Complicaciones, clínica y tratamiento de pacientes con hepatocarcinoma, posterior a quimioembolización en dos hospitales de Quito / Complications, symptoms and treatment of patients with hepatocellular carcinoma, after chemoembolization in two hospitals in Quito

INTRODUCCIÓN. La quimioembolización transarterial ha demostrado mejorar la tasa de sobrevida en los pacientes con hepatocarcinoma, se ha descrito como tratamiento paliativo; es útil, efectivo y bien tolerado. Esta terapéutica tiene el objetivo de disminuir el volumen tumoral. OBJETIVO. Determinar las complicaciones que presentan los pacientes con diagnóstico de hepatocarcinoma, posterior a la realización de quimioembolización transarterial del servicio de Gastroenterología del Hospital de Especialidades Carlos Andrade Marín y Hospital de Especialidades Eugenio Espejo, durante el período enero 2015 - enero 2020. MATERIALES Y MÉTODOS. Es un estudio retrospectivo observacional transversal; se diseñó un formulario de recolección de información, utilizando media y desvío estándar para variables cuantitativas; frecuencia y porcentaje para cualitativas; en las variables con distribución no paramétrico se recurrió a la mediana, rango intercuartil y sus intervalos, además se utilizó Chi Cuadrado, Índice de Yates y test de U Mann Whitney. Se trabajó en el paquete estadístico SPSS versión 26. RESULTADOS. Se analizaron 97 pacientes, el 60,8% fue de sexo masculino de los cuales el 56.7% presentó alguna comorbilidad; la mayoría de los pacientes no tuvieron complicaciones, sin embargo, la hipertensión arterial se presentó como manifestación clínica post quimioembolización transarterial (10,3%); el choque, el síndrome ascítico ­ edematoso y el dolor abdominal fueron las complicaciones de mayor frecuencia. Los datos estadísticamente significativos fueron los siguientes: los pacientes con hepatocarcinoma y cirrosis hepática con severidad Child Pugh B, tuvieron un porcentaje mayor de complicaciones valor p = 0,01; un tamaño más grande del tumor sobre el número de lesiones, se relacionó con presentar alguna complicación postquimioembolización transarterial valor p = 0,001, lo que significó un aumento en la estancia hospitalaria valor p = 0,006; los pacientes que presentaron complicaciones mayores y menores tuvieron un tiempo de hospitalización más prolongado valor p < 0,05; la asociación entre la mortalidad y las complicaciones post quimioembolización en hospitalización y en UCI tuvieron una tasa general de 3,2% valor p = 0,001. CONCLUSIÓN. Las complicaciones mayores como el síndrome ascítico edematoso y el estado de choque, se mantuvieron sobre la media general. Con una tasa de mortalidad esperada según la tendencia internacional.

INTRODUCTION: Transarterial chemoembolization has been shown to improve the survival rate in patients with hepatocarcinoma, it has been described as palliative treatment; it is useful, effective and well tolerated. This therapy aims to reduce tumor volume, due to its embolic, vascular and cytotoxic effects. OBJECTIVE: To determine the complications presented by patients diagnosed with hepatocarcinoma, after performing transarterial chemoembolization of the Gastroenterology service of the Carlos Andrade Marín Specialty Hospital and Eugenio Espejo Specialty Hospital, during the period January 2015 - January 2020. METHODOLOGY: This cross-sectional observational study was conducted in patients with hepatocarcinoma who underwent transarterial chemoembolization. A form was designed for the collection of information, through a pseudonymized database, which was analyzed using the statistical package SPSS version 26. RESULTS: 97 patients were analyzed, 60.8% were male, of which 56.7% presented some comorbidity; Most of the patients had no complications, however, arterial hypertension presented as a clinical manifestation after transarterial chemoembolization in 10.3%; shock, ascites edema decompensation and abdominal pain were the most frequent complications. The statistically significant data were the following: patients with hepatocellular carcinoma and liver cirrhosis with Child Pugh B severity had a higher percentage of complications valor p = 0,01; a larger tumor size compared to the number of lesions was related to presenting some post-transarterial chemoembolization complication valor p = 0,001, which meant an increase in hospital stay valor p = 0,006; patients who presented major and minor complications had a longer hospitalization time valor p < 0,05, the association between mortality and post chemoembolization complications in hospitalization and in the ICU had an overall rate of 3.2% valor p = 0,001. CONCLUSION. Major complications, such as edematous ascitic syndrome and shock, remained above the general average. With an expected mortality rate according to the international trend.

