Table of Content

31 December 2023, Volume 10 Issue 4

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Expert

Research progress of driver gene alteration and targeted therapy for intrahepatic cholangiocarcinoma

Zhang Shihui, Li Zhuo, Yihebali·Chi, Shi Susheng

2023, 10(4):  15-22. 

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Intrahepatic cholangiocarcinoma (ICCA) is a primary liver cancer originating from the intrahepatic bile duct epithelium, which is second only to hepatocellular carcinoma in terms of incidence and is extremely malignant with a 5-year overall survival rate of less than 10%. Surgery is the perferred radical treatment choice. Patients with advanced disease are resistant to radiotherapy or chemotherapy, the efficacy is unsatisfactory, and there is an urgent need to find new and effective treatment methods. With the advent of precision medicine, research on the mechanisms of multiple driver gene alterations and signaling pathway abnormalities in intrahepatic cholangiocarcinoma in China and abroad has been intensifying in recent years, and targeted therapy and immunotherapy have been more and more widely used in clinical practice. This paper is intended to review the research progress of driver gene alterations and targeted therapies for intrahepatic cholangiocarcinoma.

Original article

Effect of aryl hydrocarbon receptor gene knockout on metabolic pathways and metabolites in hepatocellular carcinoma

Wei Zhewen, Zhu Qing, Cai Jianqiang

2023, 10(4):  23-28. 

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Objective:To investigate the effect of aryl hydrocarbon receptor (AHR) gene knockout on metabolic pathways and metabolites in hepatocellular carcinoma (HCC). Method:PLC/PRF/5 hepatoma cell line with AHR knockout was constructed by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. Untargeted metabolomics was performed on the wild type (AHR-WT) and AHR knockout (AHR-KO) hepatoma cells to detect the metabolites, and the differential metabolites between the two groups were analyzed. Metaboanalyst 4.0 was used to perform metabolic pathway enrichment analysis and find differential metabolites.
Result:The AHR-WT and AHR-KO hepatoma cells were examined for metabolites under positive and negative ionic model respectively. The results showed that the top 10 functional enrichments were mainly amino acid metabolism glutamate metabolism, glycine and serine metabolism, arginine and proline metabolism, methionine metabolism, aspartate metabolism, urea cycle, ammonia recycling, energy metabolism glutathione metabolism, Warburg effect and nucleotide metabolism purine metabolism. The pathway enrichment analysis showed that eight metabolic pathways were found including arginine and proline metabolism, arginine biosynthesis, pyrimidine metabolism, alanine, aspartic acid and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, purine metabolism, lysine degradation, ascorbic acid and uronate metabolism. Compared with AHR-WT hepatoma cells, the levels of L-arginine, L-phenylalanine, L-tyrosine, uridine and xanthine were significantly down-regulated in AHR-KO hepatoma cells. Nicotinamide adenine dinucleotide (NADH), oxidized glutathione and nicotinamide adenine dinucleotide phosphate (NADPH) were significantly up-regulated in the AHR-KO cells. Conclusion:AHR may play an important role in the metabolism of HCC, and the research on the metabonomics of HCC by targeting AHR may be a new anti-tumor treatment strategy.

Intraoperative monitoring of stroke volume variation versus central venous pressure in liver surgery: a Meta-analysis of randomized clinical trials

Du Longde, Huang Xiaozhun, Xie Yunliang, Zhou Jianguo, Bi Xinyu, Che Xu, Ni Yong

2023, 10(4):  29-37. 

