4084 Background: Previously, we reported the results of Ori-C101 from investigator initiated trial in China (ChiCTR1900028121). The data demonstrated that Ori-C101 owned a favorable safety profile and promising efficacy. Among 10 GPC3 + HCC patients (pts) treated with Ori-C101, 9 pts (90%) achieved disease control and 6 pts (60%) met partial response per RECIST 1.1. Two pts with PR attained progression-free survival of one and two years respectively, with an overall survival close to 3 years. These results implied that Ori-C101 potentially held significant clinical benefits. Subsequently, extensive optimizations and improvements in the manufacturing process were implemented to enhance its clinical efficacy and persistency. Hence, a multicenter registration study was launched in China (the BEACON study), and herein, we will present the preliminary results. Methods: This is an open-label, multi-center, dose-escalation (3+3 design) study. GPC3 + advanced HCC pts who failed at least 2 lines of systemic treatments received a single hepatic arterial infusion with a total dose of 0.9 to 6×10 8 CAR-T cells. Primary endpoints are rate of dose-limiting toxicities (DLTs) and safety with the aim to determine a recommended phase II dose (RP2D). Secondary endpoints are cellular kinetics, overall response rate by investigator assessment, duration of response, overall survival and overall safety. Results: As of Dec 17th, 2024, a total of 10 eligible pts received Ori-C101 infusion at 3 dose levels (DLs). All pts had BCLC stage B or C, with 20% (2/10) had extrahepatic metastasis. The median number of prior lines of therapy was 4.5 (range 2-9), 100% pts received immune checkpoint inhibitors and tyrosine kinase inhibitors. All pts were evaluable for safety. All adverse events were reported regardless of study drug relationship. Of 10 pts evaluable for safety, the most common ≥ grade (G) 3 AEs were lymphocyte count decreased (100%), neutrophil count decreased (60.0%), blood fibrinogen decreased (40.0%), transaminases increased (40.0%), platelet count decreased (20.0%), blood bilirubin increased (20.0%). CRS was observed in 10 (100%) pts with 3 (30.0%) ≥ G3 CRS. No ICANS was observed. One pt developed DLT event due to CRS and secondary disseminated intravascular coagulation. 9 pts were evaluable for efficacy per RECIST 1.1. While 6 pts (66%) achieved disease control at DL2 or higher, all pts at the DL3 achieved objective response. Particularly, one pt who achieved CR showed encouraging durability and no signs of relapse at 9 months follow up evaluation, and follow up is ongoing. Conclusions: These preliminary data showed Ori-C101 has manageable safety profile and exciting efficacy with encouraging sign of good durability. Currently, more pts have been enrolled at dose expansion to confirm the DLs of RP2D. More information will be presented at coming ASCO conference. Clinical trial information: NCT05652920 .

Objective To summarize the therapeutic efficacy of liver transplantation in patients with intrahepatic cholangiocarcinoma（ICC） and to analyze the prognostic risk factors. Methods The clinicopathological data of 46pathological confirmed ICC patients who underwent liver transplantation in Zhongshan Hospital Affiliated to Fudan University from April 2001 to February 2022 were analyzed retrospectively. The survival and recurrence of the patients were followed up. Kaplan Meier method was employed to analyze the overall survival（OS） rate and relapse-free survival（RFS） rate of patients, and Cox regression model was used to evaluate the risk factors affecting the prognosis. Results The median overall survival time of patients with ICC after liver transplantation was 19 months, and the 1, 3, 5-year OS rates were 64.4%, 30.2%, 20.7%, respectively. The median RFS time was 10 months, and the 1, 3 and 5-year RFS rates were 45.8%, 20.8%,10.4%, respectively. The results of multivariate analysis revealed that the level of preoperative carbohydrate antigen19-9（CA19-9）（P = 0.026） was an independent risk factor for the overall survival time of patients, and local extrahepatic structures due to direct ICC invasion（P = 0.019） was an independent risk factor for tumor recurrence and metastasis. Conclusion The prognosis of liver transplantation for intrahepatic cholangiocarcinoma is poor. The high level of preoperative CA19-9 is an independent risk factor for short postoperative survival of recipients, and direct tumor invasion of extrahepatic tissues is an independent risk factor for high recurrence rate after liver transplantation.

