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The Hedgehog （Hh） signaling pathway plays an important role in the development and progression of hepatocellular carcinoma and its tumor microenvironment， and abnormal activation of Hh signal can accelerate the growth of tumor. The crosstalk between the Hh signaling pathway and TME is closely associated with tumor growth and the formation of inhibitory tumor microenvironment. Evidence shows that inhibition of Hh signal plays an important role in inhibiting the growth of hepatocellular carcinoma. This article reviews the current research status of the role， mechanism， and potential therapeutic significance of abnormal activation of Hh signal in hepatocellular carcinoma and its tumor microenvironment， so as to provide new ideas for the treatment of hepatocellular carcinoma.
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In recent years， transcatheter arterial chemoembolization （TACE） has emerged as a common treatment modality for the treatment of hepatocellular carcinoma （HCC）. However， with the ongoing development of embolic agent techniques， the new advances in microspheres and nanoparticles have brought new hope for improving the efficacy and safety of TACE. This article reviews the latest advances and applications of microspheres and nanoparticles in TACE for HCC. First， this article introduces the background of TACE as a therapeutic approach and the emergence of microsphere and nanoparticle techniques， and then it describes the application of various types of microspheres and nanoparticles in TACE and discusses the requisite attributes of an ideal embolic agents. The article focuses on the advances in material science and engineering， as well as the clinical efficacy of drug-eluting microspheres and nanoparticles versus conventional TACE. Furthermore， it discusses the importance of radiological examination in TACE and summarizes the research advances in the radiopaque and magnetic resonance-visible embolic agents. This article also explores the future development directions and challenges of TACE. It also points out the combination of microspheres and nanoparticles with other treatment modalities， the application of personalized and precision medicine in TACE， and the potential regimen of TACE in clinical translation， and meanwhile， it raises the issues of ethics and regulation that need to be further discussed. It is believed that microspheres and nanoparticles have a potential effect in TACE， which provides a theoretical basis and technical support for innovating HCC treatment regimens and improving the prognosis of patients through TACE interventions.
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ObjectiveTo evaluate the efficacy and safety of first-line transcatheter arterial chemoembolization （TACE） combined with targeted therapy and immunotherapy in the treatment of patients with stage Ⅱb/Ⅲa hepatocellular carcinoma （HCC） based on China Liver Cancer Staging （CNLC）. MethodsA total of 198 patients who received first-line TACE combined with targeted therapy and immunotherapy or received TACE alone from January 2015 to December 2022 in the First Affiliated Hospital of Soochow University were enrolled in this study， and after propensity score matching， there were 50 patients in combination group and 50 patients in TACE group. The Kaplan-Meier method was used to calculate median overall survival （mOS） and median progression-free survival （mPFS）. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate objective response rate （ORR） and disease control rate （DCR）， and Common Terminology Criteria for Adverse Events v5.0 was used to evaluate adverse events. The chi-square test was used for comparison of categorical data between two groups； the t-test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups. The Kaplan-Meier method was used to estimate survival time and calculate 95% confidence interval （CI）， and the Log-rank test was used for comparison of mOS and mPFS between two groups. ResultsThe combination group had an mOS of 30.1 months （95%CI： 21.9 — 38.3）， and the TACE group had an mOS of 14.5 months （95%CI： 11.0 — 18.0）， with a significant difference between the two groups （χ2=17.8， P<0.001）； the combination group had an mPFS of 10.3 months （95%CI： 8.8 — 11.8）， and the TACE group had an mPFS of 7.1 months （95%CI： 5.8 — 8.4）， with a significant difference between the two groups （χ2=10.4， P<0.001）. There were significant differences between the combination group and the TACE group in ORR （84% vs 58%， P<0.05） and DCR （94% vs 80%， P<0.05）. There was no significant difference between the combination group and the TACE group in the incidence rate of adverse events （24% vs 16%， P=0.317）， and no adverse event-related deaths were observed in either group. ConclusionCompared with TACE alone， TACE combined with targeted therapy and immunotherapy has a better efficacy in the treatment of patients with CNLC stage Ⅱb/Ⅲa HCC， without increasing the incidence rate of severe adverse events.