Proteomic analysis and validation of DNA repair regulation in the process of hepatocellular carcinoma recurrence / 临床肝胆病杂志

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.

Effect of kinesin family member 15 on the proliferation of hepatocellular carcinoma cells and its mechanism of action / 临床肝胆病杂志

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.

Research advances in second-line therapies for hepatocellular carcinoma after resistance to targeted therapy combined with immunotherapy / 临床肝胆病杂志

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.

Role of NOD-like receptor protein 3 inflammasome in the development and progression of hepatocellular carcinoma / 临床肝胆病杂志

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.

Efficacy and safety of cryoablation combined with lenvatinib and anti-PD-1 monoclonal antibody in treatment of unresectable hepatocellular carcinoma / 临床肝胆病杂志

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.

Efficacy and safety of transcatheter arterial chemoembolization combined with targeted therapy and immunotherapy in treatment of patients with stage Ⅱ‍b/Ⅲ‍a hepatocellular carcinoma based on China Liver Cancer Staging / 临床肝胆病杂志

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.

Current status and prospects of transarterial chemoembolization and its combined regimens in the treatment of hepatocellular carcinoma / 临床肝胆病杂志

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.

Preoperative prediction of GPC3 positive hepatocellular carcinoma and postoperative recurrence with the LI-RADS features on gadoxetate disodium-enhanced MRI / 中华放射学杂志

Objective:To investigate the predictive ability of Glypican-3 (GPC3) positive hepatocellular carcinoma based on the hepatobiliary specific contrast agent gadoxetate disodium enhancement of the liver imaging reporting and data system version 2018 (LI-RADS v2018) imaging features, and to assess the relevant clinical imaging features for postoperative recurrence in GPC3 positive HCC patients.Methods:This study was a cohort study. A total of 122 hepatocellular carcinoma patients who underwent gadoxetate disodium enhanced MRI examination with hepatic tumor resection in Henan Provincial People′s Hospital from January 2017 to December 2021 were retrospectively collected, including 96 GPC3 positive and 26 GPC3 negative patients. The imaging features defined by LI-RADS v2018 of HCC lesions were analyzed. Patients were followed up for 40 months to determine recurrence free survival (RFS). The logistic regression was used to analyze the risk factors of GPC3 positivity. An imaging model, and a clinical-imaging model which combined the patient′s alpha-fetoprotein levels were constructed. The efficacy of the model for predicting GPC3 positivity was assessed using receiver operating characteristic curves. Kaplan-Meier method was used to draw the survival curve, and the log-rank test was used to compare the RFS between GPC3 positive and negative patients. Risk factors affecting the recurrence of GPC3 positive HCC were assessed by Cox regression.Results:The results of logistic multivariate regression analysis confirmed that rim enhancement ( OR=5.685, 95% CI 1.229-26.287, P=0.026) and irregular tumor margin at hepatobiliary phase ( OR=4.431, 95% CI 1.684-11.663, P=0.003) were independent risk factors for GPC3 positive HCC. The area under the curve for predicting GPC3 positivity was 0.745 (95% CI 0.636-0.854) for the imaging model and 0.776 (95% CI 0.677-0.876) for the clinical-imaging model. The mean RFS in the GPC3 positive group was 22 months, and it was 32 months in the negative group. There was a statistically significant difference in RFS between the two groups ( χ2=5.15, P=0.023). The multivariate Cox regression analysis showed that the arterial rim enhancement ( HR=5.460, 95% CI 1.966-15.162, P=0.001), microvascular invasion ( HR=2.402, 95% CI 1.210-4.769, P=0.012), portal vein tumor thrombus ( HR=3.226, 95% CI 1.114-9.344, P=0.031) were independent risk factors for recurrence after hepatic tumor resection for GPC3-positive HCC. Conclusions:A model based on the LI-RADS v2018 imaging features of hepatobiliary specific contrast agent gadoxetate disodium enhancement can effectively predict GPC3 positive HCC. The arterial rim enhancement, microvascular invasion and portal vein tumor thrombus are independent risk factors for postoperative recurrence of GPC3 positive HCC.

