Conversion therapy for unresectable hepatocellular carcinoma:Advances and challenges

Recently,the World Journal of Gastrointestinal Oncology published an article entitled“Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of the literature”,in which the authors shared their successful experience with complete surgical resection after multidisciplinary conversion therapy.The study by Chu et al demonstrates the great challenges that the advanced hepatocellular carcinoma(HCC)poses to surgical oncology,reveals the complexity of conversion therapy for unresectable HCC,emphasizes the important role of a multidisciplinary management model in conversion therapy,and enriches our understanding of the dynamics of personalized treatment for different patients.At present,conversion therapy is a hot research topic in the treatment of unresectable HCC,which has brought new hope to many patients with moderately advanced HCC.However,there are still many urgent problems to be solved in conversion therapy.Here,we would like to further discuss the advances and challenges of conversion therapy for unresectable HCC with the authors and the general readers.

Combined hepatocellular cholangiocarcinoma: A clinicopathological update

Combined hepatocellular-cholangiocarcinoma(cHCC-CCA)is a rare primary liver cancer associated with an appalling prognosis.The diagnosis and manage-ment of this entity have been challenging to physicians,radiologists,surgeons,pathologists,and oncologists alike.The diagnostic and prognostic value of biomarkers such as the immunohistochemical expression of nestin,a progenitor cell marker,have been explored recently.With a better understanding of biology and the clinical course of cHCC-CCA,newer treatment modalities like immune checkpoint inhibitors are being tried to improve the survival of patients with this rare disease.In this review,we give an account of the recent developments in the pathology,diagnostic approach,and management of cHCC-CCA.

Downstaging strategies for unresectable hepatocellular carcinoma

A significant number of patients with hepatocellular carcinoma(HCC)are usually diagnosed in advanced stages,that leads to inability to achieve cure.Palliative options are focusing on downstaging a locally advanced disease.It is wellsupported in the literature that patients with HCC who undergo successful conversion therapy followed by curative-intent surgery may achieve a significant survival benefit compared to those who receive chemotherapy alone or those who are successfully downstaged with conversion therapy but not treated with surgery.Hepatic artery infusion chemotherapy can be a potential downstaging strategy,since recent studies have demonstrated excellent outcomes in patients with colorectal liver metastatic disease as well as primary liver malignancies.

Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma(experience with 22 patients over a 15-year period)

AIM To evaluate the clinicopathological features and the surgical outcomes of patients with fibrolamellar hepato-cellular carcinoma(FL-HCC)over a 15-year period. METHODS This is a retrospective study including 22 patients with a pathologic diagnosis of FL-HCC who underwent hepatectomy over a 15-year period. Tumor characteristics,survival and recurrence were evaluated. RESULTS There were 11 male and 11 female with a median age of 29 years(range from 21 to 58 years). Two(9%)patients had hepatitis C viral infection and only 2(9%)patients had alpha-fetoprotein level > 200 ng/m L. The median size of the tumors was 12 cm(range from 5-20 cm). Vascular invasion was detected in 5(23%)patients. Four(18%)patients had lymph node metastases. The median follow up period was 42 mo and the 5-year survival was 65%. Five(23%)patients had a recurrent disease,4 of them had a second surgery with 36 mo median time interval. Vascular invasion is the only significant negative prognostic factor CONCLUSION FL-HCC has a favorable prognosis than common HCC and should be suspected in young patients with non cirrhotic liver. Aggressive surgical resection should be done for all patients. Repeated hepatectomy should be considered for these patients as it has a relatively indolent course.

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.

Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

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.

Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma

BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therapy[lenvatinib+sintilimab+transarterial chemoembolization(TACE)]as a first-line treatment for advanced HCC is limited.AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC.METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled.All patients were treated with lenvatinib every day and sintilimab once every 3 wk.Moreover,TACE was performed every 4-6 wk if necessary.The primary outcome of the study was overall survival(OS).The secondary outcomes were the objective response rate(ORR),disease control rate(DCR),and incidence of adverse events.RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022.With a median follow-up of 8.5 months,the 3-,6-,and 12-mo OS rates were 100%,88.5%,and 22.5%,respectively.The ORR and DCR were 45%and 90%,respectively.The median progressive free survival and median OS were not reached.Common complications were observed in 76%of the patients(grade 3,15%;grade 4,2.5%).CONCLUSION Combination therapy comprising lenvatinib,sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.

