2019,hepatitis C virus infection was the most common etiology.Most patients presented with an advanced stage disease and a poor prognosis.When comparing the two 5-year groups,we observed a statistically significant difference only in global etiology(P<0.05)and AFP levels(P<0.01).

Advances in Conversion Therapy for Primary Unresectable Hepatocellular Carcinoma

Primary liver cancer is one of the most common malignant tumours in the world, and according to statistics, about half of liver cancers occur in China, which seriously threatens the lives and health of people around the world, especially in China. Hepatocellular carcinoma is the most common type, accounting for about 90 per cent of primary liver cancers. Most patients are asymptomatic in the early stage and fail to pay attention to it. Most of the patients are in the middle or late stage when they are first diagnosed, and only 20% - 30% of them can receive radical hepatectomy. Patients are through the treatment to make the tumour shrinkage and downstaging, to achieve the condition of resectable, that is, the conversion treatment. Conversion therapy has great potential for development and has now become an indispensable treatment for intermediate and advanced hepatocellular carcinoma. However, there are various treatment options for conversion therapy, no uniform guidelines to guide clinical selection, and the overall conversion rate is still low, so it is particularly important to explore appropriate conversion therapy options. This article mainly describes the existing conversion therapies, hoping to provide help and ideas for exploring the best conversion therapies in the future.

Conversion therapy for hepatocellular carcinoma to improve treatment strategies for intermediate and advanced stages

This manuscript is based on a case reported by Song et al published in the World Journal of Clinical Cases.Several challenges remain in the field of hepatocellular carcinoma(HCC)conversion therapy.Consequently,only a limited number of patients with HCC accompanied by portal vein tumor thrombosis(PVTT)and hepatic vein tumor thrombosis(HVTT)are eligible for resection.This clinical case demonstrates that considering the complexity of the disease,a multimodal and multidisciplinary approach is essential for managing HCC accompanied by PVTT and HVTT.However,the outcomes of such surgeries remain controversial.In conclusion,research on HCC conversion therapy is extremely useful for impro-ving treatment strategies for intermediate and advanced HCC,which currently have disappointing clinical outcomes.

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

BACKGROUND 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.AIM To determine whether DEB-TACE before LT is superior to LT for advanced-stage HCC.METHODS 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.RESULTS 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 DEBTACE(HR=3.15,95%CI:1.43-6.96,P=0.004)was identified as a significant risk factor for OS.CONCLUSION DEB-TACE is a safe and efficient therapy for advanced-stage HCC and also enhances patient survival after LT.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.