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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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Objective:To explore the risk factors of microvascular invasion (MVI) in hepatocellular carcinoma (HCC), and to predict MVI preoperatively, non-invasively and accurately.Methods:A total of 150 HCC patients (183 HCC lesions) were retrospectively collected in the First Affiliated Hospital of Xi′an Jiaotong University from January 2016 to June 2022.The clinical data and hematological data, gray-scale ultrasonography (US), contrast-enhanced ultrasonography (CEUS), enhanced magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (EOB-MRI) and pathological data of these patients were recorded. According to the pathological diagnosis of MVI, the lesions were divided into MVI (+ ) group and MVI (-) group. The indicators between the two groups were compared. All 183 lesions were put into the training set, and the prediction model with nomogram was constructed according to the risk factors of MVI selected by multivariate Logistic regression. The internal verification was carried out by ten-fold cross-validation method.Results:There were significant statistical differences in the following parameters between MVI (+ ) group ( n=109) and MVI (-) group ( n=74) (all P<0.05). These were cirrhosis, serological parameters (alpha-fetoprotein, albumin, total bilirubin), qualitative indexes of US (size, boundary, internal echo), qualitative indexes of CEUS (hyper/iso/hypovascularity of lesions in arterial phase, portal phase, and delayed phase compared with hepatic parenchyma), and quantitative indexes of EOB-MRI [post enhancement rate (post ratio) and gadolinium disodium rate (EOB ratio)] calculated mainly in terms of lesions and surrounding liver parenchyma in hepatobiliary phase and unenhanced T1 images). Finally, cirrhosis of patients, the size, boundary, internal echo of lesions in US; arterial phase (AP), portal phase (PP), post-vascular phase (PVP) features in CEUS; the EOB rate and post rate of EOB-MRI entered the prediction model of MVI. The training set exhibited good calibration and net gain rate. The areas under the ROC curve for the training set and the validation set were 0.981 and 0.961, respectively, while the diagnostic accuracy were 92.9% and 85.8%, respectively. Conclusions:The model constructed mainly by multimodality imaging methods can achieve favorable predictive performance for MVI, which provides valuable ideas for noninvasively predicting the incidence of MVI and optimizing the MVI-related treatment of MVI in HCC patients.
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Objective:To analyze the effect of nucleos(t)ide analog (NAs) antiviral treatment on the clinical features and prognosis of patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC).Methods:A retrospective analysis was performed on the data of 450 HBV-HCC patients first diagnosed and treated in the Third Hospital of Hebei Medical University from January 2015 to January 2021, including 193 patients in the continuous NAs treatment group and 257 patients in the NAs treatment after hepatocellular carcinoma (HCC) group. The baseline data of the two groups were balanced by propensity score matching. The relapse-free survival rate of HCC was estimated by Kaplan-Meier method, and the risk factors for HCC recurrence were analyzed by Cox proportional risk models. Spearman correlation analysis was used to explore the association between clinical features of HCC and hepatitis B virus (HBV) DNA load in patients receiving continuous NAs treatment.Results:Before matching, the proportions of liver cirrhosis, body mass index≥25.0 kg/m 2, single tumor, maximum tumor diameter ≤5 cm, Child-Pugh grade A, China liver cancer staging Ⅰ in the continuous NAs treatment group were 93.8%(181/193), 45.1%(87/193), 70.5%(136/193), 82.4%(159/193), 74.6%(144/193) and 74.6%(144/193), respectively. All of them were higher than those in the NAs treatment after HCC group (87.5%(225/257), 44.0%(113/257), 61.1%(157/257), 55.3%(142/257), 63.8%(164/257) and 56.0%(144/257), respectively). The proportions of drinking history and portal vein tumor thrombi in the continuous NAs treatment group were 12.4%(24/193) and 3.1%(6/193), respectively, which were lower than 33.9%(87/257) and 10.5%(27/257) in the NAs treatment after HCC group.The differences were all statistically significant ( χ2=4.86, 7.58, 4.27, 36.63, 8.15, 21.05, 27.21 and 8.88, respectively, all P<0.05). After matching, the median relapse-free survival time of the patients in the continuous NAs treatment group and the NAs treatment after HCC group were 388 days and 277 days, respectively. The five-year cumulative relapse-free survival rates were 50.0% and 37.5%, respectively, with statistically significant difference ( χ2=5.30, P=0.021). Multivariate analysis showed that no antiviral therapy before diagnosis of HCC, multiple tumors, maximum tumor diameter ≥5 cm and palliative treatment were independent risk factors for HBV-HCC recurrence (hazard ratio ( HR)=1.509, 1.491, 0.446 and 1.472, respectively, all P<0.05). After matching, the maximum tumor diameter ( r=0.175, P=0.042), incidence of portal vein tumor thrombi ( r=0.210, P=0.014) and recurrence of HBV-HCC ( r=0.178, P=0.038) in the continuous NAs treatment group were positively correlated with HBV DNA load. Conclusions:Early initiation of NAs antiviral treatment can improve the tumor characteristics when the disease progresses to HBV-HCC, and improve the relapse-free survival rate of HBV-HCC patients. No antiviral therapy before diagnosis of HCC, multiple tumors, maximum tumor diameter ≥5 cm and palliative treatment are independent risk factors for HBV-HCC recurrence.
