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Objective:To investigate the clinical efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus PD-1 inhibitor (TACE+Len+PD-1) versus TACE combined with lenvatinib (TACE+Len) for patients with unresectable intermediate-advanced hepatocellular carcinoma (HCC).Methods:The data of 94 patients with intermediate-advanced HCC who received TACE+Len+PD-1 (One week after TACE, the patient were treated with lenvatinib and PD-1 inhibitor. lenvatinib, 8 or 12 mg/d, orally; PD-1 inhibitor, 200 mg/3 weeks, iv) or TACE+Len (One week after TACE, the patient were treated with lenvatinib.lenvatinib, 8 or 12 mg/d, orally) in the Second Affiliated Hospital of Guangzhou Medical University from June 2019 to February 2021 were collected and retrospectively analyzed. Among these patients, 44 were in the TACE+Len+PD-1 group and 50 were in the TACE+Len group. Tumor responses were evaluated according to modified response evaluation criteria in solid tumors. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were compared between the two groups. The potential prognostic factors for PFS and OS were determined.Results:The ORR of TACE+Len+PD-1 group and TACE+Len group was 72.8% (32/44) and 52.0% (26/50) (χ2=4.25, P=0.039), respectively. The DCR of TACE+Len+PD-1 group and TACE+Len group was 86.4% (38/44) and 62.0% (31/50) (χ2=7.12, P=0.008), respectively. The median PFS and median OS in TACE+Len+PD-1 group were significantly longer than those in TACE+Len group (PFS, 7.9 vs. 5.6 months, χ2=7.91, P=0.005; OS, 18.5 vs. 13.6 months, χ2=4.40, P=0.036). Multivariate Cox regression analyses showed that TACE+Len (HR=2.184,95%CI 1.366-3.493), incomplete tumor capsule (HR=2.002,95%CI 1.294-3.209) and extrahepatic metastasis (HR=1.765,95%CI 1.095-2.844) were the independent risk factors for PFS, while TACE+Len (HR=2.081,95%CI 1.097-3.948) and BCLC stage C (HR=7.325,95%CI 2.260-23.746) were the independent risk factors for OS. The incidence of ≥grade 3 AEs in TACE+Len+PD-1 group was similar to that in TACE+Len group (χ2=0.45, P=0.501). Conclusion:Compared with TACE+Len, TACE+Len+PD-1 resulted in a better tumor response and a longer PFS and OS in patients with intermediate-advanced HCC.
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Objective:To evaluate the efficacy and safety of anti-programmed cell death 1 (PD-1) receptor monoclonal antibody (MoAb) in patients with advanced hepatocellular carcinoma (HCC) after treatment of transcatheter arterial chemoembolization (TACE) combined with tyrosine kinase inhibitor (TKI).Methods:From February 2019 to February 2020, 56 HCC patients who relapsed after TACE-TKI treatment in Department of Interventional Radiology, The Second Affiliated Hospital of Guangzhou Medical University were enrolled. All patients received anti-PD-1 MoAb (sintilimab injection) and followed up every 6 weeks. According to mRECIST, the curative effect was evaluated as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Objective response rate (ORR) and disease control rate (DCR), progression-free survival (PFS) and treatment-related adverse events (TRAEs) were recorded. Univariate analysis by Chi-square test and binary logistic regression model was used to determine the influencing factors of DCR. The Kaplan-Meier method and Cox proportional hazard regression model were used to analyze the survival data.Results:A total of 48 patients were enrolled in this study including 42 males and 6 females, with a median age of 55 years (29-71 years). ECOG scores comprised of 0 in 24 cases, 1-2 in 24 cases. Thirty-six patients were in Child-Pugh grade A of liver function and 12 cases were grade B. The median follow-up time was 4.5 months. There were 2 patients achieved CR, 12 patients with PR and 16 with SD. ORR was 29.2%, DCR was 62.5%. The independent influencing factors of DCR was ECOG score and AFP level ( P=0.031, P=0.012). Median PFS was 4.1 months (95% CI 2.7-5.4 months), and ECOG score was the independent influencing factor of PFS ( P=0.042). Treatment-related adverse events were reported in 70.8% (34/48) patients. Incidence of grade Ⅲ-Ⅳ TRAEs was 22.9% (11/48). Conclusion:In patients with HCC who relapse from TACE and TKI treatment, anti-PD-1 monoclonal antibody is efficacious safe especially in those with ECOG 0 score.