Nomogram prediction of vessels encapsulating tumor clusters in small hepatocellular carcinoma≤3 cm based on enhanced magnetic resonance imaging

BACKGROUND Vessels encapsulating tumor clusters(VETC)represent a recently discovered vascular pattern associated with novel metastasis mechanisms in hepatocellular carcinoma(HCC).However,it seems that no one have focused on predicting VETC status in small HCC(sHCC).This study aimed to develop a new nomogram for predicting VETC positivity using preoperative clinical data and image features in sHCC(≤3 cm)patients.AIM To construct a nomogram that combines preoperative clinical parameters and image features to predict patterns of VETC and evaluate the prognosis of sHCC patients.METHODS A total of 309 patients with sHCC,who underwent segmental resection and had their VETC status confirmed,were included in the study.These patients were recruited from three different hospitals:Hospital 1 contributed 177 patients for the training set,Hospital 2 provided 78 patients for the test set,and Hospital 3 provided 54 patients for the validation set.Independent predictors of VETC were identified through univariate and multivariate logistic analyses.These independent predictors were then used to construct a VETC prediction model for sHCC.The model’s performance was evaluated using the area under the curve(AUC),calibration curve,and clinical decision curve.Additionally,Kaplan-Meier survival analysis was performed to confirm whether the predicted VETC status by the model is associated with early recurrence,just as it is with the actual VETC status and early recurrence.RESULTS Alpha-fetoprotein_lg10,carbohydrate antigen 199,irregular shape,non-smooth margin,and arterial peritumoral enhancement were identified as independent predictors of VETC.The model incorporating these predictors demonstrated strong predictive performance.The AUC was 0.811 for the training set,0.800 for the test set,and 0.791 for the validation set.The calibration curve indicated that the predicted probability was consistent with the actual VETC status in all three sets.Furthermore,the decision curve analysis demonstrated the clinical benefits of our model for patients with sHCC.Finally,early recurrence was more likely to occur in the VETC-positive group compared to the VETC-negative group,regardless of whether considering the actual or predicted VETC status.CONCLUSION Our novel prediction model demonstrates strong performance in predicting VETC positivity in sHCC(≤3 cm)patients,and it holds potential for predicting early recurrence.This model equips clinicians with valuable information to make informed clinical treatment decisions.

Jianpi-Huatan-Huoxue-Anshen formula ameliorates gastrointestinal inflammation and microecological imbalance in chemotherapytreated mice transplanted with H22 hepatocellular carcinoma

BACKGROUND Jianpi-Huatan-Huoxue-Anshen formula[Tzu-Chi cancer-antagonizing&lifeprotecting II decoction(TCCL)]is a Chinese medical formula that has been clinically shown to reduce the gastrointestinal side effects of chemotherapy in cancer patients and improve their quality of life.However,its effect and mechanism on the intestinal microecology after chemotherapy are not yet clear.AIM To discover the potential mechanisms of TCCL on gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with hepatocellular carcinoma(HCC).METHODS Ninety-six mice were inoculated subcutaneously with HCC cells.One week later,the mice received a large dose of 5-fluorouracil by intraperitoneal injection to establish a HCC chemotherapy model.Thirty-six mice were randomly selected before administration,and feces,ileal tissue,and ileal contents were collected from each mouse.The remaining mice were randomized into normal saline,continuous chemotherapy,Yangzheng Xiaoji capsulestreated,and three TCCL-treated groups.After treatment,feces,tumors,liver,spleen,thymus,stomach,jejunum,ileum,and colon tissues,and ileal contents were collected.Morphological changes,serum levels of IL-1β,IL-6,IL-8,IL-10,IL-22,TNF-α,and TGF-β,intestinal SIgA,and protein and mRNA expression of ZO-1,NF-κB,Occludin,MUC-2,Claudin-1,and IκB-αin colon tissues were documented.The effect of TCCL on the abundance and diversity of intestinal flora was analyzed using 16S rDNA sequencing.RESULTS TCCL treatment improved thymus and spleen weight,thymus and spleen indexes,and body weight,decreased tumor volumes and tumor tissue cell density,and alleviated injury to gastric,ileal,and colonic mucosal tissues.Among proteins and genes associated with inflammation,IL-10,TGF-β,SIgA,ZO-1,MUC-2,and Occludin were upregulated,whereas NF-κB,IL-1β,IL-6,TNF-α,IL-22,IL-8,and IκB-αwere downregulated.Additionally,TCCL increased the proportions of fecal Actinobacteria,AF12,Adlercreutzia,Clostridium,Coriobacteriaceae,and Paraprevotella in the intermediate stage of treatment,decreased the proportions of Mucipirillum,Odoribacter,RF32,YS2,and Rikenellaceae but increased the proportions of p_Deferribacteres and Lactobacillus at the end of treatment.Studies on ileal mucosal microbiota showed similar findings.Moreover,TCCL improved community richness,evenness,and the diversity of fecal and ileal mucosal flora.CONCLUSION TCCL relieves pathological changes in tumor tissue and chemotherapy-induced gastrointestinal injury,potentially by reducing the release of pro-inflammatory factors to repair the gastrointestinal mucosa,enhancing intestinal barrier function,and maintaining gastrointestinal microecological balance.Hence,TCCL is a very effective adjuvant to chemotherapy.