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ObjectiveTo investigate whether anti-PD-1 monoclonal antibody can improve the efficacy and safety of cryoablation combined with lenvatinib in the treatment of unresectable hepatocellular carcinoma （HCC）. MethodsA retrospective analysis was performed for 232 patients with unresectable HCC who were treated at The Fifth Medical Center of Chinese PLA General Hospital from January 2018 to December 2022， among whom 128 received cryoablation combined with lenvatinib （double combination） and 104 received cryoablation combined with lenvatinib and anti-PD-1 monoclonal antibody （triple combination）. Propensity score matching was performed at a ratio of 1∶1， and finally there were 86 patients in each group. The two groups were evaluated in terms of objective response rate （ORR）， disease control rate （DCR）， overall survival （OS）， progression-free survival （PFS）， and adverse events （AEs）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical data between two groups. Survival curves were plotted， and the Kaplan-Meier method was used to calculate the survival rate of patients in both groups， while the log-rank test was used for comparison between the two groups. The Cox regression model was used to calculate hazard ratio （HR） and 95% confidence interval （CI） and perform the univariate and multivariate analyses of influencing factors for prognosis. ResultsThe median follow-up time was 28 months， and there were 33 deaths （38.0%） in the triple combination group and 40 deaths （46.0%） in the double combination group. Compared with the double combination group， the triple combination group had significantly higher ORR （35.6% vs 14.5%， P=0.008） and DCR （86.1% vs 64.1%， P=0.003）. OS and PFS in the triple combination group were significantly higher than those in the double combination group （P=0.045 and 0.026）. The univariate and multivariate Cox proportional-hazards regression model analyses showed that treatment regimen （HR=0.60， P=0.038） and alpha-fetoprotein level （HR=2.37， P=0.001） were independent risk factors for OS， and treatment regimen （HR=0.65， P=0.025）， diabetes mellitus （HR=1.94， P=0.005）， whether or not to have received local treatment （HR=0.63， P=0.014）， and distant metastasis （HR=0.58， P=0.009） were independent risk factors for PFS. There was no significant difference in the incidence rate of AEs between the two groups （P>0.05）. ConclusionFor patients with unresectable HCC， the triple combination of cryoablation， lenvatinib， and anti-PD-1 monoclonal antibody significantly improves the treatment outcome and survival of patients compared with the double combination of cryoablation and lenvatinib， without increasing AEs， which provides a clinical basis for optimizing the treatment regimen for unresectable HCC.
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In recent years， NOD-like receptor protein 3 （NLRP3） inflammasome in tumors has become a research hotspot， especially in melanoma， colorectal cancer， lung cancer， and breast cancer， and more and more evidence has shown that inflammation plays a role in the development， progression， angiogenesis， and invasion of cancer. Hepatocellular carcinoma （HCC） is the most common type of primary liver cancer， and there are still controversies over the role of NLRP3 inflammasome in the development and progression of HCC. Therefore， this article reviews the potential impact of NLRP3 inflammasome in the progression of HCC and its mechanism of action in anticancer therapy， and it is believed that NLRP3 inflammasome can be used as an effective therapeutic target for HCC patients.
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In recent years， clinical studies on targeted therapy and immunotherapy for advanced hepatocellular carcinoma used alone or in combination have provided abundant evidence on efficacy and safety for the selection of first-line therapies. However， no consensus has been reached on the selection of second-line therapies in various clinical guidelines for hepatocellular carcinoma， which is caused by the fact that existing evidence is limited to the options after failure of sorafenib and that there is still a lack of high-level evidence for new first-line therapies such as second-line therapies after resistance to targeted therapy and immunotherapy for hepatocellular carcinoma. This article reviews the results of current clinical trials and summarizes the studies on second-line therapies for hepatocellular carcinoma after resistance to first-line targeted therapy and immunotherapy for hepatocellular carcinoma based on the different mechanisms of action of drugs， as well as the research advances in recent years. For hepatocellular carcinoma patients with resistance to first-line targeted therapy and immunotherapy， targeted combination therapy and dual-immune therapy are expected to improve treatment outcome and survival， and more prospective clinical studies are needed in the future to provide effective and safe treatment regimens for hepatocellular carcinoma patients with resistance to targeted therapy and immunotherapy.