目的:探讨术前乙型肝炎病毒(hepatitis B virus,HBV)感染状态与肝癌切除术后预后的关系.方法:选择2014年7月至2015年6月复旦大学附属中山医院收治的行根治性切除的肝细胞癌患者910例,收集术前乙肝两对半和HBV-DNA的结果,结合临床病理信息和随访资料,阐明肝癌患者乙肝感染状态和其对患者预后的影响.结果:95.1％ 的肝癌手术患者存在乙型肝炎病毒感染,其中以"小三阳"者最为多见,占54.2％.HBV-DNA的阳性患者术后无瘤生存率及总生存率显著低于阴性患者(P<0.05).HBV-DNA阳性组和阴性组的肝硬化程度、甲胎蛋白(alpha-fetoprotein,AFP)水平、肿瘤大小以及血管侵犯差异均有统计学意义(P<0.001).结论:完善乙肝血清学标志物的检测,有利于肝癌的防治以及改善患者预后.

Our previous studies revealed that tetraspanin CD151 plays multiple roles in the progression of hepatocellular carcinoma (HCC) by forming a functional complex with integrin α6β1. Herein, we generated a monoclonal antibody (mAb) that dissociates the CD151/integrin α6β1 complex, and we evaluated its bioactivity in HCCs. A murine mAb, tetraspanin CD151 (IgG1, called CD151 mAb 9B), was successfully generated against the CD151-integrin α6β1 binding site of CD151 extracellular domains. Co-immunoprecipitation using CD151 mAb 9B followed by Western blotting detected a 28 kDa protein. Both immunofluorescent and immunohistochemical staining showed a good reactivity of CD151 mAb 9B in the plasma membrane and cytoplasm of HCC cells, as well as in liver cells. In vitro assays demonstrated that CD151 mAb 9B could inhibit neoangiogenesis and both the mobility and the invasiveness of HCC cells. An in vivo assay showed that CD151 mAb 9B inhibited tumor growth potential and HCC cells metastasis. We successfully produced a CD151 mAb 9B targeting the CD151/integrin α6β1-binding domain, which not only can displayed good reactivity to the CD151 antigen but also prevented tumor progression in HCC.

Phosphomannopentaose sulfate (PI-88), an effective inhibitor of heparanase (HPSE), exhibited anti-recurrence and anti-metastasis activity in preliminary clinical trials of hepatocellular carcinoma (HCC); however, the underlying mechanisms remain uncertain. Our aim was to reveal the mechanism by which PI-88 inhibits recurrence and intrahepatic metastasis. A tissue microarray containing samples from 352 HCC patients was used to determine HPSE expression. We performed enzyme-linked immunosorbent assay (ELISA) to detect plasma levels of HPSE in 40 HCC patients. We also used quantitative polymerase chain reaction, western blot analysis, and immunohistochemical staining to assess HPSE expression of HCC cell lines and tissues. The in vitro effects of PI-88 were examined by cell proliferation and migration assays. In vivo PI-88 activity was assessed using murine orthotopic HCC models. Intratumoral HPSE was an independent prognostic marker for postsurgical overall survival (P = 0.001) and time to recurrence (P < 0.001) of HCC patients with hepatectomy. Elevated levels of HPSE were detected both in postsurgical plasma of HCC patients and an orthotopic mouse model after hepatectomy. PI-88 inhibited tumor recurrence and metastasis after liver resection in the mouse model. In vitro expression of HPSE was up-regulated by overexpression of early growth response 1 (EGR1), which is induced after hepatectomy. Up-regulation of HPSE enhanced the sensitivity of HCC cells to PI-88 and the inhibitive effect of PI-88 on cell proliferation and migration. Our data show that PI-88 effectively inhibits postoperative recurrence and intrahepatic metastasis of HCC, providing an experimental basis for the clinical application of PI-88 in HCC patients who have undergone hepatectomy.

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play an important role in chromatin remodeling and transcriptional regulation. In this study, we found that BRD4, a BET family member, is significantly upregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues. Furthermore, the overexpression of BRD4 in cancer tissues was correlated with poor prognosis in HCC patients. Using shRNA-mediated knockdown of BRD4 or lentivirus-mediated overexpression of BRD4 in HCC cells, we further showed that BRD4 was involved in HCC cell growth and invasion in vitro. Forced expression of BRD4 was sufficient to induce epithelial-mesenchymal transition (EMT) phenotypes in HCC cells. Additionally, BRD4 shRNA significantly inhibited HCC cell proliferation in vivo. Collectively, our study confirmed that BRD4 expression is a valuable predictor of recurrence and survival in patients with HCC. BRD4 can be further used as a potential therapeutic target of HCC.