Dynamic contrast enhanced ultrasound in differential diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.

Drug-eluting beads chemoembolization combined with programmed cell death 1 inhibitor and lenvatinib for large hepatocellular carcinoma

BACKGROUND The combination of transarterial chemoembolization(TACE),lenvatinib,and programmed cell death 1(PD-1)inhibitor has been widely used in the treatment of advanced hepatocellular carcinoma(HCC)and has achieved promising results.However,there are few studies comparing whether drug-eluting beads TACE(DTACE)can bring more survival benefits to patients with large HCC compared to conventional TACE(C-TACE)in this triplet therapy.AIM To compare the efficacy and adverse events(AEs)of triple therapy comprising DTACE,PD-1 inhibitors,and lenvatinib(D-TACE-P-L)and C-TACE,PD-1 inhibitors,and lenvatinib(C-TACE-P-L)in patients with large HCC(maximum diameter≥5 cm),and analyze the prognostic factors.METHODS Following a comprehensive review of our hospital’s medical records,this retrospective study included 104 patients:50 received D-TACE-P-L,and 54 received CTACE-P-L.We employed Kaplan-Meier estimation to assess the median progression-free survival(PFS)between the two groups,utilized Cox multivariate regression analysis to identify prognostic factors,and applied theχ2 test to evaluate AEs.RESULTS The objective response rate(ORR)and median PFS were significantly higher in the D-TACE-P-L group compared to the C-TACE-P-L group(ORR:66.0%vs 44.4%,P=0.027;median PFS:6.8 months vs 5.0 months,P=0.041).Cox regression analysis identified treatment option,portal vein tumor thrombus,and hepatic vein invasion as protective factors for PFS.AEs were comparable between the two CONCLUSION D-TACE-P-L may have significantly better PFS and ORR for large HCC,while exhibiting similar AEs to C-TACE-PL.

Ultrasomics in liver cancer: Developing a radiomics model for differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma using contrast-enhanced ultrasound

BACKGROUND Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)represent the predominant histological types of primary liver cancer,comprising over 99%of cases.Given their differing biological behaviors,prognoses,and treatment strategies,accurately differentiating between HCC and ICC is crucial for effective clinical management.Radiomics,an emerging image processing technology,can automatically extract various quantitative image features that may elude the human eye.Reports on the application of ultrasound(US)-based radiomics methods in distinguishing HCC from ICC are limited.METHODS In our retrospective study,we included a total of 280 patients who were diagnosed with ICC(n=140)and HCC(n=140)between 1999 and 2019.These patients were divided into training(n=224)and testing(n=56)groups for analysis.US images and relevant clinical characteristics were collected.We utilized the XGBoost method to extract and select radiomics features and further employed a random forest algorithm to establish ultrasomics models.We compared the diagnostic performances of these ultrasomics models with that of radiologists.RESULTS Four distinct ultrasomics models were constructed,with the number of selected features varying between models:13 features for the US model;15 for the contrast-enhanced ultrasound(CEUS)model;13 for the combined US+CEUS model;and 21 for the US+CEUS+clinical data model.The US+CEUS+clinical data model yielded the highest area under the receiver operating characteristic curve(AUC)among all models,achieving an AUC of 0.973 in the validation cohort and 0.971 in the test cohort.This performance exceeded even the most experienced radiologist(AUC=0.964).The AUC for the US+CEUS model(training cohort AUC=0.964,test cohort AUC=0.955)was significantly higher than that of the US model alone(training cohort AUC=0.822,test cohort AUC=0.816).This finding underscored the significant benefit of incorporating CEUS information in accurately distin-guishing ICC from HCC.CONCLUSION We developed a radiomics diagnostic model based on CEUS images capable of quickly distinguishing HCC from ICC,which outperformed experienced radiologists.

Clinical study of different interventional treatments for primary hepatocellular carcinoma based on propensity-score matching