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Objective:To systematically evaluate the relationship between rs1012068 and rs5998152 single nucleotide polymorphisms of DEPDC5 gene and susceptibility to hepatocellular carcinoma (HCC).Methods:Up to October 31, 2022, PubMed, Embase, Scopus, Web of Science and China National Knowledge Internet (CNKI) were used to search the relationship between rs1012068, rs5998152 and susceptibility to HCC. The odds ratio (OR) values and 95% CI of the five genetic models were calculated, and the RevMan5.3 software was used for meta analysis. Results:A total of 12 articles were included in this study, including 11 articles about rs1012068 locus, including 2 609 patients with HCC and 8 171 controls, and 3 articles about rs5998152 locus, including 411 patients with HCC and 1 448 controls. The results of meta analysis showed that among the five genetic models of rs1012068 locus, allele pattern (G vs T: P=0.02), dominant pattern (GG+ TG vs TT: P=0.01) and heterozygote pattern (TG vs TT: P=0.009) were significantly different between the case group and the control group. In homozygous mode (GG vs TT: P=0.05) and recessive mode (GG vs TG+ TT: P=0.08), there was no correlation between rs1012068 gene polymorphism and susceptibility to HCC. Among the five genetic models of rs5998152 locus, allele model (C vs T: P=0.03), dominant model (CC+ TC vs TT: P=0.001) and heterozygous model (TC vs TT: P<0.000 01) were significantly different between case group and control group. There was no correlation between rs5998152 gene polymorphism and susceptibility to HCC in recessive model (CC vs TC+ TT: P=0.31) and homozygous model (CC vs TT: P=0.09). Conclusions:There is a correlation between rs1012068 locus and susceptibility to HCC in allele model and dominant gene model, which is a genetic factor promoting tumorigenesis. The allele pattern, dominance pattern and heterozygote pattern of rs5998152 locus can increase the risk of liver cancer, but no correlation was found in other patterns.
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Objective:To investigate the value of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MRI in predicting the pathological grade and early recurrence rate of hepatocellular carcinoma.Methods:The imaging data, pathological data, and follow-up data of 90 patients with hepatocellular carcinoma who underwent Gd-EOB-DTPA-enhanced MRI examination and surgical treatment in People's Hospital of Baise from January 2016 to October 2017 were retrospectively analyzed. The correlation between the signal intensity of contrast-enhanced MRI and postoperative pathological grade was analyzed. Kaplan-Meier survival analysis was performed to investigate the effects of the signal characteristics of hepatobiliary lesions on the early recurrence rate of hepatocellular carcinoma.Results:A total of 59 (65.56%) patients showed low-intensity signals and 31 (34.44%) patients showed mixed-intensity signals. High-intensity signal was not found in any patients. The signal intensity of the hepatobiliary phase was significantly correlated with the pathological grade of the tumor ( χ2 = 2.26, P = 0.040) and tumor size ( t = 3.10, P = 0.033). The early recurrence rate of hepatocellular carcinoma was significantly higher in patients exhibiting mixed-intensity signals than that in patients exhibiting low-intensity signals ( χ2 = 2.25, P = 0.041). Conclusion:Gd-EOB-DTPA-enhanced MRI in the hepatobiliary phase with different signal intensities has the potential to predict the pathological grade and early recurrence rate of hepatocellular carcinoma.