The value of radiomics combined with deep learning based on preoperative CT images in predicting the curative effect of transarterial chemoembolization for hepatocellular carcinoma / 中华放射学杂志

Objective:To explore the value of radiomics and deep learning in predicting the efficacy of initial transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).Methods:This was a cohort study. The imaging and clinical information of HCC patients treated with TACE in the Second Affiliated Hospital of Harbin Medical University from January 2015 to January 2021 were collected retrospectively. A total of 265 patients were divided into response group (175 cases) and non-response group (90 cases) according to the modified solid tumor efficacy evaluation criteria (mRECIST) 1 to 2 months after initial TACE. According to the proportion of 8∶2, the patients were randomly divided into training group (212 cases, 140 responders and 72 non-responders) and test set (53 cases, 35 responders and 18 non-responders). Univariate and multivariate logistic regression was used to screen clinical variables and construct a clinical model. The radiomics features were extracted from the preoperative CT images, and radiomics model was constructed after feature dimensionality reduction. Using the deep learning method, three residual network (ResNet) models (ResNet18, ResNet50 and ResNet101) were established, and their effectiveness was compared and integrated to build a deep learning model with best performance. Univariate and multivariate logistic regression was used to combine pairwise three models to establish the combined model. The receiver operating characteristic curve was used to evaluate the performance of the model to distinguish between TACE response and non-response groups.Results:In the test set, the area under the curve (AUC) of the clinical model and the radiomics model in the differentiation between response and non-response after TACE were 0.730 (95% CI 0.569-0.891) and 0.775 (95% CI 0.642-0.907). The AUC of ResNet18, ResNet50 and ResNet101 were 0.719, 0.748 and 0.533, respectively. The AUC for deep learning model obtained by integrating ResNet18 and ResNet50 was 0.806 (95% CI 0.665-0.946). After pairwise fusion, the combined deep learning-radiomics model showed the highest performance, with an AUC of 0.843 (95% CI 0.730-0.956), which was better than those of the deep learning-clinical model (AUC of 0.838, 95% CI 0.719-0.957) and the radiomics-clinical model (AUC of 0.786, 95% CI 0.648-0.898). Conclusions:The combined model of radiomics and deep learning has high performance in predicting the curative effect of TACE in patients with HCC before operation.

Application of precision radiotherapy in the treatment of hepatocellular carcinoma / 中华放射肿瘤学杂志

With the development of radiotherapy technology, the role of radiotherapy in the treatment of primary liver cancer has been gradually recognized. In recent years, precision radiotherapy for hepatocellular carcinoma has become a research hotspot. A number of clinical trials have shown that precision radiotherapy can significantly improve clinical prognosis of patients with hepatocellular carcinoma. In this article, the research progress and existing problems of radiotherapy in the treatment of hepatocellular carcinoma were reviewed, aiming to provide literature support for the application of radiotherapy in the treatment of hepatocellular carcinoma.

Long-term efficacy of sequential surgery after immune combined with targeted therapy for initially unresectable hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To assess the long-term outcome of sequential radical surgery after immune combined with targeted therapy for patients with initially unresectable hepatocellular carcinoma (HCC).Methods:Clinical data of 100 patients with initially unresectable HCC undergoing sequential radical surgery after immune combined with targeted therapy at the Faculty of Hepato-Pancreato-Biliary Surgery of Chinese PLA General Hospital from December 2018 to August 2023 were prospectively collected, including 87 males and 13 females, with a median age of 55 (24-73) years. The pre-treatment tumor staging was determined using the China liver cancer staging (CNLC). The efficacy of immune combined with targeted therapy was accessed using the modified response evaluation criteria in solid tumor (mRECIST). The cycles of immune combined with targeted therapy were analyzed. The tumor residual of resected tissue was analyzed through a standard pathological protocol. The prognosis was analyzed using the Kaplan-Meier method.Results:Upon initial diagnosis, there were 46 cases (46.0%) staged CNLC-Ⅲa and 40 (40.0%) staged CNLC-Ⅲb. There were also 14 cases (14.0%) staged CNLC-Ⅰb, Ⅱa, and Ⅱb who underwent immune combined with targeted therapy due to rupture of tumor or insufficient liver remnant. All patients received a median of 5 (3-28) cycles of immune combined with targeted therapy and underwent radical surgery after successful conversion. According to mRECIST, 14 (14.0%) were determined as complete remission, 63 (63.0%) as partial remission, 18 (18.0%) as stable disease, and 5 (5.0%) as disease progression. Of 24 (24.0%) were defined as pathologically complete remission by postoperative pathology. Furthermore, pathological tumor residue was less than 10% in 61 (61.0%) cases and less than 50% in 82 (82.0%) cases. The 1, 3, and 5 year-overall survival rates of patients were 98.0%, 83.1%, and 74.5%, respectively. The 1, 2 and 3 year-recurrence-free survival rates were 67.5%, 54.8%, and 49.6%, respectively.Conclusion:Sequential radical surgery after immune combined with targeted therapy benefits the long-term survival of patients with initially unresectable HCC.