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Objective:To study the use of radioactive I-125 seed implantation in the treatment of transarterial chemoembolization (TACE)-refractory hepatocellular carcinoma (HCC).Methods:A retrospective study was conducted on 70 patients with HCC who were initially treated with TACE between July 1, 2016 and August 31, 2019 at the Second Affiliated Hospital of Guangzhou Medical University. After these patients were found to be refractory to TACE, 29 patients were converted to radioactive I-125 seed implantation (the 125I seed group), and 41 patients were continued with TACE (the TACE group). The objective response rate, progression-free survival (PFS), overall survival (OS), total overall survival (TOS) of the two groups were compared. Results:There were 59 males and 11 females, aged (60.5±11.9 ) years in this study. At 1, 3, 6 months after treatment, the objective response rates of the 125I seed group were 20.7%, 40.7%, 34.6%, respectively, which were significantly higher than that of the TACE group of 2.6%, 3.3%, 5.0%, respectively. The PFS, OS, TOS in the 125I seed group were 7.6, 21.1, 32.1 months, respectively, which were significantly better when compared with the TACE group (3.5, 8.5, 14.8 months, respectively, all P<0.05). There was no significant difference in the embolization syndrome between the two groups [93.1%(27/29) vs 100.0%(41/41), P>0.05]. Child-Pugh B grading ( HR=0.311, 95% CI: 0.160-0.603, P=0.005) and TACE ( HR=0.308, 95% CI: 0.159-0.597, P=0.002) were independent risk prognostic factors for survival. Conclusion:This study showed better treatment efficacy and safety using radioactive I-125 seed implantation in TACE-refractory HCC and this treatment significantly improved survival of patients when compared with TACE alone.
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Objective@#To synthesize a folic acid (FA)-modified pH-sensitive nanomicelle containing sorafenib (SF) and superparamagnetic iron oxide (SPIO), and to access its visibility in MRI and anti-cancer efficacy on hepatocellular carcinoma (HCC) in vitro.@*Methods@#The copolymer FA-PEG-Pasp (DBA/DIP) of FA, poly(ethylene glycol), N,N-dibutylethylenediamine and N,N-diisopropylethylenediamine grafted poly (L-aspartic acid) were prepared. SF and SPIO were encapsulated inside the copolymer to synthesize the targeting micelle FA-PEG-PAsp (DBA/DIP)-SPIO/SF (FPASS). The folate-free micelle[PEG-PAsp (DBA/DIP)-SPIO/SF (PASS)] was used as nontargeting micelle. The physicochemical properties and drug release behavior of the micelles were analyzed. MRI of HepG2 cells incubated with FPASS and PASS with different Fe concentrations and Prussian blue staining of cells treated with the micelles (Fe concentration of 20 μg/ml) was performed to assess the drug delivery capability and imaging function of the micelles. For the FA competitive inhibition assay in these experiments, HepG2 cells were pre-treated with an excess amount of free FA prior to the incubation with FPASS. Cell viability, cell apoptosis, cell cycle and tube formation assays were conducted for evaluating the anti-HCC effects of the micelles. Comparison between groups was analyzed by one-way ANOVA, and multiple comparisons correction was performed by LSD test.@*Results@#The diameters of FPASS and PASS were (102.3±5.2) nm and (107.1±5.7) nm, respectively; the δ potentials of them were (29.7±1.6) mV and (31.5±1.4) mV, respectively. The T2 relaxivity of both the micelles was (5.2±0.4) ml·μg-1·s-1, which was much higher than that of water soluble Fe3O4 nanoparticles [(2.3±0.1) ml·μg-1·s-1; F=76.45, P<0.01]. SF released from the micelles was much faster at pH5.0 than at pH7.4, which indicated that the micelles had a pH-triggered drug release behavior. MRI of HepG2 cell samples revealed the signal intensity on T2WI images and the T2 value on T2-map images decreased with the increasing Fe concentrations in the micelles. At the same Fe concentration (5, 10, 20 and 40 μg/ml), the cells of FPASS group exhibited a more significant decrease in T2 signal intensity and T2 value compared with those of PASS group or FA competitive inhibition group (F=8.69, 14.03, 27.27, 32.25 and 19.80, 45.76, 113.20, 66.80; P<0.01). Prussian blue staining verified the existing of SPIO in the cytoplasm of cells. Compared with PASS, FPASS presented significantly higher anticancer effects on inducing apoptosis, causing G0/G1 phase arrest on HepG2 cells and inhibiting tube formation on human umbilical vein endothelial cells (t=7.905, 4.399 and 3.454, respectively; P<0.01).@*Conclusions@#The pH-sensitive nanomicelle FPASS was successfully constructed. This micelle possessed a hypersensitive MRI-visible function and a targeting SF delivery capability which may contribute to a significant anti-HCC effect.