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Objective:To explore the best method of monitoring during hepatectomy by Meta-analysis.
Methods:From inception to December 13, 2022, The electronic databases of PubMed, Web of Science, Embase, CNKI and the Cochrane Library were searched. Randomized clinical trials reporting outcomes with comparison between stroke volume variation (SVV) guided goal-directed fluid therapy and low central venous pressure (LCVP) guided fluid therapy during liver surgery were included by inclusion and exclusion criteria. The perioperative data was statistically summarized using Review Manager 5.3 software.
Results:A total of 10 randomized clinical trials were included, with a total sample size of 702 cases, including 354 cases (50.4%) in SVV group and 348 cases (49.6%) in LCVP group. The results of Meta-analysis showed that the arterial lactate concentration in the SVV group was significantly lower than that in the LCVP group, with a statistically significant difference between the two groups (weighted mean difference =-0.84 mmol/L, 95%CI: -1.43 mmol/L to -0.25 mmol/L , P=0.005). The reduce intraoperative bleeding and the incidence of total complications without statistically significant differences(all P>0.05). There were no significant differences in surgical field, postoperative biochemical indexes, incidence of serious complications, incidence of postoperative acute renal injury, and length of hospital stay between the two groups(all P>0.05). Conclusion:The use of SVV directed fluid therapy in liver surgery is safe, does not lead to prolonged operative time, increased intraoperative bleeding, or decreased surgical field quality, and significantly reduces intraoperative lactate concentration in patients undergoing hepatectomy.

Application effect of establishing prognostic evaluation model based on prognostic nutritional index and total protein, hemoglobin, transferrin levels in patients with liver cancer radiotherapy and chemotherapy

Ren Dongjing, Ma Haiyan, Guo Fei

2023, 10(4):  38-41. 

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Objective:To explore the application effect of establishing a prognostic evaluation model based on prognostic nutritional index(PNI) and total protein (TP), hemoglobin (Hb), transferrin (TF) levels in patients with liver cancer radiotherapy and chemotherapy.
Methods:According to enrollment criteria,the research subjects selected a total of 100 patients with liver cancer treated with radiotherapy and chemotherapy in First Affiliated Hospital of Hebei North University from May 2018 to January 2021. According to the prognosis of the patients, they were divided into a stable group (46 cases) and a progressive group (54 cases). The levels of TP, ALB, Hb, and TF were detected, and the PNI was calculated according to their blood biochemical test results. Multivariate Logistic regression was used. The correlation between PNI, TP, Hb, TF levels and patient prognosis was analyzed, and prognostic evaluation model of PNI combined with TP, Hb and TF was established. The final scores of the patient outcome assessment model were observed for different baseline and clinical data, and the predictive value of prognostic evaluation model was assessed using the receiver operating characteristic (ROC) curve.
Results:The PNI, TP and Hb levels of the two groups in the stable group were significantly higher than those in the progressive group, and the TF level was significantly lower than that in the progressive group (all P<0.05). is an independent risk factor affecting the prognosis of patients (all P<0.05); the results of the prognostic evaluation model in patients with age greater than 60 years, the number of tumors greater than 3, and the largest tumor diameter greater than 5 cm were significantly lower (all P<0.05). There was no significant difference in the results (all P>0.05); the results of the prognostic evaluation model in patients with complications, survival less than 1 year, and disease progression were significantly lower (all P<0.05), and there was no statistical difference in the prognostic evaluation model results in patients with recurrence and metastasis. (all P>0.05). ROC curve showed that the cut-off value of the prognostic evaluation model was 0.621, and the predictive sensitivity was 87.04% and the specificity was 86.96%. The area under the curve is 0.913. Conclusion:The prognosis of patients with liver cancer radiotherapy and chemotherapy is closely related to the nutritional index and the levels of TP, Hb and TF, and the nutritional index combined with the levels of TP, Hb and TF to establish a prognostic evaluation model has high sensitivity and specificity for the prognosis evaluation of patients.

Compound kushen injection synergises with sorafenib to improve response in advanced hepatocellular carcinoma

Li Xianchen, Xu Qiuyan, Sheng Wenfei, Li Dongliang, Wu Qingqing, Tao Zhongyi

2023, 10(4):  42-50. 