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ObjectiveTo investigate the effect of kinesin family member 15 （KIF15） on the proliferation of hepatocellular carcinoma （HCC） cells and its mechanism of action. MethodsTCGA and GEPIA datasets were analyzed to determine the expression of KIF15 in HCC and its effect on tumor stage and survival. Quantitative real-time PCR and Western blot were used to measure the expression level of KIF15 in human-derived HCC cell lines （HepG2， Hep3B， MHCC-97H， and LM3） and human normal liver cell line L02 cultured in vitro， and Hep3B and HepG2 were selected for subsequent studies. CCK-8 assay， plate colony formation assay， and EdU staining were performed for Hep3B cells transfected with shRNA-NC or shRNA-KIF15 and HepG2 cells transfected with LV-vector or LV-KIF15 to evaluate the viability and proliferative capacity of these cells. GSEA was used to analyze the potential signaling pathways associated with KIF15 in HCC， and Western blot was used for detection. The independent-samples t test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsThe analysis of TCGA and GEPIA datasets showed that in HCC patients， the expression of KIF15 in HCC tissue was significantly higher than that in normal tissue， and the HCC patients with high KIF15 expression tended to have a poorer prognosis. Compared with sh-NC-Hep3B， sh3-Hep3B showed significant reductions in the mRNA and protein levels of KIF15 （P<0.05）， cell viability， clone formation number， and EdU positive rate （all P<0.05）. Compared with vector-HepG2， LV-KIF15-HepG2 showed significant increases in the mRNA and protein levels of KIF15 （P<0.05）， cell viability， clone formation number， and EdU positive rate （all P<0.05）. Subcutaneous tumor assay showed that compared with sh-NC-Hep3B， sh3-Hep3B showed reductions in tumor volume and tumor weight， as well as a significant reduction in the immunohistochemical score of Ki67 and a significant increase in the immunohistochemical score of TUNEL （P<0.05）. GSEA analysis showed that the PI3K/AKT/mTOR pathway was positively correlated with KIF15 in HCC （NES=1.59， P<0.001）. Western blot showed that LY294002 could inhibit the PI3K/AKT/mTOR pathway upregulated in LV-KIF15-HepG2， and compared with LV-KIF15-HepG2， LY294002+LV-KIF15-HepG2 showed significant reductions in cell viability， clone formation number， and EdU positive rate （all P<0.05）. ConclusionKIF15 enhances the viability and proliferative capacity of HCC cells by upregulating the PI3K/AKT/mTOR signaling pathway.
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ObjectiveTo investigate the role and mechanism of DNA repair regulation in the process of hepatocellular carcinoma （HCC） recurrence. MethodsHCC tissue samples were collected from the patients with recurrence within two years or the patients with a good prognosis after 5 years， and the Tandem Mass Tag-labeled quantification proteomic study was used to analyze the differentially expressed proteins enriched in the four pathways of DNA replication， mismatch repair， base excision repair， and nucleotide excision repair， and the regulatory pathways and targets that play a key role in the process of HCC recurrence were analyzed to predict the possible regulatory mechanisms. The independent samples t-test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsFor the eukaryotic replication complex pathway， there were significant reductions in the protein expression levels of MCM2 （P=0.018）， MCM3 （P=0.047）， MCM4 （P=0.014）， MCM5 （P=0.008）， MCM6 （P=0.006）， MCM7 （P=0.007）， PCNA （P=0.019）， RFC4 （P=0.002）， RFC5 （P<0.001）， and LIG1 （P=0.042）； for the nucleotide excision repair pathway， there were significant reductions in the protein expression levels of PCNA （P=0.019）， RFC4 （P=0.002）， RFC5 （P<0.001）， and LIG1 （P=0.042）； for the base excision repair pathway， there were significant reductions in the protein expression levels of PCNA （P=0.019） and LIG1 （P=0.042） in the HCC recurrence group； for the mismatch repair pathway， there were significant reductions in the protein expression levels of MSH2 （P=0.026）， MSH6 （P=0.006）， RFC4 （P=0.002）， RFC5 （P<0.001）， PCNA （P=0.019）， and LIG1 （P=0.042） in recurrent HCC tissue. The differentially expressed proteins were involved in the important components of MCM complex， DNA polymerase complex， ligase LIG1， long patch base shear repair complex （long patch BER）， and DNA mismatch repair protein complex. The clinical sample validation analysis of important differentially expressed proteins regulated by DNA repair showed that except for MCM6 with a trend of reduction， the recurrence group also had significant reductions in the relative protein expression levels of MCM5 （P=0.008）， MCM7 （P=0.007）， RCF4 （P=0.002）， RCF5 （P<0.001）， and MSH6 （P=0.006）. ConclusionThere are significant reductions or deletions of multiple complex protein components in the process of DNA repair during HCC recurrence.