Effect of thrombocytosis on prognosis of hepatocellular carcinoma after TACE / 中华肝胆外科杂志

Objective:To analyze the prognosis of hepatocellular carcinoma (HCC) patients with thrombocytosis (platelet count ≥350×10 9) after transcatheter arterial chemoembolization (TACE), and the effect of thrombocytosis on the prognosis of patients with HCC after TACE. Methods:Clinical data of 867 patients with HCC admitted to the Department of Interventional Radiology, the Affiliated Hospital of Xuzhou Medical University from January 2013 to May 2018 were retrospectively analyzed. After propensity score matching, 99 patients were enrolled, including 70 males and 29 females, aged (60.1±12.1) years. Patients were divided into the groups with thrombocytosis ( n=33) and without thrombocytosis ( n=66). The gender, maximum tumor diameter, Barcelona clinical liver cancer (BCLC) stage, and total bilirubin were compared between the two groups. The association of thrombocytosis with the prognosis of HCC after TACE treatment were analyzed using univariate and multivariate Cox regression. Results:After propensity score matching, the male proportion, maximum tumor diameter, BCLC stage, and serum level of total bilirubin were comparable between the groups (all P>0.05). Before TACE treatment, the platelet count of patients with thrombocytosis was (394.4±54.5)×10 9/L, which was higher than that after TACE [(278.2±86.4)×10 9/L, t=7.63, P<0.001]. The progression-free survival rates after TACE in without thrombocytosis group were 83.3%, 24.2%, and 7.6% at 3, 6 and 9 months, respectively, better than those in thrombocytosis group (51.5%, 3.0%, and 3.0%, respectively; χ2=31.24, P<0.001). The overall survival rates after TACE in without thrombocytosis group were 81.8%, 30.3%, and 4.5% at 1, 2 and 3 years, respectively, better than those in thrombocytosis group (15.2%, 9.1%, and 3.0%, respectively; χ2=27.89, P<0.001). Multivariate Cox regression analysis showed that patients of HCC with thrombocytosis had an increased risk of tumor progression ( HR=5.785, 95% CI: 3.291-10.168, P<0.001) and increased risk of death ( HR=4.090, 95% CI: 2.482-6.740, P<0.001) after TACE. Conclusion:The prognosis of TACE for HCC might be worse in patients with thrombocytosis. Thrombocytosis is a risk factor for cumulative survival and progression-free survival of HCC patients after TACE.

Development and validation of a postoperative infection nomogram for hepatitis B-associated hepatocellular carcinoma patients after hepatectomy / 中华肝胆外科杂志