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Objective:Clinical cohort, network pharmacological framework and molecular docking techniques were used to elucidate the material basis and molecular mechanism of compound compound kushen injection (CKI) synergising with sorafenib in the treatment of advanced hepatocellular carcinoma (HCC).
Methods:A total of 134 patients with advanced HCC treated in our hospital between July 2019 and June 2022, including 67 patients in the CKI-sorafenib group and 67 patients in the sorafenib group, were selected to analyse the response rate and overall survival rate of patients in both groups. The CKI anti-advanced HCC target genes were identified by a web-based pharmacological framework combined with the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform and GeneCards,OMIM,PharmGkb,TTD or DrugBank databases. The expression of FBJ murine osteosarcoma viral oncogene homolog (FOS) and epidermal growth factor receptor (EGFR) was verified by enzyme-linked immunosorbent assay before and after treatment in both groups.
Results:The treatment response rate and survival rate of patients in the CKI-sorafenib group were higher than those in the sorafenib group (response rate:74.6% vs. 66.2%, P=0.032; survival rate:38.8% vs. 23.9%, P=0.013).FOS and EGFR are the core target genes of CKI against advanced HCC. After 3 months of treatment, peripheral blood FOS and EGFR concentrations were significantly lower in patients in the CKI-sorafenib group compared with those in the sorafenib group (FOS: (8.41±2.17) ng/ml vs. (9.85±2.47) ng/ml, P<0.001; EGFR: (5.47±2.14) ng/ml vs. (6.28±2.04) ng/ml, P=0.027)]. Molecular docking modelling fraction confirmed that quercetin could interact with FOS and EGFR with binding energies of -8.2 kcal/mol and -7.9 kcal/mol, respectively. Conclusion:CKIs synergise with sorafenib to increase response rates and improve survival time in patients with advanced HCC, with FOS and EGFR as potential mechanisms mediating their response.

Construction of Nomogram for predicting lymph node metastasis based on clinical data of hepatocellular carcinoma

Zhang Yukun, He Du, Lai Lin, Duan Chunyan, Lyu Peng

2023, 10(4):  51-54. 

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Objective:To construct a Nomogram prediction model of risk factors for lymph node metastasis in patients with hepatocellular carcinoma (HCC) clinical data.
Methods:328 patients with hepatocellular carcinoma(HCC) in Enshi Tujia and Miao Autonomous Prefecture Central Hospital were collected, and 50 patients with lymph node metastases were included in the metastasis group, and the remaining 278 patients were included in the control group.Logistic regression analysis looked for risk factors for lymph node metastasis, based on which the Nomogram model was constructed.
Results:Alpha fetoprotein（AFP）(>243.35 μg/L), γ-Gluyl transferase(γ-GT>181.82 U/L), tumor maximum diameter (>6.17 mm) and tumor number (>1) were a risk factor for lymph node metastasis in HCC patients(all P<0.05). A Nomogram model for predicting lymph node metastasis in HCC patients was constructed. The internal verification results showed that the C-index is 0.805 (95%CI: 0.086-1.325),and risk threshold > 0.058. But the Nomogram model provided a clinical net benefit and was higher than that of AFP, γ-GT, tumor diameter, and tumor number.
Conclusions:In this study, a Nomogram model for predicting lymph node metastasis was constructed based on the clinical data of HCC. This model has practical value for clinical screening to predict the possible lymph node metastasis in HCC patients.

Correlation of STAT3 and miR-200 expression with programmed cell death-ligand 1(PD-L1) in liver cancer patients and their role in resistance to PD-L1 inhibitory

Liu Shaoqing, Qi Man

2023, 10(4):  55-59. 