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Transarterial chemoembolization （TACE） is currently the primary treatment method for advanced liver cancer. This article elaborates on the current status of application of TACE in hepatocellular carcinoma from the aspects of existing techniques， patient selection， and efficacy assessment and summarizes the research advances and prospects of TACE combined with local treatment and systemic therapy， so as to provide new ideas for clinical practice and experimental studies.
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Hepatocellular carcinoma （HCC） is one of the common malignant tumors of the digestive tract and seriously threatens the life of patients due to a high incidence rate， a high degree of malignancy， strong invasion and metastasis， and poor prognosis. At present， the main methods for the prevention and treatment of HCC include drugs， surgery， and interventional treatment， but all of these methods have certain adverse reactions and side effects. As an important intracellular signal transduction pathway in the human body， the JAK/STAT signaling pathway mainly exerts an anti-HCC effect by regulating cell invasion， metastasis， proliferation， growth， apoptosis， autophagy， angiogenesis， inflammation/immune response， iron metabolism， and drug resistance. Therefore， targeting the JAK/STAT signaling pathway plays an important role in the prevention and treatment of the development and progression of HCC. Traditional Chinese medicine has attracted wide attention due to its advantages of multiple targets， pathways， components， and levels in the treatment of HCC， and many cell or animal experiments on traditional Chinese medicine in the treatment of HCC have shown that the JAK/STAT signaling pathway is an important target for the prevention and treatment of HCC， with the effects of improving liver function， reducing HCC recurrence， and improving immunity. Based on this， this article analyzes the mechanism of action of the JAK/STAT signaling pathway in HCC， as well as the intervention effect of traditional Chinese medicine monomers， traditional Chinese medicine extracts， and traditional Chinese medicine compounds on the JAK/STAT signaling pathway， in order to provide theoretical basis and reference for the prevention and treatment of HCC and the research and development of new traditional Chinese medicine drugs.
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Intestinal microbiota plays an important role in maintaining liver metabolic homeostasis and affects the development and progression of hepatocellular carcinoma by participating in bile acid metabolism. Gut-liver axis plays an important role in the pathogenesis of liver diseases， and it might be one of the effective methods to prevent the progression of hepatocellular carcinoma by correcting intestinal ecological imbalance to restore normal bile acid level. This article summarizes the mechanism of bile acid receptor affecting hepatocellular carcinoma and the latest therapeutic targets， in order to provide a reference for the early prevention and treatment of hepatocellular carcinoma.
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Hepatocellular carcinoma （HCC） is a common malignancy in China， and molecular-targeted drugs and immune checkpoint inhibitors for the treatment of advanced HCC are currently a research hotspot； however， there are large individual differences in the treatment outcome of advanced HCC. In order to further screen for the population with benefits from such treatment， predict treatment outcome， and improve disease prognosis， this article summarizes the studies on predicting the efficacy of targeted therapy/immunotherapy for HCC， so as to provide a reference for developing individualized treatment regimens for patients with advanced HCC.
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Hepatocellular carcinoma （HCC） is a major cause of cancer-related death， and surgical resection remains an important method for radical treatment， but it is urgently needed to solve the problem of high postoperative recurrence rate. Neoadjuvant therapy can reduce the high recurrence rate after surgery， and there are little benefits from neoadjuvant therapy for HCC due to a lack of effective treatment methods in the past. At present， combination therapy based on immune checkpoint inhibitors has a relatively high response rate and has thus changed the treatment landscape for patients with advanced HCC. This urges investigators to reexamine the neoadjuvant treatment strategies for HCC， and it is expected that neoadjuvant therapy can provide new opportunities， reduce the postoperative recurrence rate， and improve the survival rate after treatment. This article discusses the current status and prospects of neoadjuvant therapy for HCC and related hot topics， so as to provide more ideas for exploring neoadjuvant therapy for HCC.