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Objective To establish two types of portal hypertension (PHT) models in mice by using bile duct ligation (BDL) method and carbon tetrachloride (CCl4) induction technique respectively. Methods A total of 24 C57BL/6 mice were randomly and equally divided into the following four groups with 6 mice in each group: group BDL, control group of BDL, group CCl4, and control group of CCI4. After the establishment of PHT, the main portal vein was punctured in all experimental mice to measure the portal vein pressure, and blood sampling was collected to test serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Using hematoxylin eosin (HE) and sirius red staining the liver tissues were pathologically examined. Immunohistochemical study of alpha smooth muscle actin (SMA) was adopted to evaluate the liver function, hepatic fibrosis and hepatic stellate cell activation status. Results Both modeling methods could make the portal vein pressure increased in experimental mice. The increasing of portal vein pressure in group CCl4 was more obvious. Compared with their corresponding control groups, the degree of liver damage, hepatic fibrosis and hepatic stellate cell activation in group BDL and group CCl4 were more serious. Conclusion Both BDL method and CCl4 induction technique can successfully establish the mouse model of PHT. All the portal venous pressure, the serum biochemical indices and the changes of liver pathology of the mouse model are well in line with the characteristics of PHT in human. (J Intervent Radiol, 2018, 27:242-246)
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Objective To evaluate the therapeutic effect of transarterial chemoembolization (TACE) combined with CT-guided 125I seed implantation in treating hepatocellular carcinoma (HCC) complicated by portal vein tumor thrombus(PVTT), and to discuss the technical points. Methods A total of 48 HCC patients with PVTT were enrolled in this study. TACE combined with CT-guided 125I seed implantation was carried out in all 48 patients. Based on the sites of PVTT, the lesions were classified into type A (PVTT within main portal vein), type B(PVTT within level-1 portal branch) and type C(PVTT within level-2 or more distal portal branch). According to whether the 125I seeds were directly implanted into the PVTT or not, the patients were divided into direct in-tumor thrombus implantation group (group A) and around tumor thrombus implantation group (group B; the 125I seeds were implanted in the liver parenchyma or in tumor tissue around the tumor thrombus within 1.7 cm region). The tumor thrombus control rate(TTCR), the disease control rate(DCR), the time to progress(TTP) and the overall survival rate of patients(OS) were determined, and the results were compared among different types and groups. Results TACE combined with CT-guided 125I seed implantation was successfully accomplished in all 48 patients. The median OS of type A, B and C was 8, 11.5 and 15 months respectively(P=0.003);the TTCR of type A, B and C was 61.5%, 70.8%and 72.7%respectively(P=0.548); the DCR of type A, B and C was 69.2%, 75%and 81.8% respectively (P=0.483); the median TTP of type A, B and C was 4.5, 8 and 11 months respectively(P=0.030);the median TTP of intra-hepatic tumor of type A, B and C was 5, 9 and 9.5 months respectively(P=0.012). The median OS in group A and group B was 10 and 11.5 months respectively (P=0.239); the TTCR in group A and group B was 69.2% and 68.2%respectively(P=0.591); the DCR of intra-hepatic tumor in group A and group B was 73.1% and 77.3%respectively(P=0.502); the median TTP of tumor thrombus in group A and group B was 7 and 10 months respectively(P=0.276); and the median TTP of intra-hepatic tumor in group A and group B was 8 and 9.5 months respectively(P=0.089). Conclusion For the treatment of hepatocellular carcinoma complicated by portal vein tumor thrombus, TACE combined with CT-guided 125I seed implantation can effectively control the progress of both the tumor thrombus and the intra- hepatic tumor and prolong patient’s survival time. Implantation of 125I seeds into the portal vein tumor thrombus and implantation of 125I seeds into the liver parenchyma around the tumor thrombus have the same therapeutic results. (J Intervent Radiol, 2015, 24:488-493)
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Objective To study the characteristics of DWI in nude mice models of hepatic Bel7402 tumors after treatment with adenovirus-mediated cytosine diaminase-thymidine kinase ( Ad.CD-TK) double suicide gene therapy, and then to identify whether DWI can be used for assessing curative effect of postoperative tumors.Methods Thirty nude mice models of hepatic Be17402 tumors were successfully created using cell suspension method,after the tumor grew to more than 1 cm in diameter,20 tumor models were treated by intratumoral administration of Ad.CD-TK for 3 days plus intraperitonea( i.p.) treatment with 5-Fc and GCV for the duration of the study.Then they were randomly divided into three groups during 5-Fc and GCV treatment.The remaining 10 tumor models were used as controls.MR scanning were performed in 10th day before and after tumor implantation in all models by using EPI-SE series and SENSE technology for treatment group. Tumor volumes and ADC values were calculated pretreatment and posttreatment. Cell apoptosis were determined by using TUNEL method.Analyze the change of ADC and apoptosis index (AI) in different times,t test was used for comparison the difference of AI and ADC values respectively. Results After 10 days,the tumor volumes of the treatment groups and controls were respectively (724.16 ±57.45 ) mm3,( 754.57 ± 66.84 ) mm3,with no significant difference ( t =0.488,P ＞ 0.05 ).The ADC values of the treatment groups were (0.98 ±0.11 ) × 10-3 mm2/s,the ones of the control groups were (0.68 ±0.04) × 10 -3mm2/s;AI of the treatment groups were(23.25 ±6.57)％,the ones of the control groups were (2.57 ± 0.58) ％.There were difference in both groups ( t =4.473,5.874 ; P ＜ 0.01 ).Conclusion DWI can be effectively to monitor the early pathological changes of hepatic Bel7402 tumors after Ad.CD-TK double suicide gene therapy,and provide experimental evidences for clinical application.