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N7-methylguanosine （m7G） is one of the most popular RNA modifications at present and has attracted wide attention from researchers in China and globally. By influencing the metabolism of various RNA molecules （including messenger RNA， ribosomal RNA， microRNA， and transfer RNA）， m7G modification actively participates in many biological processes such as cell proliferation， differentiation， and apoptosis. More and more evidence has shown that m7G plays a key role in the development of cancer， and abnormal m7G levels are closely associated with the development and progression of cancer by regulating the expression of multiple oncogenes and tumor suppressor genes. Hepatocellular carcinoma is the most common gastrointestinal tumor in China， and current treatment methods tend to have an unsatisfactory therapeutic effect. At present， the potential molecular mechanism of m7G modification in hepatocellular carcinoma remains unclear. This article reviews the potential mechanism of action of m7G modification in hepatocellular carcinoma and the m7G-related diagnosis and treatment strategies.
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ObjectiveTo determine whether HBV DNA polymerase is associated with T-cell failure and thus mediates the immune escape of HBV-related hepatocellular carcinoma （HCC） tumor cells， and to investigate the specific molecular mechanisms. MethodsLiver cancer cell lines Huh7 and HepG2 stably transfected with HBV DNA polymerase expression plasmid with Flag （Flag-HBV-P） and intercellular adhesion molecule-1 （ICAM1） were co-cultured with Jurkat cells， and MTT assay， qRT-PCR， and ELISA were used to measure Jurkat cell proliferation， activation （CD69 expression）， and secretion of the cytokine IFN-γ. RNA-seq was used to screen for differentially expressed immune-associated molecules between stably transfected cell lines and control cells， and mRNA half-life and protein half-life assays were used to determine the specific levels of the immune-associated molecules that were affected by HBV DNA polymerase. Related websites were used to predict the transcription factors that may bind to the promoter region of this immune-associated molecule， Western blot was used to verify the effect of transcription factors on the immune-associated molecule， and rescue experiment was used to determine whether HBV DNA polymerase affects the expression level of the immune-associated molecule through this transcription factor. The independent-samples t test was used for comparison between two groups. ResultsThe experimental group had significant reductions in Jurkat cell proliferation， activation， and cytokine secretion compared with the control group （all P<0.01）. Compared with the control group， the experimental group （Huh7 and HepG2 cell lines） had significant reductions in the mRNA and protein expression levels of ICAM1 （all P<0.01）. Website prediction identified the ICAM1 promoter and preliminarily highlighted NFKB1， RELA， and STAT3. Compared with the control group， the experimental group （Huh7 and HepG2 cell lines） had a significant reduction in the protein expression level of p65 （all P<0.01）. After p65 overexpression， there was a significant increase in the protein expression level of ICAM1， and after the expression of p65 was reduced， there was a significant reduction in the protein expression level of ICAM1 （all P<0.01）. In the rescue experiment， there was no significant difference in the protein expression level of ICAM1 between the control group and the experimental group after p65 overexpression （all P>0.05）. After the overexpression of ICAM1， there were no significant differences in the proliferation， activation， and cytokine secretion of Jurkat cells between the control group and the experimental group （Huh7 and HepG2 cell lines） （all P>0.05）. ConclusionHBV DNA polymerase downregulates the level of ICAM1 to mediate HCC immune escape by inhibiting the expression of p65 in NF-κB.
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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.
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The article reported one case of renal damage caused by lenvatinib in the treatment of advanced primary liver cancer. The patient was a 63-year-old male who was admitted to the hospital due to "liver cancer for 4 years, blood pressure elevation for nearly 2 years, and edema for 7 months". During the treatment of liver tumors with atezolizumab combined with lenvatinib, blood pressure increased and renal insufficiency aggravated progressively. Pathological light microscopy of renal biopsy showed endothelial cell lesion and tubulointerstitial damage, and electron microscopy showed moderate proliferation of mesangial cells and deposition of mesangial matrix. There were many agglomerated low-electron density deposits in the mesangial area, and a small amount of electron dense deposits in the subendothelium. The pathological diagnosis was endothelial cell disease (thrombotic microangiopathy) and secondary focal segmental glomerulosclerosis. Renal injury was considered as secondary to lenvatinib. After discontinuing lenvatinib and giving angiotensin receptor antagonist treatment, blood pressure was normal, urine protein turned negative, and renal function improved significantly after 8 months of outpatient follow-up.