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ObjectiveTo investigate the value of preoperative fibrosis 4 score （FIB-4） combined with prognostic nutritional index （PNI） in predicting recurrence after radiofrequency ablation （RFA） for early-stage hepatocellular carcinoma （HCC）. MethodsA retrospective analysis was performed for the clinical data of 365 patients with the initial diagnosis of early-stage HCC who underwent RFA at Tianjin Third Central Hospital from January 2013 to December 2017， and a statistical analysis was performed for recurrence and survival. The receiver operating characteristic （ROC） curve was plotted for FIB-4 and PNI with postoperative tumor recurrence as the positive event， and their optimal cut-off values were selected. FIB-4 and PNI were graded and combined as FIB-4-PNI score， based on which the patients were divided into 0-point group with 207 patients， 1-point group with 93 patients， and 2-point group with 65 patients. The chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier survival analysis and the log-rank test were used to compare the recurrence-free survival （RFS） and overall survival （OS） between groups， and the Cox regression model was used to investigate the influencing factors for RFS and OS. ResultsThe 1-， 3-， and 5-year RFS rates of all patients were 79.2%， 49.8%， and 34.3%， respectively， with a median RFS of 35 months， while the 1-， 3-， and 5-year OS rates of all patients were 98.9%， 86.9%， and 77.3%， respectively. There were significant differences in cumulative RFS and OS rates between the patients with different levels of FIB-4， PNI， and FIB-4-PNI （RFS rate： χ2=17.890， 29.826， and 32.397， all P<0.001； OS rate： χ2=16.896， 21.070， and 26.121， all P<0.001）. The multivariate Cox regression analysis showed that history of diabetes （hazard ratio ［HR］=1.418， 95% confidence interval ［CI］： 1.046 — 1.922， P=0.024）， two tumors （HR=1.516， 95%CI： 1.094 — 2.101， P=0.012）， three tumors （HR=2.146， 95%CI： 1.278 — 3.604， P=0.004）， FIB-4-PNI 1 point （HR=1.875， 95%CI： 1.385 — 2.539， P<0.001）， and FIB-4-PNI 2 points （HR=2.35， 95%CI： 1.706 — 3.236， P<0.001） were independent risk factors for RFS， while two tumors （HR=1.732， 95%CI： 1.005 — 2.983， P=0.048）， three tumors （HR=3.511， 95%CI： 1.658 — 7.433， P=0.001）， FIB-4-PNI 1 point （HR=2.094， 95%CI： 1.230 — 3.565， P=0.006）， and FIB-4-PNI 2 points （HR=3.908， 95%CI： 2.306 — 6.624， P<0.001） were independent risk factors for OS. ConclusionFIB-4-PNI score can be used as an independent predictive factor for recurrence and overall survival time after RFA for early-stage HCC， and it can be combined with tumor features to predict postoperative recurrence and survival.
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ObjectiveTo investigate the diagnostic efficacy and optimal cut-off values of alpha-fetoprotein （AFP） and alpha-fetoprotein variant L3 （AFP-L3） in hepatitis B virus （HBV）-related early-stage hepatocellular carcinoma （HCC）. MethodsA total of 1 080 patients with HBV-related HCC （HBV-HCC） who were diagnosed for the first time and not yet treated in The Third Affiliated Hospital of Sun Yat-Sen University from January 2019 to July 2022 were enrolled as HCC group in the study， among whom there were 620 patients with CNLC Ⅰa-Ⅱa HCC， and in addition， 346 patients with HBV-related chronic hepatitis B （CHB group） and 293 patients with HBV-related liver cirrhosis （LC group） were enrolled as controls. The diagnostic efficacy of AFP and AFP-L3% in screening for HBV-related early-stage HCC was analyzed， including sensitivity， specificity， and the area under the ROC curve （AUC）. The Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups； the Kruskal-Wallis H test was used for comparison between multiple groups， and the Bonferroni method was used for further comparison between two groups. ResultsThe HCC group had significantly higher levels of AFP and AFP-L3% than the CHB group and the LC group （H=542.479 and 418.974， both P<0.001）. In early-stage HCC， AFP and AFP-L3% had an optimal cut-off value of 8.7 ng/mL and 5%， respectively， and AFP alone had the largest AUC of 0.816， with a sensitivity of 66.9% and a specificity of 85.1%. There was no significant difference in AUC between AFP-L3%+AFP and AFP alone （Z=0.609， P=0.543）， but both AFP-L3%+AFP and AFP alone had a significantly larger AUC than AFP-L3% alone （AFP vs AFP-L3%： Z=8.173， P<0.001； AFP+AFP-L3% vs AFP-L3%： Z=8.802， P<0.001）. ConclusionAFP has a good value and is superior to AFP-L3% in the diagnosis of HBV-related early-stage HCC， and the screening cut-off value of AFP should be lowered in order to improve the detection rate of early-stage HCC.