The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin-specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro. Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor-interacting protein 12 (TRIP12), which induces constitutive p14(ARF) ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha-fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC. Conclusion: USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14(ARF) and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC. (Hepatology 2015;61:1603-1614)

Objective To evaluate the safety and technical feasibility of salvage liver transplantation(SLT) after liver resection,and its influence on prognosis.Methods The clinical data of 289 patients who underwent liver transplantation by cadaveric grafts treating for hepatocellular carcinoma met the UCSF criteria from June 2001 to December 2008 were analyzed retrospectively.Among them,242 patients underwent primary liver transplantation(PLT,PLT group),and 47 patients underwent SLT for recurrence(SLT group).Perioperative factors and survival were compared between two groups.Results There were no significant differences of age,gender,and pathology of tumor between two groups(P>0.05).The operation time in the SLT group was significantly longer than that in the PLT group((7.1±1.8) h versus(6.4±1.4) h,P=0.004).The differences of intraoperative blood loss((2 560.5±2 683.6) ml versus(2 042.9±2 006.2) ml,P=0.173) and blood transfusion((13.8±12.9) U versus(9.9±12.6) U,P=0.087) were not significant between two groups.The mean interval time from resection to transplantation was(32.8±32.4) months.The median follow-up was 38.7 months,3-year overall and disease-free survivals were not significantly different(82.3% versus 75.5%,P=0.312;78.8% versus 70.1%,P=0.755,respectively) between the SLT group and PLT group.According to intention-to-treat analysis,the 3-year overall survival in the SLT group was significantly longer than that in the PLT group(88.4% versus 76.2%,P=0.047).Conclusions In selected patients,liver resection prior to transplantation neither increases operative morbidity nor impairs prognosis following liver transplantation.SLT after liver resection,can be an alterative treatment for HCC.

目的: 进一步研究干扰素-α(IFN-α)对人肝癌细胞胸苷磷酸化酶(TP)表达及凋亡的双重影响.方法: 体外分别用0 、10 、100 、1000 、5000、10 000 kU/L IFN-α处理人肝癌细胞SMMC-7721, RT-PCR检测细胞TP mRNA表达水平, 免疫细胞化学方法检测细胞TP蛋白表达变化, 流式细胞仪检测凋亡细胞百分比.结果: IFN-α上调SMMC-7721细胞TP mRNA表达水平, 呈现剂量依赖性. 与未处理组相比,浓度为5000、10 000 kU/L的IFN-α处理的细胞TP mRNA表达水平显著升高( P<0.05), 而且细胞质内TP蛋白染色强度及阳性染色细胞数均较未处理组的细胞差别明显, 但不同浓度的IFN-α对凋亡细胞百分比的影响不明显, 对照组和浓度10 000 kU/L IFN-α组的凋亡细胞百分比分别为7.19%±2.76%和6.42%±3.66%,差别无统计学意义.结论: 一定剂量的IFN-α既能上调肝癌细胞TP表达水平, 又能抵消TP表达上调后抑制细胞凋亡的作用.

Objective:To explore the value of interventional therapy in the patients suffered from hydrops abdominis after liver transplantation. Methods:The data of 20 hydrops abdominis cases after liver transplantation underwent puncture or catheter drainage under the guidance of ultrasonic were analyzed retrospectively. Results:All the 20 procedure performed under the guidance of ultrasonic, including 5 patients had hydrops abdominis under right subphrenic, 4 in the cavity between liver and renal, 4 near the porta hepatic and 7 massive ascites. Three of them needed to replace the catheter for septal fruid. The symptoms were all relived without severe complications. Conclusion:Interventional ultrasonic therapy is a safe, easy and effective way to manage patients suffered from hydrops abdominis after liver transplantation.

To evaluate the prognosis value of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) patients after curative resection.