Objective:To develop and validate a postoperative infection nomogram of hepatitis B-associated hepatocellular carcinoma (HCC) after hepatectomy.Methods:Clinical data of 229 patients with HCC undergoing hepatectomy at the Department of Hepatobiliary Surgery of Tianjin Third Central Hospital from January 2014 to December 2022 were retrospectively analyzed, including 174 males and 55 females, aged (58.2±11.4) years. LASSO regression analysis screened the factors associated with hepatitis B-associated HCC infection after hepatectomy, which were further incorporated into multivariate logistic regression analysis. A nomographic prediction model was established based on the results of multivariate logistic regression analysis. Concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve were used to evaluate the model, and decision curve analysis (DCA) was used to analyze the clinical applicability of the model. Internal validation of the model was performed using bootstrap method.Results:A total of nine variables were screened as factors associated with the postoperative infections using LASSO regression, including gender, smoking history, body mass index (BMI), serum level of alpha fetoprotein, resection fashion (anatomical or non-anatomical), intraoperative blood loss, surgical method (laparoscopy or open), serum level of creatinine, and postoperative biliary fistula. Multivariate logistic regression analysis showed that BMI, resection fashion, intraoperative blood loss >500 ml, and postoperative biliary fistula were risk factors for postoperative infection (all P<0.05). Based on the above risk factors, a postoperative infection nomogram of hepatitis B-associated HCC after hepatectomy was established. The C-index was 0.839 (95% CI: 0.768-0.910), and the area under ROC curve was 0.853 (95% CI: 0.795-0.912), indicating that the model had a good predictive ability. The calibration curve was basically consistent with the ideal curve. The DCA showed that the model had a good clinical applicability. Internal validation C-index was 0.829 (95% CI: 0.766-0.892). Conclusion:The nomogram based on BMI, surgical resection fashion, intraoperative blood loss >500 ml, and postoperative biliary fistula has a high predictive accuracy and can be used to predict postoperative infections after hepatectomy for HCC.

The expression of SCAMP3 in hepatocellular carcinoma and its prognostic analysis based on TCGA database / 中华肝胆外科杂志

Objective:To study the expression and prognostic impact of secretory carrier membrane protein 3 (SCAMP3) in hepatocellular carcinoma (HCC) and its gene set enrichment analysis.Methods:SCAMP3 expression and its prognosis were analyzed using The Cancer Genome Atlas (TCGA) database. The cancer tissue and paracancerous tissue were collected from four patients with HCC undergoing surgery in Lishui Central Hospital to detect the expression of SCAMP3. Based on TCGA database, univariate and multivariate Cox regression was performed to analyze the relevance of SCAMP3 with prognosis of HCC. Gene set enrichment analysis was utilized to clarify the biological role of SCAMP3.Results:In TCGA database, SCAMP3 expression was higher in HCC tissues than that in normal liver tissues ( Z=-8.38, P<0.001). Patients were divided into the low-expression group ( n=185) and high-expression group ( n=185) based on the median SCAMP3 expression, and the overall survival rate was lower in patients with high SCAMP3 expression. In our four patients. The expression of SCAMP3 mRNA and protein in cancer tissues was higher than that in paracancerous tissues ( t=8.55, 6.24, both P<0.001). In multivariate Cox regression analysis, the higher SCAMP3 expression was associated with a higher risk of death ( HR=1.466, 95% CI: 1.143-1.881, P<0.001). Gene set enrichment analysis in patients with high SCAMP3 expression, the coagulation cascade and three signaling pathways involving the complements, retinol metabolism, and peroxisome proliferator-activated receptor were identified. Conclusion:SCAMP3 expression elevated in HCC, patients with a higher expression of SCAMP3 might have a worse prognosis. High SCAMP3 expression is a risk factor for the survival of patients with HCC. High SCAMP3 expression is associated with the coagulation cascade and the complements, retinoid metabolism, and peroxisome proliferator-activated receptor pathways.