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ObjectiveTo investigate the change in the proportion of non－B， non－C hepatocellular carcinoma （NBNC－HCC） in hepatocellular carcinoma， and to compare and analyze the clinicopathological features of NBNC－HCC. MethodsA total of 3 090 patients with hepatocellular carcinoma （HCC） who were diagnosed in Sichuan Provincial People’s Hospital from January 2011 to December 2021 were enrolled， and according to the hepatitis markers， they were divided into hepatitis virus infection－associated HCC group with 2 472 patients and NBNC－HCC group with 618 patients. According to the liver disease and metabolic risk factors， the NBNC－HCC group was further divided into metabolic disorder HCC group with 289 patients， alcoholic liver disease （ALD）－associated HCC group with 174 patients， and other HCC group with 155 patients. General information， laboratory markers， and pathological findings were collected from all HCC patients. The Mann－Whitney U test was used for comparison of continuous data between two groups， and the Kruskal－Wallis H test was used for comparison between three groups； the chi－square test was used for comparison of categorical data between groups， and the chi－square trend test was used to investigate the trend of the change in the proportion of NBNC－HCC in HCC. ResultsThe proportion of patients with NBNC－HCC in HCC increased from 13.7% in 2011 to 20.1% in 2021 （χ2=5.529， P=0.019）， and compared with the hepatitis virus infection－associated HCC group， the NBNC－HCC group had a significantly higher proportion of patients with diabetes （28.0% vs 10.3%， χ2=129.482， P<0.001） or hypertension （33.2% vs 15.2%， χ2=105.079， P<0.001）， a significantly lower proportion of patients with liver cirrhosis （44.5% vs 68.4%， χ2=122.563， P<0.001） or vascular invasion （20.4% vs 29.6%， χ2=7.749， P=0.005）， and a significantly higher body mass index （BMI） （Z=－4.015， P<0.001）. Compared with the ALD－HCC group， the metabolic disorder HCC group had a significantly higher BMI， a significantly lower FIB－4 index， and a significantly lower proportion of patients with liver cirrhosis （all P<0.05）. ConclusionThere is a tendency of increase in the proportion of patients with NBNC－HCC in HCC， and NBNC－HCC often coexists with metabolic risk factors such as obesity， diabetes， and hypertension. Patients in the metabolic disorder HCC group may develop liver cancer in the absence of liver cirrhosis or in the early stage of liver fibrosis.
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This paper discusses further on the antiviral treatment of chronic hepatitis B patients with indeterminate phase. These patients have a high proportion of significant necroinflammation and fibrosis in the liver， and a higher risk of disease progression compared with those with true HBeAg－positive chronic hepatitis B virus （HBV） infection （formerly called the immune tolerance phase） or HBeAg－negative chronic HBV infection （formerly called the immune control phase）. Antiviral therapy may reduce the risk of HBV－related hepatocellular carcinoma in chronic hepatitis B patients with indeterminate phase.
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Hepatocellular carcinoma is a typical chronic inflammatory-associated malignancy. Chronic inflammation continuously damages the reticuloendothelial system of the liver and leads to impairment of immune surveillance, which in turn leads to dysregulation of the immune environment. Immune escape caused by impaired surveillance system can improve the immunogenicity of tumor, which plays an important role in the occurrence and development of tumors. Studies have shown that the indicators including immune inflammatory cells such as neutrophils, platelets and lymphocytes can predict the prognosis of hepatocellular carcinoma, the individualized treatment and early intervention for patients on this basis is expected to improve the prognosis of patients. The article introduces the role of immune cells in the occurrence and development of hepatocellular carcinoma, and summarizes the relationship between peripheral blood immune inflammatory indicators and prognosis of hepatocellular carcinoma.