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Objective:To investigate the correlation between the expression of signal transducer and activator 3 (STAT3), microribonucleotide-200 (miR-200) and programmed cell death-ligand 1 (PD-L1) in patients with liver cancer and its role in resistance to PD-L1 inhibitory.
Methods:From February 2019 to January 2022, a total of 108 patients with advanced liver cancer who were treated in Chengde central hospital were selected according to the enrollment criteria. They were divided into a resistance group(n=75) and a non-resistance group(n=33) according to their response to treatment. The expressions of STAT3 mRNA, miR-200 and PD-L1 in the two groups were compared, and compared the expressions of STAT3 mRNA and miR-200 in tissues of patients with different PD-L1 expression levels. Pearson was used to analyze the relationship between STAT3 mRNA, miR-200 and PD-L1, and binary Logistic regression was used to analyze the resistance to PD-L1 inhibitory. Related influencing factors, the interaction coefficient γ was used to analyze the existence and type of interaction between STAT3 mRNA and miR-200.
Results:The expression of STAT3 mRNA and PD-L1 in the resistance group was higher than that in the non-resistance group, and the miR-200 was lower than that in the non-resistance group, and the differences were statistically significant (all P<0.05). The STAT3 mRNA in patients with strong PD-L1 expression was higher than that in patients with low PD-L1 expression, and the miR-200 was lower than that in patients with low PD-L1 expression, and the difference was statistically significant (all P<0.05). Pearson correlation analysis showed that STAT3 mRNA was negatively correlated with miR-200 (P<0.05). STAT3 mRNA was positively correlated with PD-L1 (P<0.05), and miR-200 was negatively correlated with PD-L1 (P<0.05) . Logistic regression analysis showed that STAT3 mRNA and PD-L1 were related risk factors for PD-L1 inhibitory resistance, and miR-200 was a related protective factor for PD-L1 inhibitory resistance (all P<0.05). The interaction analysis showed that the OR value caused by the increase of STAT3 mRNA alone was 21.000, the OR value caused by the decrease of miR-200 alone was 7.875, and the OR value caused by the coexistence of the two was 468.00. The OR value of the interaction > STAT3 alone the product of the OR value caused by the increase of mRNA and the OR value caused by the decrease of miR-200 alone. The model was a hypermultiplicative model with γ =2.019> 1 for the effect of STAT3 mRNA and miR-200 on PD-L1 inhibitor resistance and indicating a positive interaction.
Conclusions:The expression of STAT3 in patients with liver cancer is increased, which is positively correlated with PD-L1. The expression of miR-200 is decreased, and the expression of miR-200 is negatively correlated with PD-L1. The expression levels of STAT3 and miR-200 are closely related to PD-L1 inhibitory resistance, and have potential as therapeutic targets the potential value of the point, and can provide a reference for the precise and personalized application of PD-L1 inhibitors.

Review

Research progress of radiotherapy-based comprehensive therapy in primary hepatocellular carcinoma

Yin Li, Guo Wenjie, Yuan Fangqin, Xu Qingyu, Yao Chengyun, He Xia

2023, 10(4):  60-67. 

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Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and most patients present with advanced liver cancer and a poor survival prognosis. With the development of new technologies and drug therapies, the value of radiotherapy, chemotherapy, targeted and immune drugs in HCC has been valued, especially for patients without surgical resection opportunities, and combination with hepatic artery chemoembolization is expected to become a new treatment option for HCC. For inoperable small liver cancer or early liver cancer, stereotactic radiation therapy has become one of the radical means. In addition, radiotherapy can promote the effect of immunotherapy by releasing tumor antigens, the two have a synergistic effect, in the inoperable late HCC radiotherapy combined with targeted, immunotherapy has achieved remarkable results in many clinical trials, and is safe and controllable. This paper mainly summarizes the latest research progress of radiotherapy combined drug therapy in HCC, and provides more combination treatment references and clinical research exploration directions for the current clinical treatment of primary liver cancer, especially advanced liver cancer.

MDT filed

A case of intracranial solitary fibrous tumor/hemangio-pericytoma with multiple liver, lung, and bone metastases

Li Huimin, Yihebali·Chi, Xu Xiaoying, Tan Huijing

2023, 10(4):  68-71. 

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Intracranial solitary fibrous tumor(ISFT) are relatively rare in clinical practice. This article reports a case of ISFT/hemangio-pericytoma with multiple liver, lung, and bone metastases after empirical chemotherapy and targeted drug multiline several clinical cases after empirical chemotherapy and targeted drugs, and reviews the research advances in the pathological and radiological features, postoperative recurrence and metastasis of ISFT.