Expression of BCL7A in hepatocellular carcinoma and its effects on prognosis, invasion and migration of hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To analyze the expression and prognosis of B-cell lymphoma 7 protein family member A (BCL7A) in hepatocellular carcinoma, as well as the effect and mechanism of BCL7A expression on the invasion and migration of hepatocellular carcinoma cells.Methods:The cancer tissues and adjacent tissues of 40 patients with hepatocellular carcinoma who underwent radical hepatobiliary resection in the Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University from November 2017 to March 2018 were prospectively collected for protein extraction, including 29 males and 11 females, aged (58.5±10.4) years. The information of 374 cases of hepatocellular carcinoma and 50 cases of adjacent tissues were downloaded from The Cancer Genome Atlas (TCGA) database, and the hepatocellular carcinoma cell lines Hep3B and SMMC-7721 were transfected with overexpressing BCL7A plasmid and empty vector plasmid (negative control), respectively. Western blotting and immunohistochemistry were used to detect the expression of BCL7A, and Western blotting was also used to detect the expression of proteins related to epithelial-mesenchymal transition (N-cadherin, E-cadherin, snail). Transwell and cell scratch assays were used to detect cell invasion and migration.Results:Compared with adjacent tissues, the mRNA expression of BCL7A in 50 patients with hepatocellular carcinoma in TCGA was significantly increased ( t=13.38, P<0.001). According to the median mRNA expression level of BCL7A, 374 patients were divided into BCL7A high expression group ( n=187) and low expression group ( n=187), and the cumulative survival rate of BCL7A high expression patients was lower than that of low expression group, and the difference was statistically significant ( χ2=6.95, P=0.009). Western blot was used to detect the relative expression of BCL7A protein in cancer tissues, and found it was higher compared to adjacent tissues. Compared with the negative control group, the number of cells invaded by the BCL7A overexpression group of hepatoma cells Hep3B and SMMC-7721 was more than the negative control group respectively, (153.7±1.3) vs (63.7±4.7) and (307.7±25.14) vs (72.3±12.5), and the differences were statistically significant ( t=7.97, 8.38, both P=0.001) .The results of the cell scratch assay were consistent with the results of the Transwell invasion assay. The expressions of N-cadherin and snail in the BCL7A overexpression group were higher than those in the negative control group, and the E-cadherin was lower, and the difference was statistically significant (all P<0.05). Conclusions:The expression of BCL7A in cancer tissues of patients with hepatocellular carcinoma is elevated and is associated with poor prognosis. BCL7A may promote hepatocellular carcinoma cell metastasis and invasion by promoting epithelial-mesenchymal transition.

Expression and prognostic significance of nuclear matrix protein 4 in hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To investigate the expression of nuclear matrix protein 4 (NMP4) in hepatocellular carcinoma (HCC), and its relationship with clinicopathological features and survival prognosis of patients.Methods:The clinical data of 100 HCC patients who were treated with radical resection of liver cancer in the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Wenzhou Medical University from July 1, 2014 to July 1, 2019 were retrospectively analyzed. There were 63 males and 37 females, aged (58.5±10.4) years old. Immunohistochemical method was used to detect the expression of NMP4 protein in HCC cancer tissue and the corresponding adjacent normal tissue. According to the expression of NMP4 in HCC tissues, 100 patients were divided into two groups: the NMP4-positive expression group ( n=62) and the NMP4-negative expression group ( n=32). Univariate analysis was performed on the relationship between NMP4 expression and clinical pathological features as well as overall survival of HCC patients. Cox multivariate analysis was performed on the factors influencing postoperative prognosis of HCC patients. Results:Immunohistochemistry results showed that NMP4 was primarily expressed in the nucleus, the positive expression rate of NMP4 in HCC tissues was higher than that in adjacent non-cancerous tissues [62.0% (62/100) vs. 8.0%(8/100)], and the difference was statistically significant ( χ2=2.12, P=0.003). Univariate analysis revealed that the overall survival of HCC patients was correlated with the degree of tumor differentiation, tumor length, BCLC stage, number of tumor foci, vascular tumor thrombus and expression of NMP4 (all P<0.05). Cox multivariate analysis revealed that low differentiation, high BCLC stage (stage C), number of tumor foci (≥3), and positive expression of NMP4 were independent risk factors affecting postoperative survival and recurrence-free survival of HCC patients. The median overall survival and median recurrence-free survival of HCC patients in the NMP4-positive expression group were 22.3 months and 11.5 months, respectively. In contrast, that in the NMP4-negative expression group were 40.6 months and 19.4 months, respectively. The cumulative survival rate and recurrence-free survival rate of HCC patients in the NMP4-positive expression group were lower than those in the NMP4-negative expression group, and the differences were statistically significant (both P<0.05). Conclusion:Positive NMP4 expression was closely correlated with malignant biological progression and poor prognosis of HCC patients.