Objective:To investigate the therapeutic and side effects of Peginterferon-αon tumor growth in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential.Methods:The nude mice bearing highly metastatic LCI-D20 tumor were randomly distributed into 5 groups and were administered with Interferon-α2.5×10~7 U·kg~(-1)·d~(-1) tiw, Interferon-α5×10~7 U·kg~(-1)·d~(-1)tiw,Peginterferon 15μg·d~(-1) qw and Peginterferon-α30μg·d~(-1) qw for 28 consecutive days respectively.The weight of nude mice was measured once a week.The tumor size was calculated after the mice were killed. The blood was collected for the routine analysis and the examination of liver and renal function.Results:The tumor growth was not inhibited significantly in the Interferon-α2.5×10~7 U·kg~(-1)·d~(-1) tiw,Interferon-α5×10~7 U·kg~(-1)·d~(-1) tiw groups as compared with that of controls (P=0.996,P=0.287).In the Peginterferon-α15μg·d~(-1) qw and Peginterferon-α30μg·d~(-1) qw groups,no tumor was found.The efficacy of Peginterferon-αwas significantly higher than that of the common Interferon-α(P＜0.001).Peginterferon-αshowed no significant toxicity in terms of weight loss or liver and renal function damage.Con- clusion:Peginterferon-αmay inhibit the tumor growth in LCI-D20 nude mice.

OBJECTIVE To further study the impact of interferon-alpha (IFN-alpha) on thymidine phosphorylase (TP) expression and angiogenesis. METHODS Human hepatocellular carcinoma cells of the line SMMC-7721 were cultured and added with IFN-alpha of different doses: 0 (as control group), 1000, 5000 and 10,000 U/ml. Twenty-four hours later RT-PCR was used to detect the TP mRNA expression. Boyden chamber method was used to examine the endothelial cells migration. Suspension of SMMC-7721 cells was inoculated subcutaneously into 30 male BALB/c-nu/nu mice, the mice were randomly divided into 5 equal groups to be subcutaneously injected with IFN-alpha of different doses: 0 (as control group), 1.0 x 10(6), 3.0 x 10(6), 9.0 x 10(6), and 1.5 x 10(7) U.kg(-1).d(-1) for 3 weeks. The eating behavior, activity, body weight, and tumor size were observed. The rats were killed 2 days after the drug injection was stopped. The subcutaneous tumors were taken out to undergo histological examination and TP protein expression by ELISA. The microvessel density (MVD) was detected using anti-CD34 monoclonal antibody. RESULTS The TP mRNA expression of the SMMC-7721 cells induced by IFN-alpha of the doses of 5000 U/ml and 10,000 U/ml significantly increased in comparison with the un-treated SMMC-7721 cells (0 U/ml, P < 0.05). The endothelial cell migration significantly increased in the IFN-alpha 1000 U/ml group compared with the control group (P < 0.001), and then decreased along with the increase of IFN-alpha dose; there were no significant differences in the epithelial migration among the groups of 0, 5000, and 10,000 U/ml IFN-alpha doses (all P > 0.05). The TP protein expression levels of the tumor in the rats treated with IFN-alpha of the doses of 9.0 x 10(6), and 1.5 x 10(7) U.kg(-1).d(-1) were 48 ng/mg +/- 24 ng/mg and 60 ng/mg +/- 6 ng/mg respectively, 1.9 and 2.4 times that of the control group (both P < 0.01). The MVD of the tumors was 6.0 +/- 1.8 in the 9.0 x 10(6) U.kg(-1).d(-1) IFN-alpha group, significantly higher than that of the control group (P < 0.01); and was 4.0 +/- 1.5 in the 1.5 x 10(7) U.kg(-1).d(-1) group, significantly lower than that of the 9.0 x 10(6) U.kg(-1).d(-1) group (P < 0.05) and not significantly different from that of the control group. The tumor inhibiting rate of the 1.5 x 10(7) U.kg(-1).d(-1) IFN-alpha group was 68%, significantly higher than that of the untreated group (P < 0.05). CONCLUSION IFN-alpha of certain doses up-regulate the TP expression, and inhibit the angiogenesis induced by TP as well.

Purpose: To investigate the effects on sensitivity to fluoropyrimidine and endothelial cell (EC) migration by transfection with thymidine phosphorylase (TP) cDNA to a hepatocellular carcinoma (HCC) cell line SMMC-7721.

干扰素α在临床上已经广泛应用,但它的治疗疗效受限于蛋白质特性,包括蛋白质的稳定性差、半衰期短及其免疫原性.干扰素的半衰期为4～16 h,在肌内或皮下注射后3～8 h到达血浆峰浓度.