BACKGROUND Transcatheter arterial chemoembolization(TACE)is the main treatment for patients with primary hepatocellular carcinoma(PHC)who miss the opportunity to undergo surgery.Conventional TACE(c-TACE)uses iodized oil as an embolic agent,which is easily washed by blood and affects its efficacy.Drug-eluting bead TACE(DEB-TACE)can sustainably release chemotherapeutic drugs and has a long embolization time.However,the clinical characteristics of patients before the two types of interventional therapies may differ,possibly affecting the conclusion.Only a few studies have compared these two interventions using propensity-score matching(PSM).AIM To analyze the clinical effects of DEB-TACE and c-TACE on patients with PHC based on PSM.METHODS Patients with PHC admitted to Dangyang People’s Hospital(March 2020 to March 2024)were retrospectively enrolled and categorized into groups A(DEB-TACE,n=125)and B(c-TACE,n=106).Sex,age,Child-Pugh grade,tumor-node-meta-stasis stage,and Eastern Cooperative Oncology Group score were selected for 1:1 PSM.Eighty-six patients each were included post-matching.Clinical efficacy,liver function indices(aspartate aminotransferase,alanine aminotransferase,total bilirubin,and albumin),tumor serum markers,and adverse reactions were compared between the groups.RESULTS The objective response and disease control rates were significantly higher in group A(80.23%and 97.67%,respectively)than in group B(60.47%and 87.21%,respectively)(P<0.05).Post-treatment levels of aspartate aminotransferase,alanine aminotransferase,and total bilirubin were lower in group A than in group B(P<0.05),whereas post-treatment levels of albumin in group A were comparable to those in group B(P>0.05).Post-treatment levels of tumor serum markers were significantly lower in group A than in group B(P<0.05).Patients in groups A and B had mild-to-moderate fever and vomiting symptoms,which improved with conservative treatment.The total incidence of adverse reactions was significantly higher in group B(22.09%)than in group A(6.97%)(P<0.05).CONCLUSION DEB-TACE has obvious therapeutic effects on patients with PHC.It can improve liver function indices and tumor markers of patients without increasing the rate of liver toxicity or adverse reactions.

Comprehensive Analysis of Estrogen Receptor 1 Dysregulation in Liver Hepatocellular Carcinoma: Implications for Prognosis and Therapeutic Targeting - A Secondary Publication

The study investigates the expression pattern and regulatory mechanisms of estrogen receptor 1 (ESR1) in liver hepatocellular carcinoma (LIHC) through comprehensive bioinformatics analysis. Utilizing UALCAN and GEPIA2 databases, significant down-regulation of ESR1 expression is observed in LIHC samples compared to normal controls, indicating its potential role in tumor progression. Further analysis reveals consistent down-regulation across different clinical variables including patient age, gender, race, and various stages of LIHC, affirming the regulatory role of ESR1 in tumor development and progression. Additionally, promoter methylation analysis demonstrates hypermethylation of ESR1 in LIHC samples, negatively correlating with its expression. This association persists across different clinical parameters, emphasizing the inverse relationship between ESR1 methylation and expression levels. Survival analysis indicates that up- regulation of ESR1 is associated with better overall survival, suggesting its potential as a prognostic biomarker in LIHC. Furthermore, genetic mutation analysis using cBioPortal reveals a spectrum of alterations in ESR1, including amplification, missense mutation, deep deletion, splice mutation, and truncating mutation, highlighting the genetic complexity of ESR1 in LIHC. These findings collectively contribute to a deeper understanding of ESR1 dysregulation in LIHC and its clinical implications as a potential therapeutic target and prognostic marker.

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.

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.

Construction and validation of somatic mutation-derived long noncoding RNAs signatures of genomic instability to predict prognosis of hepatocellular carcinoma

BACKGROUND Long non-coding RNAs(LncRNAs)have been found to be a potential prognostic factor for cancers,including hepatocellular carcinoma(HCC).Some LncRNAs have been confirmed as potential indicators to quantify genomic instability(GI).Nevertheless,GI-LncRNAs remain largely unexplored.This study established a GI-derived LncRNA signature(GILncSig)that can predict the prognosis of HCC patients.AIM To establish a GILncSig that can predict the prognosis of HCC patients.METHODS Identification of GI-LncRNAs was conducted by combining LncRNA expression and somatic mutation profiles.The GI-LncRNAs were then analyzed for functional enrichment.The GILncSig was established in the training set by Cox regression analysis,and its predictive ability was verified in the testing set and TCGA set.In addition,we explored the effects of the GILncSig and TP53 on prognosis.RESULTS A total of 88 GI-LncRNAs were found,and functional enrichment analysis showed that their functions were mainly involved in small molecule metabolism and GI.The GILncSig was constructed by 5 LncRNAs(miR210HG,AC016735.1,AC116351.1,AC010643.1,LUCAT1).In the training set,the prognosis of high-risk patients was significantly worse than that of low-risk patients,and similar results were verified in the testing set and TCGA set.Multivariate Cox regression analysis and stratified analysis confirmed that the GILncSig could be used as an independent prognostic factor.Receiver operating characteristic curve analysis of the GILncSig showed that the area under the curve(0.773)was higher than the two LncRNA signatures published recently.Furthermore,the GILncSig may have a better predictive performance than TP53 mutation status alone.CONCLUSION We established a GILncSig that can predict the prognosis of HCC patients,which will help to guide prognostic evaluation and treatment decisions.

Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.