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Early diagnosis, effective treatment and monitoring of recurrence and metastasis of hepatocellular carcinoma have always been difficult problems for clinicians. MicroRNA (miRNA) plays an important role in hepatocellular carcinoma cells' proliferation, apoptosis, metabolism and other processes, and can be released into body fluids such as blood, urine and saliva. The peripheral blood miRNA in hepatocellular carcinoma can be used as biomarkers for the diagnosis, efficacy assessment, recurrence and metastasis monitoring and prognosis judgment, and may even become therapeutic targets for hepatocellular carcinoma. This article summarizes the research progress of circulating miRNA in peripheral blood as markers for diagnosis and treatment monitoring of hepatocellular carcinoma.
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Objective:To investigate the distribution of M2 tumor-associated macrophage (TAM) in hepatocellular carcinoma (HCC) and their correlation with clinicopathological features, and the significance of programmed death-ligand 1 (PD-L1) expression.Methods:From January 1, 2012 to December 31, 2020, a total of 320 HCC patients who underwent surgical resection at the Third People′s Hospital of Nantong were included. The distribution of CD163 labeled and PD-L1 CD163 double-labeled M2 TAM in HCC tissues was detected by immunohistochemistry, and the cell density was calculated. The cell density> the average cell density (112/mm 2) was judged as high-density, the cell density≤ the average cell density was judged as low-density. The correlation between CD163 positive and PD-L1 CD163 double positive M2 TAM density and the clinical pathological characteristics of HCC and its impact on prognosis were analyzed. Chi-square test was used to analyze the correlation between M2 TAM expression and the clinical pathological characteristics of HCC. Kaplan-Meier method was used to draw survival curves, and log-rank test was used for inter group comparison. Univariate and multivariate Cox proportional hazards regression analysis was used to indentify the relevant factors affecting the prognosis of HCC. Results:TAM were mainly distributed in the tumor edge stroma and tumor sinusoids, CD163 positive M2 TAM were the main macrophage subtype. PD-L1 expression was observed in CD163 positive M2 TAM in HCC tissues, and PD-L1 positive M2 TAM were mainly distributed in the tumor edge stroma. The rate of high-density CD163 positive M2 TAM in HCC tissues was 44.4% (142/320). High-density CD163 positive M2 TAM was correlated with histological grade, TNM stage, and PD-L1 expression on tumor infiltrating immune cells in HCC tissues ( χ2=4.65, 6.72 and 42.19, P=0.031, =0.011 and <0.001). High-density PD-L1 and CD163 double positive M2 TAM in HCC tissues was correlated with microvascular invasion and TNM stage ( χ2=11.96 and 8.74, P=0.001 and 0.004). The median disease-free survival (DFS) time and overall survival (OS) time of patients with high-density CD163 positive M2 TAM were 21 and 36 months, respectively, which were lower than those of patients with low-density CD163 positive M2 TAM (50 and 103 months, respectively); the median DFS time and OS time of patients with high-density PD-L1 CD163 double-positive M2 TAM were 12 and 15 months, respectively, which were lower than those of patients with low-density PD-L1 CD163 double-positive M2 TAM (28 and 45 months, respectively), and the differences were statistically significant (all log-rank tests, all P<0.001). The results of multivariate Cox proportional hazards regression analysis showed that high-density CD163 positive M2 TAM, microvascular invasion and high TNM stage were independent risk factors for evaluating DFS and OS of patients with HCC (DFS time: HR=2.408 (95% confidence interval (95% CI) 1.778 to 3.261), 2.603 (95% CI 1.860 to 3.641), 4.032 (95% CI 2.833 to 5.747), all P<0.001. OS time: HR=2.007 (95% CI 1.457 to 2.764), 4.144 (95% CI 2.881 to 5.960), 4.292 (95% CI 2.915 to 6.329), all P<0.001). Conclusions:High-density of CD163 positive M2 TAM in HCC tissues indicates high malignancy and poor prognosis, and it is an independent prognostic risk factor. The expression of PD-L1 in M2 TAM suggests stronger tumor aggressiveness and worse prognosis in HCC.