Transcriptomics combined with proteomics to analyze the signaling pathway of EGFL9 gene affecting the proliferation, invasion and migration of hepatocellular carcinoma / 中华肝胆外科杂志

Objective:Transcriptomics combined with proteomics was used to analyze the potential signaling pathways of epidermal growth factor-like domain 9 (EGFL9) affecting the proliferation, invasion and migration of hepatocellular carcinoma.Methods:RNA interference technique was used to build hepatocellular carcinoma cell line with EGFL9 Huh-7 gene knockdown, the control group (NC group) and experimental group (KD group), each group of three samples, were performed the transcriptome and proteomics analysis, screening differences genes and proteins, to express the correlation analysis, cluster analysis, and subsequently gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) were used for gene function and pathway annotation enrichment analysis, respectively.Results:Based on omics analysis, there were 8 335 different genes in KD group compared with NC group, among which 4 207 were up-regulated and 4 128 were down-regulated. There were 298 different proteins, of which 188 were up-regulated and 110 down-regulated. Based on the combined analysis of the two omics, 213 differentially expressed genes were found. Among them, the top three common differentially expressed genes at the level of transcription and translation were transferrin receptor 2 (TFR2), annexin A1 (ANXA1) and solute carrier family 38 member 2(SLC38A2). The common differentially expressed genes were significantly enriched in cell cycle signaling pathway, amino acid biosynthesis pathway, p53 signaling pathway and glycolysis/gluconeogenesis signaling pathway.Conclusion:EGFL9 may participate in the regulation of cell function of hepatocellular carcinoma cells by regulating the expression of TFR2, ANXA1, LC38A2 and other genes, and may play a role through the regulation of cell cycle and other molecular signaling pathways.

Research progress of vascular interventional therapy combined with systemic therapy for unresectabl hepatocellular carcinoma / 中华肝胆外科杂志

Primary liver cancer is a malignant tumor with high morbidity and mortality. It also ranks in the forefront in the incidence and mortality of malignant tumors in China, which seriously threatens the lives and health of Chinese people. Most patients have already been in the intermediate and late stage when they are diagnosed, thus the chance of surgery is lost, and the prognosis is poor. In recent years, with the advancement of vascular interventional therapy technologies such as hepatic arterial chemoembolization and hepatic arterial infusion chemotherapy, the emergence of new tyrosine kinase inhibitors, immune checkpoint inhibitors, and especially the development of multimodal combination therapy, the treatment effect of unresectable hepatocellular carcinoma has been continuously improved, and it also provides a potential possibility for sequential surgical treatment. This article reviews the research progress of vascular interventional therapy combined with systemic therapy in unresectable hepatocellular carcinoma, in order to provide a reference for the clinical treatment of unresectable hepatocellular carcinoma.

Analysis of 19 cases of resection of abdominal metastases after liver resection for hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To evaluate the reoperation of abdominal metastasis after liver resection for hepatocellular carcinoma (HCC).Methods:The data of 2748 patients with liver cancer undergoing surgical resection at the Department of Hepatobiliary and Pancreatic Surgery of Li Huili Hospital of Ningbo Medical Center from January 2010 to January 2022 were retrospectively screened. A total of 19 patients with abdominal metastases after liver resection undergoing reoperation were enrolled, which were all males with a median age of 53 years (27 to 68). The surgical procedures and diagnosis for abdominal metastases were recorded, and the recurrence and survival of patients were followed up.Results:During the follow-ups of initial resection of HCC, 10 patients were diagnosed with postoperative abdominal metastasis by enhanced CT, and seven patients were diagnosed by MRI. MRI and PET/CT were negative in two patients. Abdominal metastasis was found during reoperation in one case and liver transplantation in the other case due to postoperative liver recurrence. All 19 patients successfully underwent radical resection of abdominal metastases. Eighteen patients underwent open surgery and one underwent laparoscopic surgery. Among them, nine cases underwent simple metastases resection, six combined liver resection, one combined liver resection and right hemicolectomy, one combined partial rectal resection, one combined partial small bowel resection, and one combined liver transplantation. The 1-year, 3-year, and 5-year disease-free survival rates were 26.3%, 15.8%, 10.5%, respectively. The 1-year, 3-year, and 5-year overall survival rates were 94.7%, 26.3%, 15.8%, respectively. Three patients are currently surviving disease-free for 154.3 months, 67.3 months, and 33.4 months, respectively. These three patients all had single abdominal metastase and did not receive any targeted or immune treatments after surgery.Conclusion:For patients with localized or single abdominal metastases after HCC surgery, reoperation for metastases can bring survival benefits.